Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS).

BACKGROUND: ATLAS evaluated the efficacy and safety of the PARP inhibitor rucaparib in patients with previously treated locally advanced/unresectable or metastatic urothelial carcinoma (UC). METHODS: Patients with UC were enrolled independent of tumor homologous recombination deficiency (HRD) status and received rucaparib 600 mg BID. The primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (loss of genome-wide heterozygosity ≥10%) populations. Key secondary endpoints were progression-free survival (PFS) and safety. Disease control rate (DCR) was defined post-hoc as the proportion of patients with a confirmed complete or partial response (PR), or stable disease lasting ≥16 weeks. RESULTS: Of 97 enrolled patients, 20 (20.6%) were HRD-positive, 30 (30.9%) HRD-negative, and 47 (48.5%) HRD-indeterminate. Among 95 evaluable patients, there were no confirmed responses. However, reductions in the sum of target lesions were observed, including 6 (6.3%) patients with unconfirmed PR. DCR was 11.6%; median PFS was 1.8 months (95% CI, 1.6-1.9). No relationship was observed between HRD status and efficacy endpoints. Median treatment duration was 1.8 months (range, 0.1-10.1). Most frequent any-grade treatment-emergent adverse events were asthenia/fatigue (57.7%), nausea (42.3%), and anemia (36.1%). Of 64 patients with data from tumor tissue samples, 10 (15.6%) had a deleterious alteration in a DNA damage repair pathway gene, including four with a deleterious BRCA1 or BRCA2 alteration. CONCLUSIONS: Rucaparib did not show significant activity in unselected patients with advanced UC regardless of HRD status. The safety profile was consistent with that observed in patients with ovarian or prostate cancer. TRIAL REGISTRATION: This trial was registered in ClinicalTrials.gov (NCT03397394). Date of registration: 12 January 2018. This trial was registered in EudraCT (2017-004166-10).

AllergoOncology: ultra-low IgE, a potential novel biomarker in cancer-a Position Paper of the European Academy of Allergy and Clinical Immunology (EAACI).

Elevated serum IgE levels are associated with allergic disorders, parasitosis and specific immunologic abnormalities. In addition, epidemiological and mechanistic evidence indicates an association between IgE-mediated immune surveillance and protection from tumour growth. Intriguingly, recent studies reveal a correlation between IgE deficiency and increased malignancy risk. This is the first review discussing IgE levels and links to pathological conditions, with special focus on the potential clinical significance of ultra-low serum IgE levels and risk of malignancy. In this Position Paper we discuss: (a) the utility of measuring total IgE levels in the management of allergies, parasitosis, and immunodeficiencies, (b) factors that may influence serum IgE levels, (c) IgE as a marker of different disorders, and d) the relationship between ultra-low IgE levels and malignancy susceptibility. While elevated serum IgE is generally associated with allergic/atopic conditions, very low or absent IgE may hamper anti-tumour surveillance, indicating the importance of a balanced IgE-mediated immune function. Ultra-low IgE may prove to be an unexpected biomarker for cancer risk. Nevertheless, given the early stage of investigations conducted mostly in patients with diseases that influence IgE levels, in-depth mechanistic studies and stratification of malignancy risk based on associated demographic, immunological and clinical co-factors are warranted.

An immunologically relevant rodent model demonstrates safety of therapy using a tumour-specific IgE.

BACKGROUND: Designing biologically informative models for assessing the safety of novel agents, especially for cancer immunotherapy, carries substantial challenges. The choice of an in vivo system for studies on IgE antibodies represents a major impediment to their clinical translation, especially with respect to class-specific immunological functions and safety. Fcε receptor expression and structure are different in humans and mice, so that the murine system is not informative when studying human IgE biology. By contrast, FcεRI expression and cellular distribution in rats mirror that of humans. METHODS: We are developing MOv18 IgE, a human chimeric antibody recognizing the tumour-associated antigen folate receptor alpha. We created an immunologically congruent surrogate rat model likely to recapitulate human IgE-FcεR interactions and engineered a surrogate rat IgE equivalent to MOv18. Employing this model, we examined in vivo safety and efficacy of antitumour IgE antibodies. RESULTS: In immunocompetent rats, rodent IgE restricted growth of syngeneic tumours in the absence of clinical, histopathological or metabolic signs associated with obvious toxicity. No physiological or immunological evidence of a "cytokine storm" or allergic response was seen, even at 50 mg/kg weekly doses. IgE treatment was associated with elevated serum concentrations of TNFα, a mediator previously linked with IgE-mediated antitumour and antiparasitic functions, alongside evidence of substantially elevated tumoural immune cell infiltration and immunological pathway activation in tumour-bearing lungs. CONCLUSION: Our findings indicate safety of MOv18 IgE, in conjunction with efficacy and immune activation, supporting the translation of this therapeutic approach to the clinical arena.

AllergoOncology: Opposite outcomes of immune tolerance in allergy and cancer.

While desired for the cure of allergy, regulatory immune cell subsets and nonclassical Th2-biased inflammatory mediators in the tumour microenvironment can contribute to immune suppression and escape of tumours from immunological detection and clearance. A key aim in the cancer field is therefore to design interventions that can break immunological tolerance and halt cancer progression, whereas on the contrary allergen immunotherapy exactly aims to induce tolerance. In this position paper, we review insights on immune tolerance derived from allergy and from cancer inflammation, focusing on what is known about the roles of key immune cells and mediators. We propose that research in the field of AllergoOncology that aims to delineate these immunological mechanisms with juxtaposed clinical consequences in allergy and cancer may point to novel avenues for therapeutic interventions that stand to benefit both disciplines.

AllergoOncology - the impact of allergy in oncology: EAACI position paper.

Th2 immunity and allergic immune surveillance play critical roles in host responses to pathogens, parasites and allergens. Numerous studies have reported significant links between Th2 responses and cancer, including insights into the functions of IgE antibodies and associated effector cells in both antitumour immune surveillance and therapy. The interdisciplinary field of AllergoOncology was given Task Force status by the European Academy of Allergy and Clinical Immunology in 2014. Affiliated expert groups focus on the interface between allergic responses and cancer, applied to immune surveillance, immunomodulation and the functions of IgE-mediated immune responses against cancer, to derive novel insights into more effective treatments. Coincident with rapid expansion in clinical application of cancer immunotherapies, here we review the current state-of-the-art and future translational opportunities, as well as challenges in this relatively new field. Recent developments include improved understanding of Th2 antibodies, intratumoral innate allergy effector cells and mediators, IgE-mediated tumour antigen cross-presentation by dendritic cells, as well as immunotherapeutic strategies such as vaccines and recombinant antibodies, and finally, the management of allergy in daily clinical oncology. Shedding light on the crosstalk between allergic response and cancer is paving the way for new avenues of treatment.

Epidemiological associations of allergy, IgE and cancer.

Several epidemiological studies have evaluated potential associations between allergy and risk of malignancy. It remains clear that the relationship between allergy and cancer is complex. Three hypotheses have been proposed to account for observed relationships: these are chronic inflammation, immunosurveillance, prophylaxis, and we propose adding a fourth: inappropriate T-helper 2 (Th2) immune skewing. Each of these attempts to explain either the increased or decreased risk of different cancer types in 'allergic' patients reported in the literature. All four hypotheses are based on known mechanisms of allergic inflammation and/or IgE antibody functions, and uphold the view of an immunological basis for the relationship between allergy and malignancies. This review summarizes and draws conclusions from the epidemiological literature examining the relationships between specific types of cancer and allergic diseases. Particular emphasis is placed on the most recent contributions to the field, and on consideration of the allergic immune mechanisms that may influence positive or negative associations.

[The Marburg surgical curriculum - improving the attraction of medical education by teaching central surgical competence]. / Das Marburger chirurgische Curriculum - Attraktivitätssteigerung der studentischen Ausbildung in der Chirurgie durch Vermittlung von chirurgischen Kernkompetenzen.

The quality of medical education is an ongoing challenge due to the continuing changes of the health-care politics and general social conditions. At many German university hospitals the dominating picture is overfilled courses, lack of hands-on practice, reduced patient contact and the dull provision of theoretical, abstract knowledge. The reformed surgical curriculum at the University of Marburg university hospital is used to demonstrate that, in spite of large student numbers, a practice-oriented, small-group training at a high didactic level is possible. The surgical training courses are organized in detail and coordinated. Course contents and structure are media available in print and online versions for both students and teachers and thus fulfill not only transparency needs but also contemporary requirements. The strategy of a practice- and patient-oriented, small-group training is followed strictly in the surgical curriculum. In addition, accompanying tutorial possibilities for individual study in an up-to-date learning center are offered. Here the students have the opportunity to intensify knowledge acquired in previous or future courses with numerous attractive education means. Continuous evaluation of the individual training courses at the end of each semester not only document motivation of the students but also serve to continuously improve the training concepts.

An automated method for the measurement of a range of tyrosine kinase inhibitors in human plasma or serum using turbulent flow liquid chromatography-tandem mass spectrometry.

Tyrosine kinase inhibitors (TKIs) are used to treat a number of cancers, including chronic myeloid leukaemia and hepatocellular carcinoma. Therapeutic drug monitoring (TDM) may be indicated to (1) monitor adherence, (2) guide dosage, and (3) minimise the risk of drug-drug interactions and dose-related toxicity. On-line, automated sample preparation provided by TurboFlow technology (ThermoFisher Scientific) in conjunction with the sensitivity and selectivity of tandem mass spectrometry (MS/MS) detection may be applied to the analysis of single drugs and metabolites. We report the use of TurboFlow LC-MS/MS for the analysis of nine TKIs and metabolites (imatinib, N-desmethylimatinib, dasatinib, nilotinib, erlotinib, gefitinib, lapatinib, sorafenib, sunitinib) in human plasma or serum for TDM purposes. An Aria Transcend TLX-II system coupled with a TSQ Vantage was used. Samples (50 µL) were vortex mixed with internal standard solution (150 µL imatinib-D(8), gefitinib-D(8), sunitinib-D(10), and nilotinib-(13)C (2) (15) N(2) in acetonitrile) and, after centrifugation 100 µL supernatant were injected directly onto a 50 × 0.5-mm Cyclone TurboFlow column. Analytes were focussed onto a 50 × 2.1-mm (3 µm) Hypersil GOLD analytical column and eluted with an acetonitrile/water gradient. Analytes were monitored in selected reaction monitoring mode (positive APCI). Total analysis time was 7 min without multiplexing. Calibration was linear (R(2) > 0.99) for all analytes. Inter- and intra-assay precision (in percent relative standard deviation, RSD) was <11 % and accuracy 89-117 % for all analytes. No matrix effects were observed. This method is suitable for high-throughput TDM in patients undergoing chronic therapy with TKIs and has been utilised in the analysis of clinical samples.

Harnessing engineered antibodies of the IgE class to combat malignancy: initial assessment of FcɛRI-mediated basophil activation by a tumour-specific IgE antibody to evaluate the risk of type I hypersensitivity.

BACKGROUND: IgE antibodies, sequestered into tissues and retained locally by the high-affinity IgE receptor, FcɛRI, on powerful effector cells such as mast cells, macrophages and eosinophils, may offer improvements in the therapy of solid tumours. The chimeric antibody, MOv18 IgE, against the human ovarian carcinoma antigen, folate receptor α (FRα), is more effective than its IgG1 counterpart in xenograft models of ovarian cancer. Although MOv18 IgE binds to a single epitope on FRα and cannot cross-link IgE receptors on basophils, there remains a risk that components in the circulation of ovarian cancer patients might cross-link FRα-MOv18-IgE-receptor-FcɛRI complexes on basophils to cause type I hypersensitivity. OBJECTIVE: To assess the propensity for MOv18 used in a therapeutic setting to cause FcɛRI-mediated type I hypersensitivity. METHODS: As validated readouts of the potential for MOv18 to cause FcɛRI-mediated type I hypersensitivity we measured release of a granule-stored mediator from a rat basophilic leukaemia cell line RBL SX-38 stably transfected with human tetrameric (αßγ2) FcɛRI, and induction of CD63 on blood basophils from patients with ovarian carcinoma and healthy controls ex vivo. RESULTS: Serum FRα levels were increased in ovarian cancer patients compared with healthy controls. MOv18 IgE alone, or in the presence of its antigen recombinant human FRα, or of healthy volunteer (n=14) or ovarian carcinoma patient (n=32) sera, did not induce RBL SX-38 cell degranulation. Exposure to FRα-expressing ovarian tumour cells at target-to-effector ratios expected within tumours induced degranulation. MOv18 IgE did not induce expression of CD63 in blood basophils from either healthy volunteers (n=6), or cancer patients, despite detectable levels of circulating FRα (n=5). CONCLUSION AND CLINICAL RELEVANCE: These encouraging data are compatible with the hypothesis that, when ovarian carcinoma patients are treated with MOv18, FcɛRI-mediated activation of effector cells occurs within the tumour mass but not in the circulation mandating, with due caution, further pre-clinical studies.

Current approaches to the use of generic antiepileptic drugs.

Generic substitution is encouraged as a cost containment strategy for the management of health care resources. However, in epilepsy, the consequences of loss of symptom control are important, and antiepileptic drugs have narrow therapeutic indices. For this reason, generic substitution may be problematic, and certain health authorities have excluded antiepileptic drugs from overall policy recommendations on generic prescribing. The absence of bioequivalence data among generic forms and the relatively broad criteria for bioequivalence with the branded drug allow differences in drug exposure to arise that may be clinically relevant and necessitate monitoring of plasma levels when switching formulations to avoid loss of seizure control or emergence of side effects. Management of these issues carries a significant cost, which should be weighed carefully against the cost savings acquired when purchasing the drug. Both physicians and patients have a right to be informed and approve before pharmacists make a generic substitution or switch between generics.

Promotion of proinflammatory interactions between platelets and monocytes by unfractionated heparin.

OBJECTIVES: To determine the in vitro effects of unfractionated heparin, fractionated heparin and direct thrombin inhibition on platelet-monocyte aggregation, and to establish the in vivo effects of unfractionated heparin and direct thrombin inhibition on platelet-monocyte aggregates in patients scheduled for percutaneous coronary intervention (PCI). DESIGN: Platelet-monocyte aggregates were assessed in whole blood from 18 healthy volunteers after the addition of unfractionated heparin (1 U/ml), enoxaparin (0.8 U/ml) or lepirudin (5.6 microg/ml), and in 28 patients scheduled for elective PCI before and after administration of 100 U/kg of unfractionated heparin or 0.75 mg/kg bivalirudin. The influence of P-selectin-mediated platelet-monocyte aggregation was assessed with specific blocking antibodies. RESULTS: Addition of unfractionated heparin in vitro was associated with a higher level of platelet-monocyte aggregates than in controls (20.1 (1.9)% v 16.2 (1.6)%, respectively, p < 0.001). However, platelet-monocyte aggregation was not affected by enoxaparin or lepirudin (16.9 (2.0)% and 17.0 (2.2)%, respectively, NS). Intravenous unfractionated heparin in vivo also resulted in an increase in platelet-monocyte aggregates (absolute Delta 7.1 (2.7)%, p < 0.01), whereas intravenous bivalirudin had no effect (absolute Delta -1.5 (2.4)%, NS). The addition of P-selectin blockade abolished any increase in platelet-monocyte aggregates associated with heparin. CONCLUSIONS: In vitro and in vivo unfractionated heparin is associated with increased platelet-monocyte aggregation through a P-selectin-dependent mechanism. These findings provide a potential explanation for the superior cardiovascular outcomes associated with fractionated heparins and direct thrombin inhibitors.

Upregulation of the CD40/CD40 ligand dyad and platelet-monocyte aggregation in cigarette smokers.

BACKGROUND: Smoking is a potent cardiovascular risk factor and is associated with proinflammatory and prothrombotic responses. The CD40/CD40 ligand (CD40L) dyad and platelet-monocyte aggregation mediate a range of proinflammatory and prothrombotic processes thought to be important in atherothrombosis. We investigated whether expression of the CD40/CD40L dyad and platelet-monocyte aggregation are altered in cigarette smokers. METHODS AND RESULTS: C-reactive protein (CRP), soluble (s) CD40L, and surface expression of CD40L on platelets and T cells and of CD40 on monocytes and platelet-monocyte aggregates were compared in 25 cigarette smokers and 25 age- and gender-matched nonsmokers. Cigarette smokers had increased serum CRP (2.47+/-2.60 versus 0.94+/-0.96 mg/L, P=0.008) and appeared to have elevated plasma sCD40L (0.8+/-1.09 versus 0.37+/-0.21 ng/mL, P=0.07) concentrations. Smokers also had increased surface expression of CD40 on monocytes (45.9+/-7.7% versus 39.9+/-6.5%, P=0.006), of CD40L on platelets (2.9+/-1.0% versus 2.3+/-0.6%, P=0.03), and of platelet-monocyte aggregates (26.6+/-10.9% versus 19.7+/-8.6%, P=0.02). Plasma cotinine concentrations correlated with monocyte CD40 expression, platelet CD40L expression, and platelet-monocyte aggregates. CONCLUSIONS: Cigarette smokers have upregulation of the CD40/CD40L dyad and platelet-monocyte aggregation that may account for the atherothrombotic consequences of this major cardiovascular risk factor.

Health care needs of Appalachian trail hikers.

BACKGROUND: With a growing interest and participation in hiking, predictions indicate that over 45 million Americans will participate in backpacking and day hiking in 1993. There has been very little assessment of the health care needs of this group. The purpose of this study was to assess the health care needs of Appalachian Trail backpackers. METHODS: Backpackers who completed hiking the Appalachian Trail in 1987 or 1988 received a 3-page survey questionnaire. The survey contained questions to elicit demographic information, general health characteristics, and health care experiences during the hike. Information about injuries, medications carried and used during the backpacking activities, health care needs, and trail time lost because of health problems was also requested. RESULTS: Injuries and illnesses were reported by 82% of the respondents, incurring an average loss of 4.7 days of hiking. Musculoskeletal complaints, traumatic injuries, and gastrointestinal complaints were most often reported. The severity of these problems was such that medical attention was sought in 25% of these events. CONCLUSIONS: Hikers need to anticipate that musculoskeletal, gastrointestinal, and skin problems may occur during hiking. It is prudent to carry medications such as analgesics in the form of aspirin or other nonsteroidal anti-inflammatory agents, topical antibiotics, and bandages. Methods to purify water need to be used regularly, and adequate preparation of food needs to be a priority.

Campylobacter enteritis associated with the consumption of free school milk.

A large outbreak of campylobacter enteritis associated with the consumption of free school milk is described. The outbreak had an abrupt onset, and lasted for about 3 weeks; it involved mainly school children in the 2-4 and 5-7 year old age groups. During this period it was established from epidemiological and microbiological data that some 2500 children were infected. The source of the epidemic was almost certainly contaminated milk, although bacteriological proof could not be obtained. Biotyping of isolates was of considerable epidemiological value and showed the involvement of two distinct strains, one of which was dominant. Epidemiological evidence of limited person to person transmission of the infection was obtained; febrile convulsions as a prodromal sign of the illness was recognized for the first time. Strains of Campylobacter jejuni, and samples of patients' serum collected during this outbreak have enabled subsequent studies to be initiated on the serotyping of the responsible organism, on the serological response of patients infected with the organism, and on experimental infection of the bovine udder which demonstrated its potential as a source of C. jejuni in raw milk. A careful search of the literature suggests that this is the largest documented outbreak of campylobacter enteritis.