Early clinical trial unit tumor board: a real-world experience in a national cancer network.

PURPOSE: Early clinical trials are the first step into clinical therapies for new drugs. Within the six Bavarian university-based hospitals (Augsburg, Erlangen, Regensburg, Munich (LMU and TU), Würzburg) we have enrolled a virtual network platform for patient discussion. METHODS: The virtual Early Clinical Trial Unit Tumor Board (ECTU Tumor Board) is a secured web-based meeting to evaluate early clinical trial options for patients, where representatives from local ECTUs participate. We retrospectively analyzed patient cases discussed between November 2021 and November 2022. RESULTS: From November 2021 to November 2022, a total of 43 patients were discussed in the ECTU Tumor Board. Median age at diagnosis was 44.6 years (range 10-76 years). The median number of previous lines of therapies was 3.7 (range 1-9 therapies) including systemic treatment, surgery, and radiation therapy. A total of 27 different tumor entities were presented and 83.7% (36/43) patients received at least one trial recommendation. In total, 21 different active or shortly recruiting clinical trials were recommended: ten antibody trials, four BiTE (bispecific T cell engager) trials, six CAR (chimeric antigen receptor) T-cell trials, and one chemotherapy trial. Only six trials (28.6%) were recommended on the basis of the previously performed comprehensive genetic profiling (CGP). CONCLUSION: The ECTU Tumor Board is a feasible and successful network, highlighting the force of virtual patient discussions for improving patient care as well as trial recruitment in advanced diseases. It can provide further treatment options after local MTB presentation, aiming to close the gap to access clinical trials.

Patient-reported outcome measures obtained via E-Health tools ease the assessment burden and encourage patient participation in cancer care (PaCC Study).

Patient-reported outcome measures obtained via E-Health tools ease the assessment burden and encourage patient participation in cancer care (PaCC Study) BACKGROUND: E-health based patient-reported outcome measures (PROMs) have the potential to automate early identification of both nutrition status and distress status in cancer patients while facilitating treatment and encouraging patient participation. This cross-sectional study assessed the acceptability, accuracy, and clinical utility of PROMs collected via E-Health tools among patients undergoing treatment for stomach, colorectal, and pancreatic tumors. RESULTS: Eight-nine percent mostly, or completely, agreed that PROMs via tablets should be integrated in routine clinical care. Men were significantly more likely to require help completing the questionnaires than women (inv.OR= 0.51, 95% CI=(0.27, 0.95), p = 0.035). The level of help needed increased by 3% with each 1-year increase in age (inv. OR=1.03, 95% CI=(1.01, 1.06), p = 0.013). On average, a patient tended to declare weight which was 0.84 kg inferior to their true weight (Bland and Altman 95 % CI=(-3.9, 5.6); SD: 2.41) and a height which was 0.95 cm superior to their true height (Bland and Altman 95 % CI=(-5, 3.1); SD 2.08). Patient-reported nutrition status was significantly associated with the professionally generated assessment (95% CI=(2.27, 4.15), p < 0.001). As nutrition status declined, the distress score increased (95%CI=(0.88, 1.68), p < 0.001). Of the patients, 48.8% who were both distressed and malnourished requested supportive care to address their problems. CONCLUSION: Patient-reported assessments utilizing E-health tools are an accurate and efficient method to encourage patient participation in cancer care while simultaneously ensuring that regular assessment of psycho-social and nutritional aspects of care are efficiently integrated in the daily clinical routine.

Bioactivity and Mechanical Stability of 45S5 Bioactive Glass Scaffolds Based on Natural Marine Sponges.

Bioactive glass (BG) based scaffolds (45S5 BG composition) were developed by the replica technique using natural marine sponges as sacrificial templates. The resulting scaffolds were characterized by superior mechanical properties (compression strength up to 4 MPa) compared to conventional BG scaffolds prepared using polyurethane (PU) packaging foam as a template. This result was ascribed to a reduction of the total scaffold porosity without affecting the pore interconnectivity (>99%). It was demonstrated that the reduction of total porosity did not affect the bioactivity of the BG-based scaffolds, tested by immersion of scaffolds in simulated body fluid (SBF). After 1 day of immersion in SBF, a homogeneous CaP deposit on the surface of the scaffolds was formed, which evolved over time into carbonate hydroxyapatite (HCA). Moreover, the enhanced mechanical properties of these scaffolds were constant over time in SBF; after an initial reduction of the maximum compressive strength upon 7 days of immersion in SBF (to 1.2 ± 0.2 MPa), the strength values remained almost constant and higher than those of BG-based scaffolds prepared using PU foam (<0.05 MPa). Preliminary cell culture tests with Saos-2 osteoblast cell line, namely direct and indirect tests, demonstrated that no toxic residues remained from the natural marine sponge templates and that cells were able to proliferate on the scaffold surfaces.

Silica-supported TEMPO catalysts: synthesis and application in the Anelli oxidation of alcohols.

The application of silica-supported TEMPO as a recyclable catalyst in the Anelli oxidation of alcohols is reported. The catalyst is easily obtained in a one-step reductive amination procedure starting from a commercially available aminopropyl-functionalized silica. Details of the synthesis of the supported catalyst and its analysis by MAS NMR are presented. Various alcohol oxidations according to the Anelli protocol have been carried out and the stability of the applied silica-supported TEMPO has been studied.

3,5-Bis(trifluoromethyl)pyrazoles: a novel class of NFAT transcription factor regulator.

A series of bis(trifluoromethyl)pyrazoles (BTPs) has been found to be a novel inhibitor of cytokine production. Identified initially as inhibitors of IL-2 synthesis, the BTPs have been optimized in this regard and even inhibit IL-2 production with a 10-fold enhancement over cyclosporine in an ex vivo assay. Additionally, the BTPs show inhibition of IL-4, IL-5, IL-8, and eotaxin production. Unlike the IL-2 inhibitors, cyclosporine and FK506, the BTPs do not directly inhibit the dephosphorylation of NFAT by calcineurin.

Regulating radiology: ethical issues in mammography and federal legislation.

One in nine women can expect to develop breast cancer over the course of a lifetime, which suggests that a posture of vigilance is appropriate. The form of breast imaging known as mammography will detect masses that self-examination and yearly clinical examinations may miss. Given that most types of breast cancer are not clinically preventable, early detection of such masses offers the best opportunity for survival for the affected women. Recognizing the need to ensure quality testing and interpreting procedures for so many women, the federal government has enacted legislation that requires breast imagers to read 240 mammograms in 6 months to qualify for certification and another 960 mammograms in the following 2 years. The burdensome nature of these requirements has had the effect of reducing the number of radiologists certified to read mammograms, and this has decreased the overall availability of this service to women. I explore two possible rationales for instituting such strict federal regulation of breast imagers: that breast cancer is more prevalent than other diseases that affect women and that legislating such high standards ensures the accuracy of interpretation. On neither ground is such legislation justified. Instead, I contend that this regulation was instituted as a way for politicians to make up for disregarding women and women's health concerns in the past by focusing on a current issue that predominantly affects women. As a consequence, I argue that more women may be harmed than benefited by such legislation.

A macrolactam inhibitor of T helper type 1 and T helper type 2 cytokine biosynthesis for topical treatment of inflammatory skin diseases.

T lymphocytes play a critical part in inflammatory skin diseases but are targeted by available therapies that have only partial efficacy, significant side-effects, or both. Because psoriasis, atopic dermatitis, and allergic contact hypersensitivity are associated with T helper type 1 (Th1), T helper type 2 (Th2), or mixed Th1-Th2 cell subsets and cytokine types, respectively, there is a need for a better broad-based inhibitor. The macrolactam ascomycin analog, ABT-281, was found to inhibit potently T cell function across species and to inhibit expression of multiple cytokines in human peripheral blood leukocytes which have been found in human skin disease cells and tissues. These included immunoregulatory Th1 (interleukin-2 and interferon-gamma) and Th2 (interleukin-4 and interleukin-5) cytokines. ABT-281 was shown to have potent topical activity (ED50 = 0.6% in acetone/olive oil) in a stringent swine model of allergic contact hypersensitivity, but its potency was markedly reduced compared with ascomycin when administered systemically due to more rapid clearance. Topical application of 3% ABT-281 in acetone/olive oil over 25% of the body surface in swine resulted in undetectable blood levels. Compared with a wide potency range of topical corticosteroids in clinical formulations, 0.3% and 1% ABT-281 ointments profoundly inhibited dinitrochlorobenzene-induced contact hypersensitivity in the pig by 78% and 90%, respectively, whereas super-potent steroids such as clobetasol propionate only inhibited in the 50% range and mild to moderate potency steroids such as fluocinolone acetonide were inactive. The potent topical activity of ABT-281 in swine, its superior efficacy, its rapid systemic clearance following uptake into the bloodstream, and its ability to inhibit cytokine biosynthesis of both Th1 and Th2 cell subsets, suggests that it will have a broad therapeutic value in inflammatory skin diseases, including psoriasis, atopic dermatitis, and allergic contact dermatitis.

Ex vivo assessment of immunosuppression in undiluted whole blood from pigs dosed with tacrolimus (FK506).

To assess the duration of immunosuppression in FK506-dosed pigs, an undiluted whole blood assay was established to measure reactivities of T cells in their physiological milieu. PMA and ionomycin were shown to induce IL-2 production in swine blood. The IC50 of FK506 in inhibiting IL-2 production in whole blood and isolated PBMC stimulated with PMA and ionomycin measured 1.2 and 0.04 nM, respectively. These data underscore the influence of red blood cells and plasma proteins on drug potency. IL-2 levels were determined in blood drawn immediately before and 1, 24, 48, and 72 h after iv dosing. For pigs dosed with 0.05 mg/kg, 50% recovery of IL-2 production was observed at 16 h and 100% at 35 h after dosing. For pigs dosed with 0.15 mg/kg, 50% recovery was observed at 38 h and 100% at 72 h. Blood concentrations of FK506 at 50 and 100% recovery of IL-2 production measured 10.8 and 2.2 nM for pigs dosed with 0.05 mg/kg and 6.1 and 1.1 nM for pigs dosed with 0.15 mg/kg, respectively. These concentrations are severalfold higher than predicted from the IC50 of FK506 for inhibiting IL-2 production in the whole blood assay. These data suggest that the true potency of FK506 in blood after dosing is influenced by additional factors, which could include plasma protein binding, the presence of active or interfering metabolites, serum interfering factors, and sequestration of drug in blood cells. Our results demonstrate the utility of an undiluted whole blood assay for assessing the duration of immunosuppression in drug-dosed animals and emphasize the importance of assessing drug potency in the whole blood environment ex vivo.

Improved methods for transplanting split-heart neonatal cardiac grafts into the ear pinna of mice and rats.

The rodent heterotopic ear-heart transplant method is a useful alternative to the more technically demanding vascularized graft technique. We modified the procedure to improve efficiency and used it in mice and rats to determine the survival times of both isologous and allogeneic grafts and compare reference immunosuppressants. Bisected rat and mouse cardiac (split-heart) isografts were uniformly viable up to 4 weeks postimplant; however, by 24 weeks only 90% of Lewis rat or C3H mouse split-heart isografts retained electrocardiographic activity, regressing to 81% by 60 weeks for the Lewis rat and to less than 50% for the C3H mouse by 43 weeks post-implant. The potency of tacrolimus, sirolimus, and cyclosporine for prevention of allograft rejection was comparable whether using split-hearts or whole hearts in the Balb/C to C3H mouse model. The maximally effective doses at 2 weeks postimplant for intraperitoneally administered tacrolimus, sirolimus, cyclosporine, and oral leflunomide with Brown-Norway (BN) to Lewis rat ear-split-heart allografts (0.3, 0.1, 3.0, 10, mg/kg/day, respectively) agreed extremely well with published data for the rat primary vascularized heterotopic heart model. This reproducible and efficient transplantation model was improved by using split-hearts to double available donor tissue, a gonadotropin-enhanced breeding strategy that enables routine use of low-fecundity inbred rats as donors, implantation devices that speed and simplify the procedure, and defined electrocardiographic evaluation criteria to maximize sensitivity and provide an objective endpoint for defining rejection.

Nephrotoxicity studies of the immunosuppressants tacrolimus (FK506) and ascomycin in rat models.

The nephrotoxic potential of ascomycin, the C21-ethyl analogue of FK506, was defined and ways explored to enhance its detection. After 14-day dosing in the Fischer-344 rat, FK506 and ascomycin reduced creatinine clearance by >50% at doses of 1 and 3 mg/kg, i.p., respectively. Ascomycin also had a 3-fold lower immunosuppressive potency in a popliteal lymph node hyperplasia assay, resulting in an equivalent therapeutic index consistent with a common mechanistic dependence on calcineurin inhibition. Renal impairment with different routes of administration was correlated with pharmacokinetics. Sensitivity of detection was not adequate with shorter dosing durations in rats with unilateral nephrectomy or in mice using a cytochrome P-450 inhibitor, SKF-525A. In 14-day studies, nephrotoxicity was not induced by continuous i.p. infusion of ascomycin at 10 mg/kg/day or daily oral administration (up to 50 mg/kg/day) in rats on a normal diet, nor by continuous i.v. infusion (up to 6 mg/kg/day) in rats on a low salt diet to enhance susceptibility. The lack of toxicity at high oral doses of FK506 or ascomycin, and the finding of non-linear oral pharmacokinetics of ascomycin show that this drug class has an oral absorption ceiling. The negative results with continuous infusion suggest that ascomycin nephrotoxicity is governed by peak drug levels. In addition to defining ways to meaningfully compare the nephrotoxic potential of FK506 derivatives, these results have implications for overall safety assessment and improved clinical use.

Discovery of ascomycin analogs with potent topical but weak systemic activity for treatment of inflammatory skin diseases.

Drug therapy for the major inflammatory skin diseases, which include atopic dermatitis, psoriasis and allergic contact dermatitis, is often inadequate due to poor efficacy, toxicity, or both. Much research has focused on the macrolactam T cell inhibitors as a promising new class of agents for immunotherapy, and medicinal chemistry efforts to design novel ascomycin analogs have produced clinically promising agents. A synthetic program to modify the ascomycin nucleus to alter its physicochemical properties and promote systemic clearance is described. A biologic screening strategy to identify analogs with reduced systemic activity and rapid pharmacokinetic elimination led to identification of the clinical candidate, ABT-281. A swine contact hypersensitivity model was used as a stringent indicator of skin penetration as human doses of topical corticosteroids produced inhibition only in the 50% range and ED50 values were 100-fold less potent than in rat. Also, cyclosporine was confirmed to be topically inactive in swine, as seen in human. ABT-281 had topical potency equal to tacrolimus (FK506) despite a severalfold lower potency for inhibiting swine T cells in vitro, consistent with superior skin penetration. ABT-281 was found to have a shorter duration of action after i.v. dosing in monkeys using an ex vivo whole blood IL-2 production assay. Systemic potency was reduced by 30-fold or more in rat popliteal lymph node hyperplasia and contact hypersensitivity assays. Following i.v. or i.p. administration in the swine contact hypersensitivity model, ABT-281 was 19- and 61-fold less potent, respectively, than FK506. Pharmacokinetic studies showed that ABT-281 had a shorter half life and higher rate of clearance than FK506 in all three species. The potent topical activity and reduced systemic exposure of ABT-281 may thus provide both efficacy and a greater margin of safety for topical therapy of skin diseases.

Discovery of less nephrotoxic FK506 analogs and determining immunophilin dependence of immunosuppressant nephrotoxicity with a novel single-dose rat cisplatin potentiation assay.

Comparing nephrotoxicity of numerous drug analogs is impractical with chronic in vivo models. We devised a new cisplatin potentiation assay (CISPA) that sensitively detects renal injury as a serum creatinine increase when only one dose of test compound is followed by cisplatin. Reference nephrotoxins known to act on various sites in kidney tubules, glomeruli or renal papilla were all detected by the CISPA at single doses that without cisplatin gave little change, which showed that this simple, sensitive assay has broad potential utility for mechanistic studies of nephrotoxicity. We used the CISPA both to probe the nephrotoxic mode of action of immunosuppressants and to search for safer compounds. Although several non-nephrotoxic immunosuppressants were inactive, cyclosporine, FK506, ascomycin (C21-ethyl-FK506) and rapamycin were nephrotoxic in the CISPA at single doses equal to the daily amounts required to reduce creatinine clearance with 14 days of treatment. Similar therapeutic indices were derived comparing toxicity by either method to prevention of rat ear-heart allograft rejection. C18-OH-ascomycin, an FK506-binding protein (FKBP) antagonist, reversed in vivo immunosuppression by FK506 and ascomycin in the rat, and pretreatment in the CISPA blocked FK506 and ascomycin nephrotoxicity, which showed a common immunophilin dependence. Rapamycin nephrotoxicity was unaffected (as with cyclosporine), which indicated that binding to FKBP was not required. Rapamycin nephrotoxicity thus appears mechanistically unrelated to its immunosuppressive mode of action. Screening with the CISPA enabled discovery of A-119435, a less nephrotoxic ascomycin analog having a 10-fold higher therapeutic index.

[Broadband ultrasound attenuation (BUA) in the diagnosis of osteoporosis]. / Breitband-Ultraschall-Abschwächung (BUA) in der Diagnostik der Osteoporose.

The measurement of broadband ultrasound attenuation (BUA) of the calcaneus has been introduced as a new technique that provides information about both bone mass and structure without the use of ionizing radiation. BUA measurements of the calcaneus were obtained in 324 patients, 109 of whom had osteoporosis. Two hundred and fifteen patients served as control group. BUA values were compared with dual-energy X-ray absorptiometry (DXA) measurements of the lumbar spine, the neck and the heel. The precision error of BUA was 4.1%. The correlation with spinal bone mineral density was r = 0.49, with DXA of the neck r = 0.52 and of the calcaneus r = 0.56, respectively. Patients with osteoporosis showed a significant decrease in BUA compared with healthy subjects (61.4 dB/MHz vs 74.6 dB/MHz). Roc analysis demonstrated that BUA was inferior to DXA of the lumbar spine in detecting osteoporosis.

Dunaimycins, a new complex of spiroketal 24-membered macrolides with immunosuppressive activity. III. Immunosuppressive activities of dunaimycins.

The immunosuppressive effects of the dunaimycins, a new complex of spiroketal 24-membered macrolides, were compared to cyclosporin A, ascomycin, and rapamycin. Each dunaimycin was a potent inhibitor of the mitogenic response observed in mixed murine splenocyte or human leukocyte cultures, and like immunosuppressive drugs these compounds were relatively less potent inhibitors of the constitutive proliferation of murine EL4 thymoma cells. Dunaimycin D4S showed no selectivity in inhibiting the mitogenic response of spleen cells to concanavalin A, pokeweed mitogen, lipopolysaccharide, or phytohemagglutinin. Cyclosporin A and ascomycin did not inhibit interleukin 2 dependent proliferation, whereas the dunaimycins and rapamycin blocked the uptake of [3H]thymidine in mixed cultures supplemented with exogenous interleukin 2. In addition, dunaimycin D4S had no apparent affinity for cyclosporin A or FK-506 immunophilins. Although the dunaimycins inhibited the activity of Na+, K(+)-ATPase, inhibition of this enzyme appeared insufficient to explain the biological activity of these new macrolides. Over a narrow concentration range, dunaimycin D4S showed in vivo immunosuppressive activity in the murine popliteal lymph node hyperplasia model.

C5a structural requirements for neutrophil receptor interaction.

A number of C5a modifications were tested to determine effects on receptor binding to polymorphonuclear leukocyte (PMNL) membrane receptors and triggering of PMNL chemokinesis and myeloperoxidase (MPO) release. Site-directed mutagenesis was used to probe relationships of key C-terminal residues, and suggested a role for additional sites, particularly Lys19-20. A synthetic peptide based on C5a 19-30, weakly inhibited C5a binding. Potency of the C-terminal octapeptide, a full agonist, was markedly improved by a single Phe substitution for His67, and a Phe point mutation at this site was shown to enhance activity of the full recombinant protein.

Identification of receptor-binding residues in the inflammatory complement protein C5a by site-directed mutagenesis.

C5a is an inflammatory mediator potentially involved in a number of diseases. To help define which of its 74 residues are important for receptor binding and response triggering, changes in the amino acid sequence of C5a were introduced by site-directed mutagenesis. Synthetic C5a-encoding genes incorporating point mutations were expressed in Escherichia coli, and the mutant proteins were purified to homogeneity. Modifications of the C5a molecule causing parallel reductions in binding to polymorphonuclear leukocyte membranes and in stimulation of polymorphonuclear leukocyte locomotion (chemokinesis) suggest that carboxyl-terminal residues Lys-68, Leu-72, and Arg-74 interact with the receptor. Substitutions in the disulfide-linked core of C5a revealed involvement of Arg-40 or nearby residues, because potency losses were associated with only localized conformational changes as detected by NMR. Surprisingly, a substitution at core residue Ala-26, which did not alter C5a core structure, appeared from NMR results to reduce potency by causing a long-distance conformational change centered on residue His-15. Thus, at least three discontinuous regions of the C5a molecule appear to act in concert to achieve full potency.