Clinical Pharmacokinetics and Pharmacodynamics of Atezolizumab in Metastatic Urothelial Carcinoma.

Atezolizumab, a humanized immunoglobulin G1 (IgG1) monoclonal antibody targeting human programmed death-ligand 1 (PD-L1), is US Food and Drug Administration (FDA) approved in metastatic urothelial carcinoma (MUC) and is being investigated in various malignancies. This analysis based upon 906 patients from two phase I and one phase II MUC studies, is the first report of the clinical pharmacokinetics (PK) and pharmacodynamics (PD) of atezolizumab. Atezolizumab exhibited linear PK over a dose range of 1-20 mg/kg, including the labeled 1,200 mg dose. The clearance, volume of distribution, and terminal half-life estimates from population pharmacokinetic (PopPK) analysis of 0.200 L/day, 6.91 L, and 27 days, respectively, were as expected for an IgG1. Exposure-response analyses did not identify statistically significant relationships with either objective response rate or adverse events of grades 3-5 or of special interest. None of the statistically significant covariates from PopPK (body weight, gender, antitherapeutic antibody, albumin, and tumor burden) would require dose adjustment.

Should Therapeutic Drug Monitoring for Monoclonal Antibodies Remain the Exception or Become the Norm?

Therapeutic drug monitoring (TDM) aims to maintain circulating drug concentrations at a desired level to optimize clinical outcome. The vast majority of marketed drugs do not require TDM, suggesting the clinical benefit of TDM has not been sufficiently demonstrated in most cases. With the continued emergence and prominence of monoclonal antibodies (mAbs) as drugs, especially in inflammation and cancer therapeutic areas, we are at a juncture to consider applicability of TDM for mAbs.

Challenges and Opportunities for Quantitative Clinical Pharmacology in Cancer Immunotherapy: Something Old, Something New, Something Borrowed, and Something Blue.

Cancer immunotherapy (CIT) initiates or enhances the host immune response against cancer. Following decades of development, patients with previously few therapeutic options may now benefit from CIT. Although the quantitative clinical pharmacology (qCP) of previous classes of anticancer drugs has matured during this time, application to CIT may not be straightforward since CIT acts via the immune system. Here we discuss where qCP approaches might best borrow or start anew for CIT.

Translation of anticancer efficacy from nonclinical models to the clinic.

Mouse cancer models have provided critical insights into tumor biology; however, clinical translation of these findings has been challenging. This perspective posits that factors impacting on successful translation start with limitations in capturing human cancer pathophysiology and end with challenges in generating robust translatable preclinical end points. A comprehensive approach that considers clinically relevant mouse models with both an integrated biomarker strategy and a complementary modeling and simulation effort will strengthen the current oncology drug development paradigm.

X-ray flares in early GRB afterglows.

The Swift X-ray Telescope (XRT) has discovered that flares are quite common in early X-ray afterglows of gamma-ray bursts (GRBs), being observed in roughly 50% of afterglows with prompt follow-up observations. The flares range in fluence from a few per cent to approximately 100% of the fluence of the prompt emission (the GRB). Repetitive flares are seen, with more than four successive flares detected by the XRT in some afterglows. The rise and fall times of the flares are typically considerably smaller than the time since the burst. These characteristics suggest that the flares are related to the prompt emission mechanism, but at lower photon energies. We conclude that the most likely cause of these flares is late-time activity of the GRB central engine.

Cholera toxin binding affinity and specificity for gangliosides determined by surface plasmon resonance.

The present study determines the affinity of cholera toxin for the ganglioside series GM1, GM2, GM3, GD1A, GD1B, GT1B, asialo GM1, globotriosyl ceramide, and lactosyl ceramide using real time biospecific interaction analysis (surface plasmon resonance, SPR). SPR shows that cholera toxin preferably binds to gangliosides in the following sequence: GM1 > GM2 > GD1A > GM3 > GT1B > GD1B > asialo-GM1. The measured binding affinity of cholera toxin for the ganglioside sequence ranges from 4.61 x 10-12 M for GM1 to 1.88 x 10-10 M for asialo GM1. The picomolar values obtained by surface plasmon resonance are similar to Kd values determined with whole-cell binding assays. Both whole-cell assays and SPR measurements on synthetic membranes are higher than free solution measurements by several orders of magnitude. This difference may be caused by the effects of avidity and charged lipid head-groups, which may play a major role in the binding between cholera toxin, the receptor, and the membrane surface. The primary difference between free solution binding studies and surface plasmon resonance studies is that the latter technique is performed on surfaces resembling the cell membrane. Surface plasmon resonance has the further advantage of measuring apparent kinetic association and dissociation rates in real time, providing direct information about binding events at the membrane surface.

A 'litmus test' for molecular recognition using artificial membranes.

BACKGROUND: Sensitive and selective molecular recognition is important throughout biology. Certain organisms and toxins use specific binding at the cell surface as a first step towards invasion. A new series of biomolecular materials, with novel optical and interfacial properties, have been designed to sense molecular recognition events. These polymers, the diacetylenic lipids, have previously been shown to undergo chromatic transitions in response to virus binding to the surface of the material. RESULTS: Gangliosides that specifically bind cholera toxin, heat-labile Escherichia coli enterotoxin and botulinum neurotoxin were incorporated into a matrix of diacetylenic lipids, 5-10% of which were derivatized with sialic acid. The lipids were self-assembled into Langmuir-Blodgett layers and polymerized with ultraviolet irradiation, yielding a polydiacetylene membrane with a characteristic blue color into which the ganglioside is non-covalently incorporated. When toxin is added, the polymerized membrane turns red. The response is specific and selective, and can be quantified by visible absorption spectrophotometry. CONCLUSIONS: Polydiacetylenic lipid membranes offer a general 'litmus test' for molecular recognition at the surface of a membrane. A concentration of 20 ppm of protein could be detected using polymerized thin films. The speed, sensitivity and simplicity of the design offers a new and general approach towards the direct colorimetric detection of a variety of different molecules.

HMO innovations. Video-enhanced medical advice; senior zoo walkers; Group Health Resource Line; enhancing health education programs through desktop publishing; home health beat; innovative school health partnership.

The editors of HMO PRACTICE asked clinicians and health educators in HMOs across the country to submit reports on their unique, successful patient education programs. The following HMO Innovations testify to the wide range of new technologies, enterprising partnerships, and creative ideas that are shaping health education in HMOs today.

[Early operation for acute gallbladder as a therapeutic principle]. / Die Frühoperation der "akuten Galle" als therapeutisches Prinzip.

Between 1 January 1969 and 30 June 1984 904 patients with acute cholecystitis were treated as inpatients. Including 1976, initial treatment was conservative, and interval operation was recommended after 6-8 weeks. Commencing in 1977 early operation was preferred. Immediate operation within a few hours after admission and preparation for operation was done only in threatening or demonstrable complications of acute cholecystitis. Multimorbidity was highest (39%) in conservatively treated patients (n = 204), it was 26% in immediately operated patients (n = 201) and 23% in patients operated in the interval (n = 199). Early operation (n = 300) was associated with a multimorbidity of only 13%. Postoperative complications occurred most frequently (33%) after immediate operation, and in only 11% after early operation. Exploration of the choledochus was required in 27% of immediately operated cases and in only 19% of early and interval operations. Mortality after exclusively conservative treatment was 3%, after immediate operation 16%, after interval operation 3% and after early operation only 1.3%. Follow-up assessment of 137 primarily non-operated patients (7-15 years) showed a mortality of 48% on subsequently necessary immediate operation (16 out of 33 patients). No symptoms were seen in 14 out of 32 patients, only two of them had no gallstones. The high reliability of establishing the diagnosis (98% correct diagnosis) justifies early operation as preferred concept of treatment. Primary conservative treatment of acute cholecystitis and subsequently planned interval operation should be limited to justifiable exceptions.

[Indication and technic of interlocking nailing of the femur]. / Indikation und Technik der Verriegelungsnagelung am Oberschenkel.

Between 1973 and 1982 we treated 569 fractures of the femoral shaft by means of osteosynthesis. The internal nailing was performed in 41.6%. We used an interlocking nailing in 170 cases, 116 times statically and 54 times dynamically. An open reposition was performed in 48.2%. With only a very small incision we exposed the area of the fracture to insert the reamer guide under control of the fingers into the distal part of the femoral shaft. By using this technique there is no danger of disposing the fragments in order to achieve stabilisation in the correct position. 52.4% of the patients were younger than 30 years and 25.9% older than 30 years and 25.9% older than 60 years. In all cases we observed an osseous healing, twice a secondary cancellous bone craft was necessary. As complications we had an infection rate of 2.9%, loosening of the bolt in 0.6%, axial malalignment greater than 10 degrees in 0.6%, a rotary malalignment greater than 10 degrees in 1.2%. We did not observe any refracture. Less complications can be observed in interlocking nailing in comparison with plate osteosynthesis. Technique, indication, mistakes, and dangers as well as careful timing of operation are discussed. In open fractures delayed osteosynthesis by means of interlocking nailing is to be preferred to primary plate osteosynthesis. Fractures fixed by interlocking nailing had comparatively less complications in fracture healing and especially no more shortenings and rotation deformities, but the advantage of early full weightbearing. The interlocking nail has a very important value in the management of femoral shaft fractures.

[Ender nailing of subcapital fractures of the femur neck (Garden I)]. / Ender-Nagelung subkapitaler Schenkelhalsbrüche (Garden I).

In the period between 1968 and 1982 we observed 441 subcapital fractures of the femoral neck, 55 times a tight impaction in valgus position. Including the year 1976 a conservative treatment was employed (group I); from 1977 onwards operations with the Ender-nailing technique were performed (group II). The patients' average age was 81 to 84 years. In 7 out of 32 cases the conservative functional treatment led to disimpacted fractures between the 5th and 54th day after the accident. Neither a slightly gaping fracture line nor an up to ten-degree antecurvatoral position are a radiologic-morphological criterion for a prognostic assessment. For that reason we performed the Ender-nailing operation in 23 cases from 1977 on. Under immediate postoperative and complete load it was only once we obtained a partial dislocation of fracture which had a compact osseous healing up in varus deformity. A cranial displacement of the nails caused by the operation was observed three times. All patients regained their ability to walk. Until the end of the first year of the accident there was no case of death, nor could we perceive any total necrosis of the femoral head. One pseudarthrosis was found after conservative treatment. The average clinical treatment was 42 respectively 21 days. We transferred 19 out of 32 respectively 7 out of 23 patients to a convalescent hospital. The impacted subcapital fracture of the femoral neck should nowadays be treated operatively. The Ender-nailing technique represents a simple, gentle, and a low-risk procedure for surgical stabilization.

[Pediatric problems arising from surgery of the pancreas in childhood (author's transl)]. / Pädiatrisch bedeutsame kinderchirurgische Probleme des Pankreas.

The annular pancreas which is responsible for one third of the cases of duodenal obstruction plays a central role in pancreatic malformations. Therapy of choice is a duodeno-duodenostomy. Prognosis is deteriorated by frequent premature delivery, Down's syndrome and associated malformations. Among pancreatic tumors the congenital pancreatic cyst, the cysto-papillary adenoma and the insulinoma are particularly considered the latter in connection with the discussion of hyperinsulinism which also nesidioblastosis is associated. Pancreatic tumors to require surgical therapy and a subtotal excision of the pancreas is frequently necessary in nesidioblastosis. Besides pancreatitis which is diagnosed in Germany also pancreatic rupture with subsequent posttraumatic pancreatitis leading to pancreatic pseudocysts is discussed. There are no deaths after isolated pancreatic trauma or surgery of pancreatic pseudocysts.