Combining Melphalan Percutaneous Hepatic Perfusion with Ipilimumab Plus Nivolumab in Advanced Uveal Melanoma: First Safety and Efficacy Data from the Phase Ib Part of the Chopin Trial.

PURPOSE: To define a safe treatment dose of ipilimumab (IPI) and nivolumab (NIVO) when applied in combination with percutaneous hepatic perfusion with melphalan (M-PHP) in metastatic uveal melanoma (mUM) patients (NCT04283890), primary objective was defining a safe treatment dose of IPI/NIVO plus M-PHP. Toxicity was assessed according to Common Terminology Criteria for Adverse Events version 4.03 (CTCAEv4.03). Secondary objective was response rate, PFS and OS. MATERIALS AND METHODS: Patients between 18-75 years with confirmed measurable hepatic mUM according to RECIST 1.1 and WHO performance score 0-1 were included. Intravenous IPI was applied at 1 mg/kg while NIVO dose was increased from 1 mg/kg in cohort 1 to 3 mg/kg in cohort 2. Transarterial melphalan dose for M-PHP was 3 mg/kg (maximum of 220 mg) in both cohorts. Treatment duration was 12 weeks, consisting of four 3-weekly courses IPI/NIVO and two 6-weekly M-PHPs. RESULTS: Seven patients were included with a median age of 63.6 years (range 50-74). Both dose levels were well tolerated without dose-limiting toxicities or deaths. Grade III/IV adverse events (AE) were observed in 2/3 patients in cohort 1 and in 3/4 patients in cohort 2, including Systemic Inflammatory Response Syndrome (SIRS), febrile neutropenia and cholecystitis. Grade I/II immune-related AEs occurred in all patients, including myositis, hypothyroidism, hepatitis and dermatitis. There were no dose-limiting toxicities. The safe IPI/NIVO dose was defined as IPI 1 mg/kg and NIVO 3 mg/kg. There was 1 complete response, 5 partial responses and 1 stable disease (3 ongoing responses with a median FU of 29.1 months). CONCLUSION: Combining M-PHP with IPI/NIVO was safe in this small cohort of patients with mUM at a dose of IPI 1 mg/kg and NIVO 3 mg/kg.

[The importance of HLA-matching before kidney transplantation: a recommendation of the Health Council of the Netherlands]. / Het belang van HLA-matching bij niertransplantatie; een advies van de Gezondheidsraad.

In a recent report, the Health Council of the Netherlands concluded, on the basis of the literature, that HLA-matching is still relevant for graft survival in renal transplant patients. Since the HLA DR antigen system is less heterogeneous than the class I HLA antigen system, it would seem wise to match primarily for these antigens, since this may lead to a reduced exchange of organs between countries and shorten the cold ischaemia period. This may in turn improve the results of transplantation. In the Netherlands, the number of living donor kidney transplants has recently shown a remarkable increase, due partly to the introduction of the paired, living donor, kidney exchange protocol. The introduction of a living donor list exchange programme may further increase this number. Finally, citizens need to be motivated to list themselves as possible organ donors.

Ethical and legal issues in non-heart-beating organ donation.

Procurement of kidneys and livers from non-heart-beating donors (NHBDs) raises ethical and legal issues that need to be considered carefully before wider use of these donors. Although NHBDs were used in kidney transplantation as early as the 1960s, retrieval of these organs is by no means universally accepted today. From a medical point of view, these organs have long been considered "marginal" because the majority show delayed or impaired graft function. Legal problems include determination of death by cardiopulmonary criteria, the issue of proper consent, and the use of organ preservation measures. Among ethical issues raised are the observance of the Dead-donor Rule, the decision-making surrounding resuscitation, the withdrawal of life-support, the respect for a dying patient and the dead body, as well as proper information to and guidance for the family. In the Netherlands NHB donation was pioneered in the Maastricht Medical Center in 1980s. Today, all seven transplant centers retrieve and transplant organs from these donors, and NHBDs have become an important source of transplantable kidneys and livers. Recent legislation in the Netherlands also supports the use of NHBDs by making possible the use of organ preservation measures after circulatory arrest, even in the absence of family consent. As a result, one of every three kidneys transplanted in the Netherlands in 2004 was obtained from a NHBD. In this study, Dutch NHBD protocols, practice, and results are analyzed and compared with international practices.

['New pathways to organ donation'; a recommendation of the Dutch Health Council]. / 'Nieuwe wegen naar orgaandonatie'; een advies van de Gezondheidsraad.

Despite recent efforts at improvement, the current status of postmortem organ donation in the Netherlands is a reason for serious concern. The waiting lists for all organ transplantations are increasing in length. The Dutch Health Council was asked by the Minister of Health to report on any available alternative sources of donor organs, focusing especially on donation from living donors and postmortem donors in whom the heart is no longer beating. Kidney donation by living relatives is a well-known procedure that has been performed since 1950. Since HLA-matching is now less important due to new immunosuppressive regimens, transplants from unrelated living volunteers are also possible with good results. Live donation from emotionally involved persons should be encouraged. In case of ABO incompatibility, donors could be exchanged via the organ exchange institution. Live donation of liver segments by an adult to benefit a child recipient is justified. In case of an adult recipient this should be performed only under exceptional circumstances. Live donation of lung lobes and segments of intestine is still in a developmental phase. Postmortem donation of kidneys and livers from donors in whom the heart is no longer beating should also be encouraged. Donation of the lungs and pancreas from these donors is still an experimental procedure.

Interfacial rheological properties of adsorbed protein layers and surfactants: a review.

Proteins and low molecular weight (LMW) surfactants are widely used for the physical stabilisation of many emulsions and foam based food products. The formation and stabilisation of these emulsions and foams depend strongly on the interfacial properties of the proteins and the LMW surfactants. Therefore these properties have been studied extensively. In this review an overview is given of interfacial properties of proteins at a mesoscopic scale and the effect of LMW surfactants (emulsifiers) on them. Properties addressed are the adsorbed amount, surface tension (reduction), network formation at interfaces and possible conformational changes during and after adsorption. Special attention is given to interfacial rheological behaviour of proteins at expanding and compressing interfaces, which simulate the behaviour in real emulsions and foams. It will be illustrated that information on interfacial rheological properties, protein conformation and interactions between adsorbed molecules can be obtained by changing experimental conditions. The relation between interfacial rheology and emulsion and foam stabilisation is subsequently addressed. It is concluded that there is a need for new measuring devices that monitor several interfacial properties on a mesoscopic and microscopic scale at the same time, and for physical models describing the various processes of importance for proteins. Real progress will only be possible if both are combined in an innovative way.

Infrastructure for radiotherapy in The Netherlands: development from 1970 to 2010.

In 1993 the radiotherapy advisory committee of the Dutch Health Council published its report on the developments of infrastructure for radiotherapy in The Netherlands during the last 10 years and the prognosis for future needs until 2010. Based on demographic trends, the expected incidence of cancer, the role of radiotherapy in the treatment of cancer, and the workload assessment in a model department, two scenarios are presented for the development of infrastructure. According to the committee, the Quality Scenario would be the most appropriate.

Procyanidins from tormentil: antioxidant properties towards lipoperoxidation and anti-elastase activity.

Procyanidins extracted from the rhizomes of Potentilla tormentilla were fractionated according to their degree of polymerization by chromatography on Sephadex LH20. Dimers and trimers displayed the highest anti-radical activity towards lipoperoxidation. Pentamers and hexamers possessed the most marked anti-elastase properties.

Determination of the orientation distribution of adsorbed fluorophores using TIRF. I. Theory.

The spectroscopic technique total internal reflection fluorescence can be used for determination of the orientation of adsorbed fluorescent molecules. The underlying theory is presented in general terms and elaborated in detail for the case that the fluorescent group is a porphyrin ring. It is shown that order parameters of the orientation distribution can be obtained if both the fluorescence intensity and its polarization are measured as functions of the polarization of the incident laser beam. From these order parameters an approximation of the orientation distribution can be derived by the maximum-entropy method.

Determination of the orientation distribution of adsorbed fluorophores using TIRF. II. Measurements on porphyrin and cytochrome c.

The theory for determination of the orientation of adsorbed fluorescent molecules using total internal reflection fluorescence, as explained in part I of this series, is illustrated by measurements on adsorbed tetramethylpyridinium porphyrin (H2TMPyP) and porphyrin cytochrome c molecules. The results are encouraging, although for porphyrin cytochrome c the scatter in the obtained order parameters is substantial. For H2TMPyP molecules adsorbed on glass the orientation distribution depends on the solution concentration. At low concentration, the H2TMPyP molecules are more or less randomly oriented, whereas at high concentrations a broad distribution around an angle of 46 degrees between the porphyrin plane and surface was found. For cytochrome c adsorbed on glass and indium tin oxide it was impossible to interpret the data in terms of orientation distributions because of the scatter in the results. The total fluorescence as a function of the polarization angle psi of the incident light beam corresponds to an average angle between the porphyrin group and the surface of 30 degrees-40 degrees. Despite the strong electric dipole moment of the protein, the orientation distribution seems to be independent on the (imposed) electrical potential of the interface.

Procyanidins from tormentil: fractionation and study of the anti-radical activity towards superoxide anion.

A standardised water-soluble extract was prepared from rhizomes of Potentilla tormentilla. The procyanidins in the extract were fractionated according to their degree of polymerisation by chromatography on Sephadex LH20. The anti-radical activities of the different fractions towards superoxide anion were compared when pentamers and hexamers were found to be the most active.

The diffusion of organ transplantation in Western Europe.

The moment of introduction of clinical organ transplantations varied in Western Europe from country to country. In retrospect, one can distinguish pioneering countries (most notably the U.K. and France), and countries that were early or late adopters of the new technologies. An early start did not necessarily lead to extensive diffusion of organ transplantations, as shown by the example of the U.K. In general, Western Europe is lagging behind the U.S.A. In diffusion of organ transplantation technologies. With few exceptions, the introduction and diffusion of organ transplantations in Western Europe have been largely autonomous developments, not regulated by government or third party payers and only slowed down by lack of organs, facilities or funds. The lack of organs has been reduced by the activities of organ procurement and exchange organisations, and perhaps by legislation promoting organ donation. Nevertheless, the growth of the number of patients waiting for an organ is in almost all countries outpacing the increase in availability of organs.