Adcitmer® , a new CD56-targeting monomethyl auristatin E-conjugated antibody, is a potential therapeutic approach in Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer, whose tumour cells often express CD56. While immune checkpoint inhibitors constitute a major advance for treating patients with MCC with advanced disease, new therapeutic options are still urgently required. OBJECTIVES: To produce and evaluate the therapeutic performance of a new antibody-drug conjugate (Adcitmer® ) targeting CD56 in preclinical models of MCC. METHODS: CD56 expression was evaluated in a MCC cohort (immunohistochemistry on a tissue microarray of 90 tumour samples) and MCC cell lines. Interaction of an unconjugated CD56-targeting antibody with CD56+ MCC cell lines was investigated by immunohistochemistry and imaging flow cytometry. Adcitmer® product was generated by the bioconjugation of CD56-targeting antibody to a cytotoxic drug (monomethyl auristatin E) using the McSAF Inside® bioconjugation process. The chemical properties and homogeneity of Adcitmer® were characterized by hydrophobic interaction chromatography. Adcitmer® cytotoxicity was evaluated in vitro and in an MCC xenograft mice model. RESULTS: Similar to previous reports, CD56 was expressed by 66% of MCC tumours in our cohort, confirming its relevance as a therapeutic target. Specific binding and internalization of the unconjugated CD56-targeting antibody was validated in MCC cell lines. The high homogeneity of the newly generated Adcitmer® was confirmed by hydrophobic interaction chromatography. The CD56-mediated cytotoxicity of Adcitmer® was demonstrated in vitro in MCC cell lines. Moreover, Adcitmer® significantly reduced tumour growth in a MCC mouse model. CONCLUSIONS: Our study suggests that Adcitmer® should be further assessed as a therapeutic option in patients with MCC, as an alternative therapy or combined with immune checkpoint inhibitors.

Fourteen years of experience in uncontrolled organ donation after cardio-circulatory death.

BACKGROUND: Since 1999, a protocol for uncontrolled donation after cardio-circulatory death (DCD) has been carried out in our institution. We aimed at evaluating those 14 years of local experience. METHODS: We reviewed the charts of uncontrolled donors from 1999 till 2013. Potential donors with a no-flow period less than 30 minutes were considered. Kidneys were perfused by the use of a double balloon triple lumen catheter after at least a 2-minute period of no touch. We analyzed grafts outcome and warm and cold ischemia times. RESULTS: Thirty-nine procedures were initiated: 19 were aborted because of family refusal (n = 7), medical reasons (n = 7), or canulation failures (n = 5) and 20 harvesting procedures were completed. Transplantation was considered for 35 kidneys (cold storage [n = 5] and hypothermic preservation system [n = 30]). The causes of withdrawal from transplantation were mostly macroscopic lesions (poor perfusion, macroscopic parenchyma or vascular lesions, or infectious risk). We transplanted 22 kidneys locally and 3 were shipped to another Eurotransplant center. Mean donor age was 40 ± 13 years. Among the 20 donors, 13 came from the emergency unit and 7 from the intensive care unit. Mean no-flow time for out-hospital management was 8.7 ± 3.6 minutes. Mean time of cardiopulmonary resuscitation was 71 ± 46 minutes. Mean cold ischemia time was 19 ± 5 hours. Primary nonfunction and delayed graft function occurred in 1 and 12 cases (4.5% and 54%), respectively. Graft survival was 86% at 1 year. Causes of graft loss during the entire follow-up were graft rejection (n = 3), ischemically damaged kidney (n = 2), and recurrence of focal segmental glomerulosclerosis (n = 1). CONCLUSION: In our experience, uncontrolled donors represent a valuable source of kidney grafts, with a prognosis of graft function and survival similar to the literature. To increase the number of available DCD organs, new techniques, such as the use of Normothermic ExtraCorporeal Membrane Oxygenation (NECMO), as well as improvement of recruitment of out of hospital potential donors have to be considered.

Anaemia of chronic disease: diagnostic significance of erythrocyte and serological parameters in iron deficient rheumatoid arthritis patients.

Erythrocyte and serological parameters were assessed in 44 anaemic rheumatoid arthritis (RA) patients to detect iron deficiency as assessed by stainable bone marrow iron. The anaemia was normochromic normocytic in 60% and hypochromic normocytic in 30% of those with anaemia of chronic disease (ACD). Iron deficiency was present in 55% and the anaemia was hypochromic microcytic in 54% and hypochromic normocytic or normochromic normocytic in 21%. Iron absorption was found to be higher in iron deficient patients. In ACD patients, iron absorption correlated inversely with ESR and CRP. For the detection of iron deficiency among RA patients with ACD, the MCV showed the highest specificity (90%) and predictive value (87%). Serum ferritin was the most sensitive (82%) and valid (86%) test. Combination of MCV, ferritin and transferrin resulted in 100% validity. It was concluded that iron deficiency can be detected accurately without bone marrow aspiration using combinations of blood parameters.