Early-drug development in the era of immuno-oncology: are we ready to face the challenges?

The classical development of drugs has progressively faded away, and we are currently in an era of seamless drug-development, where first-in-human trials include unusually big expansion cohorts in the search for early signs of activity and rapid regulatory approval. The fierce competition between different pharmaceutical companies and the hype for immune combinations obliges us to question the current way in which we are evaluating these drugs. In this review, we discuss critical issues and caveats in immunotherapy development. A particular emphasis is put on the limitations of pre-clinical toxicology studies, where both murine models and cynomolgus monkeys have underpredicted toxicity in humans. Moreover, relevant issues surrounding dose determination during phase I trials, such as dose-escalation methods or flat versus body-weight dosing, are discussed. A proposal of how to face these different challenges is offered, in order to achieve maximum efficacy with minimum toxicity for our patients.

Estudio descriptivo del patrón de diseminación visceral del melanoma cutáneo / Patterns of Visceral Metastasis in Cutaneous Melanoma: A Descriptive Study

Introducción y objetivos: Algunas formas de cáncer tienden a producir metástasis en determinados órganos. En cuanto al melanoma, el melanoma uveal produce metástasis casi exclusivamente en el hígado, mientras que el melanoma cutáneo se disemina también a otros órganos. A pesar de importantes avances en el conocimiento de las bases moleculares del melanoma, hay pocos estudios recientes sobre el patrón de diseminación visceral del melanoma cutáneo. Nuestro objetivo fue analizar retrospectivamente una posible asociación entre tipo clinicopatológico y localización del melanoma cutáneo con el patrón de diseminación visceral y su cronología. Material y métodos: Se incluyeron en el estudio los pacientes diagnosticados de melanoma cutáneo entre 1988-2009 con más de 2 años de seguimiento. Resultados: De un total de 1.083 pacientes 92 desarrollaron metástasis viscerales: 21 en el sistema nervioso central (SNC), 24 en los pulmones, 17 en el hígado, 7 en el tubo digestivo y 23 en múltiples órganos simultáneamente. Las recidivas en el pulmón, el hígado y el tubo digestivo se produjeron mayoritariamente antes de los 5 años, mientras que las metástasis al SNC y a múltiples órganos simultáneamente fueron más tardías (38 y 43% después de los 5 años respectivamente). Conclusiones: A diferencia del melanoma ocular, el melanoma cutáneo se disemina por igual a múltiples órganos. No hemos detectado asociación significativa respecto al órgano diana de las metástasis según el tipo histológico y tampoco según la localización del tumor primario. A pesar de que la mayoría de metástasis viscerales se producen antes de los 5 años, también pueden producirse metástasis viscerales más allá de los 10 años de seguimiento (AU)

Background and objectives: Some types of cancer tend to spread to certain organs. In the case of melanoma, uveal melanoma spreads almost exclusively to the liver, while cutaneous melanoma spreads to the liver and other organs. Although important advances have been made in our understanding of the molecular mechanisms underlying melanoma, few recent studies have focused on the patterns of visceral metastasis in cutaneous melanoma. The aim of this study was to retrospectively investigate whether clinicopathologic variants of cutaneous melanoma and primary tumor site might be associated with pattern and time of onset of metastasis to visceral sites, including the central nervous system (CNS). Materials and methods: We included patients diagnosed with cutaneous melanoma between 1988 and 2009 with at least 2 years’ follow-up. Results: Of the 1083 patients studied, 92 developed visceral metastasis. The CNS was affected in 21 cases, the lungs in 24, the liver in 17, the digestive tract in 7, and multiple organs simultaneously in 23. Metastasis to the lungs, the liver, and the digestive tract occurred within 5 years in most cases, while metastasis to the CNS and multiple organs occurred later (> 5 years in 38% and 43% of cases, respectively). Conclusions: Unlike uveal melanoma, cutaneous melanoma spreads to different organs without any particular predilection. We observed no significant associations between the site of visceral metastasis and either clinicopathologic variant or location of the primary tumor. Metastasis occurred within 5 years of diagnosis in most cases, but it can occur after 10 years (AU)

Patterns of visceral metastasis in cutaneous melanoma: a descriptive study.

BACKGROUND AND OBJECTIVES: Some types of cancer tend to spread to certain organs. In the case of melanoma, uveal melanoma spreads almost exclusively to the liver, while cutaneous melanoma spreads to the liver and other organs. Although important advances have been made in our understanding of the molecular mechanisms underlying melanoma, few recent studies have focused on the patterns of visceral metastasis in cutaneous melanoma. The aim of this study was to retrospectively investigate whether clinicopathologic variants of cutaneous melanoma and primary tumor site might be associated with pattern and time of onset of metastasis to visceral sites, including the central nervous system (CNS). MATERIALS AND METHODS: We included patients diagnosed with cutaneous melanoma between 1988 and 2009 with at least 2 years' follow-up. RESULTS: Of the 1083 patients studied, 92 developed visceral metastasis. The CNS was affected in 21 cases, the lungs in 24, the liver in 17, the digestive tract in 7, and multiple organs simultaneously in 23. Metastasis to the lungs, the liver, and the digestive tract occurred within 5 years in most cases, while metastasis to the CNS and multiple organs occurred later (>5 years in 38% and 43% of cases, respectively). CONCLUSIONS: Unlike uveal melanoma, cutaneous melanoma spreads to different organs without any particular predilection. We observed no significant associations between the site of visceral metastasis and either clinicopathologic variant or location of the primary tumor. Metastasis occurred within 5 years of diagnosis in most cases, but it can occur after 10 years.

[Rapidly progressive glomerular disease treated with plasmapheresis (author's transl)]. / Glomerulonefritis rápidamente progresiva tratada con plasmaféresis.

A case of rapidly progressive glomerular disease with 100% of epithelial crescents completely enveloping each glomerulus, prolonged anuria and renal failure requiring dialysis. There were no indications of either streptococcal etiology or systemic disease. Improvement in renal function in response to plasmapheresis and immunosuppressants was spectacular. During two subsequent episodes of renal failure with diminished diuresis response to plasmapheresis was again striking. Assay for circulating immune-complex was always negative. No anti-basement membrane antibodies were found. Due to the lack of an adequate vascular access plasmapheresis was discontinued and the patient died 7 months after onset. Tendency to interstitial glomerular sclerosis was established with three renal biopsy specimens taken during progression of the disease. Intense metabolic acidosis suggestive of tubular acidosis, disproportionate to renal insufficiency presented during the last months. Pathologic and prognostic aspects as well as possible access for plasmapheresis are discussed.

[Burkitt's lymphoma. Report of six cases (author's transl)]. / Linfoma de Burkitt. Aportación de seis casos.

Authors report six cases on Burkitt's lymphoma seen during the last 18 months. In all of them a large ileocecal tumor was present and five of them had a bone marrow involvement. The ascitic fluid was positive in all cases. Three of the patients had a marked jaundice at diagnosis. The immunologic markers study on two of the cases, made evident that they belonged to type B. One of these two cases showed a component M in serum of the IgM type. As soon as chemotherapy started two of the cases showed marked metabolic disturbances. Three of the cases died and the three others remain free of disease for as long as two, 26 and 21 months. This report arises a comment epidemiologic importance of the increased frequency of Burkitt's lymphoma during the last months, as well as the clinic features of the six reported cases as compared to series published in non endemic areas on this topic.