Top Ten Contributions of Pediatric Hematology/Oncology to the Diagnosis and Treatment of Acute Lymphoblastic Leukemia.

Monumental progress has occurred in the diagnosis and treatment of childhood acute lymphoblastic leukemia dating back to the classic paper of Farber and colleagues in 1948. This historical review from the perspective of an individual, familiar with many of the waystations on this superhighway, will offer an admittedly personal review of the top 10 major contributions to the field. Fortunately, there have been many more additional advances beyond these 10 as we have witnessed an impressive improvement in overall survival from a few months 75 years ago to a cure rate of 85% in the world's more advanced countries. Other workers in the field assuredly would create a different list and ranking of these advances but the takeaway summation of the make-up and order of these lists is that advances have yielded improved and prolonged responses, a rational understanding of factors, both clinical and biological, that predict response and prognosis, the application of those factors to tailor therapy's intensity and duration to those factors and to discover and design modalities and targets of therapy that target our much more complete understanding of this most common malignancy of infants and children. On a very personal note, I vividly recall an early, ill-advised decision to devote my academic career to hematology/oncology, with one glaring exception, acute lymphoblastic leukemia, and other malignancies. The stark realities of clinical practice and the harsh unmet needs and mostly unanswered challenges redirected my path that resulted in participation in many of these advances, making my own journey so gratifying and that of most of our patients so favorable.

A tribute to Sidney Farber-- the father of modern chemotherapy.

Sidney Farber, world-renowned paediatric pathologist, made major contributions to his field but is acknowledged as the father of the modern era of chemotherapy. He recognised that folic acid stimulated leukaemic cell growth and enhanced disease progression. He hypothesised that folic acid antagonists would inhibit or arrest the proliferation of cancer cells. His landmark study, published in 1948, demonstrated that a number of folic acid antagonists, including 4-aminopteroyl-glutamic acid (aminopterin) produced temporary remissions in children with acute undifferentiated leukaemia. These observations lead to the development and use of other chemotherapeutic agents, either singly or, more effectively, in combination for treating childhood and adult malignancies. He introduced actinomycin D for the treatment of metastatic and localised Wilms tumour. Under his guidance and leadership, both the 'Jimmy Fund', one of the first comprehensive paediatric oncology treatment centres, and the Children's Cancer Research Foundation, which later became the Dana-Farber Cancer Institute, were founded.

The usefulness of in vitro models to predict the bioavailability of iron and zinc: a consensus statement from the HarvestPlus expert consultation.

A combination of dietary and host-related factors determines iron and zinc absorption, and several in vitro methods have been developed as preliminary screening tools for assessing bioavailability. An expert committee has reviewed evidence for their usefulness and reached a consensus. Dialyzability (with and without simulated digestion) gives some useful information but cannot predict the correct magnitude of response and may sometimes predict the wrong direction of response. Caco-2 cell systems (with and without simulated digestion) have been developed for iron availability, but the magnitude of different effects does not always agree with results obtained in human volunteers, and the data for zinc are too limited to draw conclusions about the validity of the method. Caco-2 methodologies vary significantly between laboratories and require experienced technicians and good quality cell culture facilities to obtain reproducible results. Algorithms can provide semi-quantitative information enabling diets to be classified as high, moderate, or low bioavailability. While in vitro methods can be used to generate ideas and develop hypotheses, they cannot be used alone for important decisions concerning food fortification policy, selection of varieties for plant breeding programs, or for new product development in the food industry. Ultimately human studies are required for such determinations.