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This is a protocol for a Cochrane Review (intervention). The objectives are as follows: The objectives of this systematic Review are to try to answer the following questions based on the results of randomised clinical trials (RCTs) comparing IFN versus no intervention, placebo, or other interventions irrespective of blinding, publication status, or language: 1) Does IFN reduce mortality and tumour recurrences in patients with HCC when used as primary treatment? 2) Does IFN reduce mortality and tumour recurrences when used as adjuvant or neoadjuvant therapy in patients treated by surgical or other ablative procedures? 3) Does IFN cause adverse events? 4) Does IFN affect quality of life and health economics?

Clear cell renal cell carcinoma (ccRCC) accounts for ∼80% of all RCC, and biallelic Von Hippel-Lindau (VHL) gene defects occur in ∼75% of sporadic ccRCC. The etiopathogenesis of VHL mutant metastatic RCC, based on our understanding to date of molecular mechanisms involved, is a sequence of events which can be grouped under the following: (i) loss of VHL activity (germline/somatic mutation + inactivation of the wild-type copy); (ii) constitutive activation of the hypoxia-inducible factor (HIF) pathway due to loss of VHL activity and transcription of genes involved in angiogenesis, epithelial-mesenchymal transition, invasion, metastasis, survival, anaerobic glycolysis and pentose phosphate pathway; (iii) interactions of the HIF pathway with other oncogenic pathways; (iv) genome-wide epigenetic changes (potentially driven by an overactive HIF pathway) and the influence of epigenetics on various oncogenic, apoptotic, cell cycle regulatory and mismatch repair pathways (inhibition of multiple tumor suppressor genes); (v) immune evasion, at least partially caused by changes in the epigenome. These mechanisms interact throughout the pathogenesis and progression of disease, and also confer chemoresistance and radioresistance, making it one of the most difficult metastatic cancers to treat. This article puts together the sequential pathogenesis of VHL mutant ccRCC by elaborating these mechanisms and the interplay of oncogenic pathways, epigenetics, metabolism and immune evasion, with a perspective on potential therapeutic strategies. We reflect on the huge gap between our understanding of the molecular biology and currently accepted standard of care in metastatic ccRCC, and present ideas for better translational research involving therapeutic strategies with combinatorial drug approach, targeting different aspects of the pathogenesis.

The clinician - the doctor who treats sick people - should be able to establish a good human relationship with his or her patients and their family; should be able to reach a diagnosis even in patients with rare diseases, or atypical presentations - or should refer the patient to a senior colleague; and should be able to recommend the best treatment (or no treatment at all). And he - or she - should be able to draw these abilities from the "deliberate practice" according to Ericsson, i.e. from the combination of experience with reflection - not, or with much lesser strength, from the medical literature as suggested by Evidence-Based Medicine. The diagnosis is often an easy task, i.e. by pattern recognition or recognizing a frequent illness script - "fast thinking" in the vocabulary of Kahneman; or a difficult task, sometimes very difficult for rare diseases or atypical presentations - "slow thinking" of Kahneman. The decisions about the use of therapeutic interventions, whether for individuals or entire healthcare systems, should be based on the totality of the available evidence. The idea that evidence can be reliably or usefully placed in "hierarchies" is illusory, and the pedestal deserved to the RCT is inappropriate.

This is an essay dealing with the 1785 cohort study by William Withering (the "account"), in which he reported the results of the treatment with foxglove (Digitalis purpurea) in 163 patients suffering from various forms of hydropsy (water retention). Withering reported the results of all patients, and classified them into responders and non-responders. He identified the responders as suffering from heart failure. In the 18th century, medical treatments were judged as successful if they complied with the criteria a priori of the theory of the four humors, and not on the patient's response to the treatment. Withering was the first not only to compare the patient's conditions before and after treatment, but also to identify the individual clinical characteristics of the patients who responded. In modern medicine, drugs are released on the market and approved for use after what is known as "population-derived clinical research", principally randomized controlled trials, and guidelines. More than 200 years ago, Withering anticipated the current and growing trend towards individual responses to treatment, and personalized medicine.