BackgroundThe contribution of low-penetrant susceptibility variants to cancer is not clear. With the aim of searching for genetic factors that contribute to cancer at one or more sites in the body, we have analyzed familial aggregation of cancer in extended families based on all cancer cases diagnosed in Iceland over almost half a century.Methods and FindingsWe have estimated risk ratios (RRs) of cancer for first- and up to fifth-degree relatives both within and between all types of cancers diagnosed in Iceland from 1955 to 2002 by linking patient information from the Icelandic Cancer Registry to an extensive genealogical database, containing all living Icelanders and most of their ancestors since the settlement of Iceland.We evaluated the significance of the familial clustering for each relationship separately, all relationships combined (first- to fifth-degree relatives) and for close (first- and second-degree) and distant (third- to fifth-degree) relatives. Most cancer sites demonstrate a significantly increased RR for the same cancer, beyond the nuclear family. Significantly increased familial clustering between different cancer sites is also documented in both close and distant relatives. Some of these associations have been suggested previously but others not.ConclusionWe conclude that genetic factors are involved in the etiology of many cancers and that these factors are in some cases shared by different cancer sites. However, a significantly increased RR conferred upon mates of patients with cancer at some sites indicates that shared environment or nonrandom mating for certain risk factors also play a role in the familial clustering of cancer. Our results indicate that cancer is a complex, often non-site-specific disease for which increased risk extends beyond the nuclear family.

Breakthrough pain or transient worsening of pain in patients with an ongoing steady pain is a well known feature in cancer pain patients, but it is also seen in non-malignant pain conditions with involvement of nerves, muscles, bones or viscera. Continuous and intermittent pain seems to be a general feature of these different pain conditions, and this raises the possibility of one or several common mechanisms underlying breakthrough pain in malignant and non-malignant disorders. Although the mechanisms of spontaneous ongoing pain and intermittent flares of pain (BTP) may be difficult to separate, we suggest that peripheral and/or central sensitization (hyperexcitability) may play a major role in many causes of BTP. Mechanical stimuli (e.g. micro-fractures) changes in chemical environments and release of tumour growth factors may initiate sensitization both peripherally and centrally. It is suggested that sensitization could be the common denominator of BTP in malignant and non-malignant pain.

III.

Acute peripheral facial nerve palsy (FNP) is a well-described cranial nerve dysfunction of the seventh cranial nerve. The facial nerve carries motor fibres to the facial musculature, efferent secretory fibres to the lacrimal and salivary glands as well as afferent sensory fibres from the anterior two-thirds of the tongue and the external auditory canal. The onset of FNP is normally acute and causes inability to control facial muscles on the affected side. The annual incidence of FNP in children has been reported from 5 to 21 per 100 000 children/year 1-5 with up to 43/100 000 among children under 6 years of age. 4 Differential diagnosis for acquired FNP is infections (ie Lyme borreliosis/neuroborreliosis, members of the herpesvirus family and enteroviruses), trauma, tumours, leukaemia, vascular diseases, iatrogenic causes and idiopathic facial palsy (IFP) (FNP of unknown cause despite appropriate diagnostic measures). Neuroborreliosis, a tick-borne infection, is the most common identifiable cause among children and is significantly more common in children than adults. 1,4,6 In Borrelia high-endemic areas, neuroborreliosis has been reported as the cause in 23%-65% of children with FNP. 1-4,7 Whereas FNP attributable to infections is more prevalent in children, the majority of FNP among adults is IFP. The incidence of IFP increases with age as shown in a UK study where the lowest incidence was among children 0-6 years of age; 6.6 per 100 000 person years, compared to 20.1 per 100 000 years among those 15-29 years of age. 8 Larger cohorts in adults have shown a yearly incidence of IFP around 30 per 100 000. 9

Background Children with acute peripheral facial nerve palsy cannot yet be recommended corticosteroid treatment based on evidence. Adults with idiopathic facial nerve palsy are treated with corticosteroids, according to guidelines resulting from a meta-analysis comprising two major randomized placebo-controlled trials. Corresponding trials in children are lacking. Furthermore, acute facial nerve palsy in childhood is frequently associated with Lyme neuroborreliosis, caused by the spirochete Borrelia burgdorferi. The efficacy and safety of corticosteroid treatment of acute facial nerve palsy associated with Lyme neuroborreliosis, has not yet been determined in prospective trials in children, nor in adults. Method This randomized double-blind, placebo-controlled study will include a total of 500 Swedish children aged 1–17 years, presenting with acute facial nerve palsy of either idiopathic etiology or associated with Lyme neuroborreliosis. Inclusion is ongoing at 12 pediatric departments, all situated in Borrelia burgdorferi endemic areas. Participants are randomized into active treatment with prednisolone 1 mg/kg/day (maximum 50 mg/day) or placebo for oral intake once daily during 10 days without taper. Cases associated with Lyme neuroborreliosis are treated with antibiotics in addition to the study treatment. The House-Brackmann grading scale and the Sunnybrook facial grading system are used for physician-assessed evaluation of facial impairment at baseline, and at the 1- and 12-month follow-ups. Primary outcome is complete recovery, measured by House-Brackmann grading scale, at the 12-month follow-up. Child/parent-assessed questionnaires are used for evaluation of disease-specific quality of life and facial disability and its correlation to physician-assessed facial impairment will be evaluated. Furthermore, the study will evaluate factors of importance for predicting recovery, as well as the safety profile for short-term prednisolone treatment in children with acute facial nerve palsy. Discussion This article presents the rationale, design and content of a protocol for a study that will determine the efficacy of corticosteroid treatment in children with acute facial nerve palsy of idiopathic etiology, or associated with Lyme neuroborreliosis. Future results will attribute to evidence-based treatment guidelines applicable also in Borrelia burgdorferi endemic areas. Trial registration The study protocol was approved by the Swedish Medical Product Agency (EudraCT nr 2017–004187-35) and published at ClinicalTrials.gov (NCT03781700, initial release 12/14/2018).