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On The Pulse - April 2018

On The Pulse

Tertius Lydgate

Friday, 20 April 2018

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Unintended weight loss
The BJGP has featured a systematic review and meta-analysis examining the association between cancer and unintended weight loss – a symptom that can present a real challenge for GPs who want to make or rule out cancer diagnosis at an early stage, but who also want to avoid putting patients through unnecessary tests. A total of 25 studies were included, with 23 using primary care records. Positive associations between weight loss and cancer were found for 10 cancer sites: prostate, colorectal, lung, gastro-oesophageal, pancreatic, non-Hodgkin’s lymphoma, ovarian, myeloma, renal tract, and biliary tree. Sensitivity ranged from 2% to 47%, and specificity from 92% to 99%, across cancer sites. The positive predictive value for cancer in male and female patients with weight loss for all age groups ≥60 years exceeded the 3% risk threshold that current UK guidance proposes for further investigation. The authors conclude that a primary care clinician’s decision to code for weight loss is highly predictive of cancer and for such patients, urgent referral pathways are justified to investigate for cancer across multiple sites.

The impact of prenatal exposure to SSRI
While selective serotonin reuptake inhibitor (SSRI) use among pregnant women is increasing, research in JAMA Pediatrics suggests that prenatal SSRI exposure has an association with foetal brain development, particularly in brain regions critical to emotional processing. The observational cohort study included 98 infants (16 with in utero SSRI exposure, 21 with in utero untreated maternal depression exposure, and 61 healthy controls) whose brain development was assessed via MRI (mean age at time of scan: 3.43 weeks). SSRI-exposed infants showed significant gray matter volume expansion in the right amygdala (Cohen d = 0.65; 95% CI, 0.06-1.23) and right insula (Cohen d = 0.86; 95% CI, 0.26-1.14) compared with both healthy controls and infants exposed to untreated maternal depression. The SSRI group also showed a significant increase in white matter connection strength between the two regions with a large effect size (Cohen d = 0.99; 95% CI, 0.40-1.57). The authors call for further research on the potential long-term behavioural and psychological outcomes of these neurodevelopmental changes.

Combination therapy in advanced renal-cell carcinoma
After an encouraging pilot study, a phase 3 trial in the NEJM has shown that overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma. 1,096 adults were randomly assigned in a 1:1 ratio to receive either nivolumab (3 mg/kg of body weight) plus ipilimumab (1 mg/kg) intravenously every three weeks for four doses, followed by nivolumab (3 mg/kg) every two weeks (n=550), or sunitinib (50 mg) orally once daily for four weeks (six-week cycle) (n=546). At a median follow-up of 25.2 months, the 18-month overall survival rate was 75% (95% CI, 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib. The objective response rate was 42% versus 27%, and the complete response rate was 9% versus 1%. An accompanying editorial ponders whether a cure for advanced renal cancer is possible with immunotherapy.

New drug may show promise in MS
Most cases of multiple sclerosis (MS) present as relapsing-remitting MS, and more than half of these patients later develop secondary progressive MS within 15-20 years, a severe form of the disease for which there is currently no treatment to prevent progression. A phase 3 randomised trial, published in The Lancet has shown positive results. 1,645 patients, aged 18-60 with moderate or advanced disability were either given 2mg of siponimod (a selective sphingosine 1-phosphate (S1P) receptor modulator) once a day (n=1,099), or a placebo (n=546) for up to three years or until their disability had progressed after six months. Patients whose disease progressed were offered open-label siponimod. The risk of a patient’s disability getting worse was 21% lower for people given siponimod, compared to those given placebo. From the start of the trial to 24 months, the reduction in brain volume was also less severe for people given the drug, compared to placebo. But a linked commentary expressed caution, as the treatment effect was small and the drug did not have an effect on all of the secondary outcomes.

Impact of age on CHD excess risk in patients with FH
Familial hypercholesterolaemia (FH) affects around one in every 200–300 people and increases the risk of premature coronary heart disease (CHD), but little data exist on the impact of age on the excess risk. A registry-based prospective cohort study, in Heart, including 3,071 patients with an FH mutation but without prior acute myocardial infarction (AMI) and 2,795 patients without prior CHD, found that standardised incidence ratios (SIRs) for AMI (95% CIs) were highest in the age group 25–39 years; 7.5 (3.7 to 14.9) in men and 13.6 (5.1 to 36.2) in women and decreased with age to 0.9 (0.4 to 2.1) in men and 1.8 (0.9 to 3.7) in women aged 70–79 years. Similarly, SIRs for CHD were highest among patients 25–39 years old; 11.1 (7.1–17.5) in men and 17.3 (9.6–31.2) in women and decreased 2.4 (1.4–4.2) in men and 3.2 (1.5–7.2) in women at age 70–79. For all age groups, combined SIRs for CHD were 4.2 (3.6–5.0) in men and 4.7 (3.9–5.7) in women. The findings suggest more action is needed to find and treat patients with FH early in life.

Women with PCOS have increased NAFLD rate
Recent research has shown rates of non-alcoholic fatty liver disease (NAFLD) may be higher in women with polycystic ovary syndrome (PCOS) and that androgens may play a causative role in its pathogenesis. A new population-based retrospective cohort study, in PLOS Medicine, utilising a large UK primary care database including more than 63,000 women with PCOS and 121,000 matched controls, found that rates of NAFLD were increased in women with PCOS (HR = 2.23, 95% CI 1.86–2.66) also after adjusting for BMI or dysglycaemia (abnormality with blood glucose stability). Androgen excess (evidenced as high testosterone, low sex hormone-binding globulin - SHBG) was also identified as a potential additional contributing risk factor for NAFLD development in PCOS. For serum testosterone 3–3.49 nmol/L the Hazard Ratio (HR) was 2.30 (95% CI 1.16–4.53), and 2.40 (95% CI 1.24–4.66), for serum testosterone >3.5 nmol/L. For SHBG 20–29.99 nmol/L the HR was 4.75 (95% CI 2.44–9.25), and 4.98 (95% CI 2.45–10.11) for SHBG <20 nmol/L. The authors conclude screening for NAFLD should be considered in women with PCOS-related androgen excess and call for research to establish if antiandrogen medication can reduce NAFLD risk.

The BMJ Case Reports describes the case of a 28-year-old, healthy woman with a history of abdominal pain of almost six years presenting after having seen several physicians at several different hospitals over the years. The chief presenting complaint had remained consistent: intermittent right abdominal pain that tended to exacerbate in the upright position and improve in the supine position. The change in position was also associated with a feeling of ‘a ball rolling’ inside of her. There were no other symptoms. Intravenous pyelography revealed a 6 cm craniocaudal migration of the right kidney between the supine and upright postures and a diagnosis of nephroptosis was made, which was successfully treated with robot-assisted laparoscopic nephropexy. The authors point out that nephroptosis is an important differential diagnosis in young, thin women with unexplained abdominal pain following exclusion of common aetiologies, which can be readily diagnosed with simple dynamic imaging tests and effectively treated with nephropexy.

Tai chi for fibromyalgia
Although there is no cure for fibromyalgia, core treatments combine multidisciplinary approaches including drugs, exercise, CBT, and health education. A comparative effectiveness randomised controlled trial in The BMJ suggests that tai chi treatment results in similar or greater improvement in symptoms than aerobic exercise, the current most commonly prescribed non-drug treatment, for a variety of outcomes for patients with fibromyalgia. 226 adults with fibromyalgia were included in the intention to treat analyses: 151 were assigned to one of four tai chi groups and 75 to an aerobic exercise group. Fibromyalgia impact questionnaire scores improved in all five treatment groups, but the combined tai chi groups improved statistically significantly more than the aerobic exercise group at 24 weeks (difference between groups=5.5 points, 95% CI 0.6 to 10.4) and in several secondary outcomes: patient’s global assessment=0.9 points, 0.3 to 1.4; anxiety=1.2 points, 0.3 to 2.1; self-efficacy=1.0 points, 0.5 to 1.6; and coping strategies, 2.6 points, 0.8 to 4.3. Longer duration of tai chi showed greater improvement and the authors conclude this approach may be considered a therapeutic option in the multidisciplinary management of fibromyalgia.

Author's Image

Tertius Lydgate

Originally from Northumberland, Tertius Lydgate studied medicine in Edinburgh, London and Paris. There he developed a special interest in communicable diseases and hoped to make great advances in treating and preventing them. But, after a promising start in a provincial centre of excellence in middle England, he was forced by circumstances (please, don't inquire) to abandon his high ideals. He now scrapes a living by pouring cold water on the over-enthusiastic at his private cryohydrotherapy clinic. Dreaming of the contributions he once hoped to make himself, he finds consolation in the latest medical journals and is happy to share his discoveries with his readers. He thinks that his creator, George Eliot, would have approved.
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