Polymorphisms in MIR27A Associated with Early-Onset Toxicity in Fluoropyrimidine-Based Chemotherapy

PURPOSE The microRNA miR-27a was recently shown to directly regulate dihydropyrimidine dehydrogenase (DPD), the key enzyme in fluoropyrimidine catabolism. A common polymorphism (rs895819A>G) in the miR-27a genomic region (MIR27A) was associated with reduced DPD activity in healthy volunteers, but the clinical relevance of this effect is still unknown. Here, we assessed the association of MIR27A germline variants with early-onset fluoropyrimidine toxicity. EXPERIMENTAL DESIGN MIR27A was sequenced in 514 patients with cancer receiving fluoropyrimidine-based chemotherapy. Associations of MIR27A polymorphisms with early-onset (cycles 1-2) fluoropyrimidine toxicity were assessed in the context of known risk variants in the DPD gene (DPYD) and additional covariates associated with toxicity. RESULTS The association of rs895819A>G with early-onset fluoropyrimidine toxicity was strongly dependent on DPYD risk variant carrier status (Pinteraction = 0.0025). In patients carrying DPYD risk variants, rs895819G was associated with a strongly increased toxicity risk [OR, 7.6; 95% confidence interval (CI), 1.7-34.7; P = 0.0085]. Overall, 71% (12/17) of patients who carried both rs895819G and a DPYD risk variant experienced severe toxicity. In patients without DPYD risk variants, rs895819G was associated with a modest decrease in toxicity risk (OR, 0.62; 95% CI, 0.43-0.9; P = 0.012). CONCLUSIONS These results indicate that miR-27a and rs895819A>G may be clinically relevant for further toxicity risk stratification in carriers of DPYD risk variants. Our data suggest that direct suppression of DPD by miR-27a is primarily relevant in the context of fluoropyrimidine toxicity in patients with reduced DPD activity. However, miR-27a regulation of additional targets may outweigh its effect on DPD in patients without DPYD risk variants.

Changes in Left Ventricular Torsion Early Postoperatively After Aortic Valve Replacement and at Long-Term Follow-up.

OBJECTIVE In patients with aortic stenosis, left ventricular systolic torsion (pT) is increased to overcome excessive afterload. This study assessed left ventricular torsion before and immediately after surgical valve replacement and tested the instant effect of fluid loading. DESIGN Prospective, clinical single-center study. SETTING Intensive care unit of a university hospital. PARTICIPANTS 12 patients undergoing elective aortic valve replacement for aortic stenosis. INTERVENTIONS Echocardiography was performed on the day before surgery, within 18 hours after surgery including a fluid challenge, and after 2.5 years. MEASUREMENTS AND MAIN RESULTS pT decreased early postoperatively by 21.2% (23.4° ± 5.6° to 18.4° ± 6.9°; p = 0.012) and reached preoperative values at 2.5 years follow-up (24 ± 7). Peak diastolic untwisting velocity occurred later early postoperatively (13% ± 8% to 21% ± 9.4%; p = 0.019) and returned toward preoperative values at follow-up (10.2 ± 4.7°). The fluid challenge increased central venous pressure (8 ± 4 mmHg to 11 ± 4 mmHg; p = 0.003) and reduced peak systolic torsion velocity (138.7 ± 37.6/s to 121.3 ± 32/s; p = 0.032). pT decreased in 3 and increased in 8 patients after fluid loading. Patients whose pT increased had higher early mitral inflow velocity postoperatively (p = 0.04) than those with decreasing pT. Patients with reduced pT after fluid loading received more fluids (p = 0.04) and had a higher positive fluid balance during the intensive care unit stay (p = 0.03). Torsion after fluid loading correlated with total fluid input (p = 0.001) and cumulative fluid balance (p = 0.002). CONCLUSIONS pT decreased early after aortic valve replacement but remained elevated despite elimination of aortic stenosis. After 2.5 years, torsion had returned to preoperative levels.

Early reherniation of disk material in eleven dogs with surgically treated thoracolumbar intervertebral disk extrusion.

OBJECTIVE To report findings and outcomes of dogs with reherniation of nuclear material within 7 days of hemilaminectomy for acute thoracolumbar (TL) intervertebral disk extrusion. STUDY DESIGN Retrospective case series. ANIMALS Chondrodystrophic dogs (n = 11). METHODS Dogs with acute neurologic decline within 1 week of surgical decompression for TL disk extrusion were identified. Advanced imaging was used to document extradural spinal cord compression at the previous surgery site. Ten dogs had a 2nd decompressive surgery to remove extruded nuclear material. RESULTS All dogs had acute neurologic deterioration (average, 2 neurologic grades) 2-7 days after initial hemilaminectomy. Computed tomography (CT; n = 10) or myelography (n = 1) documented extradural spinal cord compression compatible with extruded disk material at the previous hemilaminectomy site. Dogs that had a 2nd surgical decompression improved neurologically within 24 hours and were paraparetic at discharge. The single dog that did not have decompressive surgery did not regain deep nociception during 185-day follow-up. CONCLUSIONS Early reherniation at the site of previous hemilaminectomy can produce acute deterioration of neurologic function and should be investigated with diagnostic imaging. Repeat decompressive surgery can lead to functional recovery.

Predicting 5- and 10-year survival in older women with early-stage breast cancer: self-rated health and walking ability.

OBJECTIVES To determine life expectancy for older women with breast cancer. DESIGN Prospective longitudinal study with 10 years of follow-up data. SETTING Hospitals or collaborating tumor registries in four geographic regions (Los Angeles, California; Minnesota; North Carolina; Rhode Island). PARTICIPANTS Women aged 65 and older at time of breast cancer diagnosis with Stage I to IIIA disease with measures of self-rated health (SRH) and walking ability at baseline (N = 615; 17% aged ≥80, 52% Stage I, 58% with ≥2 comorbidities). MEASUREMENTS Baseline SRH, baseline self-reported walking ability, all-cause and breast cancer-specific estimated probability of 5- and 10-year survival. RESULTS At the time of breast cancer diagnosis, 39% of women reported poor SRH, and 28% reported limited ability to walk several blocks. The all-cause survival curves appear to separate after approximately 3 years, and the difference in survival probability between those with low SRH and limited walking ability and those with high SRH and no walking ability limitation was significant (0.708 vs 0.855 at 5 years, P ≤ .001; 0.300 vs 0.648 at 10 years, P < .001). There were no differences between the groups in breast cancer-specific survival at 5 and 10 years (P = .66 at 5 years, P = .16 at 10 years). CONCLUSION The combination of low SRH and limited ability to walk several blocks at diagnosis is an important predictor of worse all-cause survival at 5 and 10 years. These self-report measures easily assessed in clinical practice may be an effective strategy to improve treatment decision-making in older adults with cancer.

A 2-year multicentre, open-label, randomized, controlled study of growth hormone (Genotropin(®) ) treatment in very young children born small for gestational age: Early Growth and Neurodevelopment (EGN) Study

OBJECTIVE In Europe, growth hormone (GH) treatment for children born small for gestational age (SGA) can only be initiated after 4 years of age. However, younger age at treatment initiation is a predictor of favourable response. To assess the effect of GH treatment on early growth and cognitive functioning in very young (<30 months), short-stature children born SGA. DESIGN A 2-year, randomized controlled, multicentre study (NCT00627523; EGN study), in which patients received either GH treatment or no treatment for 24 months. PATIENTS Children aged 19-29 months diagnosed as SGA at birth, and for whom sufficient early growth data were available, were eligible. Patients were randomized (1:1) to GH treatment (Genotropin(®) , Pfizer Inc.) at a dose of 0·035 mg/kg/day by subcutaneous injection, or no treatment. MEASUREMENTS The primary objective was to assess the change from baseline in height standard deviation score (SDS) after 24 months of GH treatment. RESULTS Change from baseline in height SDS was significantly greater in the GH treatment vs control group at both month 12 (1·03 vs 0·14) and month 24 (1·63 vs 0·43; both P < 0·001). Growth velocity SDS was significantly higher in the GH treatment vs control group at 12 months (P < 0·001), but not at 24 months. There was no significant difference in mental or psychomotor development indices between the two groups. CONCLUSIONS GH treatment for 24 months in very young short-stature children born SGA resulted in a significant increase in height SDS compared with no treatment.