Stereotactic Ablative Radiation for Oligoprogressive Cancers: Results of the Randomized Phase 2 STOP Trial.

PURPOSE: This trial examined if patients with ≤5 sites of oligoprogression benefit from the addition of SABR to standard of care (SOC) systemic therapy. METHODS AND MATERIALS: We enrolled patients with 1 to 5 metastases progressing on systemic therapy, and after stratifying by type of systemic therapy (cytotoxic vs noncytotoxic), randomized 1:2 between continued SOC treatment versus SABR to all progressing lesions plus SOC. The trial was initially limited to non-small cell lung cancer but was expanded to include all nonhematologic malignancies to meet accrual goals. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), lesional control, quality of life, adverse events, and duration of systemic therapy postrandomization. RESULTS: Ninety patients with 127 oligoprogressive metastases were enrolled across 8 Canadian institutions, with 59 randomized to SABR and 31 to SOC. The median age was 67 years, and 39 (43%) were women. The most common primary sites were lung (44%), genitourinary (23%), and breast (13%). Protocol adherence in the SOC arm was suboptimal, with 11 patients (35%) either receiving high-dose/ablative therapies (conflicting with trial protocol) or withdrawing from the study. The median follow-up was 31 months. There was no difference in PFS between arms (median PFS 8.4 months in the SABR arm vs 4.3 months in the SOC arm, but curves cross and 2-year PFS was 9% vs 24%, respectively; P = .91). The median OS was 31.2 months versus 27.4 months, respectively (P = .22). Lesional control was superior with SABR (70% vs 38%, respectively; P = .0015). There were 2 (3.4%) grade 3 and no grade 4/5 adverse events attributable to SABR. CONCLUSIONS: SABR was well-tolerated with superior lesional control but did not improve PFS or OS. Accrual to this study was difficult, and the results may have been impacted by an unwillingness to forgo ablative treatments on the SOC arm. (NCT02756793).

Optimization of hemolysis, icterus and lipemia interference thresholds for 35 clinical chemistry assays.

OBJECTIVES: Interference of chemistry assays by hemolysis, icterus and lipemia (HIL) was investigated on the Abbott Alinity c system. We sought to empirically establish optimized HIL index thresholds for the purposes of reporting HIL interference in a hospital laboratory and advising clinicians on the interpretation of laboratory results in the presence of hemolysis, icterus or lipemia. METHODS: HIL index values measured by spectrophotometry were compared with concentrations of hemoglobin, bilirubin and Intralipid. HIL interference of 35 Abbott Alinity chemistry assays was subsequently investigated by pairwise comparison of test results in pooled serum or plasma with those in test preparations spiked with hemolysate, bilirubin or Intralipid. Data generated from the interference experiments were critically assessed according to assay-specific acceptance criteria adapted from multiple sources, and optimized thresholds for HIL indices were established. RESULTS: Correlations between HIL index values and their corresponding concentrations of hemoglobin, bilirubin and Intralipid were, in general, very good within the ranges of interferent concentrations tested. Hemolysis significantly affected 12 of 35 assays, whereas bilirubin and Intralipid interfered with four and three assays, respectively. Both the direction and magnitude of Intralipid interference with the direct bilirubin assay were dependent on the concentrations of the analyte. CONCLUSIONS: HIL interference of the Abbott Alinity clinical chemistry assays investigated in this study was not uncommon. At present, there are no universally accepted criteria for defining significant assay interference for clinical practice. In establishing acceptance criteria for defining assay interference, each assay should be assessed according to both analytical criteria and clinical relevance.

Association of Cord Blood Thyroid-Stimulating Hormone Levels with Maternal, Delivery and Infant Factors.

INTRODUCTION: This study examined maternal, delivery and infant factors associated with cord thyroid-stimulating hormone (TSH) concentrations in an Asian population. METHODS: The Growing Up in Singapore Towards healthy Outcomes (GUSTO) study is a mother-offspring birth cohort from 2 major hospitals in Singapore. Cord serum TSH was measured using the Abbott ARCHITECT TSH Chemiluminescent Microparticle Immunoassay and the ADVIA Centaur TSH-3 Immunoassay. After excluding infants with a maternal history of thyroid disease, screening cord TSH results from 604 infants were available for multivariable regression analysis in relation to the factors of interest. RESULTS: Babies born by vaginal delivery had significantly higher cord serum TSH concentrations than babies born by caesarean section. Cord serum TSH concentrations differed significantly by measurement method. There was no association of cord TSH concentrations with ethnicity, sex, birth weight, gestational age, maternal body mass index, gestational weight gain, gestational diabetes mellitus status and other maternal, delivery and infant factors studied. CONCLUSION: Interpretation of cord serum TSH results may need to take into account mode of delivery and measurement method.

Commutable whole blood reference materials for hemoglobin A1c validated on multiple clinical analyzers.

Background The measurement of hemoglobin A1c (HbA1c) is important for diagnosing diabetes mellitus as well as assessing glycemic control in diabetic patients. Commutable whole blood certified reference materials (CRMs) are needed in the measurement of HbA1c for method validation and/or as quality controls. Methods We developed three levels of hemolyzed whole blood CRMs for HbA1c. The certified values were determined using liquid chromatography-isotope dilution tandem mass spectrometry method (LC-IDMS/MS) where two "signature" hexapeptides of HbA1c and hemoglobin A0 (HbA0) were used as the calibration standards. The concentrations of the hexapeptide solutions were determined by amino acid analysis by the LC-IDMS/MS method using amino acid CRMs as the calibration standards. The commutability study was conducted by measuring 25 patient specimens and the whole blood CRMs by both LC-IDMS/MS method and various routine methods using six different clinical analyzers. Results The certified values were determined to be 35.1±2.0, 50.3±1.9 and 65.8±2.6 mmol/mol, respectively. These CRMs showed good commutability on five of the six clinical analyzers but showed poor commutability on one of the clinical analyzers that used similar method as two other analyzers where good commutability was observed. Conclusions With certified target values based on metrological traceability and good commutability on most of the clinical analyzers, the developed whole blood CRMs can be used for method validation or as quality control materials in the measurement of HbA1c. The commutability study results also underscored the need of commutability testing of clinical CRMs using various clinical analyzers.

Pragmatic and evidence-based approach to paediatric cerebrospinal fluid reference limits for white cell count and concentrations of total protein and glucose.

BACKGROUND: It is often impractical for each laboratory to establish its own paediatric reference intervals. This is particularly true for specimen types collected using invasive procedures, for example, cerebrospinal fluid (CSF). METHODS: Published CSF reference intervals for white cell count, and concentrations of total protein and glucose were reviewed by stakeholders in a paediatric hospital. Consensus reference intervals for the three CSF parameters were then subjected to verification using guidelines from the Clinical Laboratory Standards Institute and residual CSF specimens. RESULTS: Consensus paediatric reference intervals adapted from published studies with minor modifications were locally verified as follows. White cell count (x106 cells/L): 0-20 (<1 month); 0-10 (1-2 months); 0-5 (>2 months). Total protein (g/L): 0.3-1.2 (<1 month); 0.2-0.6 (1-3 months); 0.1-0.4 (>3 months). Glucose (mmol/L): 2.0-5.6 (<6 months); 2.4-4.3 (6 months or older).

A population-based study examining the influence of a specialized rapid-access cancer clinic on initial treatment choice in localized prostate cancer.

INTRODUCTION: Treatment decisions in localized prostate cancer are complicated by the available choices. A rapid-access cancer clinic (RAC) has been unique to Calgary, AB, since 2007. This RAC offers multidisciplinary prostate cancer education by a urologist, medical oncologist, and radiation oncologist. It is hypothesized that treatment utilization data from decisions taken at RAC may serve to benchmark the appropriateness of treatment decisions on a population level. METHODS: Records of patients with clinically localized prostate cancer in Alberta between October 1, 2007 and September 30, 2009 were reviewed with ethics approval. Records were linked to the Alberta Cancer Registry database. Clinical, treatment, and health services characteristics pertaining to patients attending RAC were compared to the general population. The primary endpoint was utilization rates of each initial treatment. RESULTS: During this two-year period, 2838 patients were diagnosed with localized prostate cancer; 375 attended RAC. The utilization rates among RAC patients vs. the whole Alberta population were: prostatectomy 60.3% (95% confidence interval [CI] 55.3-65.2) vs. 48.0% (95% CI 47.1-50.7; χ2 p<0.001); active surveillance 16.0% (95% CI 12.3-19.7%) vs. 13.5% (95% CI 12.2-15.8; χ2 p=0.214); radiotherapy 11.7% (95% CI 8.5-15.0) vs. 18.0% (95% CI 16.9-20.5; χ2 p=0.002); and hormone therapy 8.0% (95% CI 5.2-10.8) vs. 17.4% (95% CI 16.1-18.9; χ2 p<0.001). CONCLUSIONS: A specialized clinic for localized prostate cancer may be associated with a higher likelihood of receiving surgery or active surveillance as initial treatment compared to the prostate cancer population in Alberta.

Long-term outcomes following proton therapy for prostate cancer in young men with a focus on sexual health.

BACKGROUND: We investigated long-term outcomes for men ≤60 years old treated with proton therapy (PT). METHODS: Of 254 men ≤60 years old were treated with proton therapy alone for prostate cancer. Risk stratification included 56% with low-, 42% with intermediate- and 2% with high-risk disease. Patients received 76-82 Gy at 2 Gy/fraction or 70-72.5 Gy at 2.5 Gy/fraction. Before treatment and every 6-12 months for 5 years, patients were evaluated by a physician, answered health-related quality of life surveys, including the EPIC, IIEF and IPSS, and had PSA evaluated. RESULTS: Median follow-up for the cohort was 7.1 years; 7-year biochemical-free survival was 97.8%. Eight men (one high-risk; five intermediate-risk and two low-risk) experienced biochemical progression, including one who died of disease 9 years after treatment. Potency (erections firm enough for sexual intercourse) was 90% at baseline and declined to 72% at the first-year follow-up, but declined to only 67% at 5 years. Only 2% of patients developed urinary incontinence requiring pads. The bowel habits mean score declined from a baseline of 96 to 88 at 1 year, which improved over the following years to 93 at 5 years. CONCLUSIONS: Young men with prostate cancer continue to have excellent results with respect to 7-year biochemical control and 5-year erectile function, without clinically significant urinary incontinence 5 years after proton therapy. Comparative effectiveness studies of proton therapy with surgery and IMRT are needed.

Gestational age-specific reference intervals for serum thyroid hormone levels in a multi-ethnic population.

BACKGROUND: Thyroid disorders are common during pregnancy. To date, a limited number of studies have reported differences in serum thyroid hormone concentrations between different ethnic groups. We sought to establish gestational age-specific reference intervals for serum levels of thyroid hormones in a multi-ethnic population and investigate whether separate reference intervals should be used for different ethnic groups. METHODS: A total of 926 pregnant women from multiple ethnic groups attended four separate study visits spanning the three trimesters. Venous blood samples were taken at 9 to 14 weeks, 18 to 22 weeks, 28 to 32 weeks, and 34 to 39 weeks of gestation. Serum concentrations of thyroid-stimulating hormone (TSH), free thyroxine (T4), free triiodothyronine (T3), total T4, total T3, thyroid peroxidase antibody and thyroglobulin antibody were measured using Abbott Architect immunoassays. A total of 562 women with singleton pregnancies were found to be negative for both thyroid autoantibodies at all four study visits and thus included in the reference sample group for the establishment of reference intervals (2.5th to 97.5th percentiles). RESULTS: Reference intervals for serum thyroid hormones at 9-14 weeks of gestation derived from the combined group of pregnant women are as follows: TSH, 0.01-2.39 mIU/L; free T4, 11.4-19.5 pmol/L; free T3, 4.23-6.69 pmol/L; total T4, 77.8-182.4 nmol/L; total T3, 1.39-2.97 nmol/L. No differences in the five thyroid parameters' reference intervals are detectable among the ethnic groups except that at study visit 3 (28-32 weeks of gestation), the upper reference limit of total T3 in Malays (3.20 nmol/L; 90% CI, 2.99-3.76 nmol/L) is slightly higher than that in Chinese (2.86 nmol/L; 90% CI, 2.70-2.98 nmol/L). CONCLUSIONS: The findings from this study on a multi-ethnic cohort highlight the importance of establishing locally derived and gestational age-specific reference intervals for the five thyroid hormone parameters.

Transient Neonatal Zinc Deficiency Caused by a Novel Mutation in the SLC30A2 Gene.

This is a case report of a 4-month-old full-term, fully breastfed boy who presented with a persistent periorificial and groin rash associated with poor weight gain and irritability. His serum zinc level was low. The mother's breast milk zinc level was found to be low despite her serum zinc levels being normal, confirming the diagnosis of transient neonatal zinc deficiency. Mutational analysis revealed a novel mutation in the mother's SLC30A2 gene, which encodes a zinc transporter expressed in mammary gland epithelial cells.

Significance of Co-expression of Epidermal Growth Factor Receptor and Ki67 on Clinical Outcome in Patients With Anal Cancer Treated With Chemoradiotherapy: An Analysis of NRG Oncology RTOG 9811.

PURPOSE: To measure co-expression of EGFR and Ki67 proteins in pretreatment tumor biopsies of anal cancer patients enrolled on NRG Oncology RTOG 9811, a phase III trial comparing 5-fluorouracil/mitomycin-C/radiation therapy (Arm A) versus 5-fluorouracil/cisplatin/radiation therapy (Arm B), and to correlate expression with clinical outcome. METHODS AND MATERIALS: EGFR and Ki67 co-expression was measured after constructing a tissue microarray using fluorescence immunohistochemistry and automated quantitative image analysis. The Ki67 score within EGFR high versus low areas (Ki67ratio in EGFRhigh:low) in each tumor core was analyzed at the median, quartiles, and as a continuous variable. Associations between the tumor markers and clinical endpoints (overall and disease-free survival, locoregional and colostomy failure, and distant metastases) were explored. RESULTS: A total of 282 pretreatment tumors were analyzed from NRG Oncology RTOG 9811. Of evaluated specimens, 183 (65%, n=89, Arm A; n=94, Arm B) were eligible and analyzable. There were no significant differences in baseline characteristics or outcomes between analyzable and unanalyzable patient cases. Median follow-up was 6.0 years. On multivariate analysis, after adjusting for gender, patients with Ki67ratio in EGFRhigh:low ≥median had worse overall survival (hazard ratio 2.41, 95% confidence interval 1.38-4.19, P=.0019). After adjusting for N stage and largest tumor dimension, patients with Ki67ratio in EGFRhigh:low ≥ median had a higher risk of a disease-free failure (hazard ratio 1.85, 95% confidence interval 1.18-2.92, P=.0078). Technical validation with an independent anal cancer patient cohort was performed and shows a very similar biomarker score distribution. CONCLUSIONS: High Ki67ratio in EGFRhigh:low is associated with worse clinical outcome in this subset of patients with anal cancer treated with chemoradiation on NRG Oncology RTOG 9811. Evaluation within a clinical trial will be required to determine whether patients with these tumor characteristics may specifically benefit from an EGFR-targeted therapeutic agent.

LDLR gene synonymous mutation c.1813C>T results in mRNA splicing variation in a kindred with familial hypercholesterolaemia.

Familial hypercholesterolaemia, one of the most common inherited diseases in the general population, is associated with mutations in at least three different genes including the low density lipoprotein receptor (LDLR), apolipoprotein B (APOB) and protein convertase subtilisin/kexin type 9 (PCSK9) genes. In this report, we describe an unclassified DNA variant (c.1813C>T; p.Leu605Leu) within exon 12 of the LDLR gene in a kindred in which familial hypercholesterolaemia is associated with c.1813C>T heterozygosity. In silico analysis suggested that c.1813C>T might affect splicing of the LDLR gene by creating a cryptic donor splice site, which was confirmed by RT-PCR coupled with cDNA sequencing, to result in the loss of 34 base pairs in the coding sequence. The latter truncated mRNA is predicted to generate a frameshift leading to a premature stop at codon 652 and early termination of the low density lipoprotein receptor polypeptide chain, and thus provides a molecular basis for the hypercholesterolaemic phenotype. This case report highlights the emerging utility of RNA studies for the molecular diagnosis of familial hypercholesterolaemia in patients with potential mRNA splicing variants.

Proton therapy in the management of lymphoma.

Hodgkin lymphoma and non-Hodgkin lymphoma are common hematologic malignancies with such a favorable prognosis that many survivors live decades after combined chemotherapy and radiotherapy. These survivors, however, are at risk of developing late treatment adverse effects from collateral damage, including secondary malignancies, cardiac toxicities, and ischemic heart diseases. Recent efforts have successfully reduced the radiation dose and treatment field without compromising cure rates. Proton therapy has the potential of further lowering the treatment-related toxicity owing to its ability to deposit a high dose only at the target. Although this finding has been supported by several current dosimetric studies, its utilization in the management of lymphoma has been limited during the past 5 years because of the paucity of facilities and the difficulty of obtaining insurance coverage. With diligent follow-up, the clinical impact of proton therapy will be established to improve the therapeutic ratio and to reduce late treatment-related morbidity.

The role of ω-3 fatty acid supplemented parenteral nutrition in critical illness in adults: a systematic review and meta-analysis.

OBJECTIVE: To determine whether the supplementation of parenteral nutrition with ω-3 fatty acids confers treatment benefits to critically ill adult patients. DATA SOURCE: We performed computerized searches for relevant articles from 1996 to June 2011 on MEDLINE, EMBASE, and the Cochrane register of controlled trials and abstracts of scientific meetings from 2005 to 2011. STUDY SELECTION: Randomized controlled trials of ω-3 fatty acid supplemented parenteral nutrition in critically ill adult patients admitted to the intensive therapy unit, given in addition to their routine care, compared with parenteral nutrition without ω-3 fatty acid supplementation. DATA SYNTHESIS: Five fully published trials and three trials published in abstract form with 391 participants have been included. Overall trial quality was poor. Mortality data were pooled from eight studies with 391 participants. No differences were found with a risk ratio for death of 0.83 (95% confidence interval 0.57, 1.20; p = 0.32). Data for infectious complications were available from five studies with 337 participants. No differences were found, with a risk ratio for infection of 0.78 (95% confidence interval 0.43, 1.41; p = 0.41). Data for intensive therapy unit and hospital length of stay were available from six and three studies with 305 and 117 participants, respectively. With respect to intensive therapy unit length of stay, no differences were observed with a mean difference of 0.57 days in favor of the ω-3 fatty acid group (95% confidence interval -5.05, 3.90; p = 0.80). A significant reduction in hospital length of stay of 9.49 days (95% confidence interval -16.51, -2.47; p = 0.008) was observed for those receiving ω-3 fatty acid supplemented parenteral nutrition, but results were strongly influenced by one small study. CONCLUSIONS: On the basis of this systematic review, it can be concluded that ω-3 fatty acid supplementation of parenteral nutrition does not improve mortality, infectious complications, and intensive therapy unit length of stay in comparison with standard parenteral nutrition. Although ω-3 fatty acids appear to reduce hospital length of stay, the poor methodology of the included studies and the absence of other outcome improvements mean they cannot be presently recommended.

Statins and their interactions with other lipid-modifying medications: safety issues in the elderly.

Inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, commonly known as statins, are widely used in both primary and secondary prevention of occlusive cardiovascular disease. Statins are effective not only in improving total and low-density lipoprotein cholesterol concentrations in blood but also in decreasing morbidity and mortality associated with cardiovascular diseases resulting from underlying atheroma. There is, however, evidence that statins are underutilized in elderly patients, possibly due to concerns about safety/tolerability issues or potential drug interactions, including interactions with other lipid-modifying medications, or both. In this review, we summarize the major adverse events associated with statin use, with particular reference to the elderly patient, including factors which might increase the risk of adverse effects. Potential drug interactions between statins and other lipid-modifying medications including fibrates, ezetimibe, nicotinic acid, bile acid sequestrants and omega-3-acid ethyl esters (fish oils) are specifically discussed. Clinical management strategies to avoid these drug interactions are outlined.

Vitamin D deficiency is common and associated with metabolic risk factors in patients with polycystic ovary syndrome.

Both vitamin D deficiency and polycystic ovary syndrome (PCOS) are associated with aspects of metabolic syndrome, but it is unclear whether vitamin D deficiency contributes to the metabolic disturbances commonly found in women with PCOS. This study sought to investigate (1) the prevalence of vitamin D deficiency in PCOS women in Scotland and (2) the relationship between vitamin D status and metabolic risk factors. This was an observational study on 52 women (25 in PCOS group and 27 in control group). Serum 25-hydroxyvitamin D concentrations less than 25 nmol/L were classified as severe vitamin D deficiency and were found in 44.0% and 11.2% of subjects in the PCOS and control groups, respectively (P = .047). Among the PCOS subjects, 25-hydroxyvitamin D concentrations were negatively correlated with body mass index (P = .033), C-reactive protein (P = .027), and free androgen index (P = .025) and positively correlated with quantitative insulin sensitivity check index (P = .035), high-density lipoprotein cholesterol (HDL-C) (P = .033), and sex hormone binding globulin (P = .038). Associations of vitamin D deficiency with quantitative insulin sensitivity check index and HDL-C were independent of body mass index and waist-to-hip ratio. Vitamin D deficiency is highly prevalent in PCOS women in Scotland, and a larger proportion of PCOS patients than control women were found to be vitamin D deficient. We also demonstrate correlations of vitamin D status with insulin sensitivity, HDL-C, and C-reactive protein in PCOS patients, which support the increasing evidence that vitamin D deficiency is associated with multiple metabolic risk factors in PCOS women.

Late-onset male hypogonadism: clinical and laboratory evaluation.

Late-onset male hypogonadism (LOH) is a clinical and biochemical syndrome associated with advancing age and characterised by low serum testosterone concentrations. An understanding of the physiology of androgens in the ageing man is essential for the appropriate diagnosis of LOH. Clinical assessment of androgen status relevant to clinical biochemists and chemical pathologists is outlined in this review. Laboratory investigations of androgen status in men are not without pitfalls and the authors highlight problems associated with measuring and calculating serum testosterone and its fractions, the interpretation of which can be problematic. Current clinical guidelines and recommendations regarding the diagnosis and monitoring of LOH are also summarised.

Estrogen and androgen signaling in the pathogenesis of BPH.

Estrogens and androgens have both been implicated as causes of benign prostatic hyperplasia (BPH). Although epidemiological data on an association between serum androgen concentrations and BPH are inconsistent, it is generally accepted that androgens play a permissive role in BPH pathogenesis. In clinical practice, inhibitors of 5α-reductase (which converts testosterone to the more potent androgen dihydrotestosterone) have proven effective in the management of BPH, confirming an essential role for androgens in BPH pathophysiology. To date, multiple lines of evidence support a role for estrogens in BPH pathogenesis. Studies of the two estrogen receptor (ER) subtypes have shed light on their differential functions in the human prostate; ERα and ERß have proliferative and antiproliferative effects on prostate cells, respectively. Effects of estrogens on the prostate are associated with multiple mechanisms including apoptosis, aromatase expression and paracrine regulation via prostaglandin E2. Selective estrogen receptor modulators or other agents that can influence intraprostatic estrogen levels might conceivably be potential therapeutic targets for the treatment of BPH.

Testosterone testing in adult males.

The number of requests for testosterone testing in adult males has been increasing in recent years. In this review, the biochemistry and physiology of testosterone in males relevant to the chemical pathologist or clinical biochemist is outlined. The methodology for total testosterone and various laboratory tests associated with the assessment of testosterone status including free testosterone, calculated free testosterone (CFT), bioavailable testosterone (BAT) and free androgen index (FAI) is then summarised. Clinical and laboratory criteria for the diagnosis of late-onset hypogonadism (LOH) in men are critically discussed with particular emphasis on the interpretation of laboratory test results. Finally, other indications for testosterone testing in adult men such as infertility are also reviewed.