Borderline Results Research Articles

Utility of the T-SPOT®.TB test's borderline category to increase test resolution for results around the cut-off point

BackgroundAccurate identification of individuals with TB infection, is required to achieve the WHO's End TB Strategy goals. While there is general acceptance that the T-SPOT.TB test borderline category provides an opportunity to increase test resolution of results around the test cut-off point, this has not been investigated. Methods645,947 tests were analyzed to determine frequency of borderline results, effect of age and time between tests and associations between subjects' clinical risk factors and retest results. Results645,947 tests produced 93.5% negatives, 4% positives, 0.6% invalids, and 1.8% borderlines. Within the borderline results, 5044 were repeated, with 59.2%, 20.0% and 20.2% resolving to negative, positive and borderline, respectively. Age of subject did not affect retest results; however, time between tests indicated that retest resolution occurred with greatest frequency after 90 days. TB risk factors were provided for 2640 subjects and 17% of low risk subjects with a high initial borderline resolved to negative while 27.6% of subjects with high risk and an initial low borderline resolved to positive, suggesting that these subjects could have been inappropriately classified if using a single cut-off point test with no borderline category. ConclusionThis study demonstrates the utility of the T-SPOT.TB test's borderline category to increase test resolution around the test cut-off point.

Newborn Screening in the US May Miss Mild Persistent Hypothyroidism

To determine if newborn screening (NBS) programs for congenital hypothyroidism in the US use thyroid-stimulating hormone (TSH) cutoffs that are age adjusted to account for the physiologic 4-fold reduction in TSH concentrations over the first few days of life. All NBS programs in the US were contacted and asked to provide information on their NBS protocols, TSH cutoffs, and whether these cutoffs were age adjusted. Of 51 NBS programs, 28 request a repeat specimen if the initial eluted serum TSH concentration is mildly increased (between the cutoff and a median upper limit of 50 mU/L), whereas 14 programs perform a routine second screen in all infants. Although these specimens are typically collected between 1 week and 1 month of life, 16 of the 28 programs with a discretionary second test and 8 of 14 programs with a routine second test do not have age-adjusted TSH cutoffs after the first 48 hours of life. There is variation in NBS practices for screening for congenital hypothyroidism across the US, and many programs do not adjust the TSH cutoff beyond the first 2 days of life. Samples are processed when received from older infants, often to retest borderline initial results. This approach will miss congenital hypothyroidism in infants with persistent mild TSH elevations. We recommend that all NBS programs provide age-adjusted TSH cutoffs, and suggest developing a standard approach to screening for congenital hypothyroidism in the US.

A borderline range for Quantiferon Gold In-Tube results.

ObjectiveInterferon gamma release assays like Quantiferon Gold In-Tube (QFT) are used to identify individuals infected with Mycobacterium tuberculosis. A dichotomous cut-off (0.35 IU/ml) defines a positive QFT without considering test variability. Our objective was to evaluate the introduction of a borderline range under routine conditions.MethodsResults of routine QFT samples from Sweden (2009–2014) were collected. A borderline range (0.20–0.99 IU/ml) was introduced in 2010 recommending a follow-up sample. The association between borderline results and incident active TB within 3 to 24 months was investigated through linkage with the national TB-register.ResultsUsing the recommended QFT cut-off, 75.1% tests were negative, 21.4% positive and 3.5% indeterminate. In total, 9% (3656/40773) were within the borderline range. In follow-up samples, individuals with initial results between 0.20–0.34 IU/ml and 0.35–0.99 IU/ml displayed negative results below the borderline range (<0.20 IU/ml) in 66.1% (230/348) and 42.5% (285/671) respectively, and none developed incident TB. Among 6712 individuals with a positive initial test >0.99 IU/ml, 65 (0.97%) developed incident TB within 3–24 months.ConclusionsWe recommend retesting of subjects with QFT results in the range 0.20–0.99 IU/ml to enhance reliability and validity of the test. Half of the subjects in the borderline range will be negative at a level <0.20 IU/ml when retested and have a very low risk of developing incident active TB.

Is It Necessary to Repeat Fecal Occult Blood Tests with Borderline Results for Colorectal Cancer Screening?

The fecal immunochemical test (FIT) is the initial non-invasive investigation of choice for population-based colorectal cancer (CRC) screening. We evaluated the positivity rate in repeated tests using the same fecal specimen that showed borderline results in the FIT. A total of 6,465 patients were tested with the FIT in a tertiary-care hospital from July to December 2016. FIT was done using OC-Sensor PLEDIA (Eiken Chemical Co., Tokyo, Japan). Among 6,465 patients, 364 (5.6%) patients showed a positive FIT result of over 20 µg Hb/g feces. A total of 112 (1.7%) patients showed borderline scores of 10.2–20 µg Hb/g feces, and 5,989 (92.6%) patients showed negative results of less than 10 µg Hb/g feces. Among the 101 repeat-tested patients, 19 (18.8%) of the patients' scores converted to levels above the positive cut-off threshold. Repeated results of 19 patients showed score elevations from 20.2 to 68 µg Hb/g feces. These results suggest that it is most important to analyze properly prepared samples, even if only once. Therefore, the laboratory staff should ensure the proper preparation of stool specimens for FIT. Laboratory directors should choose the best cut-off value for detecting CRC at their respective institutions.

Zika Virus Serologic Diagnosis by NS1 ELISA in Curacao

Abstract Background Zika virus (ZIKV) was introduced in the Caribbean island of Curacao in January 2016. A commercially available ZIKV IgM and IgG ELISA was evaluated on patients that were PCR-positive for ZIKV. Methods ZIKV infection was established by PCR in urine samples. Samples from PCR-positive patients were selected for validation of a ZIKV NS1 IgG and IgM ELISA. Patients with a follow-up sample ≥ 2 weeks after initial presentation were used to assess the sensitivity of the assay. Samples of 15 historical controls with serological evidence of Dengue, Chikungunya or an unrelated viral infection were included to establish specificity and cross-reactivity. Results Fourteen patients with positive ZIKV PCR diagnosis had repeated serum samples drawn ≥ 2 weeks after the initial sample. The combined results of these repeated IgM and IgG tests resulted in a sensitivity of 92%. One pregnant female showed no presence of IgG or IgM in any of the two samples. Testing of the panel of historical ZIKV-negative controls resulted in a specificity of 100% in both the quantitative and semi-quantitative setting of the ELISA. One patient with known high-titers of antibodies against Chikungunya virus in the respective panel displayed borderline reactive results for ZIKV IgG in both quantitative and semi-quantitative setting of the assay. Conclusion In this PCR-positive ZIKV cohort of patients, the newly available ZIKV NS1 ELISA displayed excellent performance characteristics. Cross-reactivity was indicated for Chikungunya in one case. No cross-reactivity was found for Dengue virus infection. One pregnant female showed no signs of developing anti-ZIKV IgM or IgG in this study. In the light of intrauterine pathogenesis, the lack of development of maternal IgG during ZIKV infection is a concern. Disclosures All authors: No reported disclosures.

On the use of one-sided statistical tests in biomedical research.

There is a tendency to automatically use two-sided tests to assess the statistical significance of experimental results. Yet if a theory predicts the direction of an experimental outcome, or if for some practical (eg clinical) reason an outcome in that direction is the only one of interest, then it makes sense to use a one-sided test. The use of a two-sided test in these situations will lead to too many false negatives. Consequently treatment effects that corroborate a theory or that are of practical importance may be missed. This problem becomes particularly acute in the case of borderline results. Following a nonsignificant one-sided test, the possibility of an effect in the direction opposite to that predicted or required can be assessed in an exploratory fashion by computing the odds in favour of such an effect. Anyone is then at liberty to pursue this possibility as they see fit. The question of whether to use a one-sided or two-sided statistical test should always be decided on logical grounds not statistical ones, and suspicions regarding the motives of the investigator(s) should be disregarded. On the other hand, this choice can be avoided altogether by assuming that a treatment always has some effect (however small) and then computing the strength of the evidence in favour of the observed or predicted/required effect (ie 1-P, where P is the one-sided significance level of the test). With this approach one-sided and two-sided tests yield identical results, and so there is effectively only one type of test.

OCT Glaucoma Staging System: a new method for retinal nerve fiber layer damage classification using spectral-domain OCT.

PurposeTo describe a new method, the Optical Coherence Tomography (OCT) Glaucoma Staging System, for classifying retinal nerve fiber layer (RNFL) damage assessed with OCT.Patients and methodsThe OCT Glaucoma Staging System was created based on data obtained from Nidek RS 3000 spectral-domain (sd)-OCT. This system uses the superior and inferior quadrant RNFL thickness values, plotted on an x-y diagram for staging structural damage severity in glaucoma. A non-linear equation and two regression lines describe the boundary lines which separate the different sectors of the diagram. These mathematical formulas have been used to create a software, which provides a quick classification of the RNFL damage. Sensitivity and specificity of the system were assessed in a different cohort including 64 patients with early OAG, and 62 normal subjects.ResultsThree hundred and two OCT tests from 98 healthy controls and 284 patients affected by either ocular hypertension or chronic open-angle glaucoma were considered in order to design the new classification system. The OCT Glaucoma Staging System classifies RNFL defects into 6 stages of increasing severity ranging from borderline to stage 5, and 3 groups according to defect localization (superior, inferior, or diffuse). Sensitivity and specificity in discriminating between healthy and glaucomatous eyes were 95.2 and 91.9%, respectively, considering borderline results as abnormal.ConclusionsThe OCT Glaucoma Staging System appears to provide a standardized and objective classification of glaucomatous RNFL damage. It can be used in day-to-day clinical practice for an easy and fast interpretation of RNFL measurements obtained with OCT.

Public spirometry campaign in chronic obstructive pulmonary disease screening - hope or hype?

Underdiagnosis of COPD seems to be a relevant clinical and social problem. We hypothesized that active public spirometry campaign may help identify subjects with airflow limitation consistent with COPD. The aim of the study was (1) to evaluate the willingness of random smokers to undergo public spirometry, (2) to assess the ability to obtain an acceptable quality spirometry during a public campaign, and (3) to assess the relationships between the presence and severity of respiratory symptoms and readiness to undergo spirometry. Pedestrians aged > 40 years and a smoking history >10 pack-years were recruited by medical students to fill a questionnaire and perform spirometry. Those with obstructive or borderline ventilatory insuffciency were invited and encouraged to undergo stationary spirometry in a pulmonary outpatient department. Nine hundred and five subjects meeting the inclusion criteria were invited to the study. Only 178 subjects agreed to complete the questionnaire and undergo spirometry. Airway obstruction and borderline spirometry result (classified as possible airway obstruction) were found in 22 and 37 subjects, respectively. Of these, only 15 patients attended follow-up visit to verify public spirometry results. Extrapolation of the limited data showed the incidence of newly diagnosed airway obstruction as 10.7%. Public spirometry campaign does not seem to be an effective way of COPD screening. Smokers are reluctant to undergo complimentary spirometry even in the presence of pronounced respiratory symptoms. Our observations may be helpful in elaborating future screening programs for COPD.

Cut-off optimization for 13C-urea breath test in a community-based trial by mathematic, histology and serology approach

The performance of diagnostic tests in intervention trials of Helicobacter pylori (H.pylori) eradication is crucial, since even minor inaccuracies can have major impact. To determine the cut-off point for 13C-urea breath test (13C-UBT) and to assess if it can be further optimized by serologic testing, mathematic modeling, histopathology and serologic validation were applied. A finite mixture model (FMM) was developed in 21,857 subjects, and an independent validation by modified Giemsa staining was conducted in 300 selected subjects. H.pylori status was determined using recomLine H.pylori assay in 2,113 subjects with a borderline 13C-UBT results. The delta over baseline-value (DOB) of 3.8 was an optimal cut-off point by a FMM in modelling dataset, which was further validated as the most appropriate cut-off point by Giemsa staining (sensitivity = 94.53%, specificity = 92.93%). In the borderline population, 1,468 subjects were determined as H.pylori positive by recomLine (69.5%). A significant correlation between the number of positive H.pylori serum responses and DOB value was found (rs = 0.217, P < 0.001). A mathematical approach such as FMM might be an alternative measure in optimizing the cut-off point for 13C-UBT in community-based studies, and a second method to determine H.pylori status for subjects with borderline value of 13C-UBT was necessary and recommended.

Clinical value of prenatal MRI in the diagnosis of fetal simple expansion of lateral ventricle and follow-up after birth

Objective: To explore the value of prenatal MRI in the diagnosis of fetal simple expansion of lateral ventricle (ventriculomegaly) , and follow up the nervous system development status after birth. Methods: Simple expansion of the lateral ventricle fetus by prenatal MRI examination were collected in Huzhou Maternal and Child Care Hospital from May 2013 to June 2015, 126 cases of live births in expansion group, 50 normal cases were recruited in the same period as the control group. In expansion group, fetal subgroup analysis was done: (1) unilateral or bilateral lateral ventricle expasion: one group was 98 cases was lateral ventricle expansion (77.8%, 98/126), expansion of bilateral ventricle group was 28 cases (22.2%, 28/126). (2) Prenatal MRI in the diagnosis of the lateral ventricle of expansion: expansion of the lateral ventricle width was greater than 10.0 mm, if both sides were expanding, the expand width was the heavier one side, divided into 3 subgroups: ①Expansion in group A (lateral ventricle width 10.0-12.0 mm) were 88 cases (69.8%, 88/126). ②Expansion in group B (lateral ventricle width 12.1-15.0 mm) were 29 cases (23.0%, 29/126). ③Expansion of group C (lateral ventricle width> 15.0 mm) were 9 cases (7.12%, 9/126). All 176 cases were followed up after birth at the 3rd, 6th, 12th, 18th month (corrected age was used for premature babies), and Gesell developmental schedules (GDS) were used to evaluate the neurobehavioral development. Results: (1) The MRI results after birth: 21 cases were followed up by MRI after birth. In group A, 11 cases had MRI and 9 were normal (the ventricular width <10.0 mm after birth), the other 2 cases were stable (the ventricular width measured first time after birth was ≥10.0 mm, but the difference was within 2.0 mm from the MRI before birth). In group B, 4 cases had MRI, 1 was normal, 1 was stable, and 2 cases were getting better (the ventricular width measured first time after birth was ≥10.0 mm, but the width decreased more than 2.0 mm from the MRI before birth). In group C, 6 cases had MRI. 3 cases were getting better and 3 cases were stable. (2) Overall GDS results: expansion group after the birth of the 3rd, 6th, 12th, 18th month GDS evaluation results compared with control group, respectively, the differences were not statistically significant (all P>0.05). (3) The GDS results among the subgroups: in each evaluation after birth, there were no statistically significant differences between group A and the control group (all P>0.05). The GDS results of group B at the 3rd and 6th month were lower than those of the control group (P<0.05); while there were no statistically significant differences between the 2 goups at the 12th and 18th month (P>0.05). And for group C, statistically significant differences were found compared to the control group at each follow-up time (all P<0.05). (4) GDS results at different times after birth in the expansion group: there was no statistically significant difference between the results at the 3rd and 6th month (P>0.05). But when the result at the 3rd month was compared to the results of the 12th or 18th month, the differences were statistically significant (P<0.05). GDS result of 6th months after birth compared with 12th and 18th months, respectively, there were no statistically significant differences (P>0.05). There was no statistically significant difference between the results at the 12th and 18th month (P>0.05). (5) The GDS results in unilateral and bilateral ventricle expansion: at the 18th month, among the 98 unilateral cases, 86 (87.8%, 86/98) had normal GDS results(>85 scores); 8 (8.2%, 8/98) had borderline results (75-85 scores); 4 (4.1%, 4/98) had delayed results (<75 scores). Among the 28 bilateral cases, 23 (82.1%, 23/28) had normal GDS results; 3 (10.7%, 3/28) had borderline results; 2 (7.1%, 2/28) had delayed results. There was no statistically significant difference (P>0.05). Conclusions: Among the simple expansion of lateral ventricle, those whose ventricular width are ≤12.0 mm may not need clinical treatment. If the width is between 12.1 to 15.0 mm, closely follow-up and targeted rehabilitation training after birth are recommended. When the width is more than 15.0 mm, the risk of the central nervous system function delay is significantly increased, and early intervention might improve the prognosis.

Performance of Hepatitis E Virus (HEV)-antibody tests: a comparative analysis based on samples from individuals with direct contact to domestic pigs or wild boar in Germany

In Europe, Hepatitis E virus (HEV) genotype 3 causes most human infections, and domestic pigs and wild boar represent the main reservoirs. Contact to these animals represents one source of human infection. However, interpretation of studies is challenged in the absence of a serological gold standard. Hence, this study compared results of different HEV immunoassays. Plasma samples from 139 individuals who had professional contact to pigs (veterinarians, meat inspectors, slaughterhouse workers; n = 114) or hunted regularly (n = 25) were tested with assays specific for HEV IgG, HEV IgM, HEV IgA, and total HEV immunoglobulin as well as for viral RNA. Furthermore, overall HEV IgG was defined (i.e., two of three IgG assays reveal the same result) to compare serological findings. Borderline results were always quoted as positive. For IgG, apparent prevalence was higher in Wantai (48.2%) compared to Euroimmun (11.5%) and Mikrogen assays (17.3%) (p = 0.0001). The overall IgG prevalence was estimated to be 18.7%. For total Ig, Wantai (40.3%) also yielded higher prevalence than Euroimmun (15.8%) (p = 0.0001). The HEV IgM prevalence ranged from 0% (Euroimmun) to 4.3% (Mikrogen). Four percent of individuals tested IgA positive, whilst none harboured HEV RNA. Our results support previous studies that the higher IgG prevalence estimated with the Wantai assay result from a higher sensitivity of this test. However, further studies are needed to verify specificity given the challenge of defining true negative samples. The high percentage of individuals with HEV IgG observed in this study underlines that direct contact to pigs represents a risk factor for HEV infection.

A study of the clinical utility of a 20-minute secretin-stimulated endoscopic pancreas function test and performance according to clinical variables

Direct pancreas juice testing of bicarbonate, lipase, or trypsin after stimulation by secretin or cholecystokinin is used to determine exocrine function, a surrogate for diagnosing chronic pancreatitis (CP). Endoscopic pancreas function tests (ePFTs), where a peak bicarbonate concentration (PBC)≥80 mEq/L in pancreas juice is considered normal, are now used more frequently. In this ePFT, aspirates start 35 minutes after secretin administration because pancreas output peaks 30 minutes after secretagogue administration. The performance of ePFT in a cohort of patients with a presumptive diagnosis of CP referred to a pancreas clinic for consideration of an intervention including total pancreatectomy and islet autotransplantation was studied, compared with EUS, ERCP, histology, and consensus diagnosis. The effect of sedation, narcotic use, aspirate volume, body mass index, age, and proton pump inhibitors (PPIs) on test performance is reported. After a test dose, synthetic human secretin was administered intravenously, and 30 minutes later sedation was achieved with midazolam and fentanyl or propofol. A gastroscope was advanced to the major papilla where 4 continuous aspiration samples were performed at 5-minute intervals in sealed bottles. PBC≥80 mEq/L was normal. Eighty-one patients had ePFTs from August 2010 through October 2015. Twenty-seven patients (33%) were diagnosed with CP. Eighteen of the 27 patients with CP and 1 of the 54 patients without CP had an abnormal ePFT, producing a sensitivity of 66% (95% CI, 46.0-83.5), specificity 98% (95% CI, 90.1-99.9), positive predictive value 94.7% (95% CI, 74-99.9), and negative predictive value 85.5% (95% CI, 74.2-93.1). ERCP and PBC concordance was generally poor, but none of the patients without CP had major EUS changes, and only 3 patients with a PBC<80 mEq/L had a normal EUS. The PBC was affected by narcotics and PPI use. A 20-minute ePFT after secretin administration had a marginal sensitivity for diagnosis of CP. The diagnosis of CP should not rely on a single study and certainly not a PFT. The duodenal aspirate volume did not correlate with the PBC, which contrasts with current secretin-enhanced MRCP knowledge; therefore, further studies on this subject are warranted. Neither type of sedation, BMI, nor age affected test performance. Narcotics and PPIs may affect the PBC, so borderline results should be interpreted with caution in these groups.

Comparative performances of serologic and molecular assays for detecting human T lymphotropic virus type 1 and type 2 (HTLV-1 and HTLV-2) in patients infected with human immunodeficiency virus type 1 (HIV-1)

The present study evaluated several techniques currently available (commercial kits and in-house assays) for diagnosing human T lymphotropic viruses types 1 and 2 in two groups of patients enrolled at HIV/AIDS specialized care services in São Paulo: Group 1 (G1), n=1608, 1237 male/371 female, median age 44.3 years old, majority using highly active antiretroviral therapy (HAART); G2, n=1383, 930 male/453 female, median age of 35.6 years old, majority HAART naïve. Enzyme immunoassays [(EIA) Murex and Gold ELISA] were employed for human T lymphotropic viruses types 1 and 2 screening; Western blotting (WB), INNO-LIA (LIA), real-time PCR pol (qPCR), and nested-PCR-RFLP (tax) were used to confirm infection. Samples were considered human T lymphotropic viruses types 1 and 2 positive when there was reactivity using at least one of the four confirmatory assays. By serological screening, 127/2991 samples were positive or borderline, and human T lymphotropic virus infection was confirmed in 108 samples (three EIA-borderline): 56 human T lymphotropic virus type 1 [G1 (27)+G2 (29)]; 45 human T lymphotropic virus type 2 [G1 (21)+G2 (24)]; one human T lymphotropic virus type 1+human T lymphotropic virus type 2 (G2); six human T lymphotropic virus [G1 (2)+G2 (4)]. Although there were differences in group characteristics, human T lymphotropic viruses types 1 and 2 prevalence was similar [3.1% (G1) and 4.2% (G2), p=0.113]. The overall sensitivities of LIA, WB, qPCR, and PCR-RFLP were 97.2%, 82.4%, 68.9%, and 68.4%, respectively, with some differences among groups, likely due to the stage of human T lymphotropic virus infection and/or HAART duration. Indeterminate immunoblotting results were detected in G2, possibly due to the seroconversion period. Negative results in molecular assays could be explained by the use of HAART, the occurrence of defective provirus and/or the low circulating proviral load. In conclusion, when determining the human T lymphotropic virus infection, the findings highlight that there is a need to consider the blood samples with borderline results in screening assays. Of all the tested assays, LIA was the assay of choice for detecting human T lymphotropic virus type 1 and human T lymphotropic virus type 2 in human immunodeficiency virus type 1-infected patients.

Safety and Efficacy of Magnetic Resonance-Guided Vacuum-Assisted Large-Volume Breast Biopsy (MR-Guided VALB).

Magnetic resonance (MR)-guided vacuum-biopsy is technically demanding and may fail depending on target-lesion size or breast size, and location of lesions within the breast. We developed an MR-guided vacuum-assisted biopsy protocol that collects larger amounts of tissue, aiming at an at least partial or complete ablation of the target-lesion, just as it is intended during surgical (excisional) biopsy. Rationale is to avoid biopsy failures (false-negative results due to undersampling) by collecting larger amounts of tissue. We report on our experience with MR-guided vacuum-assisted large-volume breast biopsy (VALB) (MR-guided VALB) with regard to clinical success and complication rates. Institutional review board-approved analysis of 865 patients with 1414 MR imaging (MRI)-only breast lesions who underwent tissue sampling under MRI guidance. Magnetic resonance-guided VALB was performed on a 1.5 T-system with a 9G system. Per target lesion, we collected at least 24 samples, with the biopsy notch directed toward the position of the target until on postbiopsy control imaging the target lesion appeared completely or at least greatly removed. The standard-of-reference was established by at least 24-months follow-up (for benign biopsy results), or results of surgical histology (for malignant or borderline results). We investigated the technical success rates as a function of factors that usually interfere with MR-guided vacuum biopsy. Target lesions were located in the central versus peripheral parts of the breast in 66.6% (941/1414) versus 33.6% (473/1414), occurred in large, intermediate, or small breasts in 22.7% (321/1414), 56.4% (797/1414), or 20.9% (296/1414), corresponded to nonmass enhancement (NME) versus mass enhancement (ME) in 64.0% (905/1414) vs. 36.0% (509/1414), with an average size of 23 mm for NME versus 9 mm for ME, respectively. Primary technical failures, that is, inability to reach the target lesion occurred in 0.2% of patients (2/865) and 0.1% of target lesions (2/1414). Successful biopsy, that is, an MR-guided VALB diagnosis matching with the standard of reference, was achieved in 99.5% (859/863) of patients and 99.7% (1408/1412) target lesions that had been amenable to MR-guided VALB. In 0.5% of patients (4/863) and 0.3% of target lesions (4/1412), a radiologic-pathologic mismatch suggested a false-negative biopsy, confirmed by secondary excisional biopsy. The likelihood of failure was independent of the lesion's location in the breast, breast size, target lesion size, or target lesion type (NME vs ME). None of the patients with benign MR-guided VALB diagnoses developed breast cancer at the biopsy site during follow-up of 2 years. None of the patients developed major complications. Magnetic resonance-guided VALB is a safe procedure that is associated with a high success rate (99.7%) that is independent of the size, type, or location of a target lesion, or the size of the breast, and is associated with a very low complication rate.

Repeated Cell Therapy

Although treatment with stem/progenitor cells is a promising approach to heart disease, enthusiasm for cell therapy has been dampened by the inconsistent, modest, borderline, or undetectable benefits reported in clinical trials (all of which have used 1 dose of cells).1–4 As a result, clinical translation has not occurred (no cell-based therapy is close to being approved for heart disease), and a rising tide of skepticism has bedeviled the field,5,6 leading some critics even to question whether clinical studies should continue. Here, I propose that a major reason for the modest, borderline, or disappointing results is the administration of only 1 dose of cells, which causes the benefits of cell therapy to be underestimated. I argue that just as most pharmacological agents are ineffective when given once but can be highly effective when given repeatedly, so a cell product may be ineffective, or modestly effective, when given as a single treatment, but may turn out to be quite efficacious if given repeatedly. This concept constitutes a major paradigm shift (a “game changer”), with potentially vast implications for the entire field of reparative medicine . The efficacy of cell therapy is limited by the poor engraftment of the cells, which disappear rapidly after transplantation. For example, after administration of c-kitPOS cardiac progenitor cells (CPCs) in mice, rats, and pigs, the number of cells remaining in the heart declines precipitously to very low values1,2,7,8; in the mouse heart, <8% of the CPCs present immediately after transplantation remain 1 week later, and after 35 days this number falls to <3%.8 Despite this, administration of CPCs improves left ventricular (LV) function, and the improvement is long lasting (at least 1 year).1,2,7,8 Rapid disappearance of transplanted cells …

Viewpoint: Doing nothing.

As a newly qualified GP I sometimes feel I’m walking a tightrope. Non-specific symptoms may represent early undifferentiated disease, yet overzealous blood tests and investigations can lead to patient harms.1 How can we get the right balance? Skill in general practice lies in dealing with uncertainty; inevitably this involves risk. Yet, risk management is an increasingly dirty word in a culture where health professionals face criminalisation for missed diagnoses2 with ‘zero tolerance’ for patient harms.3 This fuels a wave of fearfulness among GPs, who often use blood tests and investigations to reassure themselves that they are not ‘missing something’. Unfortunately this can lead to a vicious cycle; rather than reassuring ourselves, inconclusive or borderline results can generate increased uncertainty and anxiety.4 This in turn …

P1.08-007 The Significant Improvement of Lung Function after Preoperative Rehabilitation in Patients with Thoracic Tumors and Abnormal Spirometry

The evaluation of degree of improvement of exercise tolerance and rest lung function parameters after preoperative pulmonary rehabilitation in patients with thoracic tumors and baseline borderline abnormal spirometry results. Clinical inclusion criteria were: diagnosis of thoracic tumors and reduced values of FEV1 and FVC predicting postoperative complications. We observed 29 patients (16 women, 13 men) in mean age of 68 (range 57-68) years. Spirometry, six minute walking test distance (6MWT) and maximum metabolic equivalent during exercise on treadmill (MET) were chosen for evaluation of lung function and physical performance during rehabilitation. The tests were performed twice during screening phase to eliminate the factors of learning, and were repeated after first and second week of rehabilitation. Pulmonary rehabilitation included two weeks of training on the treadmill with individually selected speed, physiotherapy exercises and breathing training with using of Triflo. The significant differences were observed after pulmonary rehabilitation: 1). FEV 1 (L): 1.41 vs 1.58 (p=0.000027) 2). FEV1 (%N): 60.49 vs 71.49 (p=0.000021) 3). FVC (L): 2.34 vs 2.64 (p=0. 000520) 4). FVC (%N): 79 vs 95 (p=0.000269) 5). 6MWT Distance (m): 350 vs 400 (p=0.000007) 6). MET: 2.66 vs 2.905 (p=0.000007). A two-week pulmonary rehabilitation leads to significantly improvement of lung function and physical performance in patients with thoracic tumors and borderline abnormal spirometry results which may provide significantly better outcome of patients in short- and longtime follow-up.

The borderline range of toxicological methods: Quantification and implications for evaluating precision_suppl

Test methods to assess the skin sensitization potential of a substance usually use threshold criteria to dichotomize continuous experimental read-outs into yes/no conclusions. The threshold criteria are prescribed in the respective OECD test guidelines and the conclusion is used for regulatory hazard assessment, i.e., classification and labelling of the substance. We can identify a borderline range (BR) around the classification threshold within which test results are inconclusive due to a test method’s biological and technical variability. We quantified BRs in the prediction models of the non-animal test methods DPRA, LuSens and h-CLAT, and of the animal test LLNA, respectively. Depending on the size of the BR, we found that between 6% and 28% of the substances in the sets tested with these methods were considered borderline. When the results of individual non-animal test methods were combined into integrated testing strategies (ITS), borderline test results of individual tests also affected the overall assessment of the skin sensitization potential of the testing strategy. This was analyzed for the 2-out-of-3 ITS: Four out of 40 substances (10%) were con&shy;sidered borderline. Based on our findings we propose expanding the standard binary classification of substances into “positive”/“negative” or “hazardous”/“non-hazardous” by adding a “borderline” or “inconclusive” alert for cases where test results fall within the borderline range.

The borderline range of toxicological methods: Quantification and implications for evaluating precision.

Test methods to assess the skin sensitization potential of a substance usually use threshold criteria to dichotomize continuous experimental read-outs into yes/no conclusions. The threshold criteria are prescribed in the respective OECD test guidelines and the conclusion is used for regulatory hazard assessment, i.e., classification and labelling of the substance. We can identify a borderline range (BR) around the classification threshold within which test results are inconclusive due to a test method's biological and technical variability. We quantified BRs in the prediction models of the non-animal test methods DPRA, LuSens and h-CLAT, and of the animal test LLNA, respectively. Depending on the size of the BR, we found that between 6% and 28% of the substances in the sets tested with these methods were considered borderline. When the results of individual non-animal test methods were combined into integrated testing strategies (ITS), borderline test results of individual tests also affected the overall assessment of the skin sensitization potential of the testing strategy. This was analyzed for the 2-out-of-3 ITS: Four out of 40 substances (10%) were considered borderline. Based on our findings we propose expanding the standard binary classification of substances into "positive"/"negative" or "hazardous"/"non-hazardous" by adding a "borderline" or "inconclusive" alert for cases where test results fall within the borderline range.

Survival analysis, more than meets the eye.

The log-rank test is a cornerstone of phase III oncology clinical trials. However, there are at least three different mathematical procedures that can be named the log-rank test and two of them are widely used by commercial statistical programs. Consequently, different P values can be obtained. In the case of a borderline statistical significance, this can mean the difference between the evidence (significant P value) and merely an observation. Since all three methods can be reported under the same name, space for possible data manipulation occurs. This should be of a particular concern in a drug regulatory context. Randomized clinical trials with borderline significant results should perhaps be required to report P values calculated by all three methods, in order to properly evaluate drug efficacy. An interactive MS Excel spreadsheet that uses all three logrank test variants is prepared as a supplementary file accompanying this article. Association of high grade of bone marrow fibrosis with poor outcome in patients with myelofibrosis is used as an example.