Use of modifying phrases in surgical pathology reports: is there a different understanding between pathologists and treating physicians?

When not all the histopathologic and clinical features necessary for a pathology diagnosis are present in a particular specimen, pathologists may use modifying phrases to convey various degrees of certainty, e.g., "consistent with…" and "suggestive of…." However, it is unclear whether pathologists use such phrases consistently or whether treating physicians fully understand their intended meaning. A questionnaire concerning six common modifying phrases ("consistent with, suggestive of, suspicious for, highly consistent with, highly suggestive of, some features of") was sent to all physicians from a single institution who either issued or routinely received surgical pathology reports. Physicians were asked to rank their understanding of each phrase on a printed scale between 1 ("no evidence of") and 10 ("diagnostic of"). One hundred sixty physicians (74.3%) responded. Despite wide variation, there was a hierarchy (from more to less diagnostic): highly consistent > highly suspicious > consistent > suspicious > suggestive > some features (p < 1 × 10-7). There were no significant differences between pathologists and treating physicians (p = 0.72) or attendings and residents (p = 0.9). Pathologists and treating physicians share an overall common understanding of their hierarchical relationship, albeit with wide ranges. Based upon our results, we propose to use only three qualifying phrases to convey the degree of certainty for a particular diagnosis: "suggestive of" (> 25 ≤ 50% certainty), "suspicious for" (> 50 ≤ 75%), and "consistent with" (> 75%). The phrase "no evidence of" should probably be used only when there is ≤ 5% confidence in a diagnosis, and conversely, "diagnostic of" should probably be used only when there is ≥ 95% confidence in a diagnosis.

Protecting quantum entanglement from leakage and qubit errors via repetitive parity measurements.

Protecting quantum information from errors is essential for large-scale quantum computation. Quantum error correction (QEC) encodes information in entangled states of many qubits and performs parity measurements to identify errors without destroying the encoded information. However, traditional QEC cannot handle leakage from the qubit computational space. Leakage affects leading experimental platforms, based on trapped ions and superconducting circuits, which use effective qubits within many-level physical systems. We investigate how two-transmon entangled states evolve under repeated parity measurements and demonstrate the use of hidden Markov models to detect leakage using only the record of parity measurement outcomes required for QEC. We show the stabilization of Bell states over up to 26 parity measurements by mitigating leakage using postselection and correcting qubit errors using Pauli-frame transformations. Our leakage identification method is computationally efficient and thus compatible with real-time leakage tracking and correction in larger quantum processors.

Fast, High-Fidelity Conditional-Phase Gate Exploiting Leakage Interference in Weakly Anharmonic Superconducting Qubits.

Conditional-phase (cz) gates in transmons can be realized by flux pulsing computational states towards resonance with noncomputational ones. We present a 40 ns cz gate based on a bipolar flux pulse suppressing leakage (0.1%) by interference and approaching the speed limit set by exchange coupling. This pulse harnesses a built-in echo to enhance fidelity (99.1%) and is robust to long-timescale distortion in the flux-control line, ensuring repeatability. Numerical simulations matching experiment show that fidelity is limited by high-frequency dephasing and leakage by short-timescale distortion.

KIT mutations and CD117 overexpression are markers of better progression-free survival in vulvar melanomas.

BACKGROUND: Few studies have addressed prognostic markers and none has correlated molecular status and prognosis in vulvar melanomas. OBJECTIVES: To evaluate the clinicopathological features of 95 cases of vulvar melanoma. METHODS: p53, CD117, Ki-67, neurofibromin, brafv600e and nrasq61r immunostains, and molecular analyses by either targeted next-generation or direct sequencing, were performed on available archival materials. RESULTS: Molecular testing detected mutations in KIT (44%), BRAF (25%), NF1 (22%), TP53 (17%), NRAS (9%) and TERT promoter (9%). Co-mutation of KIT and NF1 and of KIT and NRAS were identified in two and one cases, respectively. KIT mutations were significantly associated with better progression-free survival in univariate analyses. In multivariate analyses CD117 expression was significantly associated with better progression-free survival. Tumour thickness was significantly associated with worse progression-free and overall survival, and perineural invasion significantly correlated with reduced melanoma-specific survival and reduced overall survival. Cases were from multiple centres and only a subset of samples was available for molecular testing. CONCLUSIONS: KIT mutations and CD117 overexpression are markers of better progression-free survival. In addition to its prognostic value, molecular testing may identify cases that might respond to targeted agents or immunotherapeutic approaches.

The Potato Cryobank at The International Potato Center (Cip): A Model for Long Term Conservation of Clonal Plant Genetic Resources Collections of the Future.

BACKGROUND: Cryobanks are a secure, efficient and low cost method for the long-term conservation of plant genetic resources for theoretically centuries or millennia with minimal maintenance. OBJECTIVE: The present manuscript describes CIP's modified protocol for potato cryopreservation, its large-scale application, and the establishment of quality and operational standards, which included a viability reassessment of material entering the cryobank. MATERIALS AND METHODS: In 2013, CIP established stricter quality and operational standards under which 1,028 potato accessions were cryopreserved with an improved PVS2-droplet protocol. In 2014 the viability of 114 accessions cryopreserved in 2013 accessions were reassessed. RESULTS: The average recovery rate (full plant recovery after LN exposure) of 1028 cryopreserved Solanum species ranged from 34 to 59%, and 70% of the processed accessions showed a minimum recovery rate of ≥20% and were considered as successfully cryopreserved. CONCLUSION: CIP has established a new high quality management system for cryobanking. Periodic viability reassessment, strict and clear recovery criteria and the monitoring of the percent of successful accessions meeting the criteria as well as contamination rates are metrics that need to be considered in cryobanks.

Evaluation of an epithelial plasticity biomarker panel in men with localized prostate cancer.

BACKGROUND: Given the potential importance of epithelial plasticity (EP) to cancer metastasis, we sought to investigate biomarkers related to EP in men with localized prostate cancer (PC) for the association with time to PSA recurrence and other clinical outcomes after surgery. METHODS: Men with localized PC treated with radical prostatectomy at the Durham VA Medical Center and whose prostatectomy tissues were included in a tissue microarray (TMA) linked to long-term outcomes. We performed immunohistochemical studies using validated antibodies against E-cadherin and Ki-67 and mesenchymal biomarkers including N-cadherin, vimentin, SNAIL, ZEB1 and TWIST. Association studies were conducted for each biomarker with baseline clinical/pathologic characteristics an risk of PSA recurrence over time. RESULTS: Two hundred and five men contributed TMA tissue and had long-term follow-up (median 11 years). Forty-three percent had PSA recurrence; three died of PC. The majority had high E-cadherin expression (86%); 14% had low/absent E-cadherin expression. N-cadherin was rarely expressed (<4%) and we were unable to identify an E-to-N-cadherin switch as independently prognostic. No associations with clinical risk group, PSA recurrence or Gleason sum were noted for SNAIL, ZEB1, vimentin or TWIST, despite heterogeneous expression between patients. We observed an association of higher Ki-67 expression with Gleason sum (P=0.043), National Comprehensive Cancer Network risk (P=0.013) and PSA recurrence (hazard ratio 1.07, P=0.016). CONCLUSIONS: The expression of EP biomarkers in this cohort of men with a low risk of PC-specific mortality was not associated with aggressive features or PSA relapse after surgery.

Disparate results between proliferation rates of surgically excised prostate tumors and an in vitro bioassay using sera from a positive randomized controlled trial.

In vitro bioassay has been used extensively to test the effects of culturing cancer cells in sera from humans participating in dietary interventions, i.e, studies of modified intake of nutrients for the purpose of reducing cancer risk or progression. It has been hypothesized that cell proliferation rates determined by the in vitro bioassay indicate whether modification of dietary intake could decrease cancer cell growth in vivo. It has been suggested, however, that the in vitro bioassay may not correlate with tumor cell proliferation rates in prostate cancer. We investigated the concordance of cell proliferation rates from surgically excised prostate tumor tissue with the in vitro bioassay using sera from matched patients. We used samples from an earlier randomized clinical trial that showed that supplementation with flaxseed significantly inhibited prostate cancer cell proliferation rates in vivo as indicated by Ki67 staining in tumor specimens. Proliferation rates of LNCaP, DU145 and PC3 cell lines cultured in 10% human sera from participants in the flaxseed trial were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Spearman's Rho correlation coefficients (ρ) indicated no association between Ki67 staining in prostate tumors and the in vitro bioassay for the three cell lines. These disparate findings suggest that the in vitro bioassay may not provide an accurate assessment of the environment in vivo.

Prostate biopsies from black men express higher levels of aggressive disease biomarkers than prostate biopsies from white men.

A wide array of biomarkers is being investigated as predictors of prostate cancer (PCa) diagnosis and recurrence. We compared the expression of a small panel of these biomarkers as a function of race among men undergoing radical prostatectomy (RP). Prostate needle biopsy specimens from 131 patients treated with RP at the Durham Veterans Affairs Medical Center were hematoxylin and eosin stained and immunofluorescent assayed for α-methylacyl CoA racemase (AMACR), androgen receptor (AR) and Ki67. Proprietary image analysis was used to identify six biometric feature combinations that were significantly associated with progression in a previous study. Analysis of population characteristics, stratified by race, was performed using rank-sum and χ(2)-test. The effect of race on expression of these biomarker profiles was analyzed using multivariate linear regression. All six biomarker features were expressed at higher levels in black men than white men, with Norm AR (P=0.006) and Ki67 (P=0.02) attaining statistical significance. On multivariate analysis, all markers were expressed at higher levels in black men, with Norm AR (P=0.001), Ki67 (P=0.007) and Ki67/lum (P=0.022) reaching significance. These data support the hypothesis that PCa may be biologically more aggressive among black men.

Prognostic value of various morphometric measurements of tumour extent in prostate needle core tissue.

AIMS: Predicting prostatic cancer patients' outcome is a major objective for clinicians and patients. Several nomograms are currently implemented prior to treatment to help predict clinical and pathological outcome. The aim of this study was to investigate the prognostic significance of morphometric measurements of cancer on the needle biopsy specimen in relation to the final pathological stage or the biochemical failure status following radical prostatectomy, and to determine which measurement of tumour length in cases with discontinuous foci of cancer (DFC) is most reliably reflective of the pathological stage. METHODS AND RESULTS: Of the 100 patients included in this study, 34% had high-stage disease (pT >or= 3 and/or pN1) and 16% experienced biochemical recurrence. The analysis showed that fraction of positive cores, total percentage of cancer and both total and greatest millimetric cancer lengths were the variables most closely associated with pathological stage and biochemical failure status. CONCLUSIONS: This study confirms the prognostic value of recording tumour extent in prostatic needle biopsy reporting. However, the results are inconclusive in determining the best method to record tumour length in cores with DFC and larger studies are needed to answer this question fully.

Oxytocin gene deletion mice overconsume palatable sucrose solution but not palatable lipid emulsions.

We previously reported that oxytocin knockout (OT KO) mice display markedly enhanced intake of sweet and nonsweet carbohydrate solutions compared with intake by wild-type (WT) mice of the same background strain. The present study was conducted to determine whether OT KO mice demonstrate enhanced intake of Intralipid, a palatable lipid emulsion. Male or female mice of both genotypes that were naive to the test solution were given continuous two-bottle access to Intralipid and water with food available ad libitum for 3 days. Throughout the experiment, mice of both genotypes showed a marked preference for Intralipid over water. On the 1st day, OT KO mice displayed twofold greater preference and consumed nearly twice as much Intralipid compared with WT cohorts. However, on subsequent days of exposure, Intralipid preference and intake did not differ between genotypes over a range of lipid concentrations presented in descending or ascending order. Daily and hourly measures of lipid vs. sucrose intake confirmed that OT KO mice consumed more sucrose solution, but not lipid emulsion, than WT mice. During ad libitum access to Intralipid, both genotypes consumed significantly more calories from the emulsion as concentration increased. Both genotypes maintained consistent total daily caloric intake (lipid plus chow) and compensated by decreasing chow intake over the course of the study. These findings, coupled with prior reports from our laboratory, support the view that OT signaling pathways participate in limiting intake of palatable carbohydrate-containing solutions, but do not appear to play a role in limiting intake of Intralipid.

Anxiety and stress responses in female oxytocin deficient mice.

Oxytocin is believed to attenuate the response of the hypothalamic-pituitary-adrenal axis to stress and to be anxiolytic. Stressors with a psychological component evoke both central and peripheral secretion of oxytocin in laboratory rodents. Oxytocin gene deletion mice provide a novel way to understand the role of oxytocin in stress and anxiety-related behaviours. We present our experience with female oxytocin deficient mice that were tested in an elevated plus maze (EPM), a behavioural test of anxiety, or exposed to psychogenic stressors (platform shaker or novel environment). Oxytocin-deficient mice not only displayed more anxiety-related behaviour, but also released more corticosterone after a psychogenic stressor and manifested greater stress-induced hyperthermia compared to wild-type mice. The diurnal variation of corticosterone and the response of corticosterone to corticotropin-releasing factor were not significantly different between genotypes. We also measured Fos-immunoreactive protein, an index of neuronal activation, in the medial amygdala of female mice after EPM testing. The medial amygdala is important for processing of psychogenic stress and anxiety and also contains oxytocin pathways and oxytocin receptors. The expression of Fos in the medial amygdala of mice not exposed to the EPM was not different between genotypes. Following EPM exposure, Fos expression was greater in oxytocin null compared to wild-type mice. Our findings support the hypothesis that central oxytocin is anxiolytic, and attenuates the stress response to psychogenic provocation in female mice.

Hydroporation as the mechanism of hydrodynamic delivery.

We have reported that a rapid tail vein injection of a large volume of plasmid DNA solution into a mouse results in high level of transgene expression in the liver. Gene transfer efficiency of this hydrodynamics-based procedure is determined by the combined effect of a large volume and high injection speed. Here, we show that the hydrodynamic injection induces a transient irregularity of heart function, a sharp increase in venous pressure, an enlargement of liver fenestrae, and enhancement of membrane permeability of the hepatocytes. At the cellular level, our results suggest that hepatic delivery by the hydrodynamic injection is accomplished by the generation of membrane pores in the hepatocytes.

Spin-polarized electron energy loss spectroscopy of high energy, large wave vector spin waves in ultrathin fcc Co films on Cu(001).

The realm of high energy, large wave vector spin waves in ultrathin films and at surfaces is unexplored because a suitable method was not available up to now. We present experimental data for an 8 ML thick Co film deposited on Cu(001) which show that spin-polarized electron energy loss spectroscopy can be used to measure spin-wave dispersion curves of ultrathin ferromagnetic films up to the surface Brillouin zone boundary.

Low-temperature specific heat of the heavy-fermion superconductor PrOs4Sb12.

We report the magnetic field dependence of the specific-heat C of single crystals of the first Pr-based heavy-fermion superconductor Pr(Os4Sb12. The variation of C at low temperature and the magnetic phase diagram inferred from C, the resistivity and magnetization provide compelling evidence of a doublet ground state. Two distinct superconducting anomalies in C indicate an unconventional superconducting state, where the splitting may arise from a weak lifting of the ground state degeneracy. In combination this identifies Pr(Os4Sb12 as a strong contender for quadrupolar pairing, i.e., superconductivity that is neither electron-phonon nor magnetically mediated.

Mice deficient in oxytocin manifest increased saline consumption following overnight fluid deprivation.

Male mice (9-13 mo of age) in which the gene for oxytocin (OT) had been deleted (OT -/-) were administered 0.5 M sodium chloride (NaCl) solution or tap water as a two-bottle choice test following overnight fluid deprivation (1600 to 1000 the following day). Compared with wild-type cohorts (OT +/+), OT-deficient mice ingested sevenfold greater amounts of saline in the first hour following reintroduction of fluids, P < 0.001, and fourfold greater amounts at the end of 6 h, P < 0.02. No significant difference in total water ingested was noted between the two genotypes at the end of either 1 or 6 h. If food deprivation accompanied the overnight fluid deprivation and food was reintroduced 1 h after the reintroduction of both water and saline, OT -/- mice still ingested greater amounts of saline, but not water, than OT +/+ mice at both 1 h, P < 0.001, and 6 h, P < 0.02. No differences were noted between genotypes in the daily intake of 0.5 M NaCl solution or water during a 3-day observation period before the overnight fluid deprivation. The volume of saline consumed in each 24-h observation period represented about one-tenth of the total fluids ingested in each genotype. We conclude that OT -/- mice display an enhanced salt appetite compared with OT +/+ mice when fluid deprived overnight. The salt appetite was only apparent in the presence of a perturbation such as fluid deprivation, which predisposes the animal to moderate hypovolemia. The observations support an inhibitory role for OT in the control of sodium appetite in mice.

Pilot study of dietary fat restriction and flaxseed supplementation in men with prostate cancer before surgery: exploring the effects on hormonal levels, prostate-specific antigen, and histopathologic features.

OBJECTIVES: Dietary fat and fiber affect hormonal levels and may influence cancer progression. Flaxseed is a rich source of lignan and omega-3 fatty acids and may thwart prostate cancer. The potential effects of flaxseed may be enhanced with concomitant fat restriction. We undertook a pilot study to explore whether a flaxseed-supplemented, fat-restricted diet could affect the biomarkers of prostatic neoplasia. METHODS: Twenty-five patients with prostate cancer who were awaiting prostatectomy were instructed on a low-fat (20% of kilocalories or less), flaxseed-supplemented (30 g/day) diet. The baseline and follow-up levels of prostate-specific antigen, testosterone, free androgen index, and total serum cholesterol were determined. The tumors of diet-treated patients were compared with those of historic cases (matched by age, race, prostate-specific antigen level at diagnosis, and biopsy Gleason sum) with respect to apoptosis (terminal deoxynucleotidyl transferase [TdT]-mediated dUTP-biotin nick end-labeling [TUNEL]) and proliferation (MIB-1). RESULTS: The average duration on the diet was 34 days (range 21 to 77), during which time significant decreases were observed in total serum cholesterol (201 +/- 39 mg/dL to 174 +/- 42 mg/dL), total testosterone (422 +/- 122 ng/dL to 360 +/- 128 ng/dL), and free androgen index (36.3% +/- 18.9% to 29.3% +/- 16.8%) (all P <0.05). The baseline and follow-up levels of prostate-specific antigen were 8.1 +/- 5.2 ng/mL and 8.5 +/- 7.7 ng/mL, respectively, for the entire sample (P = 0.58); however, among men with Gleason sums of 6 or less (n = 19), the PSA values were 7.1 +/- 3.9 ng/mL and 6.4 +/- 4.1 ng/mL (P = 0.10). The mean proliferation index was 7.4 +/- 7.8 for the historic controls versus 5.0 +/- 4.9 for the diet-treated patients (P = 0.05). The distribution of the apoptotic indexes differed significantly (P = 0.01) between groups, with most historic controls exhibiting TUNEL categorical scores of 0; diet-treated patients largely exhibited scores of 1. Both the proliferation rate and apoptosis were significantly associated with the number of days on the diet (P = 0.049 and P = 0.017, respectively). CONCLUSIONS: These pilot data suggest that a flaxseed-supplemented, fat-restricted diet may affect prostate cancer biology and associated biomarkers. Further study is needed to determine the benefit of this dietary regimen as either a complementary or preventive therapy.

Coexistence of superconductivity and ferromagnetism in the d-band metal ZrZn2.

It has generally been believed that, within the context of the Bardeen-Cooper-Schrieffer (BCS) theory of superconductivity, the conduction electrons in a metal cannot be both ferromagnetically ordered and superconducting. Even when the superconductivity has been interpreted as arising from magnetic mediation of the paired electrons, it was thought that the superconducting state occurs in the paramagnetic phase. Here we report the observation of superconductivity in the ferromagnetically ordered phase of the d-electron compound ZrZn2. The specific heat anomaly associated with the superconducting transition in this material appears to be absent, and the superconducting state is very sensitive to defects, occurring only in very pure samples. Under hydrostatic pressure superconductivity and ferromagnetism disappear at the same pressure, so the ferromagnetic state appears to be a prerequisite for superconductivity. When combined with the recent observation of superconductivity in UGe2 (ref. 4), our results suggest that metallic ferromagnets may universally become superconducting when the magnetization is small.

Hyper-excretion of human immunodeficiency virus type 1 RNA in saliva.

Anatomical compartments (e.g., the reproductive tract) are reservoirs of human immunodeficiency virus type-1 (HIV-1) and potential sites of residual infection in patients receiving anti-retroviral therapy (ART). Viral hyper-excretion relative to blood is a hallmark of reservoirs. To determine whether hyper-excretion can occur in the oral cavity, we compared viral loads in blood plasma and saliva of 67 adults. Salivary viral hyperexcretion was defined as a four-fold or higher viral load in saliva than in plasma. HIV-1 RNA was detected in 79% of plasma samples, in 44% of unfiltered saliva samples, in 16% of filtered saliva samples, and in 59% of saliva-derived cell pellets. Compared with non-hyper-excretors (n = 62), hyper-excretors (n = 5) had elevated levels of viral RNA in unfiltered saliva and saliva-derived cells, HIV-associated periodontal disease, gingival inflammation, and no combination ART. Morphological characterization of cell pellets identified lymphocytes as a likely HIV-1 source. These collective findings are consistent with an oral HIV-1 reservoir in selected individuals.

Depletion of brown fat norepinephrine content by acute cold exposure and adrenoceptor blockade.

Experiments were conducted to characterize the effects of acute cold exposure, with and without adrenoceptor blockade, on intrascapular brown adipose tissue (IBAT) and adrenal catecholamine content in male Sprague-Dawley rats. Groups of animals with indwelling temperature transmitters were tested following treatment with saline, the alpha-adrenoceptor blocker phentolamine, the beta-adrenoceptor blocker propranolol, combined blockade with phentolamine plus propranolol, and the ganglionic blocker chlorisondamine. IBAT norepinephrine (NE) content was not affected in animals tested at 22 degrees C, but was reduced in 4 degrees C-exposed animals treated with phentolamine (-57%), phentolamine plus propranolol (-97%), and chlorisondamine (-42%). Adrenal NE and epinephrine (EPI) content were not altered by the treatments at 4 degrees C or 22 degrees C. None of the treatments affected the temperature of animals at 22 degrees C, but significant hypothermia occurred at 4 degrees C after chlorisondamine (-2.3+/-0.3 degrees C) and the combination of phentolamine and propranolol (-1.5+/-0.4 degrees C). These results suggest that cold exposure alone did not affect IBAT NE content, but when cold exposure was combined with adrenoceptor blockade, the sympathetic activation was sufficient to cause a reduction in IBAT NE content. In addition, alpha- and beta-adrenoceptor-mediated mechanisms contribute to the maintenance of core temperature. However, both alpha- and beta-receptor mechanisms had to be interrupted before a deficit in body temperature was detected.