Comparing hospital and telephone follow-up for patients treated for stage-I endometrial cancer (ENDCAT trial): a randomised, multicentre, non-inferiority trial.

OBJECTIVE: To evaluate the effectiveness of nurse-led telephone follow-up (TFU) for patients with stage-I endometrial cancer. DESIGN: Multicentre, randomised, non-inferiority trial. SETTING: Five centres in the North West of England. SAMPLE: A cohort of 259 women treated for stage-I endometrial cancer attending hospital outpatient clinics for routine follow-up. METHODS: Participants were randomly allocated to receive traditional hospital based follow-up (HFU) or nurse-led TFU. MAIN OUTCOME MEASURES: Primary outcomes were psychological morbidity (State Trait Anxiety Inventory, STAI-S) and patient satisfaction with the information provided. Secondary outcomes included patient satisfaction with service, quality of life, and time to detection of recurrence. RESULTS: The STAI-S scores post-randomisation were similar between groups [mean (SD): TFU 33.0 (11.0); HFU 35.5 (13.0)]. The estimated between-group difference in STAI-S was 0.7 (95% confidence interval, 95% CI -1.9 to 3.3); the confidence interval lies above the non-inferiority limit (-3.5), indicating the non-inferiority of TFU. There was no significant difference between groups in reported satisfaction with information (odds ratio, OR 0.9; 95% CI 0.4-2.1; P = 0.83). Women in the HFU group were more likely to report being kept waiting for their appointment (P = 0.001), that they did not need any information (P = 0.003), and were less likely to report that the nurse knew about their particular case and situation (P = 0.005). CONCLUSIONS: The TFU provides an effective alternative to HFU for patients with stage-I endometrial cancer, with no reported physical or psychological detriment. Patient satisfaction with information was high, with similar levels between groups. TWEETABLE ABSTRACT: ENDCAT trial shows effectiveness of nurse-led telephone follow-up for patients with stage-I endometrial cancer.

HMGCR-associated myositis: a New Zealand case series and estimate of incidence.

Statins are one of the most commonly prescribed drugs in New Zealand, with 525 772 or 16.5% of the adult New Zealand population prescribed a statin between June 2013 and July 2014. While generally well-tolerated, statins are known to cause a range of muscle-related side effects, ranging from myalgia to life-threatening rhabdomyolysis. Recently, it has been recognised that in rare instances, statins can induce an immune-mediated necrotising myositis with antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the enzymatic target of statins. In 2014, anti-HMGCR antibody testing was introduced to Canterbury Health Laboratories (CHL), with this being the only laboratory in New Zealand performing this test during the period of this case series. This article describes an index case and characterises the clinical features of a subsequent 12-month series. From this series, we estimated the yearly incidence of HMGCR-associated myositis at 1.7/million/year or ~1/90 000 New Zealand statin users.

Infrared spectroscopy with multivariate analysis to interrogate endometrial tissue: a novel and objective diagnostic approach.

BACKGROUND: Endometrial cancer is the most common gynaecological malignancy in the United Kingdom. Diagnosis currently involves subjective expert interpretation of highly processed tissue, primarily using microscopy. Previous work has shown that infrared (IR) spectroscopy can be used to distinguish between benign and malignant cells in a variety of tissue types. METHODS: Tissue was obtained from 76 patients undergoing hysterectomy, 36 had endometrial cancer. Slivers of endometrial tissue (tumour and tumour-adjacent tissue if present) were dissected and placed in fixative solution. Before analysis, tissues were thinly sliced, washed, mounted on low-E slides and desiccated; 10 IR spectra were obtained per slice by attenuated total reflection Fourier-transform IR (ATR-FTIR) spectroscopy. Derived data was subjected to principal component analysis followed by linear discriminant analysis. Post-spectroscopy analyses, tissue sections were haematoxylin and eosin-stained to provide histological verification. RESULTS: Using this approach, it is possible to distinguish benign from malignant endometrial tissue, and various subtypes of both. Cluster vector plots of benign (verified post-spectroscopy to be free of identifiable pathology) vs malignant tissue indicate the importance of the lipid and secondary protein structure (Amide I and Amide II) regions of the spectrum. CONCLUSION: These findings point towards the possibility of a simple objective test for endometrial cancer using ATR-FTIR spectroscopy. This would facilitate earlier diagnosis and so reduce the morbidity and mortality associated with this disease.

The association of an HPV16 oncogene variant with HLA-B7 has implications for vaccine design in cervical cancer.

HLA-restricted cytotoxic T-lymphocyte (CTL) recognition of human papillomavirus (HPV) oncogene products may be important in the control of the HPV infections associated with the development of cervical cancer. We have identified, in HLA-B7 individuals, a consistent variation in the HPV16 E6 oncoprotein sequence, which alters an HLA-B7 peptide binding epitope in a way likely to influence immune recognition by CTLs. These results illustrate a biologically relevant mechanism for escape from immune surveillance of HPV16 in HLA-B7 individuals. Thus, both HLA type and HPV16 strain variation need to be considered in the screening of at-risk individuals and for the rational design of anti-HPV vaccines.

Loss of transporter protein, encoded by the TAP-1 gene, is highly correlated with loss of HLA expression in cervical carcinomas.

Malignant tumor cells can escape CD8+ cytotoxic T cell killing by downregulating class I major histocompatibility complex (MHC) expression. Stable class I MHC surface expression requires loading of the heavy chain/light chain dimer with antigenic peptide, which is delivered to class I MHC molecules in the endoplasmic reticulum by the presumed peptide transporter, encoded by the transporter associated with antigen presentation (TAP) 1 and 2 genes. We have investigated whether loss of class I MHC expression frequently observed in different cancers could result from interference with TAP function. A polyclonal antiserum, raised against a bacterial glutathione S-transferase/human TAP-1 fusion protein, was used for the immunohistochemical analysis of TAP-1 expression in 76 cervical carcinomas. Results showed loss of TAP-1 expression in neoplastic cells in 37 out of 76 carcinomas. Immunohistochemical double staining procedures in combination with HLA-specific antibodies revealed congruent loss at the single cell level of TAP-1 and HLA-A/B expression in 28 out of 37 carcinomas. The remaining samples expressed HLA(-A) in the absence of TAP-1 (n = 6) or showed loss of HLA(-A/B) while TAP-1 was expressed (n = 3). These data strongly indicate that inhibition of peptide transport by downregulation of TAP-1 is a potential strategy of malignant cells to evade immune surveillance.

A randomised controlled trial comparing two different local anaesthetic injection techniques prior to LLETZ.

The aim of this study was to compare two different anaesthetic injection techniques and assess whether one was less painful than the other when used prior to LLETZ. A total of 60 women undergoing LLETZ were randomised into two groups. The control group received local anaesthesia by deep injection into the substance of the cervix. The study group received an equivalent amount of local anaesthetic but this was injected superficially prior to deep injection into the cervix. Pain was assessed using a visual analogue scale. Women in the study arm experienced less pain than controls during injection of local anaesthetic.

Suppression of tumor-derived Semaphorin 7A and genetic ablation of host-derived Semaphorin 7A impairs tumor progression in a murine model of advanced breast carcinoma.

Solid tumors can generate a plethora of neurogenesis-related molecules that enhance their growth and metastasis. Among them, we have identified axonal guidance molecule Semaphorin 7A (SEMA7A) in breast cancer. The goal of this study was to determine the therapeutic effect of suppressing SEMA7A levels in the 4T1 murine model of advanced breast carcinoma. We used anti-SEMA7A short hairpin RNA (shRNA) to gene silence SEMA7A in 4T1 mammary tumor cells. When implanted into the mammary fat pads of syngeneic mice, SEMA7A shRNA-expressing 4T1 tumors exhibited decreased growth rates, deferred metastasis and reduced mortality. In vitro, SEMA7A shRNA-expressing 4T1 cells had weakened proliferative, migratory and invasive abilities, and decreased levels of mesenchymal factors. Atomic force microscopy studies showed that SEMA7A shRNA-expressing 4T1 cells had an increase in cell stiffness that corresponded with their decreased malignant potential. Genetic ablation of host-derived SEMA7A further enhanced the antitumor effects of SEMA7A shRNA gene silencing in 4T1 cells. Our preclinical findings demonstrate a critical role for SEMA7A in mediating mammary tumor progression.

Indels and imperfect duplication have driven the evolution of human Complement Receptor 1 (CR1) and CR1-like from their precursor CR1 alpha: importance of functional sets.

This study examines the effects of duplication and insertions-deletions (indels) by comparing human complement receptor 1 (CR1) and human CR1-like (CR1L) with syntenic genes from four other vertebrates (chimpanzee, baboon, rat, and mouse). By phylogenetic analysis, the domains of these genes can be classified into 10 distinct subfamilies (a, b, c, d, e, f, g(-like), h, j, and k), which have been largely conserved throughout vertebrate and invertebrate evolution. In spite of many complex and diverse duplications and indels, the subfamily order of domains (a, j, e, f, b, k, d, g(-like)) has been maintained. The number of domain sets has increased progressively, thereby expanding the functional repertoire.

Maternal thyroid-blocking immunoglobulins in congenital hypothyroidism.

We evaluated 24 mothers whose babies had congenital hypothyroidism (CH) for the presence of immunoglobulins (Igs) that inhibited [125I]bovine TSH binding and blocked TSH-induced growth and function of FRTL-5 cells. Results were compared with those from 2 mothers with known primary myxedema (atrophic thyroiditis) whose babies had transient CH and with normal controls. Only 1 prospectively evaluated CH mother had potent TSH binding inhibitory, growth inhibitory, and function inhibitory IgGs. Further study of this discordant mother's serum indicated that she was hypothyroid, probably due to atrophic thyroiditis. Both mothers with known primary myxedema had blocking IgGs. The thyroid growth-blocking activity was verified by cell count, could be absorbed by and eluted from Staphylococcal protein-A, indicating that it was an IgG, and was not an anti-TSH idiotype. Half-maximal inhibition was similar in the three different assays for thyroid-blocking activity, suggesting that TSH binding inhibitory, growth inhibitory, and function inhibitory IgGs in some patients with primary myxedema may be the same antibody population. There was no correlation with the titer of antimicrosomal antibodies. These data suggest that maternal thyroid-blocking IgGs interacting with the TSH receptor do not play a role in most cases of sporadic CH. Determination of TSH binding inhibitory IgGs, but not antimicrosomal antibodies, is a sensitive screening test for the presence of TSH receptor-blocking antibodies.

Detection of thyrotropin binding inhibitory activity in neonatal blood spots.

Recent studies have suggested that maternal TSH receptor-blocking antibodies might be of primary etiological importance in some cases of transient congenital hypothyroidism (CH). Because these antibodies are extremely potent, we evaluated the feasibility of identifying babies at risk by using readily available newborn blood spots. Blood spots obtained from 84 normal babies (group 1) and from 354 infants whose initial T4 was less than the tenth percentile for the assay and whose TSH was 40 mU/L or more (group 2) were studied without knowledge of the diagnosis. Blood was eluted from spots overnight and evaluated for [125I]TSH binding inhibition (TBI) to solubilized porcine thyroid membranes. Four spots obtained from 3 group 2 babies, but none of those from the group 1 infants, exhibited TBI activity greater than 3 SD above the normal mean (33.9%). Four additional hypothyroxinemic infants whose mothers had Graves' disease were also negative. Subsequent follow-up revealed that all 3 positive babies had transient CH, and all 3 mothers had primary myxedema. Potent TBI activity was confirmed in the serum of all 3 mothers and in the 2 babies in whom it was evaluated at birth. We conclude that newborn blood spots can be used to detect potent maternal TBI activity, and that this identifies a baby likely to have transient, rather than permanent, CH. Because of their stability and ease of collection and handling, newborn blood spots should offer a convenient tool for future studies aimed at defining in more detail the incidence and clinical characteristics of this unique syndrome.

The optimisation of a novel iodide microassay and its application in an immunoassay for human antibody levels in serum.

Radioactive iodine has been used as an antibody label in many immunoassays. The feasibility of using non-radioactive iodine as a label was investigated. A microassay for iodide based on the Sandell-Kolthoff reaction was optimised. It was used to detect iodine-labelled antibody and successfully applied to the detection of human IgG in serum samples. The performance of this assay system compared with enzyme-linked immunosorbent assay using HRP was evaluated.

Loss of HLA class I expression in prostate cancer: implications for immunotherapy.

OBJECTIVES: There is currently no reliable predictor of the metastatic potential of apparently localized prostate cancer in an individual patient or satisfactory treatment for patients with advanced disease. One of the factors that may influence tumor progression is the cellular arm of the immune response, and central to this is the human leukocyte antigen (HLA) system, which acts to restrict T-cell recognition of potential tumor antigens. It has been reported in some cancers that down regulation of HLA class I expression by the tumor cells is associated with poor prognosis. In this report, HLA class I and II expression have been investigated in both benign and malignant prostate disease, first to define the extent of altered HLA expression and second to assess whether HLA expression may be related to disease progression. METHODS: HLA expression was assessed by immunohistochemistry utilizing a set of monoclonal antibodies that recognize both monomorphic determinants and the commoner HLA class I allelic products. RESULTS: In contrast to the normal HLA class I expression of the benign tissue, complete loss of HLA class I expression occurred in 34% of primary prostate cancers and 80% of lymph node metastases. When individual allelic expression was assessed, the minimum estimate of down regulation was 85% in the primary prostate cancers and 100% of the metastases. CONCLUSIONS: This investigation has demonstrated a higher rate of HLA class I loss than has been reported in other tumors and would suggest that the immune system may have an important role in the progression of prostate cancer, as well as having implications for the design and success of immunotherapy regimens in advanced disease.

Cultured fetal tectal tissue grafted to the midbrain of newborn rats: morphology of grafts and innervation by host retinal and cortical axons.

It has been shown previously that tectal tissue obtained from young embryos can be successfully transplanted to the neonatal rat brain. In the present study, tecta from E15 rat embryos were maintained as free-floating explants for 3-14 days in vitro (DIV) before being transplanted to the midbrain of newborn rats. We wished to determine how explant culture affected (i) graft survival, (ii) the subsequent morphological and histochemical development of tectal grafts and (iii) the specificity with which host retinal and cortical axons grew into and innervated the graft neuropil. Grafts were examined 6-40 weeks posttransplantation. Host retinal input was assessed by injecting the host eyes with either [3H]proline, horseradish peroxidase (HRP) or wheat-germ agglutinin conjugated HRP. The host cortical projection was examined using anterograde degeneration techniques. Frozen tissue sections were also stained for Nissl, neurofibrils or reacted for acetylcholinesterase (AChE). All 3 DIV and 7 DIV explants survived transplantation and many grew considerably in size within the host brain. 14 DIV grafts were smaller and were found in only 50% of host brains. The cellular organization, fibre architecture and pattern of AChE staining in cultured grafts was similar to that found in non-cultured tectal transplants. Furthermore, host retina and cortex projected into the grafts in a manner similar to their innervation of non-cultured tectal tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Thyroid growth immunoglobulins in feline hyperthyroidism.

Feline hyperthyroidism bears a strong clinical and pathologic resemblance to toxic nodular goiter in humans. To evaluate whether the observed thyroid growth might be due to circulating thyroid antibodies, as has been postulated in humans, we studied the effect of purified immunoglobulin (Ig) G preparations on a rat thyroid follicular (FRTL-5) cell line. When compared with control, hyperthyroid cat IgG caused significantly increased [3H]-thymidine (Tdr) incorporation into DNA (p less than 0.02) and stimulated cellular proliferation 15-fold. Stimulation of 3H-Tdr incorporation tended to be biphasic and could be inhibited completely by a potent, specific TSH receptor blocking antibody. Hyperthyroid cat IgG also significantly inhibited 125I-bTSH binding to porcine thyroid membranes, an effect that could be reproduced using electrophoretically pure IgG and normal cat thyroid membranes. Unlike its effect on growth, hyperthyroid cat IgG did not stimulate intracellular cAMP, and there was no correlation between thyroid function in vivo and IgG growth-promoting activity in vitro. These data suggest that elevated titers of thyroid growth IgGs, probably acting through the TSH receptor, are present in feline hyperthyroidism and may play a role in goiter formation. Unlike growth, the thyroid hyperfunction observed is not IgG dependent. Further study of feline hyperthyroidism may contribute important insights into human nodular goiter and into the mediation of thyroid growth in general.

Personality correlates of homophobia.

This study explored the relationship between homophobia and several personality traits (empathy, religiosity, and coping style) in the context of respondents' gender and age. The sample consisted of 714 college students who responded to the Homophobia Attitude Scale (HAS) and personality trait scales. Results revealed that women endorsed fewer homophobic attitudes, beliefs, and behaviors than men and that age was negatively correlated with homophobia. Empathic concern and perspective taking were significantly correlated with lower overall homophobic attitudes, less affect discomfort in regard to gays, and less likelihood to abridge the human rights of gays. Religiosity was significantly correlated with more biased beliefs about the origins of homophobia, greater affective discomfort around gays, less endorsement of human rights for gays, and greater homophobia. Use of denial and isolation as coping styles were positively related to homophobia and use of turning against style was negatively correlated.