Surviving glioblastoma and a sense of disconnection.

Given the poor prognosis of glioblastoma, little focus has been placed on the needs of long-term survivors (those alive at least two years following diagnosis). The aim of this project was to explore the lived experience of long-term survivors of glioblastoma using a qualitative approach. Long-term survivors of glioblastoma diagnosed between 1/1/2006-31/12/2016 were identified at the tertiary centre involved. Participants underwent a semi-structured qualitative interview and caregiver dyads were collected if available. Thematic analysis was undertaken where themes were gradually generated from the data alongside data collection and confirmed or contrasted as data collection proceeded. Participants were selected and interviewed until data saturation was reached at 10 interviews. The overarching theme explaining the data was a sense of disconnection, beginning with the shock of diagnosis, and evolving over time, leading survivors to feel disconnected from (1) 'who I was', redefining their work, independence and social self; (2) 'who I am', contributing to social isolation, disavowal, and anxiety and depression; and (3) 'who I could be', reassessing their future. This unique study highlights the acute emotional distress and disconnection that begins with diagnosis and its evolving impact on the lived experience. Clinicians need to consider the emotional impact of survival when managing these patients and adopt a holistic approach, including the early introduction of psychosocial support to patients and their caregivers. Further validation of these findings in a larger cohort is desirable.

Impact of type 2 diabetes on hospitalization and mortality in people with malignancy.

AIM: To compare the characteristics of and outcomes for people with malignancies with and without a co-diagnosis of diabetes. METHODS: Emergency department and hospital discharge data from a single centre for the period between 1 January 2015 and 31 December 2017 were used to identify people with a diagnosis of a malignancy and diabetes. Multivariate Cox regression models were used to estimate the effect of diabetes on all-cause mortality. A truncated negative binomial regression model was used to assess the impact of diabetes on length of hospital inpatient stay. Prentice-Williams-Peterson total time models were used to assess the effect of diabetes on number of emergency department re-presentations and inpatient re-admissions. RESULTS: Of 7004 people identified with malignancies, 1195 (17.1%) were also diagnosed with diabetes. A diagnosis of diabetes was associated with a greater number of inpatient re-admissions [adjusted hazard ratio 1.13 (95% CI 1.03, 1.24)], a greater number of emergency department re-presentations [adjusted hazard ratio 1.13 (95% CI 1.05, 1.22)] and longer length of stay [adjusted incidence rate ratio 1.14 (95% CI 1.04, 1.25)]. A co-diagnosis of diabetes was also associated with a 48% increased risk of all-cause mortality [adjusted hazard ratio 1.48 (95% CI 1.22-1.76)]. CONCLUSIONS: People with malignancies and diabetes had significantly more emergency department presentations, more inpatient admissions, longer length of hospital stay and higher rates of all-cause mortality compared to people with a malignancy without diabetes.

Molecular profile of long-term survivors of glioblastoma: A scoping review of the literature.

Molecular aberrations of malignancy are becoming widely recognized as important predictive and prognostic markers for treatment response and survival in oncology and have been linked to the discovery of novel treatment targets. This area of research in glioblastoma continues to evolve. The aim of this scoping review was to document the hallmark molecular characteristics of long-term survivors of glioblastoma. MEDLINE, Scopus and EMBASE were searched with core concepts: (1) glioblastoma, (2) long-term survivor and (3) molecular OR mutation. A thematic analysis was undertaken of the 18 included studies. Four main classes of characteristics were obtained: IDH mutation, MGMT methylation, other known characteristics and novel discoveries. While MGMT methylation or the combination with IDH mutation are suggested to be hallmark characteristics, there remains enough uncertainty to suggest further factors may be involved, such as CD34 expression. Further research is required to accurately describe hallmark molecular characteristics of long-term survivors to assist in defining these patients at diagnosis, preventing treatment complications and discovering novel treatments.

Ferritin levels throughout childhood and metabolic syndrome in adolescent stage.

BACKGROUND AND AIM: Increased ferritin levels have been widely associated with cardiovascular risk in adults. Whether ferritin levels and their changes during childhood are related to metabolic syndrome (MetS) at adolescence is unknown. We aimed to evaluate these associations using levels of ferritin at 5, 10 and 16 years and their linear increases and patterns of sustained increased levels across childhood. METHODS AND RESULTS: There were four samples evaluated according to non-missing values for study variables at each stage (5 years: 562; 10 years: 381; and 16 years: 567 children; non-missing values at any stage: 379). MetS risk was evaluated as a continuous Z score. Patterns of sustained increased ferritin (highest tertile) and slope of the change of ferritin per year across the follow-up were calculated. Ferritin levels in the highest versus lowest tertile at five and 16 years were significantly positively associated with MetS risk Z score at adolescence in boys and these associations were unaffected by adjustment for covariates. Having high, compared to low/moderate ferritin level at 2 or more time periods between 5 and 16 years was related to higher Mets Z-score in boys only [e.g. 5-10 years adjusted-beta (95 %CI):0.26 (0.05-0.48),P < 0.05]. In girls, ferritin Z score at 10 and 16 years was positively and independently associated with HOMA-IR Z score. In girls, the slope of ferritin per year in the highest tertile was positively associated with MetS risk Z-score [adjusted-beta (95 %CI):0.21 (0.05-0.38),P < 0.05]. CONCLUSIONS: Ferritin levels throughout childhood are positively related to cardiometabolic risk in adolescence, with associations varying by sex.

To reflect human autoimmune thyroiditis, thyroid peroxidase (not thyroglobulin) antibodies should be measured in female (not sex-independent) NOD.H2h4 mice.

NOD.H2h4 mice are the most commonly used model for human autoimmune thyroiditis. Because thyroid autoimmunity develops slowly (over months), NOD.H2h4 mice are usually exposed to excess dietary iodide to accelerate and amplify the process. However, unlike the female bias in human thyroid autoimmunity, autoantibodies to thyroglobulin (TgAb) are reported to be similar in male and female NOD.H2h4 . We sought evidence for sexual dimorphism in other parameters in this strain maintained on regular or iodized water. Without iodide, TgAb levels are higher in males than in females, the reverse of human disease. In humans, autoantibodies to thyroid peroxidase (TPOAb) are a better marker of disease than TgAb. In NOD.H2h4 mice TPOAb develop more slowly than TgAb, being detectable at 6 months of age versus 4 months for the latter. Remarkably, unlike TgAb, TPOAb levels are higher in female than male NOD.H2h4 mice on both regular and iodized water. As previously observed, serum T4 levels are similar in both sexes. However, thyroid-stimulating hormone (TSH) levels are significantly higher in males than females with or without iodide exposure. TSH levels correlate with TgAb levels in male NOD.H2h4 mice, suggesting a possible role for TSH in TgAb development. However, there is no correlation between TSH and TPOAb levels, the latter more important than TgAb in human disease. In conclusion, if the goal of an animal model is to closely reflect human disease, TPOAb rather than TgAb should be measured in older female NOD.H2h4 mice, an approach requiring patience and the use of mouse TPO protein.

Risk of uterine cancer for BRCA1 and BRCA2 mutation carriers.

BACKGROUND: Whether BRCA1 and BRCA2 mutation carriers have a clinically relevant elevated risk of uterine cancer has implications for risk-reducing surgery. AIM: This multicentre, prospective cohort study assessed uterine cancer risk for mutation carriers compared with the general population. METHODS: Eligible mutation carriers were enrolled in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) cohort study, had a uterus present and no history of uterine cancer at cohort entry. Epidemiological, lifestyle and clinical data were collected at cohort entry and updated three-yearly. Cancer events were verified using pathology reports. Follow-up was censored at death or last contact. Relative risk of uterine cancer was estimated using the standardised incidence ratio (SIR), with the expected number of cases determined using population-based data for Australia. RESULTS: Of 1,111 mutation carriers in kConFab, 283 were excluded due to prior hysterectomy (N = 278), prior uterine cancer (N = 2) or being non-residents (N = 3). After a median follow-up of 9.0 years, five incident uterine cancers were reported in the 828 eligible women (419 had prior breast cancer and 160 had prior tamoxifen use), compared to 2.04 expected (SIR = 2.45; 95% confidence interval [CI]: 0.80-5.72; P = 0.11). In 438 BRCA1 mutation carriers and 390 BRCA2 mutation carriers, three and two incident cases of uterine cancer were reported, respectively, compared to 1.04 expected (SIR = 2.87; 95% CI: 0.59-8.43; P = 0.18) and 0.99 expected (SIR = 2.01; 95% CI: 0.24-7.30; P = 0.52), respectively. All cases were endometrioid subtype, International Federation of Gynaecology and Obstetrics stage I-II disease. No serous uterine cancers were reported. CONCLUSIONS: Our findings are consistent with those from most other reports and do not support routine risk-reducing hysterectomy for BRCA1 and BRCA2 mutation carriers.

Improved quality of risk-reducing salpingo-oophorectomy in Australasian women at high risk of pelvic serous cancer.

OBJECTIVES: The quality of risk-reducing salpingo-oophorectomy (RRSO) performed in Australasian women was previously reported to be suboptimal. Here we describe the quality of RRSO performed since 2008 in women enrolled in the same cohort and determine whether it has improved. DESIGN: Prospective cohort study of women at high risk of pelvic serous cancer (PSC) in kConFab. Eligible women had RRSO between 2008 and 2014 and their RRSO surgical and pathology reports were reviewed. "Adequate" surgery and pathology were defined as complete removal and paraffin embedding of all ovarian and extra-uterine fallopian tube tissue, respectively. Associations between clinical factors and "adequate" pathology were assessed using logistic regression. Data were compared with published cohort data on RRSO performed prior to 2008 using Chi square test. RESULTS: Of 164 contemporary RRSOs performed in 78 centres, 158/159 (99%) had "adequate" surgery and 108/164 (66%) had "adequate" pathology. Surgery performed by a gynaecologic oncologist rather than a general gynaecologist [OR 8.2, 95%CI (3.6-20.4), p < 0.001], surgery without concurrent hysterectomy [OR 2.5, 95%CI (1.1-6.0), p = 0.03], more recent year of surgery [OR 1.4, 95%CI (1.1-1.8), p = 0.02], and clinical notation that indicated high risk [OR 19.4, 95%CI (3.1-385), p = 0.008] were independently associated with "adequate" pathology. Both surgery and pathology were significantly more likely to be "adequate" (p < 0.001) in this contemporary sample. CONCLUSION: The quality of RRSOs has significantly improved since our last report. Surgery by a gynaecologic oncologist who informs the pathologist that the woman is at high risk for PSC is associated with optimal RRSO pathology.

Life beyond a diagnosis of glioblastoma: a systematic review of the literature.

BACKGROUND: The median survival of glioblastoma is 12-14 months with less than 10% of patients surviving at least 2 years from diagnosis. Patients diagnosed with glioblastoma face poor prognosis, significant symptom burden, and high care needs. The aim of this study is to undertake a literature review to document the issues encountered by long-term survivors of glioblastoma, a small but important subset of patients. METHODS: MEDLINE, PsychInfo, and EMBASE were searched with core concepts: (1) glioblastoma, (2) survivor, and (3) terms pertaining to survivorship issues. A thematic analysis was undertaken of the three included studies. RESULTS: Long-term survivors of glioblastoma encounter neurologic deficits, impairment in cognition, psychological distress, reduced social function, and future uncertainty. These issues result in the inability to return to work and financial difficulties. Independence in activities of daily living, working memory, and overall quality of life appears to be preserved. CONCLUSIONS: Long-term survivors of glioblastoma continue to have significant symptom burden and care needs. There is currently a paucity of literature surrounding this topic. Further research is required to accurately describe these issues in order for improved supportive care to be implemented in the community and the outpatient setting. IMPLICATIONS FOR CANCER SURVIVORS: Understanding the issues faced by long-term survivor of glioblastoma will provide insight into the care needs of patients as well as support networks required for patients and their carers.

High-level intrathymic thyrotrophin receptor expression in thyroiditis-prone mice protects against the spontaneous generation of pathogenic thyrotrophin receptor autoantibodies.

The thyrotrophin receptor (TSHR) A-subunit is the autoantigen targeted by pathogenic autoantibodies that cause Graves' hyperthyroidism, a common autoimmune disease in humans. Previously, we reported that pathogenic TSHR antibodies develop spontaneously in thyroiditis-susceptible non-obese diabetic (NOD).H2h4 mice bearing a human TSHR A-subunit transgene, which is expressed at low levels in both the thyroid and thymus (Lo-expressor transgene). The present study tested recent evidence that high intrathymic TSHR expression protects against the development of pathogenic TSHR antibodies in humans. By successive back-crossing, we transferred to the NOD.H2h4 background a human TSHR A-subunit transgene expressed at high levels in the thyroid and thymus (Hi-expressor transgene). In the sixth back-cross generation (> 98% NOD.H2h4 genome), only transgenic offspring produced spontaneously immunoglobulin (Ig)G class non-pathogenic human TSHR A-subunit antibodies. In contrast, both transgenic and non-transgenic offspring developed antibodies to thyroglobulin and thyroid peroxidase. However, non-pathogenic human TSHR antibody levels in Hi-expressor offspring were lower than in Lo-expressor transgenic mice. Moreover, pathogenic TSHR antibodies, detected by inhibition of TSH binding to the TSHR, only developed in back-cross offspring bearing the Lo-expressor, but not the Hi-expressor, transgene. High versus low expression human TSHR A-subunit in the NOD.H2h4 thymus was not explained by the transgene locations, namely chromosome 2 (127-147 Mb; Hi-expressor) and chromosome 1 (22.9-39.3 Mb; low expressor). Nevertheless, using thyroiditis-prone NOD.H2h4 mice and two transgenic lines, our data support the association from human studies that low intrathymic TSHR expression is associated with susceptibility to developing pathogenic TSHR antibodies, while high intrathymic TSHR expression is protective.

TACTIC: a multicentre, open-label, single-arm phase II trial of panitumumab, cisplatin, and gemcitabine in biliary tract cancer.

PURPOSE: The phase II TACTIC trial prospectively selected patients with KRAS wild-type advanced biliary tract cancer for first-line treatment with panitumumab and combination chemotherapy. METHODS: Of 78 patients screened, 85 % had KRAS wild-type tumours and 48 were enrolled. Participants received cisplatin 25 mg/m(2) and gemcitabine 1000 mg/m(2) on day 1 and day 8 of each 21-day cycle and panitumumab 9 mg/kg on day 1 of each cycle. Treatment was continued until disease progression, unacceptable toxicity, or request to discontinue. The primary endpoint was the clinical benefit rate (CBR) at 12 weeks (complete response, partial response, or stable disease). CBR of 70 % was considered to be of clinical interest. Secondary outcomes were progression-free survival, time to treatment failure, overall survival, CA19.9 response and safety. RESULTS: Thirty-four patients had a clinical benefit at 12 weeks, an actuarial rate of 80 % (95 % CI 65-89 %). 46 % had a complete or partial response. Median progression-free survival was 8.0 months (95 % CI 5.1-9.9) and median overall survival 11.9 months (95 % CI 7.4-15.8). Infection accounted for 27 % of the grade 3 or 4 toxicity, with rash (13 %), fatigue (13 %), and hypomagnesemia (10 %) among the more common grade 3 or 4 non-haematological toxicities. CONCLUSION: A marker-driven approach to patient selection was feasible in advanced biliary tract cancer in an Australian population. The combination of panitumumab, gemcitabine, and cisplatin in KRAS wild-type cancers was generally well tolerated and showed promising clinical efficacy. Further exploration of anti-EGFR therapy in a more selected population is warranted.

Associations between the IASLC/ATS/ERS lung adenocarcinoma classification and EGFR and KRAS mutations.

We sought to investigate the frequency of mutations in epidermal growth factor receptor (EGFR) and Kirsten-RAS (KRAS) by each pathological subtype for patients with resected pulmonary adenocarcinoma as defined by the IASLC/ATS/ERS classification. Histological examination determined the predominant subtype according to the IASLC/ATS/ERS classification. EGFR and KRAS mutations were determined by high-resolution melting and Sanger sequencing. Clinical data were collected from medical records and clinicians. The 178 consecutive patients consisted of 48% males, median age 68 years (range 20-87) and smoking history 78%. The tumour stage was I in 62%, II in 18% and III in 20%. The mutation rates were: EGFR 30%; KRAS 28%. The rate of EGFR mutations in the acinar predominant reference group (n=76), was 37%. The solid predominant subtype showed significantly fewer EGFR mutations [3/33 (9%), odds ratio 0.17 (0.05-0.61), p=0.007]. No differences in mutation rate were observed in other subtypes. No association was found between KRAS mutations and predominant histological subtype. Advanced stage and solid predominant subtype were negative prognostic factors. EGFR mutations can be present in adenocarcinoma of any predominant subtype, however rarely in solid predominant tumours. No association was found between KRAS mutation and the predominant histological subtype.

Evidence that MHC I-E dampens thyroid autoantibodies and prevents spreading to a second thyroid autoantigen in I-A(k) NOD mice.

NOD.H2(k) and NOD.H2(h4) mice carry the major histocompatibility complex (MHC) class II molecule I-A(k) associated with susceptibility to experimentally induced thyroiditis. Dietary iodine-enhanced spontaneous thyroid autoimmunity, well known in NOD.H2(h4) mice, has not been investigated in NOD.H2(k) mice. We compared NOD.H2(h4) and NOD.H2(k) strains for thyroiditis and autoantibodies to thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) without or with dietary sodium iodide (NaI) for up to 32 weeks. TgAb levels were significantly higher in NOD.H2(h4) compared with NOD.H2(k) mice on NaI, and TPOAb developed in NOD.H2(h4) mice but not in NOD.H2(k) mice. DNA exome analysis revealed, in addition to the differences in the chromosome (Chr) 17 MHC regions, that NOD.H2(k) mice, and particularly NOD.H2(h4) mice, have substantial non-MHC parental DNA. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis highlighted thyroid autoimmunity and immune-response genes on Chr 17 but not on Chr 7, and 15 parental B10.A4R DNA. Studies of parental strains provided no evidence for non-MHC gene contributions. The exon 10 Tg haplotype, associated with experimentally induced thyroiditis, is absent in NOD.H2(h4) and NOD.H2(k) mice and is not a marker for spontaneous murine thyroid autoimmunity. In conclusion, the absence of I-E is a likely explanation for the difference between NOD.H2(h4) and NOD.H2(k) mice in TgAb levels and, as in humans, autoantibody spreading to TPO.

Hepatic steatosis and non-alcoholic fatty liver disease are not associated with decline in renal function in people with Type 2 diabetes.

AIMS: We aimed to determine whether the presence of hepatic steatosis and/or non-alcoholic fatty liver disease was associated with decline in renal function or onset of microalbuminuria in a cohort of people with Type 2 diabetes, including those managed in both primary and secondary care. METHODS: Nine hundred and thirty-three patients from the Edinburgh Type 2 Diabetes Study, a cohort of Scottish men and women aged 60-74 years with Type 2 diabetes, underwent assessment for hepatic steatosis by liver ultrasonography 1 year after recruitment. Non-alcoholic fatty liver disease was defined as the presence of steatosis following exclusion of secondary causes of liver disease. Patients were followed for 4 years and decline in renal function was assessed by the change in estimated glomerular filtration rate over time. RESULTS: Of the 933 subjects, 530 had hepatic steatosis and, of those with hepatic steatosis, 388 had non-alcoholic fatty liver disease. Neither hepatic steatosis nor non-alcoholic fatty liver disease were significantly associated with rate of decline in renal function, with the mean rate of decline in estimated glomerular filtration rate being -1.55 ml min(-1) 1.73 m(-2) per year for participants with hepatic steatosis compared with -1.84 ml min(-1) 1.73 m(-2) for those without steatosis (P = 0.19). Similar results were obtained when the analysis was restricted to participants with and without non-alcoholic fatty liver disease (-1.44 vs. -1.64 ml min(-1) 1.73 m(-2) per year, respectively; P = 0.44). Additionally, neither hepatic steatosis nor non-alcoholic fatty liver disease were associated with the onset or regression of albuminuria during follow-up (all P ≥ 0.05). CONCLUSIONS: The presence of hepatic steatosis/non-alcoholic fatty liver disease was not associated with decline in renal function during a 4-year follow-up in our cohort of older people with Type 2 diabetes.

Psychological morbidity and stress but not social factors influence level of fear of cancer recurrence in young women with early breast cancer: results of a cross-sectional study.

BACKGROUND: Fear of cancer recurrence (FCR) is a common problem amongst survivors. Past research has shown that young women with breast cancer are particularly vulnerable to FCR, yet few previous studies have specifically examined FCR in this subgroup. AIMS: The aim of the study is to explore the relationship between FCR, psychological morbidity and social factors. A secondary aim was to explore the relationship between clinical levels of FCR and generalised anxiety disorder (GAD) and hypochondriasis. METHOD: Two hundred eighteen breast cancer survivors (aged 18-45 years at diagnosis) diagnosed at least 1 year prior were recruited through seven metropolitan oncology clinics and two breast cancer consumer groups. Participants completed a web-based questionnaire, which assessed FCR, psychological functioning, generalised anxiety, hypochondriasis and items exploring past cancer-related experiences, attitudes to future childbearing, social support and correlates were identified using linear regression. RESULTS: Psychological morbidity scales measuring anxiety and psychological functioning and stressful life events were significantly associated with FCR in adjusted and unadjusted models (p < 0.0001). Past cancer experiences, children, social support and attitudes to childrearing were not associated with FCR. Among those with clinical levels of FCR (n = 152), 43% met screening criteria for hypochondriasis, and 36% met screening criteria for GAD. CONCLUSIONS: This study shows psychological morbidity is associated with FCR, but the majority of women with high levels of FCR do not also meet the criteria for a clinical level of GAD or hypochondriasis. Understanding the factors that make young women vulnerable to FCR is important to help guide the development of FCR-specific interventions for this subgroup.

Prospective study of breast cancer risk for mutation negative women from BRCA1 or BRCA2 mutation positive families.

Published studies have reached contradictory conclusions regarding breast cancer risk for women from families segregating a BRCA1 or BRCA2 mutation who do not carry the family-specific mutation. Accurate estimation of breast cancer risk is crucial for appropriate counselling regarding risk management. The aim of this study is to prospectively assess whether breast cancer risk for mutation negative women from families segregating BRCA1 or BRCA2 mutations is greater than for women in the general population. Eligible women were 722 first-, second- and third-degree relatives of a BRCA1 or BRCA2 mutation carrier from 224 mutation positive (128 BRCA1, 96 BRCA2) families, had no personal cancer history at baseline, and had been tested and found not to carry the family-specific mutation. Self-reported family history of cancer, preventive interventions and verified cancer diagnoses were collected at baseline, and every 3 years thereafter. Median follow-up was 6.1 years (range 0.1-12.4 years). Time at risk of breast cancer was censored at cancer diagnosis or risk-reducing surgery. Standardised incidence ratios (SIR) were estimated by comparing observed to population incidences of invasive breast cancer using Australian Cancer Incidence and Mortality Books. Six cases of invasive breast cancer were observed. The estimated SIRs were 1.14 (95% CI: 0.51-2.53) overall (n = 722), 1.29 (95% CI: 0.58-2.88) when restricted to first- and second-degree relatives of an affected mutation carrier (n = 442) and 0.48 (95% CI: 0.12-1.93) when restricted to those with no family history of breast cancer in the non-mutation carrying parental lineage (n = 424). There was no evidence that mutation negative women from families segregating BRCA1 or BRCA2 mutations are at increased risk of breast cancer. Despite this being the largest prospective cohort to assess this issue, moderately increased breast cancer risk (2-fold) cannot be ruled out.

Adequacy of risk-reducing gynaecologic surgery in BRCA1 or BRCA2 mutation carriers and other women at high risk of pelvic serous cancer.

The aim of this study was to describe the type of risk-reducing gynaecologic surgery (RRGS) and the extent of pathological evaluation being undertaken for Australasian women at high familial risk of pelvic serous cancer. Surgical and pathology reports were reviewed for women with BRCA1/BRCA2 mutations, or a family history of breast and ovarian cancer, who underwent RRGS between 1998 and 2008. "Adequate" surgery was defined as complete removal of all ovarian and extra-uterine fallopian tube tissue. "Adequate" pathology was defined as paraffin embedding of all removed ovarian and tubal tissue. Predictors of adequacy were assessed using logistic regression. There were 201 women, including 173 mutation carriers, who underwent RRGS. Of these, 91% had adequate surgery and 23% had adequate pathology. Independent predictors of adequate surgery were surgeon type (OR = 20; 95% CI 2-167; P = 0.005 for gynaecologic oncologists versus general gynaecologists), more recent surgery (OR = 1.33/year; 95% CI 1.07-1.67; P = 0.012) and younger patient age (OR = 0.93/year of age; 95% CI 0.87-0.99; P = 0.028). Independent predictors of adequate pathology were more recent surgery (OR = 1.26/year; 95% CI 1.06-1.49; P = 0.008) and surgeon type (OR = 3.1; 95% CI 1.4-6.7; P = 0.004 for gynaecologic oncologists versus general gynaecologists). Four serous ovarian cancers and one endometrioid endometrial cancer were detected during surgery or pathological examination. In conclusion Australasian women attending a specialist gynaecologic oncologist for RRGS are most likely to have adequate surgery and pathological examination. Additional education of clinicians and consumers is needed to ensure optimal surgery and pathology in these women.

Immunoglobulin heavy chain variable region genes contribute to the induction of thyroid-stimulating antibodies in recombinant inbred mice.

Graves' hyperthyroidism is an autoimmune disease occurring spontaneously in humans and caused by autoantibodies that stimulate the thyrotropin receptor. In mice, inducing Graves'-like hyperthyroidism requires in vivo expression of the thyrotropin receptor using plasmid or adenovirus vectors. However, mice with different genetic backgrounds vary markedly in their susceptibility to induced hyperthyroidism. Further, in some strains major disparities exist between the induction of hyperthyroidism and detection of thyroid-stimulating antibodies. To break tolerance, virtually all Graves' mouse models involve immunization with human thyrotropin-receptor DNA and the standard thyroid-stimulating antibody bioassay uses cells expressing the human thyrotropin receptor. We hypothesized, and now report, that disparities between hyperthyroidism and thyroid-stimulating antibody bioactivity are explained, at least in part, by differential antibody recognition of the human vs the mouse thyrotropin receptor. The genetic basis for these species differences was explored using genotyped, recombinant-inbred mouse strains. We report that loci in the immunoglobulin heavy chain variable region as well as in the major histocompatibility complex region contribute in a strain-specific manner to the development of antibodies specific for the human or the mouse thyrotropin receptor. The novel finding of a role for immunoglobulin heavy chain variable region gene involvement in thyroid-stimulating antibody epitopic specificity provides potential insight into genetic susceptibility in human Graves' disease.

Assessing the unmet supportive care needs of newly diagnosed patients with cancer.

Adequate monitoring in cancer control needs to include measures of psychosocial outcomes so as to take account of the totality of the felt cancer experience. There is a need to know whether the experience of cancer is changing, as well as a need for tools to identify where supportive care interventions or services could be targeted to good effect. The aim of this study was to investigate the utility of using a telephone-administered survey to identify the unmet needs of cancer patients. Participants were identified from a statewide population-based cancer registry following an episode of hospitalized care in Victoria (Australia). Of the 506 eligible patients, 236 completed a telephone adaptation of the Supportive Care Needs Survey-Short Form (SCNS-SF31). Sampling from the cancer registry was shown to provide timely contact with patients. Results from the survey indicated that perceived needs for this newly diagnosed group of cancer patients were mostly in the area of information provision. Results also showed that some socio-demographic and disease-specific variables affected the level of perceived unmet needs. Overall, this study indicated that registry-based sampling was practical and the telephone adaptation of the SCNS-SF31 provided a reliable method to explore the unmet needs of newly diagnosed patients with cancer.

Predictors of the use of complementary and alternative medicine (CAM) by women at high risk for breast cancer.

BACKGROUND: Few data exist regarding the use of complementary and alternative medicine (CAM) by unaffected women at high risk of breast cancer. METHODS: Self-reported CAM use by women from multiple-case breast cancer families was obtained by questionnaire. Factors associated with CAM use were assessed using multiple logistic regression. RESULTS: Of 892 women, 55% (n=489) used CAM, 6% (n=53) specifically to prevent cancer. CAM use was independently associated with tertiary education level (OR 2.56, 95% CI 1.83-3.58, p<0.001), greater physical activity (OR 1.05 per hour of physical activity/week, 95% CI 1.00-1.10, p=0.049), greater anxiety (OR 1.92, 95% CI 1.16-3.16, p=0.01), not currently smoking (OR 0.64, 95% CI 0.42-0.97, p=0.037) and lower perceived BC risk (OR 0.82 per 20 percentage points, 95% CI 0.72-0.94, p=0.005). CONCLUSIONS: The majority of high-risk women use CAM, but mostly for reasons other than cancer prevention. Most predictors of CAM use are consistent with the limited literature for women at high risk for cancer.

Role of the transgenic human thyrotropin receptor A-subunit in thyroiditis induced by A-subunit immunization and regulatory T cell depletion.

Transgenic BALB/c mice that express intrathyroidal human thyroid stimulating hormone receptor (TSHR) A-subunit, unlike wild-type (WT) littermates, develop thyroid lymphocytic infiltration and spreading to other thyroid autoantigens after T regulatory cell (T(reg)) depletion and immunization with human thyrotropin receptor (hTSHR) adenovirus. To determine if this process involves intramolecular epitope spreading, we studied antibody and T cell recognition of TSHR ectodomain peptides (A-Z). In transgenic and WT mice, regardless of T(reg) depletion, TSHR antibodies bound predominantly to N-terminal peptide A and much less to a few downstream peptides. After T(reg) depletion, splenocytes from WT mice responded to peptides C, D and J (all in the A-subunit), but transgenic splenocytes recognized only peptide D. Because CD4(+) T cells are critical for thyroid lymphocytic infiltration, amino acid sequences of these peptides were examined for in silico binding to BALB/c major histocompatibility complex class II (IA-d). High affinity subsequences (inhibitory concentration of 50% < 50 nm) are present in peptides C and D (not J) of the hTSHR and mouse TSHR equivalents. These data probably explain why transgenic splenocytes do not recognize peptide J. Mouse TSHR mRNA levels are comparable in transgenic and WT thyroids, but only transgenics have human A-subunit mRNA. Transgenic mice can present mouse TSHR and human A-subunit-derived peptides. However, WT mice can present only mouse TSHR, and two to four amino acid species differences may preclude recognition by CD4+ T cells activated by hTSHR-adenovirus. Overall, thyroid lymphocytic infiltration in the transgenic mice is unrelated to epitopic spreading but involves human A-subunit peptides for recognition by T cells activated using the hTSHR.