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Molecular subtyping of breast cancer is based mostly on HR/HER2 and gene expression-based immune, DNA repair deficiency, and luminal signatures. We extend this description via functional protein pathway activation mapping using pre-treatment, quantitative expression data from 139 proteins/phosphoproteins from 736 patients across 8 treatment arms of the I-SPY 2 Trial (ClinicalTrials.gov: NCT01042379). We identify predictive fit-for-purpose, mechanism-of-action-based signatures and individual predictive protein biomarker candidates by evaluating associations with pathologic complete response. Elevated levels of cyclin D1, estrogen receptor alpha, and androgen receptor S650 associate with non-response and are biomarkers for global resistance. We uncover protein/phosphoprotein-based signatures that can be utilized both for molecularly rationalized therapeutic selection and for response prediction. We introduce a dichotomous HER2 activation response predictive signature for stratifying triple-negative breast cancer patients to either HER2 or immune checkpoint therapy response as a model for how protein activation signatures provide a different lens to view the molecular landscape of breast cancer and synergize with transcriptomic-defined signatures.

BackgroundThe COVID-19 pandemic profoundly impacted the delivery of care and timing of elective surgical procedures. Most endocrine-related operations were considered elective and safe to postpone, providing a unique opportunity to assess clinical outcomes under protracted treatment plans.MethodsAmerican Association of Endocrine Surgeon members were surveyed for participation. A Research Electronic Data Capture survey was developed and distributed to 27 institutions to assess the impact of COVID-19-related delays. The information collected included patient demographics, primary diagnosis, resumption of care, and assessment of disease progression by the surgeon.ResultsTwelve out of 27 institutions completed the survey (44.4%). Of 850 patients, 74.8% (636) were female; median age was 56 (interquartile range, 44-66) years. Forty percent (34) of patients had not been seen since their original surgical appointment was delayed; 86.2% (733) of patients had a delay in care with women more likely to have a delay (87.6% vs 82.2% of men, χ2 = 3.84, P = .05). Median duration of delay was 70 (interquartile range, 42-118) days. Among patients with a delay in care, primary disease site included thyroid (54.2%), parathyroid (37.2%), adrenal (6.5%), and pancreatic/gastrointestinal neuroendocrine tumors (1.3%). In addition, 4.0% (26) of patients experienced disease progression and 4.1% (24) had a change from the initial operative plan. The duration of delay was not associated with disease progression (P = .96) or a change in operative plan (P = .66).ConclusionAlthough some patients experienced disease progression during COVID-19 delays to endocrine disease-related care, most patients with follow-up did not. Our analysis indicated that temporary delay may be an acceptable course of action in extreme circumstances for most endocrine-related surgical disease.

Ductal carcinoma in situ (DCIS) is a biologically heterogenous entity with uncertain risk for invasive ductal carcinoma (IDC) development. Standard treatment is surgical resection often followed by radiation. New approaches are needed to reduce overtreatment. This was an observational study that enrolled patients with DCIS who chose not to pursue surgical resection from 2002 to 2019 at a single academic medical center. All patients underwent breast MRI exams at 3- to 6-month intervals. Patients with hormone receptor-positive disease received endocrine therapy. Surgical resection was strongly recommended if clinical or radiographic evidence of disease progression developed. A recursive partitioning (R-PART) algorithm incorporating breast MRI features and endocrine responsiveness was used retrospectively to stratify risk of IDC. A total of 71 patients were enrolled, 2 with bilateral DCIS (73 lesions). A total of 34 (46.6%) were premenopausal, 68 (93.2%) were hormone-receptor positive, and 60 (82.1%) were intermediate- or high-grade lesions. Mean follow-up time was 8.5 years. Over half (52.1%) remained on active surveillance without evidence of IDC with mean duration of 7.4 years. Twenty patients developed IDC, of which 6 were HER2 positive. DCIS and subsequent IDC had highly concordant tumor biology. Risk of IDC was characterized by MRI features after 6 months of endocrine therapy exposure; low-, intermediate-, and high-risk groups were identified with respective IDC rates of 8.7%, 20.0%, and 68.2%. Thus, active surveillance consisting of neoadjuvant endocrine therapy and serial breast MRI may be an effective tool to risk-stratify patients with DCIS and optimally select medical or surgical management.SignificanceA retrospective analysis of 71 patients with DCIS who did not undergo upfront surgery demonstrated that breast MRI features after short-term exposure to endocrine therapy identify those at high (68.2%), intermediate (20.0%), and low risk (8.7%) of IDC. With 7.4 years mean follow-up, 52.1% of patients remain on active surveillance. A period of active surveillance offers the opportunity to risk-stratify DCIS lesions and guide decisions for operative management.

An international randomized phase II trial of Globo H (GH) vaccine, adagloxad simolenin/OBI-821 in 349 patients with metastatic breast cancer showed longer progression-free survival (PFS) in vaccinated patients who developed anti-Globo H (anti-GH) IgG than those who did not and the placebo group. The impacts of anti-GH IgM and GH expression on peak anti-GH IgG and clinical outcome were further evaluated. The titers of anti-GH IgG and IgM were determined by ELISA. GH expression in tumor was examined by immunohistochemical staining. Immunophenotyping was conducted by flow cytometry. Adagloxad simolenin elicited anti-GH IgM which peaked at titers ≥1:80 between weeks 5 and 13. The mean anti-GH IgG titer peaked at week 41 and decreased thereafter on the completion of vaccination. One log increase in peak IgM was associated with 10.6% decrease in the HR of disease progression (HR: 0.894, 95% CI: 0.833 to 0.960, p=0.0019). Patients with anti-GH IgM ≥1:320 within first 4 weeks after vaccination had significantly higher maximum anti-GH IgM (p

ObjectiveCancer patients and survivors may be disproportionately affected by COVID-19. We sought to determine the effects of the pandemic on thyroid cancer survivors' health care interactions and quality of life.MethodsAn anonymous survey including questions about COVID-19 and the Patient-Reported Outcomes Measurement Information System profile (PROMIS-29, version 2.0) was hosted on the Thyroid Cancer Survivors' Association, Inc website. PROMIS scores were compared to previously published data. Factors associated with greater anxiety were evaluated with univariable and multivariable logistic regression.ResultsFrom May 6, 2020, to October 8, 2020, 413 participants consented to take the survey; 378 (92%) met the inclusion criteria: diagnosed with thyroid cancer or noninvasive follicular neoplasm with papillary-like nuclear features, located within the United States, and completed all sections of the survey. The mean age was 53 years, 89% were women, and 74% had papillary thyroid cancer. Most respondents agreed/strongly agreed (83%) that their lives were very different during the COVID-19 pandemic, as were their interactions with doctors (79%). A minority (43%) were satisfied with the information from their doctor regarding COVID-19 changes. Compared to pre-COVID-19, PROMIS scores were higher for anxiety (57.8 vs 56.5; P < .05) and lower for the ability to participate in social activities (46.2 vs 48.1; P < .01), fatigue (55.8 vs 57.9; P < .01), and sleep disturbance (54.7 vs 56.1; P < .01). After adjusting for confounders, higher anxiety was associated with younger age (P < .01) and change in treatment plan (P = .04).ConclusionDuring the COVID-19 pandemic, thyroid cancer survivors reported increased anxiety compared to a pre-COVID cohort. To deliver comprehensive care, providers must better understand patient concerns and improve communication about potential changes to treatment plans.

BackgroundHypoparathyroidism is a common complication following thyroidectomy. There is a need for technology to aid surgeons in identifying the parathyroid glands. In contrast to near infrared technologies, fluorescence lifetime imaging (FLIm) is not affected by ambient light and may be valuable in identifying parathyroid tissue, but has never been evaluated in this capacity.MethodsWe used FLIm to measure the UV induced (355 nm) time-resolved autofluorescence signatures (average lifetimes in 3 spectral emission channels) of thyroid, parathyroid, lymphoid and adipose tissue in 21 patients undergoing thyroid and parathyroid surgery. The Mann-Whitney U test was used to assess the ability of FLIm to discriminate normocellular parathyroid from each of the other tissues. Various machine learning classifiers (random forests, neural network, support vector machine) were then evaluated to recognize parathyroid through a leave-one-out cross-validation.ResultsStatistically significant differences in average lifetime were observed between parathyroid and each of the other tissue types in spectral channels 2 and 3 respectively. The largest change was observed between adipose tissue and parathyroid (P < 0.001), while less pronounced but still significant changes were observed when comparing parathyroid with lymphoid tissue (P < 0.05) and thyroid (P < 0.01). A random forest classifier trained on average lifetimes was found to detect parathyroid tissue with 100% sensitivity and 93% specificity at the acquisition run level.ConclusionWe found that FLIm derived parameters can distinguish the parathyroid glands and other adjacent tissue types and has promise in scanning the surgical field to identify parathyroid tissue in real-time.

Abstract Background The benefit of self-monitoring of blood glucose (SMBG) in people with type 2 diabetes on diet or oral agents other than sulphonylureas remains uncertain. Trials of interventions incorporating education about self-monitoring of blood glucose have reported mixed results. A recent systematic review concluded that SMBG was not cost-effective. However, what was unclear was whether a cheaper method of self-monitoring (such as urine glucose monitoring) could produce comparable benefit and patient acceptability for less cost. Methods/Design The DESMOND SMBG trial is comparing two monitoring strategies (blood glucose monitoring and urine testing) over 18 months when incorporated into a comprehensive self-management structured education programme. It is a multi-site cluster randomised controlled trial, conducted across 8 sites (7 primary care trusts) in England, UK involving individuals with newly diagnosed Type 2 diabetes. The trial has 80% power to demonstrate equivalence in mean HbA1c (the primary end-point) at 18 months of within ± 0.5% assuming 20% drop out and 20% non-consent. Secondary end-points include blood pressure, lipids, body weight and psychosocial measures as well as a qualitative sub-study. Practices were randomised to one of two arms: participants attend a DESMOND programme incorporating a module on self-monitoring of either urine or blood glucose. The programme is delivered by accredited educators who received specific training about equipoise. Biomedical data are collected and psychosocial scales completed at baseline, and 6, 12, and 18 months post programme. Qualitative research with participants and educators will explore views and experiences of the trial and preferences for methods of monitoring. Discussion The DESMOND SMBG trial is designed to provide evidence to inform the debate about the value of self-monitoring of blood glucose in people with newly diagnosed type 2 diabetes. Strengths include a setting in primary care, a cluster design, a health economic analysis, a comparison of different methods of monitoring while controlling for other components of training within the context of a quality assured structured education programme and a qualitative sub-study. Trial registration ISRCTN: ISRCTN95696668.

Abstract Background Polycystic ovary syndrome (PCOS) is the most common chronic endocrine disorder affecting women of reproductive age. This study aimed to compare the HRQoL of South Asian and white Caucasian women with PCOS, given that it is particularly common among women of South Asian origin and they have been shown to have more severe symptoms. Methods The Polycystic Ovary Syndrome Questionnaire (PCOSQ) and the Short Form-36 (SF-36) were administered in a cross-sectional survey to 42 South Asian and 129 Caucasian women diagnosed with PCOS recruited from the gynaecology outpatient clinics of two university teaching hospitals in Sheffield and Leeds. Additional clinical data was abstracted from medical notes. Normative data, collected as part of the Oxford Health and Lifestyles II survey, was obtained to compare SF-36 results with ethnically matched women from the general UK population. Using the SF-36, normative HRQoL scores for women of South Asian origin were lower than for Caucasian women. Given this lower baseline we tested whether the same relationship holds true among those with PCOS. Results Although HRQoL scores for women with PCOS were lower than normative data for both groups, South Asian women with PCOS did not have poorer HRQoL than their Caucasian counterparts. For both the SF-36 and PCOSQ, mean scores were broadly the same for both Asian and Caucasian women. For both groups, the worst two HRQoL domains as measured on the PCOSQ were 'infertility' and 'weight', with respective scores of 35.3 and 42.3 for Asian women with PCOS compared to 38.6 and 35.4 for Caucasian women with PCOS. The highest scoring domain for South Asian women with PCOS was 'menstrual problems' (55.3), indicating best health, and was the only statistically significant difference from Caucasian women (p = 0.01). On the SF-36, the lowest scoring domain was 'Energy & Vitality' for Caucasian women with PCOS, but this was significantly higher for Asian women with PCOS (p = 0.01). The best health status for both groups was 'physical functioning', although this was significantly lower for South Asian women with PCOS (p = 0.005). Interestingly, only two domains differed significantly from the normative data for the Asian women with PCOS, while seven domains were significantly different for the Caucasian women with PCOS compared to their normative counterparts. Conclusions The HRQoL differences that exist between South Asian and Caucasian women in the general population do not appear to be replicated amongst women with PCOS. PCOS reduces HRQoL to broadly similar levels, regardless of ethnicity and differences in the normative baseline HRQoL of these groups.

Abstract Background In 2004, a review of pilot studies published in seven major medical journals during 2000-01 recommended that the statistical analysis of such studies should be either mainly descriptive or focus on sample size estimation, while results from hypothesis testing must be interpreted with caution. We revisited these journals to see whether the subsequent recommendations have changed the practice of reporting pilot studies. We also conducted a survey to identify the methodological components in registered research studies which are described as 'pilot' or 'feasibility' studies. We extended this survey to grant-awarding bodies and editors of medical journals to discover their policies regarding the function and reporting of pilot studies. Methods Papers from 2007-08 in seven medical journals were screened to retrieve published pilot studies. Reports of registered and completed studies on the UK Clinical Research Network (UKCRN) Portfolio database were retrieved and scrutinized. Guidance on the conduct and reporting of pilot studies was retrieved from the websites of three grant giving bodies and seven journal editors were canvassed. Results 54 pilot or feasibility studies published in 2007-8 were found, of which 26 (48%) were pilot studies of interventions and the remainder feasibility studies. The majority incorporated hypothesis-testing (81%), a control arm (69%) and a randomization procedure (62%). Most (81%) pointed towards the need for further research. Only 8 out of 90 pilot studies identified by the earlier review led to subsequent main studies. Twelve studies which were interventional pilot/feasibility studies and which included testing of some component of the research process were identified through the UKCRN Portfolio database. There was no clear distinction in use of the terms 'pilot' and 'feasibility'. Five journal editors replied to our entreaty. In general they were loathe to publish studies described as 'pilot'. Conclusion Pilot studies are still poorly reported, with inappropriate emphasis on hypothesis-testing. Authors should be aware of the different requirements of pilot studies, feasibility studies and main studies and report them appropriately. Authors should be explicit as to the purpose of a pilot study. The definitions of feasibility and pilot studies vary and we make proposals here to clarify terminology.

Ductal carcinoma in situ (DCIS) is a risk factor for the subsequent development of invasive breast cancer. High-risk features include age 5 cm, high-grade, palpable mass, hormone receptor negativity, and HER2 positivity. We have previously shown that immune infiltrates are positively associated with these high-risk features, suggesting that manipulating the immune microenvironment in high-risk DCIS could potentially alter disease progression. Patients with high-risk DCIS were enrolled in this 3 × 3 phase 1 dose-escalation pilot study of 2, 4, and 8 mg intralesional injections of the PD-1 immune checkpoint inhibitor, pembrolizumab. Study participants received two intralesional injections, three weeks apart, prior to surgery. Tissue from pre-treatment biopsies and post-treatment surgical resections was analyzed using multiplex immunofluorescence (mIF) staining for various immune cell populations. The intralesional injections were easily administered and well-tolerated. mIF analyses demonstrated significant increases in total T cell and CD8+ T cell percentages in most patients after receiving pembrolizumab, even at the 2 mg dose. T cell expansion was confined primarily to the stroma rather than within DCIS-containing ducts. Neither cleaved caspase 3 (CC3) staining, a marker for apoptosis, nor DCIS volume (as measured by MRI) changed significantly following treatment. Intralesional injection of pembrolizumab is safe and feasible in patients with DCIS. Nearly all patients experienced robust total and CD8+ T cell responses. However, we did not observe evidence of cell death or tumor volume decrease by MRI, suggesting that additional strategies may be needed to elicit stronger anti-tumor immunity.

Abstract Background: The coronavirus (COVID-19) pandemic has led to rapid changes in our society and healthcare system. Cancer patients and survivors may be disproportionately affected by these changes, including decreased access to healthcare, increased infection risk, and economic challenges. We sought to determine the effects of the pandemic on thyroid cancer survivors’ quality of life. Methods: An anonymous web-based survey was administered in collaboration with ThyCa: Thyroid Cancer Survivors’ Association, consisting of questions about (1) demographics, (2) thyroid cancer clinical characteristics, (3) attitudes toward and impact of COVID-19, and (4) the Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item profile. The survey was linked on the ThyCa homepage. PROMIS measures were scored using item response theory models with a T-score metric relative to U.S. reference data via the HealthMeasures Scoring Service (https://www.healthmeasures.net). T-scores were analyzed using Mann-Whitney U, Wilcoxon signed-rank, Kruskal-Wallis, and Spearman’s rank correlation tests. Results: From 5/6/2020 - 10/8/2020, 505 participants accessed the survey, and all completed surveys by U.S.-based thyroid cancer survivors were analyzed (n=378, 75%). Mean age was 53 years, 89% were female, 90% were white, 74% had papillary thyroid cancer, 97% had surgery, and 70% received radioactive iodine. The vast majority agreed or strongly agreed (83%) that their lives were very different during COVID-19, as was the way they interacted with their doctors (79%). Less than half (43%) agreed or strongly agreed that they were satisfied with the amount of information from their doctor’s office regarding COVID-19 changes. Compared to previously-published PROMIS data for this population, T-scores were significantly higher in the domain of anxiety/fear (57.8 vs. 56.5, p

Abstract Background Few patients with lower bowel symptoms who consult their general practitioner need a specialist opinion. However data from referred patients suggest that those who are referred would benefit from detailed assessment before referral. Methods A cluster randomised factorial trial. 44 general practices in North Trent, UK. Practices were offered either an electronic interactive referral pro forma, an educational outreach visit by a local colorectal surgeon, both or neither. The main outcome measure was the proportion of cases with severe diverticular disease, cancer or precancerous lesions and inflammatory bowel disease in those referred by each group. A secondary outcome was a referral letter quality score. Semi-structured interviews were conducted to identify key themes relating to the use of the software Results From 150 invitations, 44 practices were recruited with a total list size of 265,707. There were 716 consecutive referrals recorded over a six-month period, for which a diagnosis was available for 514. In the combined software arms 14% (37/261) had significant pathology, compared with 19% (49/253) in the non-software arms, relative risk 0.73 (95% CI: 0.46 to 1.15). In the combined educational outreach arms 15% (38/258) had significant pathology compared with 19% (48/256) in the non-educational arms, relative risk 0.79 (95% CI: 0.50 to 1.24). Pro forma practices documented better assessment of patients at referral. Conclusion There was a lack of evidence that either intervention increased the proportion of patients with organic pathology among those referred. The interactive software did improve the amount of information relayed in referral letters although we were unable to confirm if this made a significant difference to patients or their health care providers. The potential value of either intervention may have been diminished by their limited uptake within the context of a cluster randomised clinical trial. A number of lessons were learned in this trial of novel innovations.

Abstract Background Health Related Quality of Life (HRQoL) studies on children with chronic illness such as thalassaemia are limited. We conducted the first study to investigate if children with thalassaemia have a lower quality of life in the four dimensions as measured using the PedsQL 4.0 generic Scale Score: physical, emotional, social and role (school) functioning compared to the healthy controls allowing for age, gender, ethnicity and household income. Methods The PedsQL 4.0 was administered to children receiving blood transfusions and treatments at Hospital Kuala Lumpur, Malaysia using PedsQL 4.0 generic Scale Score. Accordingly, the questionnaire was also administered to a control group of healthy school children. Socio-demographic data were also collected from patients and controls using an interview schedule designed for the study. Results Of the 96 thalassaemia patients approached, 78 gave consent to be interviewed giving a response rate of 81.3%. Out of 235 healthy controls approached, all agreed to participate giving a response rate of 100%. The mean age for the patients and schoolchildren is 11.9 and 13.2 years respectively. The age range for the patients and the schoolchildren is between 5 to 18 years and 7 to 18 years respectively. After controlling for age and demographic background, the thalassaemia patients reported having significantly lower quality of life than the healthy controls. Conclusion Thalassaemia has a negative impact on perceived physical, emotional, social and school functioning in thalassaemia patients which was also found to be worse than the children's healthy counterparts. Continuing support of free desferal from the Ministry of Health should be given to these patients. More understanding and support especially from health authorities, school authorities and the society is essential to enhance their quality of life.

Abstract Stroke is a major cause of death and disability. About 5.3 million people die every year from stroke worldwide with over 9 million people surviving at any one time after suffering a stroke. About 1 in 4 men and 1 in 5 women aged 45 years will suffer a stroke if they live to their 85th year. It is estimated that by 2023 there will be an absolute increase in the number of people experiencing a first ever stroke of about 30% compared with 1983. In the UK, stroke is the third commonest cause of death and the most common cause of adult physical disability and consumes 5% of the health and social services budget. Stroke is assuming strategic public health importance because of increased awareness in society, an ageing population and emerging new treatments. It is an NHS health service and research priority, being identified as a target in Our Healthier Nation and the NSF for Older People for prevention and risk factor control and in the NHS Plan as a disease requiring intermediate care planning and reduction in inequalities of care. Whilst a number of risk factors for stroke are well known (e.g. increasing age, ethnicity, socioeconomic deprivation, hypertension), the potential importance of outdoor air pollution as a modifiable risk factor is much less well recognised. This is because studies to date are inconclusive or have methodological limitations. In Sheffield, we estimated that 11% of stroke deaths may be linked to current levels of outdoor air pollution and this high figure is explained by the fact that so many people are exposed to air pollution. We plan to study the effects of outdoor air pollution on stroke using a series of epidemiological (i.e. population based) studies. The purpose of this project is: • to examine if short term increases in pollution can trigger a stroke in susceptible individuals; • to investigate if the occurrence of stroke is higher amongst people living in more polluted areas (which would be explained by a combination of exposure to short term increases and longer term exposure to higher pollution levels); and • to see if people living in more polluted areas have reduced survival following their stroke. We will use geographical information systems, robust statistical methods and powerful grid computing facilities to link and analyse the data. The datasets we will use are the South London Stroke Register database, daily monitored pollution data from national monitoring networks and modelled pollution data for London from the Greater London Authority. The South London Stroke Register records information on all patients who suffer a stroke ("incident" cases) living within a defined area. This stroke incidence dataset offers major advantages over previous studies examining the effects of pollution on hospital admissions and mortality, as not all patients with stroke are admitted or die and there may be a delay between the onset of stroke and admission or death. In addition, it contains other useful information, particularly the type of stroke people have suffered. Air pollution is a potentially modifiable risk factor for stroke. This study will provide robust population level evidence regarding the effects of outdoor air pollution on stroke. If it confirms the link, it will suggest to policy-makers at national and international levels that targeting policy interventions at high pollution areas may be a feasible option for stroke prevention.

Understanding the contribution of the host's genetic background to cancer immunity may lead to improved stratification for immunotherapy and to the identification of novel therapeutic targets. We investigated the effect of common and rare germline variants on 139 well-defined immune traits in ∼9000 cancer patients enrolled in TCGA. High heritability was observed for estimates of NK cell and T cell subset infiltration and for interferon signaling. Common variants of IFIH1, TMEM173 (STING1), and TMEM108 were associated with differential interferon signaling and variants mapping to RBL1 correlated with T cell subset abundance. Pathogenic or likely pathogenic variants in BRCA1 and in genes involved in telomere stabilization and Wnt-β-catenin also acted as immune modulators. Our findings provide evidence for the impact of germline genetics on the composition and functional orientation of the tumor immune microenvironment. The curated datasets, variants, and genes identified provide a resource toward further understanding of tumor-immune interactions.

Abstract Health-Related Quality of Life (HRQoL) measures are becoming increasingly used in clinical trials as primary outcome measures. Investigators are now asking statisticians for advice on how to analyse studies that have used HRQoL outcomes. HRQoL outcomes, like the SF-36, are usually measured on an ordinal scale. However, most investigators assume that there exists an underlying continuous latent variable that measures HRQoL, and that the actual measured outcomes (the ordered categories), reflect contiguous intervals along this continuum. The ordinal scaling of HRQoL measures means they tend to generate data that have discrete, bounded and skewed distributions. Thus, standard methods of analysis such as the t-test and linear regression that assume Normality and constant variance may not be appropriate. For this reason, conventional statistical advice would suggest that non-parametric methods be used to analyse HRQoL data. The bootstrap is one such computer intensive non-parametric method for analysing data. We used the bootstrap for hypothesis testing and the estimation of standard errors and confidence intervals for parameters, in four datasets (which illustrate the different aspects of study design). We then compared and contrasted the bootstrap with standard methods of analysing HRQoL outcomes. The standard methods included t-tests, linear regression, summary measures and General Linear Models. Overall, in the datasets we studied, using the SF-36 outcome, bootstrap methods produce results similar to conventional statistical methods. This is likely because the t-test and linear regression are robust to the violations of assumptions that HRQoL data are likely to cause (i.e. non-Normality). While particular to our datasets, these findings are likely to generalise to other HRQoL outcomes, which have discrete, bounded and skewed distributions. Future research with other HRQoL outcome measures, interventions and populations, is required to confirm this conclusion.

Abstract Background Many medical specialities have reviewed the statistical content of their journals. To our knowledge this has not been done in general practice. Given the main role of a general practitioner as a diagnostician we thought it would be of interest to see whether the statistical methods reported reflect the diagnostic process. Methods Hand search of three UK journals of general practice namely the British Medical Journal (general practice section), British Journal of General Practice and Family Practice over a one-year period (1 January to 31 December 2000). Results A wide variety of statistical techniques were used. The most common methods included t-tests and Chi-squared tests. There were few articles reporting likelihood ratios and other useful diagnostic methods. There was evidence that the journals with the more thorough statistical review process reported a more complex and wider variety of statistical techniques. Conclusions The BMJ had a wider range and greater diversity of statistical methods than the other two journals. However, in all three journals there was a dearth of papers reflecting the diagnostic process. Across all three journals there were relatively few papers describing randomised controlled trials thus recognising the difficulty of implementing this design in general practice.

Multiplex immunofluorescence (mIF) allows simultaneous antibody-based detection of multiple markers with a nuclear counterstain on a single tissue section. Recent studies have demonstrated that mIF is becoming an important tool for immune profiling the tumor microenvironment, further advancing our understanding of the interplay between cancer and the immune system, and identifying predictive biomarkers of response to immunotherapy. Expediting mIF discoveries is leading to improved diagnostic panels, whereas it is important that mIF protocols be standardized to facilitate their transition into clinical use. Manual processing of sections for mIF is time consuming and a potential source of variability across numerous samples. To increase reproducibility and throughput we demonstrate the use of an automated slide stainer for mIF incorporating tyramide signal amplification (TSA). We describe two panels aimed at characterizing the tumor immune microenvironment. Panel 1 included CD3, CD20, CD117, FOXP3, Ki67, pancytokeratins (CK), and DAPI, and Panel 2 included CD3, CD8, CD68, PD-1, PD-L1, CK, and DAPI. Primary antibodies were first tested by standard immunohistochemistry and single-plex IF, then multiplex panels were developed and images were obtained using a Vectra 3.0 multispectral imaging system. Various methods for image analysis (identifying cell types, determining cell densities, characterizing cell-cell associations) are outlined. These mIF protocols will be invaluable tools for immune profiling the tumor microenvironment.

Objective: Management of thyroid nodules with Bethesda Category III and IV cytology on fine needle aspiration (FNA) is challenging as they cannot be adequately classified as benign or malignant. Ultrasound (US) patterns have demonstrated utility in evaluating the risk of malignancy (ROM) of Bethesda Category III nodules. This study aims to evaluate the value of three well established US grading systems (ATA, Korean-TIRADS, and ACR-TIRADS) in determining ROM in Bethesda Category IV nodules. Methods: 92 patients with 92 surgically resected thyroid nodules who had Bethesda Category IV cytology on FNA were identified. Nodule images were retrospectively graded using the three systems in a blinded manner. Associations between US risk category and malignant pathology for each system were analyzed. Results: Of the 92 nodules, 56 (61%) were benign and 36 (39%) were malignant. 47% of ATA high risk nodules, 53% of K-TIRADS category 5 nodules, and 50% of ACR-TIRADS category 5 nodules were malignant. The ATA high-risk category had 25% sensitivity, 82% specificity, 47% PPV for malignancy. K-TIRADS category 5 had 25% sensitivity, 85% specificity, 53% PPV for malignancy. ACR-TIRADS category 5 had 25% sensitivity, 84% specificity, 50% PPV for malignancy. None of the three grading systems yielded statistically significant correlation between US risk category and the ROM (p =0.30, 0.72, 0.28). Conclusion: The ATA, Korean-TIRADS, and ACR-TIRADS classification systems are not helpful in stratifying ROM in patients with Bethesda Category IV nodules. Clinicians should be cautious of using ultrasound alone when deciding between therapeutic options for patients with Bethesda Category IV thyroid nodules.

Adrenal collision tumors are rare and produce unique diagnostic challenges for clinicians. We report the case of a 45-year-old woman with obesity and diabetes mellitus and an incidentally-discovered adrenal mass containing macroscopic fat, thought to be a myelolipoma. A functional workup confirmed adrenocorticotropic hormone- (ACTH-) independent Cushing's syndrome. The patient underwent a successful laparoscopic adrenalectomy with pathology showing an adrenal collision tumor consisting of an adrenocortical adenoma and a myelolipoma. Postoperatively, the clinical symptoms, body mass index, and hemoglobin A1C all improved. Clinicians should consider a functional workup in patients with radiographically diagnosed myelolipomas as some may prove to be hormonally active collision tumors.

This database study uses the 2005-2011 American College of Surgeons National Surgical Quality Improvement Project database to evaluate the association of patient frailty with complications after adrenalectomy.