Circulating tumor DNA and radiological tumor volume identify patients at risk for relapse with resected, early-stage non-small-cell lung cancer.

BACKGROUND: Predicting relapse and overall survival (OS) in early-stage non-small-cell lung cancer (NSCLC) patients remains challenging. Therefore, we hypothesized that detection of circulating tumor DNA (ctDNA) can identify patients with increased risk of relapse and that integrating radiological tumor volume measurement along with ctDNA detectability improves prediction of outcome. PATIENTS AND METHODS: We analyzed 366 serial plasma samples from 85 patients who underwent surgical resections and assessed ctDNA using a next-generation sequencing liquid biopsy assay, and measured tumor volume using a computed tomography-based three-dimensional annotation. RESULTS: Our results showed that patients with detectable ctDNA at baseline or after treatment and patients who did not clear ctDNA after treatment had a significantly worse clinical outcome. Integrating radiological analysis allowed the stratification in risk groups prognostic of clinical outcome as confirmed in an independent cohort of 32 patients. CONCLUSIONS: Our findings suggest ctDNA and radiological monitoring could be valuable tools for guiding follow-up care and treatment decisions for early-stage NSCLC patients.

Distinct tumor-infiltrating lymphocyte landscapes are associated with clinical outcomes in localized non-small-cell lung cancer.

BACKGROUND: Despite the importance of tumor-infiltrating T lymphocytes (TILs) in cancer biology, the relationship between TIL phenotypes and their prognostic relevance for localized non-small-cell lung cancer (NSCLC) has not been well established. PATIENTS AND METHODS: Fresh tumor and normal adjacent tissue was prospectively collected from 150 patients with localized NSCLC. Tissue was comprehensively characterized by high-dimensional flow cytometry of TILs integrated with immunogenomic data from multiplex immunofluorescence, T-cell receptor sequencing, exome sequencing, RNA sequencing, targeted proteomics, and clinicopathologic features. RESULTS: While neither the magnitude of TIL infiltration nor specific TIL subsets were significantly prognostic alone, the integration of high-dimensional flow cytometry data identified two major immunotypes (IM1 and IM2) that were predictive of recurrence-free survival independent of clinical characteristics. IM2 was associated with poor prognosis and characterized by the presence of proliferating TILs expressing cluster of differentiation 103, programmed cell death protein 1, T-cell immunoglobulin and mucin-domain containing protein 3, and inducible T-cell costimulator. Conversely, IM1 was associated with good prognosis and differentiated by an abundance of CD8+ T cells expressing cytolytic enzymes, CD4+ T cells lacking the expression of inhibitory receptors, and increased levels of B-cell infiltrates and tertiary lymphoid structures. While increased B-cell infiltration was associated with good prognosis, the best prognosis was observed in patients with tumors exhibiting high levels of both B cells and T cells. These findings were validated in patient tumors from The Cancer Genome Atlas. CONCLUSIONS: Our study suggests that although the number of infiltrating T cells is not associated with patient survival, the nature of the infiltrating T cells, resolved in distinct TIL immunotypes, is prognostically relevant in NSCLC and may inform therapeutic approaches to clinical care.

The efficacy of remote virtual care in comparison to traditional clinical visits for elective orthopaedic patients: A meta-analysis of prospective randomised controlled trials.

INTRODUCTION: The Orthopaedic Trauma Association has recommended limitation of in-person encounters to absolute necessity. One method of ensuring standard patient care within these guidelines is through the implementation of telemedicine. AIMS: To evaluate the efficacy of telemedicine for elective orthopaedic patients in the recovery and/or rehabilitation period. METHODS: A systematic review and meta-analysis of articles in Medline/PubMed and The Cochrane Library databases was performed according to the PRISMA guidelines for prospective randomised controlled trials to compare clinical and symptomatic measures for elective patients managed routinely with remote care compared to those managed with standard in-clinic management. To be included for meta-analysis, parameters must be evaluated in ≥3 studies. RESULTS: Eleven studies were included in the meta-analyses. Both telemedicine and control cohorts were comparable for patient satisfaction (RR, 0.98; 95% CI, 0.90-1.07; I2 = 0%; p = 0.52) and patient retention analysis (RR, 1.25; 95% CI, 0.51-3.06; p = 0.54; I2 = 0%). Similarly, there was no statistical difference appreciated between cohorts for overall Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score (p = 0.30), Timed Up and Go Test (p = 0.40), and Stair Test (p = 0.18). Significant difference did exist for visual analogue scale (VAS) scores (p = 0.02) in favour of in-clinic management. CONCLUSION: Telemedicine will serve an integral aspect of healthcare delivery throughout the current COVID-19 pandemic and beyond in an effort to deliver safe, efficient and time-sensitive care to the orthopaedic patient population. The results of our meta-analyses indicate that virtual consultations are as effective as traditional in-person consultations for the care of elective orthopaedic patients in the recovery and rehabilitation period. However, further studies are needed to evaluate for initial consultations and certain sub-specialties of orthopaedics.

Suppressed immune microenvironment and repertoire in brain metastases from patients with resected non-small-cell lung cancer.

BACKGROUND: The tumor immune microenvironment (TIME) of lung cancer brain metastasis is largely unexplored. We carried out immune profiling and sequencing analysis of paired resected primary tumors and brain metastases of non-small-cell lung carcinoma (NSCLC). PATIENTS AND METHODS: TIME profiling of archival formalin-fixed and paraffin-embedded specimens of paired primary tumors and brain metastases from 39 patients with surgically resected NSCLCs was carried out using a 770 immune gene expression panel and by T-cell receptor beta repertoire (TCRß) sequencing. Immunohistochemistry was carried out for validation. Targeted sequencing was carried out to catalog hot spot mutations in cancer genes. RESULTS: Somatic hot spot mutations were mostly shared between both tumor sites (28/39 patients; 71%). We identified 161 differentially expressed genes, indicating inhibition of dendritic cell maturation, Th1, and leukocyte extravasation signaling pathways, in brain metastases compared with primary tumors (P < 0.01). The proinflammatory cell adhesion molecule vascular cell adhesion protein 1 was significantly suppressed in brain metastases compared with primary tumors. Brain metastases exhibited lower T cell and elevated macrophage infiltration compared with primary tumors (P < 0.001). T-cell clones were expanded in 64% of brain metastases compared with their corresponding primary tumors. Furthermore, while TCR repertoires were largely shared between paired brain metastases and primary tumors, T-cell densities were sparse in the metastases. CONCLUSION: We present findings that suggest that the TIME in brain metastases from NSCLC is immunosuppressed and comprises immune phenotypes (e.g. immunosuppressive tumor-associated macrophages) that may help guide immunotherapeutic strategies for NSCLC brain metastases.

In vitro co-culture and ex vivo organ culture assessment of primed and cryopreserved stromal cell microcapsules for intervertebral disc regeneration.

Priming towards a discogenic phenotype and subsequent cryopreservation of microencapsulated bone marrow stromal cells (BMSCs) may offer an attractive therapeutic approach for disc repair. It potentially obviates the need for in vivo administration of exogenous growth factors, otherwise required to promote matrix synthesis, in addition to providing 'off-the-shelf' availability. Cryopreserved and primed BMSC microcapsules were evaluated in an in vitro surrogate co-culture model system with nucleus pulposus (NP) cells under intervertebral disc (IVD)-like culture conditions and in an ex vivo bovine organ culture disc model. BMSCs were microencapsulated in alginate microcapsules and primed for 14 d with transforming growth factor beta-3 (TGF-ß3) under low oxygen conditions prior to cryopreservation. For the in vitro phase, BMSC microcapsules (unprimed or primed) were cultured for 28 d in a surrogate co-culture model system mimicking that of the IVD. For the ex vivo phase, microcapsules (unprimed or primed) were injected into the NP of bovine discs that underwent nucleotomy. In vitro results revealed that although NP cells produced significantly more matrix components in co-culture with BMSC microcapsules regardless of the differentiation state, unprimed microcapsules were inadequate at synthesising matrix as compared to primed microcapsules. However, this difference was diminished when evaluated in the ex vivo organ culture model,withboth unprimed and primed BMSC microcapsules accumulating large amounts of sulphated glycosaminoglycan (sGAG) and collagen and filling the defect cavity. Both models demonstrated that cryopreservation of BMSC microcapsules may offer a feasible strategy for predesigned delivery through cryobanking for on-demand regeneration of the IVD.

Operative Management of Perinatal Lumbar Disc Herniation and Cauda Equina Syndrome: A Case Series

Introduction Perinatal lumbar discectomy for lumbar disc herniation or cauda equina syndrome is a rare clinical scenario. This case series outlines the surgical management of this clinical scenario at a national tertiary referral centre over a 10-year period Methods A retrospective review of all females who underwent discectomy / decompression for lumbar disc herniation or cauda equina syndrome in the perinatal period at a national tertiary referral centre for spine surgery over a 10-year period between January 2008 to December 2017. Results 6 cases required surgical intervention. All patients were successfully managed with surgical decompressive procedures and recovered well in the postoperative period without complication. Conclusions The principles of management remain the same in the pregnant and non-pregnant populations, although treatment options are complicated by the desire to avoid risk to the developing foetus. Surgical intervention is safe to both mother and baby and if performed promptly is associated with an excellent functional outcome.

Whole-exome sequencing and immune profiling of early-stage lung adenocarcinoma with fully annotated clinical follow-up.

Background: Lung adenocarcinomas (LUADs) lead to the majority of deaths attributable to lung cancer. We performed whole-exome sequencing (WES) and immune profiling analyses of a unique set of clinically annotated early-stage LUADs to better understand the pathogenesis of this disease and identify clinically relevant molecular markers. Methods: We performed WES of 108 paired stage I-III LUADs and normal lung tissues using the Illumina HiSeq 2000 platform. Ten immune markers (PD-L1, PD-1, CD3, CD4, CD8, CD45ro, CD57, CD68, FOXP3 and Granzyme B) were profiled by imaging-based immunohistochemistry (IHC) in a subset of LUADs (n = 92). Associations among mutations, immune markers and clinicopathological variables were analyzed using ANOVA and Fisher's exact test. Cox proportional hazards regression models were used for multivariate analysis of clinical outcome. Results: LUADs in this cohort exhibited an average of 243 coding mutations. We identified 28 genes with significant enrichment for mutation. SETD2-mutated LUADs exhibited relatively poor recurrence- free survival (RFS) and mutations in STK11 and ATM were associated with poor RFS among KRAS-mutant tumors. EGFR, KEAP1 and PIK3CA mutations were predictive of poor response to adjuvant therapy. Immune marker analysis revealed that LUADs in smokers and with relatively high mutation burdens exhibited increased levels of immune markers. Analysis of immunophenotypes revealed that LUADs with STK11 mutations exhibited relatively low levels of infiltrating CD4+/CD8+ T-cells indicative of a muted immune response. Tumoral PD-L1 was significantly elevated in TP53 mutant LUADs whereas PIK3CA mutant LUADs exhibited markedly down-regulated PD-L1 expression. LUADs with TP53 or KEAP1 mutations displayed relatively increased CD57 and Granzyme B levels indicative of augmented natural killer (NK) cell infiltration. Conclusion(s): Our study highlights molecular and immune phenotypes that warrant further analysis for their roles in clinical outcomes and personalized immune-based therapy of LUAD.

Mutation profiles in early-stage lung squamous cell carcinoma with clinical follow-up and correlation with markers of immune function.

Background: Lung squamous cell carcinoma (LUSC) accounts for 20­30% of non-small cell lung cancers (NSCLCs). There are limited treatment strategies for LUSC in part due to our inadequate understanding of the molecular underpinnings of the disease. We performed whole-exome sequencing (WES) and comprehensive immune profiling of a unique set of clinically annotated early-stage LUSCs to increase our understanding of the pathobiology of this malignancy. Methods: Matched pairs of surgically resected stage I-III LUSCs and normal lung tissues (n = 108) were analyzed by WES. Immunohistochemistry and image analysis-based profiling of 10 immune markers were done on a subset of LUSCs (n = 91). Associations among mutations, immune markers and clinicopathological variables were statistically examined using analysis of variance and Fisher's exact test. Cox proportional hazards regression models were used for statistical analysis of clinical outcome. Results: This early-stage LUSC cohort displayed an average of 209 exonic mutations per tumor. Fourteen genes exhibited significant enrichment for somatic mutation: TP53, MLL2, PIK3CA, NFE2L2, CDH8, KEAP1, PTEN, ADCY8, PTPRT, CALCR, GRM8, FBXW7, RB1 and CDKN2A. Among mutated genes associated with poor recurrence-free survival, MLL2 mutations predicted poor prognosis in both TP53 mutant and wild-type LUSCs. We also found that in treated patients, FBXW7 and KEAP1 mutations were associated with poor response to adjuvant therapy, particularly in TP53-mutant tumors. Analysis of mutations with immune markers revealed that ADCY8 and PIK3CA mutations were associated with markedly decreased tumoral PD-L1 expression, LUSCs with PIK3CA mutations exhibited elevated CD45ro levels and CDKN2A-mutant tumors displayed an up-regulated immune response. Conclusion(s): Our findings pinpoint mutated genes that may impact clinical outcome as well as personalized strategies for targeted immunotherapies in early-stage LUSC.

The lymph node ratio does not provide additional prognostic information compared with the N1/N2 classification in Stage III colon cancer.

AIM: The ratio of positive nodes to total nodes, the lymph node ratio (LNR), is a proposed alternative to the current N1/N2 classification of nodal disease. The true clinical benefit of adopting the LNR, however, has not been definitively demonstrated. This study compared the LNR with the current N1/N2 classification of Stage III colon cancer. METHOD: Patients with Stage III colon cancer were identified from a prospectively maintained database (1996-2012). The specificity and sensitivity of the N1/N2 classification in the prediction of overall survival were determined using R. A cut-off point for the LNR was determined by setting the specificity the same as for the N1/N2 classification. The sensitivity of the two methods was then compared, and bootstrapping 1000-fold was performed. This was then repeated for disease-specific survival. RESULTS: The specificity and sensitivity of the N1/N2 classification in predicting 3-year overall survival in this cohort (n = 402) was 62.2% and 52.1%, respectively. The cut-off point for the LNR was determined to be 0.27 for these data. On comparing LNR with the N1/N2 classification showed that for a given specificity, the LNR did not provide a statistically significant improvement in sensitivity (52.8% vs 52.1%, P = 0.31). For disease-specific death at 3 years, the specificity and sensitivity were 60.8% and 54.6%, respectively. The LNR did not provide a statistically significant improvement (55.4% vs 54.6%, P = 0.44). CONCLUSION: Both the N1/N2 system and the LNR predict survival in colon cancer, but both have low specificity and sensitivity. The LNR does not provide additional prognostic value to current staging for overall or disease-specific survival for a given cut-off point.

Systematic review and meta-analysis of the impact of tumour budding in colorectal cancer.

BACKGROUND: Tumour budding is a histological finding in epithelial cancers indicating an unfavourable phenotype. Previous studies have demonstrated that it is a negative prognostic indicator in colorectal cancer (CRC), and has been proposed as an additional factor to incorporate into staging protocols. METHODS: A systematic review of papers until March 2016 published on Embase, Medline, PubMed, PubMed Central and Cochrane databases pertaining to tumour budding in CRC was performed. Study end points were the presence of lymph node metastases, recurrence (local and distal) and 5-year cancer-related death. RESULTS: A total of 7821 patients from 34 papers were included, with a mean rate of tumour budding of 36.8±16.5%. Pooled analysis suggested that specimens exhibiting tumour budding were significantly associated with lymph node positivity (OR 4.94, 95% CI 3.96-6.17, P<0.00001), more likely to develop disease recurrence over the time period (OR 5.50, 95% CI 3.64-8.29, P<0.00001) and more likely to lead to cancer-related death at 5 years (OR 4.51, 95% CI 2.55-7.99, P<0.00001). CONCLUSIONS: Tumour budding in CRC is strongly predictive of lymph node metastases, recurrence and cancer-related death at 5 years, and its incorporation into the CRC staging algorithm will contribute to more effective risk stratification.

A radiological and pathological assessment of ileocolic pedicle length as a predictor of lymph node retrieval following right hemicolectomy for caecal cancer.

BACKGROUND: In colon cancer, the number of harvested lymph nodes is critical for pathological staging. It has been proposed that the more central the mesenteric vascular ligation, the greater the nodal yield. The aim of the current study was to determine the association of radiological and pathological ileocolic pedicle length on nodal harvest following right hemicolectomy for caecal cancer. METHODS: A series of 50 patients undergoing right hemicolectomy for adenocarcinoma underwent specimen evaluation. Preoperative computed tomography images were reconstructed and analysed to determine the direct (vessel origin to caecum) ileocolic pedicle length. RESULTS: The median pathological distance from the tumour to the high vascular tie was 80 mm, and median nodal yield was 16.5 nodes. Radiological pedicle length did not correlate with the pathological distance from the tumour to the high vascular tie or nodal yield; however, the pathological pedicle length did correlate with the total nodal yield (r (2): 0.343, p = 0.015). The median pathologically determined length of colon resected (r (2): 0.153, p = 0.289), ileum resected (r (2): 0.087, p = 0.568) and total specimen length resected (r (2): 0.182, p = 0.205) did not correlate with the total nodal yield. An ileal specimen length ≤25 mm [hazard ratio (HR) 14.8, 95 % confidence interval (CI) 1.1-194.5, p = 0.040] and a well-differentiated tumour (HR 10.5, 95 % CI 1.1-95.9, p = 0.037) increased the likelihood of retrieving <12 lymph nodes. CONCLUSIONS: Based on these data, pathologic pedicle length is a determining factor in lymph node retrieval. Preoperative radiological calculation of pedicle length does not help predict the number of lymph nodes retrieved.

Use of hospital admissions data to quantify the burden of emergency admissions in people with diabetes mellitus.

AIMS: Accurate measurement of emergency diabetes admissions is essential for healthcare delivery and research. This study examines whether current approaches to identifying diabetes-related admissions may underestimate the true burden on hospital care. METHODS: Data spanning the period 1 January 2006 to 31 December 2010 inclusive were extracted from Hospital Episode Statistics data for England. Emergency admissions citing diabetes (E10, E11, E13 or E14) in any diagnosis position in adults (≥ 17 years) were included. E10 and E11 were considered analogous to type 1 and type 2 diabetes mellitus respectively; E13 and E14 were grouped as 'other or unspecified' diabetes mellitus. For admissions citing diabetes multiple times, those with concordant citations were classified as appropriate; discordant citations were assigned to the 'other or unspecified' group. Frequencies of diabetes classifications and complications for each diagnosis position and frequencies of all International Classification of Diseases 10th revision codes for the primary diagnosis field were calculated. RESULTS: In total, 2 443 046 admissions were identified. Diabetes was cited as the primary diagnosis in 6.2% and most commonly cited as the third diagnosis (23.1%). Type 2 diabetes mellitus was the most common (85.0%). The majority of diabetes citations were 'without complication' (2 188 965, 89.6%). The most common primary diagnosis was 'chest pain, unspecified' (R07.4, 99 678, 4.1%). CONCLUSIONS: Reliance on the primary diagnosis field to identify emergency admissions in people with diabetes grossly underestimates the true burden placed on hospital care and leads to underestimates of effect sizes in studies utilizing admission rates as outcome measures. An alternative strategy to identify such admissions is required.

Anal intraepithelial neoplasia: a single centre 19 year review.

AIM: There is debate about whether the traditional three-tiered grading of anal intraepithelial neoplasia (AIN) should be replaced by a more reproducible two-tiered system. In this study, we review our experience with AIN to determine the most suitable classification system. METHOD: We performed a retrospective review of all histological reports over a 19 year period. All specimens were graded on haemataloxin and eosin appearance and those with dysplasia had immunohistochemistry for p16 and Ki67 performed. RESULTS: Cases included 25 condyloma acuminata, 11 dysplastic cases and 24 invasive squamous cell carcinomas. On review, 18 were classified as condyloma acuminata without dysplasia. Seven had AIN I, five had AIN II and six had AIN III when using a three-tiered system. All cases classified as dysplastic (n = 18) showed an increased proliferation index as measured by Ki67. p16 positivity was seen in all AIN III, two AIN II and none of the AIN I cases. Recurrence was not observed in any of the AIN I cases. Five of eleven AIN II and AIN III cases recurred or persisted at a similar, higher or lower grade. Both of the AIN II cases which recurred or persisted were p16 positive. None of the AIN II cases that were p16 negative recurred. Three of the p16-positive AIN III cases did not recur. None of the 18 AIN cases progressed to carcinoma. CONCLUSION: The findings support the slow progression of AIN as described in the literature. In our small series, a two-tiered system with further subclassification of the traditional AIN II group using p16 appears to be clinically useful.

Identifying immune signatures of sepsis to increase diagnostic accuracy in very preterm babies.

Bacterial infections are a major cause of mortality in preterm babies, yet our understanding of early-life disease-associated immune dysregulation remains limited. Here, we combine multi-parameter flow cytometry, single-cell RNA sequencing and plasma analysis to longitudinally profile blood from very preterm babies (<32 weeks gestation) across episodes of invasive bacterial infection (sepsis). We identify a dynamically changing blood immune signature of sepsis, including lymphopenia, reduced dendritic cell frequencies and myeloid cell HLA-DR expression, which characterizes sepsis even when the common clinical marker of inflammation, C-reactive protein, is not elevated. Furthermore, single-cell RNA sequencing identifies upregulation of amphiregulin in leukocyte populations during sepsis, which we validate as a plasma analyte that correlates with clinical signs of disease, even when C-reactive protein is normal. This study provides insights into immune pathways associated with early-life sepsis and identifies immune analytes as potential diagnostic adjuncts to standard tests to guide targeted antibiotic prescribing.

Hyaline vascular Castleman's disease involving the biliary tract.

We report a case of Castleman's Disease (CD), hyaline vascular subtype involving the biliary tract with obstruction. A 43 year old man presented with a 5 week history of abdominal and back pain with biliary obstructive symptoms. He was jaundiced with persistently high LFTs. Radiological investigation revealed a stricture in the extrahepatic biliary tract. The clinical impression at the time was of sclerosing cholangitis with bile duct cholangiocarcinoma. A Whipple's procedure was performed. Histology and immunohistochemistry supported the histologic diagnosis of CD of hyaline vascular subtype. There was no evidence of disease elsewhere and the patient was disease free after a 6 year follow-up. Our case describes the hyaline vascular subtype of CD, a relatively rare disease occurring in a previously undescribed location.

Cannabis use and non-clinical dimensions of psychosis in university students presenting to primary care.

OBJECTIVE: To explore the relationship between cannabis use and self-reported dimensions of psychosis in a population of university students presenting for any reason to primary care. METHOD: One thousand and forty-nine students attending the Student Health Unit, National University of Ireland, Galway, completed self-report questionnaires on alcohol and substance misuse, non-clinical dimensions of psychosis [Community Assessment of Psychic Experiences (CAPE)], anxiety and depression [Hospital Anxiety and Depression Scale (HADS)]. Association of cannabis use with psychiatric symptoms was explored whilst controlling for confounds. RESULTS: More frequent cannabis use was independently associated with greater intensity of positive, negative and depressive psychotic symptoms. The earlier the age of onset of cannabis use, the more positive psychotic symptoms were reported. CONCLUSION: These findings support the hypotheses that cannabis use increases the risk of developing psychotic symptoms and that this risk is further increased in those individuals who use cannabis more heavily and commence it at a younger age.

Risk factors predicting desmoid occurrence in patients with familial adenomatous polyposis: a meta-analysis.

AIM: Desmoid tumours (DT) are myofibroblastic proliferations occurring in 15% of patients with familial adenomatous polyposis (FAP). Several small series have analysed the incidence of DT and predisposing risk factors. Using meta-analytical techniques, this study aimed to identify risk factors for DT development in patients with FAP. METHOD: Studies of sporadic DT were excluded. The study end-points were the incidence of DT in FAP and DT development by gender, adenomatous polyposis coli (APC) mutation, family history of DT and previous abdominal surgery. A random effect Mantel-Haenszel model was used to calculate odds ratios for each risk factor and age group. RESULTS: Ten studies of 4625 patients with FAP fulfilled our inclusion criteria. A total of 559 (12%) patients developed DT. Cumulative analysis demonstrated that 80% of DT developed by age 40, the peak incidence rate being in the second and third decades. A positive family history of DT was the most significant risk factor (OR 7.02, 95% CI 4.15-11.9, P < 0.001). An APC mutation 3' to codon 1399 (OR 4.37, 95% CI 2.14-8.91, P < 0.001) and previous abdominal surgery (OR 3.35, 95% CI 1.33-8.41, P = 0.01) were also implicated. Women were more likely to develop DT (OR 1.57, 95% CI 1.13-2.18, P = 0.007). CONCLUSION: There is consistency amongst polyposis registries in documenting the incidence and risk factors for DT development. Having a positive family history for DT is of greater significance than a 3' mutation, suggesting the existence of modifier genes, independent of the APC genotype-phenotype correlation. Few of these risk factors are modifiable. Delaying prophylactic surgery could be appropriate in female patients with a 3' APC mutation and attenuated polyposis.

Focal thyroid incidentalomas identified with whole-body FDG-PET warrant further investigation.

Fluorodeoxyglucose (FDG) whole body positron emission computed tomography (PET-CT) detects clinically occult malignancy. The aim of this study was to assess the prevalence and significance of focal thyroid 18F - fluorodeoxyglucose uptake. A retrospective review of all patients who had FDG PET-CT examinations, in a single tertiary referral centre was performed. PET scan findings and the final pathological diagnosis were collated. 2105 scans were reviewed. Focal uptake was identified in 35 (1.66%) patients. Final surgical histology was available on eight patients, which confirmed papillary carcinoma in four (20%) patients and lymphoma and metastatic disease in two patients respectively. This gave an overall malignancy rate in focal thyroid uptake of at least 33%. Thyroid incidentalomas occurred with a frequency of 2.13%, with an associated malignancy rate of at least 33% in focal thyroid uptake. The high malignancy rate associated with focal thyroid uptake mandates further investigation in medically fit patients.

The biological activity of natural and mutant pTalpha alleles.

beta selection is a major checkpoint in early thymocyte differentiation, mediated by successful expression of the pre-T cell receptor (TCR) comprising the TCRbeta chain, CD3 proteins, and a surrogate TCRalpha chain, pTalpha. The mechanism of action of the pre-TCR is unresolved. In humans and mice, the pTalpha gene encodes two RNAs, pTalpha(a), and a substantially truncated form, pTalpha(b). This study shows that both are biologically active in their capacity to rescue multiple thymocyte defects in pTalpha(-/-) mice. Further active alleles of pTalpha include one that lacks both the major ectodomain and much of the long cytoplasmic tail (which is unique among antigen receptor chains), and another in which the cytoplasmic tail is substituted with the short tail of TCR Calpha. Thus, very little of the pTalpha chain is required for function. These data support a hypothesis that the primary role of pTalpha is to stabilize the pre-TCR, and that much of the conserved structure of pTalpha probably plays a critical regulatory role.