Uterine Leiomyosarcoma With Osteoclast-like Giant Cells: Report of 2 Cases and Review of Literature.

Leiomyosarcoma (LMS) with osteoclast-like giant cells (OLGCs) is a rare entity with only 18 reported cases thus far. It is not known whether these OLGCs are a reactive or malignant component of LMS. Herein we describe the clinical, histologic, and molecular characteristics of 2 cases of LMS with OLGCs and perform a brief literature review. In 2 of our cases, the OLGCs, marked with CD68, had a low proliferation index with Ki67 and did not show diffuse positivity for smooth muscle markers by immunohistochemistry. By next-generation sequencing, one case harbored a clinically significant TP53 mutation, which has been reported in a significant subset of conventional LMSs. In this case, based on immunohistochemistry, OLGCs showed different molecular alterations as compared with LMS. Although we did not show a distinct immunophenotype or molecular profile for LMS with OLGCs, this study provides additional data on this rare entity.

Olaparib and Ceralasertib (AZD6738) in Patients with Triple-Negative Advanced Breast Cancer: Results from Cohort E of the plasmaMATCH Trial (CRUK/15/010).

PURPOSE: Approximately 10% to 15% of triple-negative breast cancers (TNBC) have deleterious mutations in BRCA1 and BRCA2 and may benefit from PARP inhibitor treatment. PARP inhibitors may also increase exogenous replication stress and thereby increase sensitivity to inhibitors of ataxia telangiectasia and Rad3-related (ATR) protein. This phase II study examined the activity of the combination of PARP inhibitor, olaparib, and ATR inhibitor, ceralasertib (AZD6738), in patients with advanced TNBC. PATIENTS AND METHODS: Patients with TNBC on most recent biopsy who had received 1 or 2 lines of chemotherapy for advanced disease or had relapsed within 12 months of (neo)adjuvant chemotherapy were eligible. Treatment was olaparib 300 mg twice a day continuously and celarasertib 160 mg on days 1-7 on a 28-day cycle until disease progression. The primary endpoint was confirmed objective response rate (ORR). Tissue and plasma biomarker analyses were preplanned to identify predictors of response. RESULTS: 70 evaluable patients were enrolled. Germline BRCA1/2 mutations were present in 10 (14%) patients and 3 (4%) patients had somatic BRCA mutations. The confirmed ORR was 12/70; 17.1% (95% confidence interval, 10.4-25.5). Responses were observed in patients without germline or somatic BRCA1/2 mutations, including patients with mutations in other homologous recombination repair genes and tumors with functional homologous recombination deficiency by RAD51 foci. CONCLUSIONS: The response rate to olaparib and ceralasertib did not meet prespecified criteria for activity in the overall evaluable population, but responses were observed in patients who would not be expected to respond to olaparib monotherapy.

High-risk HPV testing improves accuracy in detection of CIN2+ lesions in ASC-H postmenopausal women? An academic hospital experiences.

Reflex human papilloma virus (HPV) testing with "atypical squamous cells, cannot exclude high-grade squamous lesion (ASC-H)" cytologic diagnosis is not recommended by American Society for Colposcopy and Cervical Pathology guidelines. Studies have shown human papillomavirus (HPV)-negative ASC-H patients of increased age are low risk for cervical intraepithelial neoplasia 2 or worse (CIN2+) lesions on colposcopic follow-up. We retrospectively assessed the efficacy of reflex HPV testing in postmenopausal women with ASC-H in the Los Angeles County hospitals and clinics in a 5-year period. Of a total 85 clinically postmenopausal women with ASC-H, 31 (36.5%) women were found to have CIN2+ lesions on follow-up biopsy and five of them were HPV-negative. Of the women with CIN2+ lesions and positive HPV, 13 (41.9%) were high-risk HPV (hrHPV) 16/18/45 positive and 13 (41.9%) were hrHPV-other subtype positive. Women with positive HPV had an over 3-fold increased risk of developing CIN2+ lesions (P = 0.008). Relative risk of hrHPV16/18/45 was 1.79-fold higher than that of hrHPV-other subtype. The positive predictive value and negative predictive value of hrHPV were 49.1% and 84.4%, respectively. CIN2+ detection rate in Hispanic women with positive hrHPV was higher than in non-Hispanic women (53.8% versus 35.7%). Overall, postmenopausal women with ASC-H cytology result and negative hrHPV were less likely to develop CIN2+ lesions, whereas about half of ASC-H postmenopausal women develop CIN2+ lesions if hrHPV positive, especially if hrHPV 16/18/45 positive. Therefore, triaging ASC-H postmenopausal women with cotesting or, ideally, hrHPV genotyping should be considered as optimal clinical practice to avoid overtreatment.

Performance of breast fine needle aspiration as an initial diagnostic tool: A large academic hospital experience.

BACKGROUND: The clinical performance of the Yokohama reporting system for breast cytology remains uncertain. METHODS: In this study, we retrospectively evaluated 318 breast fine needle aspirations (FNABs) from Los Angeles County Hospital over a five-year period, analysing data for breast cytology, histology, and radiology. RESULTS: Among 318 breast FNAB cases, 78.3% (249/318) were benign and 5.3% (17/318) malignant. Of 83 cases with follow-up histology, 14.5% (12/83) were insufficient, 66.3% (55/83) were benign, and 16.9% (17/83) were malignant. Of 55 benign cases, 61.8% (34/55) were fibroadenoma and 9 (9/55, 16.4%) were fibrocystic changes. Two cases were diagnosed as "atypical" but confirmed "benign" on core needle biopsy (CNB). No "suspicious" cases were found. Seventeen malignant cases were confirmed by CNB, including 70.6% (12/17) invasive ductal carcinoma, 11.8% (2/17) invasive lobular carcinoma, and one malignant phyllodes tumour. Receptor studies on cell blocks of three malignant cases showed concordant results with CNB results. In addition, 82.2% (148/180) of lesions with Breast Imaging-Reporting and Data System (BI-RADS) scores of 2 or 3 were benign and 92.3% (12/13) BI-RADS score 5 lesions were malignant on FNAB. Finally, 90% (67/74) of BI-RADS 4a lesions were benign, and 97% (36/37) of fibroadenomas were BI-RADS score 4a. CONCLUSION: This, by far the largest U.S. breast cytology study, showed 93.3% sensitivity, 100% specificity, 100% positive predictive value, and 98.2% negative predictive value for breast FNAB. Women with breast lesions of BI-RADS score 3 or less have a low risk of malignancy; FNAB would contribute to the reduction of excisional biopsies. FNAB can be considered as an initial diagnostic tool for BI-RADS 4 mass/lesions and satellite lesions, as well as for triaging patients.

Australia as a global sink for the genetic diversity of avian influenza A virus.

Most of our understanding of the ecology and evolution of avian influenza A virus (AIV) in wild birds is derived from studies conducted in the northern hemisphere on waterfowl, with a substantial bias towards dabbling ducks. However, relevant environmental conditions and patterns of avian migration and reproduction are substantially different in the southern hemisphere. Through the sequencing and analysis of 333 unique AIV genomes collected from wild birds collected over 15 years we show that Australia is a global sink for AIV diversity and not integrally linked with the Eurasian gene pool. Rather, AIV are infrequently introduced to Australia, followed by decades of isolated circulation and eventual extinction. The number of co-circulating viral lineages varies per subtype. AIV haemagglutinin (HA) subtypes that are rarely identified at duck-centric study sites (H8-12) had more detected introductions and contemporary co-circulating lineages in Australia. Combined with a lack of duck migration beyond the Australian-Papuan region, these findings suggest introductions by long-distance migratory shorebirds. In addition, on the available data we found no evidence of directional or consistent patterns in virus movement across the Australian continent. This feature corresponds to patterns of bird movement, whereby waterfowl have nomadic and erratic rainfall-dependant distributions rather than consistent intra-continental migratory routes. Finally, we detected high levels of virus gene segment reassortment, with a high diversity of AIV genome constellations across years and locations. These data, in addition to those from other studies in Africa and South America, clearly show that patterns of AIV dynamics in the Southern Hemisphere are distinct from those in the temperate north.

Operational complexity versus design efficiency: challenges of implementing a phase IIa multiple parallel cohort targeted treatment platform trial in advanced breast cancer.

BACKGROUND: Platform trial designs are used increasingly in cancer clinical research and are considered an efficient model for evaluating multiple compounds within a single disease or disease subtype. However, these trial designs can be challenging to operationalise. The use of platform trials in oncology clinical research has increased considerably in recent years as advances in molecular biology enable molecularly defined stratification of patient populations and targeted therapy evaluation. Whereas multiple separate trials may be deemed infeasible, platform designs allow efficient, parallel evaluation of multiple targeted therapies in relatively small biologically defined patient sub-populations with the promise of increased molecular screening efficiency and reduced time for drug evaluation. Whilst the theoretical efficiencies are widely reported, the operational challenges associated with these designs (complexity, cost, regulatory, resource) are not always well understood. MAIN: In this commentary, we describe our practical experience of the implementation and delivery of the UK plasmaMATCH trial, a platform trial in advanced breast cancer, comprising an integrated screening component and multiple parallel downstream mutation-directed therapeutic cohorts. plasmaMATCH reported its primary results within 3 years of opening to recruitment. We reflect on the operational challenges encountered and share lessons learnt to inform the successful conduct of future trials. Key to the success of the plasmaMATCH trial was well co-ordinated stakeholder engagement by an experienced clinical trials unit with expert methodology and trial management expertise, a federated model of clinical leadership, a well-written protocol integrating screening and treatment components and including justification for the chosen structure and intentions for future adaptions, and an integrated funding model with streamlined contractual arrangements across multiple partners. Findings based on our practical experience include the importance of early engagement with the regulators and consideration of a flexible resource infrastructure to allow adequate resource allocation to support concurrent trial activities as adaptions are implemented in parallel to the continued management of patient safety and data quality of the ongoing trial cohorts. CONCLUSION: Platform trial designs allow the efficient reporting of multiple treatment cohorts. Operational challenges can be overcome through multidisciplinary engagement, streamlined contracting processes, rationalised protocol and database design and appropriate resourcing.

Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial.

BACKGROUND: Circulating tumour DNA (ctDNA) testing might provide a current assessment of the genomic profile of advanced cancer, without the need to repeat tumour biopsy. We aimed to assess the accuracy of ctDNA testing in advanced breast cancer and the ability of ctDNA testing to select patients for mutation-directed therapy. METHODS: We did an open-label, multicohort, phase 2a, platform trial of ctDNA testing in 18 UK hospitals. Participants were women (aged ≥18 years) with histologically confirmed advanced breast cancer and an Eastern Cooperative Oncology Group performance status 0-2. Patients had completed at least one previous line of treatment for advanced breast cancer or relapsed within 12 months of neoadjuvant or adjuvant chemotherapy. Patients were recruited into four parallel treatment cohorts matched to mutations identified in ctDNA: cohort A comprised patients with ESR1 mutations (treated with intramuscular extended-dose fulvestrant 500 mg); cohort B comprised patients with HER2 mutations (treated with oral neratinib 240 mg, and if oestrogen receptor-positive with intramuscular standard-dose fulvestrant); cohort C comprised patients with AKT1 mutations and oestrogen receptor-positive cancer (treated with oral capivasertib 400 mg plus intramuscular standard-dose fulvestrant); and cohort D comprised patients with AKT1 mutations and oestrogen receptor-negative cancer or PTEN mutation (treated with oral capivasertib 480 mg). Each cohort had a primary endpoint of confirmed objective response rate. For cohort A, 13 or more responses among 78 evaluable patients were required to infer activity and three or more among 16 were required for cohorts B, C, and D. Recruitment to all cohorts is complete and long-term follow-up is ongoing. This trial is registered with ClinicalTrials.gov, NCT03182634; the European Clinical Trials database, EudraCT2015-003735-36; and the ISRCTN registry, ISRCTN16945804. FINDINGS: Between Dec 21, 2016, and April 26, 2019, 1051 patients registered for the study, with ctDNA results available for 1034 patients. Agreement between ctDNA digital PCR and targeted sequencing was 96-99% (n=800, kappa 0·89-0·93). Sensitivity of digital PCR ctDNA testing for mutations identified in tissue sequencing was 93% (95% CI 83-98) overall and 98% (87-100) with contemporaneous biopsies. In all cohorts, combined median follow-up was 14·4 months (IQR 7·0-23·7). Cohorts B and C met or exceeded the target number of responses, with five (25% [95% CI 9-49]) of 20 patients in cohort B and four (22% [6-48]) of 18 patients in cohort C having a response. Cohorts A and D did not reach the target number of responses, with six (8% [95% CI 3-17]) of 74 in cohort A and two (11% [1-33]) of 19 patients in cohort D having a response. The most common grade 3-4 adverse events were raised gamma-glutamyltransferase (13 [16%] of 80 patients; cohort A); diarrhoea (four [25%] of 20; cohort B); fatigue (four [22%] of 18; cohort C); and rash (five [26%] of 19; cohort D). 17 serious adverse reactions occurred in 11 patients, and there was one treatment-related death caused by grade 4 dyspnoea (in cohort C). INTERPRETATION: ctDNA testing offers accurate, rapid genotyping that enables the selection of mutation-directed therapies for patients with breast cancer, with sufficient clinical validity for adoption into routine clinical practice. Our results demonstrate clinically relevant activity of targeted therapies against rare HER2 and AKT1 mutations, confirming these mutations could be targetable for breast cancer treatment. FUNDING: Cancer Research UK, AstraZeneca, and Puma Biotechnology.

A truncating mutation in the autophagy gene UVRAG drives inflammation and tumorigenesis in mice.

Aberrant autophagy is a major risk factor for inflammatory diseases and cancer. However, the genetic basis and underlying mechanisms are less established. UVRAG is a tumor suppressor candidate involved in autophagy, which is truncated in cancers by a frameshift (FS) mutation and expressed as a shortened UVRAGFS. To investigate the role of UVRAGFS in vivo, we generated mutant mice that inducibly express UVRAGFS (iUVRAGFS). These mice are normal in basal autophagy but deficient in starvation- and LPS-induced autophagy by disruption of the UVRAG-autophagy complex. iUVRAGFS mice display increased inflammatory response in sepsis, intestinal colitis, and colitis-associated cancer development through NLRP3-inflammasome hyperactivation. Moreover, iUVRAGFS mice show enhanced spontaneous tumorigenesis related to age-related autophagy suppression, resultant ß-catenin stabilization, and centrosome amplification. Thus, UVRAG is a crucial autophagy regulator in vivo, and autophagy promotion may help prevent/treat inflammatory disease and cancer in susceptible individuals.

Gain of TP53 Mutation in Imatinib-treated SDH-Deficient Gastrointestinal Stromal Tumor and Clinical Utilization of Targeted Next-generation Sequencing Panel for Therapeutic Decision Support.

Patients with succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST) have few therapeutic options. Despite lack of KIT or platelet-derived growth factor receptor A (PDGFRA) driver mutations, SDH-deficient GISTs display strong expression of KIT by immunohistochemistry and these patients are often treated with tyrosine kinase inhibitors, including imatinib as a first-line therapy. Using a targeted next-generation sequencing panel of mutation hotspots of 50-clinically relevant genes, we investigated (1) concurrence of somatic/actionable mutations and (2) tumor molecular evolution by comparing 2 resection specimens 1.5 years apart while the patient was on imatinib adjuvant therapy. We found the tumors did not harbor KIT, PDGFRA, or any other clinically actionable mutations. However, a TP53 mutation (c.422G>A; p.C141Y) was detected in the second recurrent lesion. This represents the first study to monitor the molecular evolution of a SDH-deficient GIST during adjuvant treatment. These findings emphasize the critical need for next-generation sequencing testing before initiating targeted therapy.

AXIN2 expression predicts prostate cancer recurrence and regulates invasion and tumor growth.

BACKGROUND: Treatment of prostate cancer (PCa) may be improved by identifying biological mechanisms of tumor growth that directly impact clinical disease progression. We investigated whether genes associated with a highly tumorigenic, drug resistant, progenitor phenotype impact PCa biology and recurrence. METHODS: Radical prostatectomy (RP) specimens (±disease recurrence, N = 276) were analyzed by qRT-PCR to quantify expression of genes associated with self-renewal, drug resistance, and tumorigenicity in prior studies. Associations between gene expression and PCa recurrence were confirmed by bootstrap internal validation and by external validation in independent cohorts (total N = 675) and in silico. siRNA knockdown and lentiviral overexpression were used to determine the effect of gene expression on PCa invasion, proliferation, and tumor growth. RESULTS: Four candidate genes were differentially expressed in PCa recurrence. Of these, low AXIN2 expression was internally validated in the discovery cohort. Validation in external cohorts and in silico demonstrated that low AXIN2 was independently associated with more aggressive PCa, biochemical recurrence, and metastasis-free survival after RP. Functionally, siRNA-mediated depletion of AXIN2 significantly increased invasiveness, proliferation, and tumor growth. Conversely, ectopic overexpression of AXIN2 significantly reduced invasiveness, proliferation, and tumor growth. CONCLUSIONS: Low AXIN2 expression was associated with PCa recurrence after RP in our test population as well as in external validation cohorts, and its expression levels in PCa cells significantly impacted invasiveness, proliferation, and tumor growth. Given these novel roles, further study of AXIN2 in PCa may yield promising new predictive and therapeutic strategies.

Circulating Myeloid-Derived Suppressor Cells Predict Differentiated Thyroid Cancer Diagnosis and Extent.

BACKGROUND: Establishing the preoperative diagnosis and long-term prognosis of differentiated thyroid cancer (DTC) remain challenging in some patients. Myeloid-derived suppressor cells (MDSC) are tumor-induced cells mediating immune tolerance that are detectable in the peripheral blood of cancer patients. The authors previously developed a novel clinical assay to detect the phenotypes of two human MDSC subsets in peripheral blood, and hypothesize that higher MDSC levels measured by this assay correlate positively with both malignancy and worse patient outcomes. METHODS: A prospective observational pilot study was performed of patients undergoing thyroidectomy for a solitary thyroid nodule. The presence of a thyroid nodule >1 cm was confirmed sonographically, and fine-needle aspiration biopsy performed prior to surgery in all cases. Peripheral blood collected preoperatively was analyzed using a novel flow cytometry-based immunoassay to detect and quantify two subsets of human MDSC. Circulating MDSC levels were compared by histopathologic diagnosis, stage, and presence of persistent disease after treatment. RESULTS: Of 50 patients included in this study, MDSC measurement was successful in 47 (94%). One patient was found to have a concurrent cancer, leaving 46 patients for primary analysis. The cytologic diagnoses were benign in five (10.8%), atypia or follicular lesion of undetermined significance in five (10.8%), suspicious for follicular neoplasm in five (10.8%), suspicious for malignant in three (6.5%), and malignant in 28 (60.1%) of the 46 nodules. Final histopathology was benign in 11 (24%) and DTC in 35 (76%), encompassing 34 PTC cases and one follicular thyroid carcinoma. Mean percentages of CD11b(+)HLA-DR(low)HIF1a(+) MDSC (CD11b(+)MDSC) were 14.0 ± 6.2% and 7.9 ± 3.6% in DTC versus benign nodules, respectively (p < 0.005). A cutoff of 12% yielded a specificity of 0.91, a sensitivity of 0.72, and a likelihood ratio of 7.9. Mean CD11b(+)MDSC levels increased linearly with higher TNM stage (p < 0.01), and were 19.4 ± 5.4 in patients with persistent cancer after surgery compared with 13.2 ± 6.8 in those without evidence of disease (p < 0.05). CONCLUSION: MDSC measurement using this flow cytometry-based assay represents a novel approach for preoperatively assessing malignancy risk and cancer extent in patients with thyroid nodules. While further validation is needed, these data suggest that MDSC assessment may serve as a useful adjunct when cytology is indeterminate, and predict tumor stage and recurrence risk in cases of thyroid cancer.

A novel BAP1 mutation is associated with melanocytic neoplasms and thyroid cancer.

Germline mutations in the tumor suppressor gene, BRCA-1 associated protein (BAP1), underlie a tumor predisposition syndrome characterized by increased risk for numerous cancers including uveal melanoma, melanocytic tumors and mesothelioma, among others. In the present study we report the identification of a novel germline BAP1 mutation, c.1777C>T, which produces a truncated BAP1 protein product and segregates with cancer. Family members with this mutation demonstrated a primary clinical phenotype of autosomal dominant, early-onset melanocytic neoplasms with immunohistochemistry (IHC) of these tumors demonstrating lack of BAP1 protein expression. In addition, family members harboring the BAP1 c.1777C>T germline mutation developed other neoplastic disease including thyroid cancer. IHC analysis of the thyroid cancer, as well, demonstrated loss of BAP1 protein expression. Our investigation identifies a new BAP1 mutation, further highlights the relevance of BAP1 as a clinically important tumor suppressor gene, and broadens the range of cancers associated with BAP1 inactivation. Further study will be required to understand the full scope of BAP1-associated neoplastic disease.

Hyperbaric oxygen for patients with chronic bowel dysfunction after pelvic radiotherapy (HOT2): a randomised, double-blind, sham-controlled phase 3 trial.

BACKGROUND: Hyperbaric oxygen has been used as a therapy for patients experiencing chronic intestinal syndromes after pelvic radiotherapy for decades, yet the evidence to support the use of this therapy is based almost exclusively on non-randomised studies. We aimed to provide conclusive results for the clinical benefits of hyperbaric oxygen in patients with chronic bowel dysfunction after radiotherapy for pelvic malignancies. METHODS: HOT2 was a double-blind, sham-controlled, phase 3 randomised study of patients (≥18 years) with chronic gastrointestinal symptoms for 12 months or more after radiotherapy and which persisted despite at least 3 months of optimal medical therapy and no evidence of cancer recurrence. Participants were stratified by participating hyperbaric centre and randomly assigned (2:1) by a computer-generated list (block size nine or 12) to receive treatment with hyperbaric oxygen therapy or sham. Participants in the active treatment group breathed 100% oxygen at 2·4 atmospheres of absolute pressure (ATA) and the control group breathed 21% oxygen at 1·3 ATA; both treatment groups received 90-min air pressure exposures once daily for 5 days per week for a total of 8 weeks (total of 40 exposures). Staff at the participating hyperbaric medicine facilities knew the allocated treatment, but patients, clinicians, nurse practitioners, and other health-care professionals associated with patients' care were masked to treatment allocation. Primary endpoints were changes in the bowel component of the modified Inflammatory Bowel Disease Questionnaire (IBDQ) score and the IBDQ rectal bleeding score 12 months after start of treatment relative to baseline. The primary outcome was analysed in a modified intention-to-treat population, excluding patients who did not provide IBDQ scores within a predetermined time-frame. All patients have completed 12 months of follow-up and the final analysis is complete. The trial is registered with the ISRCTN registry, number ISRCTN86894066. FINDINGS: Between Aug 14, 2009, and Oct 23, 2012, 84 participants were randomly assigned: 55 to hyperbaric oxygen and 29 to sham control. 75 (89%) participants received 40 pressure exposures, all participants returned the IBDQ at baseline, 75 (89%) participants returned the IBDQ at 2 weeks post-treatment, and 79 (94%) participants returned the IBDQ at 12 months post-start of treatment. Patients were excluded from analyses of co-primary endpoints if they had missing IBDQ scores for intestinal function or rectal bleeding at baseline or at 12 months. In an analysis of 46 participants in the active treatment group and 23 participants in the control group, we found no significant differences in the change of IBDQ bowel component score (median change from baseline to 12 months of 4 (IQR -3 to 11) in the treatment group vs 4 (-6 to 9) in the sham group; Mann-Whitney U score 0·67, p=0·50). In an analysis of 29 participants in the active treatment group and 11 participants in the sham group with rectal bleeding at baseline, we also found no significant differences in the change of IBDQ rectal bleeding score (median change from baseline to 12 months of 3 [1 to 3] in the treatment group vs 1 [1 to 2] in the sham group; U score 1·69, p=0·092). Common adverse events in both groups were eye refractive changes (three [11%] of 28 patients in the control group vs 16 [30%] of 53 patients in the treatment group), increased fatigue (three [11%] vs two [4%]), and ear pain (six [21%] vs 15 [28%]). Eight serious adverse events were reported in eight patients: two were reported in two patients in the control group (tonsillitis requiring surgery [grade 3]; recurrent cancer of the vulva [grade 4]) and six serious adverse events were reported in six patients in the treatment group (malignant spinal cord compression requiring surgery [grade 3]; malignant paraortic lymph node involvement requiring surgery [grade 3]; recurrence of vomiting and dehydration [grade 3]; diarrhoea and fever associated with Campylobacter infection [grade 3]; recurrence of abdominal pain, bloating, diarrhoea, and urinary tract infection [grade 3]; aneurysm [grade 4]), none of which were deemed treatment-related. INTERPRETATION: We found no evidence that patients with radiation-induced chronic gastrointestinal symptoms, including those patients with rectal bleeding, benefit from hyperbaric oxygen therapy. These findings contrast with evidence used to justify current practices, and more level 1 evidence is urgently needed. FUNDING: Cancer Research UK and National Health Service (NHS) funding to the National Institute of Health Research Biomedical Research Centre at The Royal Marsden and the Institute of Cancer Research.

High-frequency ultrasound imaging for breast cancer biopsy guidance.

Image-guided core needle biopsy is the current gold standard for breast cancer diagnosis. Microcalcifications, an important radiographic finding on mammography suggestive of early breast cancer such as ductal carcinoma in situ, are usually biopsied under stereotactic guidance. This procedure, however, is uncomfortable for patients and requires the use of ionizing radiation. It would be preferable to biopsy microcalcifications under ultrasound guidance since it is a faster procedure, more comfortable for the patient, and requires no radiation. However, microcalcifications cannot reliably be detected with the current standard ultrasound imaging systems. This study is motivated by the clinical need for real-time high-resolution ultrasound imaging of microcalcifications, so that biopsies can be accurately performed under ultrasound guidance. We have investigated how high-frequency ultrasound imaging can enable visualization of microstructures in ex vivo breast tissue biopsy samples. We generated B-mode images of breast tissue and applied the Nakagami filtering technique to help refine image output so that microcalcifications could be better assessed during ultrasound-guided core biopsies. We describe the preliminary clinical results of high-frequency ultrasound imaging of ex vivo breast biopsy tissue with microcalcifications and without Nakagami filtering and the correlation of these images with the pathology examination by hematoxylin and eosin stain and whole slide digital scanning.

Double-Blind Randomized 12-Month Soy Intervention Had No Effects on Breast MRI Fibroglandular Tissue Density or Mammographic Density.

Soy supplementation by patients with breast cancer remains controversial. No controlled intervention studies have investigated the effects of soy supplementation on mammographic density in patients with breast cancer. We conducted a double-blind, randomized, placebo-controlled intervention study in previously treated patients with breast cancer (n = 66) and high-risk women (n = 29). We obtained digital mammograms and breast MRI scans at baseline and after 12 months of daily soy (50 mg isoflavones per day; n = 46) or placebo (n = 49) tablet supplementation. The total breast area (MA) and the area of mammographic density (MD) on the mammogram were measured using a validated computer-assisted method, and mammographic density percent (MD% = 100 × MD/MA) was determined. A well-tested computer algorithm was used to quantitatively measure the total breast volume (TBV) and fibroglandular tissue volume (FGV) on the breast MRI, and the FGV percent (FGV% = 100 × FGV/TBV) was calculated. On the basis of plasma soy isoflavone levels, compliance was excellent. Small decreases in MD% measured by the ratios of month 12 to baseline levels were seen in the soy (0.95) and the placebo (0.87) groups; these changes did not differ between the treatments (P = 0.38). Small decreases in FGV% were also found in both the soy (0.90) and the placebo (0.92) groups; these changes also did not differ between the treatments (P = 0.48). Results were comparable in patients with breast cancer and high-risk women. We found no evidence that soy supplementation would decrease mammographic density and that MRI might be more sensitive to changes in density than mammography.

Truncating mutation in the autophagy gene UVRAG confers oncogenic properties and chemosensitivity in colorectal cancers.

Autophagy-related factors are implicated in metabolic adaptation and cancer metastasis. However, the role of autophagy factors in cancer progression and their effect in treatment response remain largely elusive. Recent studies have shown that UVRAG, a key autophagic tumour suppressor, is mutated in common human cancers. Here we demonstrate that the cancer-related UVRAG frameshift (FS), which does not result in a null mutation, is expressed as a truncated UVRAG(FS) in colorectal cancer (CRC) with microsatellite instability (MSI), and promotes tumorigenesis. UVRAG(FS) abrogates the normal functions of UVRAG, including autophagy, in a dominant-negative manner. Furthermore, expression of UVRAG(FS) can trigger CRC metastatic spread through Rac1 activation and epithelial-to-mesenchymal transition, independently of autophagy. Interestingly, UVRAG(FS) expression renders cells more sensitive to standard chemotherapy regimen due to a DNA repair defect. These results identify UVRAG as a new MSI target gene and provide a mechanism for UVRAG participation in CRC pathogenesis and treatment response.

Echogenic foci in thyroid nodules: significance of posterior acoustic artifacts.

OBJECTIVE: This study was undertaken to define and evaluate echogenic foci and their posterior acoustic artifacts in thyroid nodules. Whether these findings were indicative of benignity or malignancy was assessed. MATERIALS AND METHODS: Echogenic foci were classified into five types: no posterior artifact, large comet-tail artifact, small comet-tail artifact (≤1.0 mm), and posterior shadowing (subdivided into internal versus peripheral). Nodules were also classified into four parenchymal patterns: hypoechoic, hyperechoic, >50% solid, and cystic. Results were compared with the cytologic or surgical findings. RESULTS: A total of 704 nodules had echogenic foci; 246 did not. The prevalence of malignancy ranged between 15.4% and 19.5% for all types of foci except large comet-tail artifacts (3.9%). Foci without posterior artifacts had a 21.9% rate of cancer in hypoechoic lesions and 15.8% in hyperechoic lesions. Foci with small comet-tail artifacts had a 27.6% rate of malignancy in hypoechoic nodules. For internal calcifications, no malignant nodules were found in either partially cystic group. Nodules with peripheral calcifications had prevalence rates of 20.0% in cystic nodules and 11.1% in predominately solid nodules. Identification of one additional type of high-risk focus increased the chance of malignancy 1.48 times. CONCLUSION: All categories of echogenic foci except those with large comet-tail artifacts are associated with high cancer risk. Identification of large comet-tail artifacts suggests benignity. Nodules with small comet-tail artifacts have a high incidence of malignancy in hypoechoic nodules. With the exception of nodules that have peripheral calcifications, the risk of malignancy is low when echogenic foci are present in partially cystic lesions.

Reprogramming of the human intestinal epigenome by surgical tissue transposition.

Extracellular cues play critical roles in the establishment of the epigenome during development and may also contribute to epigenetic perturbations found in disease states. The direct role of the local tissue environment on the post-development human epigenome, however, remains unclear due to limitations in studies of human subjects. Here, we use an isogenic human ileal neobladder surgical model and compare global DNA methylation levels of intestinal epithelial cells pre- and post-neobladder construction using the Infinium HumanMethylation450 BeadChip. Our study is the first to quantify the effect of environmental cues on the human epigenome and show that the local tissue environment directly modulates DNA methylation patterns in normal differentiated cells in vivo. In the neobladder, the intestinal epithelial cells lose their tissue-specific epigenetic landscape in a time-dependent manner following the tissue's exposure to a bladder environment. We find that de novo methylation of many intestine-specific enhancers occurs at the rate of 0.41% per month (P < 0.01, Pearson = 0.71), while demethylation of primarily non-intestine-specific transcribed regions occurs at the rate of -0.37% per month (P < 0.01, Pearson = -0.57). The dynamic resetting of the DNA methylome in the neobladder not only implicates local environmental cues in the shaping and maintenance of the epigenome but also illustrates an unexpected cross-talk between the epigenome and the cellular environment.

Manualised Individual Cognitive Behavioural Therapy for mood disorders in people with mild to moderate intellectual disability: a feasibility randomised controlled trial.

BACKGROUND: Evaluation of complex interventions, including standardisation of the intervention, types of outcomes selected and measures of change, is a fairly novel concept in the field of intellectual disabilities. Our aim was to explore these issues in a feasibility study of Manualised Individual Cognitive Behaviour Treatment (M-iCBT) compared to the treatment as usual alone (TAU). METHODS: Service users with mild to moderate intellectual disability experiencing a mood disorder or symptoms of depression and/or anxiety (mini PAS-ADD total score >10 or 7 respectively) were randomly assigned to either. RESULTS: In total, 32 participants were randomly assigned to 16 sessions of M-iCBT (n=16) in addition to TAU or TAU alone (n=16). We explored recruitment and accrual rates, willingness to participate, acceptability of the intervention and suitability of assessment tools. Mean change (95% CI) in the Beck Depression Inventory-Youth (BDI-Y) score from baseline to the 16 week endpoint (primary variable) was 0.10 (95% CI: -8.56, 8.76) and in the Beck Anxiety Inventory-Youth (BAI-Y) 2.42 (95% CI: -5.27, 10.12) in favour of TAU. However, there was a clear trend in favour of CBT in depressed participants with or without anxiety. LIMITATIONS: The intervention targeted both depression and anxiety following a transdiagnostic model. This may have impacted the anticipated size of change in the primary outcome. The precise impact of cognitive limitations on ability to use therapy effectively is not fully understood. CONCLUSIONS: This study demonstrates that it is feasible to carry out a pragmatic randomised controlled trial of M-iCBT for people with mild to moderate intellectual disability. However, uncertainties about its clinical and cost effectiveness can only be fully answered by further examination of its superiority against other treatments.

Occult metastases in lymph nodes predict survival in resectable non-small-cell lung cancer: report of the ACOSOG Z0040 trial.

PURPOSE: The survival of patients with non-small-cell lung cancer (NSCLC), even when resectable, remains poor. Several small studies suggest that occult metastases (OMs) in pleura, bone marrow (BM), or lymph nodes (LNs) are present in early-stage NSCLC and are associated with a poor outcome. We investigated the prevalence of OMs in resectable NSCLC and their relationship with survival. PATIENTS AND METHODS: Eligible patients had previously untreated, potentially resectable NSCLC. Saline lavage of the pleural space, performed before and after pulmonary resection, was examined cytologically. Rib BM and all histologically negative LNs (N0) were examined for OM, diagnosed by cytokeratin immunohistochemistry (IHC). Survival probabilities were estimated using the Kaplan-Meier method. The log-rank test and Cox proportional hazards regression model were used to compare survival of groups of patients. P < .05 was considered significant. RESULTS: From July 1999 to March 2004, 1,047 eligible patients (538 men and 509 women; median age, 67.2 years) were entered onto the study, of whom 50% had adenocarcinoma and 66% had stage I NSCLC. Pleural lavage was cytologically positive in only 29 patients. OMs were identified in 66 (8.0%) of 821 BM specimens and 130 (22.4%) of 580 LN specimens. In univariate and multivariable analyses OMs in LN but not BM were associated with significantly worse disease-free survival (hazard ratio [HR], 1.50; P = .031) and overall survival (HR, 1.58; P = .009). CONCLUSION: In early-stage NSCLC, LN OMs detected by IHC identify patients with a worse prognosis. Future clinical trials should test the role of IHC in identifying patients for adjuvant therapy.