Reverse Abdominoplasty: A Novel Practical Approach Using Oncoplastic Reconstruction in Managing Major Chest Wall Defects for Patients With Loco-Regional Recurrence Following Breast Cancer Surgery.

Background Loco-regional recurrence of breast cancer in patients with large chest wall defects following mastectomy poses significant oncoplastic challenges. Reverse abdominoplasty is most commonly used to treat patients with excess upper abdominal soft tissue and laxity following massive weight loss. Widely employed as a technique for aesthetic contouring of the upper anterior trunk, as well as in augmentation mammoplasty, its use to date for reconstructive purposes is mainly limited to burns and large site surgical tumour ablation. Method Here we review our experience of using reverse abdominoplasty as a novel approach to filling major anterior chest wall defects in patients with cutaneous manifestations of loco-regional or distant recurrence of breast cancer. Results Seven patients with metastatic breast cancer underwent reverse abdominoplasty for disease recurrence following mastectomy, with good patient-reported outcomes, and minimal surgical complications. Moreover, follow-up data in the patients surveyed also showed minimal to no limitations on their activities of daily living following the procedure. Conclusion Here we demonstrate the successful employment of reverse abdominoplasty - a technique not usually reserved in breast oncoplastic surgery - to treat fungating breast lesions and/or other manifestations of loco-regional recurrence in metastatic breast cancer. This may herald a paradigm shift in the way surgeons approach breast cancer recurrence in patients with pre-existing major chest wall defects.

Author Correction: Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Enhancer mapping uncovers phenotypic heterogeneity and evolution in patients with luminal breast cancer.

The degree of intrinsic and interpatient phenotypic heterogeneity and its role in tumor evolution is poorly understood. Phenotypic drifts can be transmitted via inheritable transcriptional programs. Cell-type specific transcription is maintained through the activation of epigenetically defined regulatory regions including promoters and enhancers. Here we have annotated the epigenome of 47 primary and metastatic estrogen-receptor (ERα)-positive breast cancer clinical specimens and inferred phenotypic heterogeneity from the regulatory landscape, identifying key regulatory elements commonly shared across patients. Shared regions contain a unique set of regulatory information including the motif for transcription factor YY1. We identify YY1 as a critical determinant of ERα transcriptional activity promoting tumor growth in most luminal patients. YY1 also contributes to the expression of genes mediating resistance to endocrine treatment. Finally, we used H3K27ac levels at active enhancer elements as a surrogate of intra-tumor phenotypic heterogeneity to track the expansion and contraction of phenotypic subpopulations throughout breast cancer progression. By tracking the clonality of SLC9A3R1-positive cells, a bona fide YY1-ERα-regulated gene, we show that endocrine therapies select for phenotypic clones under-represented at diagnosis. Collectively, our data show that epigenetic mechanisms significantly contribute to phenotypic heterogeneity and evolution in systemically treated breast cancer patients.

Chromatin Immunoprecipitation and High-Throughput Sequencing (ChIP-Seq): Tips and Tricks Regarding the Laboratory Protocol and Initial Downstream Data Analysis.

Chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) has become an essential tool for epigenetic scientists. ChIP-seq is used to map protein-DNA interactions and epigenetic marks such as histone modifications at the genome-wide level. Here we describe a complete ChIP-seq laboratory protocol (tailored toward processing tissue samples as well as cell lines) and the bioinformatic pipelines utilized for handling raw sequencing files through to peak calling.

Genes Predisposed to DNA Hypermethylation during Acquired Resistance to Chemotherapy Are Identified in Ovarian Tumors by Bivalent Chromatin Domains at Initial Diagnosis.

Bivalent chromatin domains containing both active H3K4me3 and repressive H3K27me3 histone marks define gene sets poised for expression or silencing in differentiating embryonic stem (ES) cells. In cancer cells, aberrantly poised genes may facilitate changes in transcriptional states after exposure to anticancer drugs. In this study, we used ChIP-seq to characterize genome-wide positioning of H3K4me3- and H3K27me3-associated chromatin in primary high-grade serous ovarian carcinomas and in normal ovarian surface and fallopian tube tissue. Gene sets with proximal bivalent marks defined in this manner were evaluated subsequently as signatures of systematic change in DNA methylation and gene expression, comparing pairs of tissue samples taken from patients at primary presentation and relapse following chemotherapy. We found that gene sets harboring bivalent chromatin domains at their promoters in tumor tissue, but not normal epithelia, overlapped with Polycomb-repressive complex target genes as well as transcriptionally silenced genes in normal ovarian and tubal stem cells. The bivalently marked genes we identified in tumors before chemotherapy displayed increased promoter CpG methylation and reduced gene expression at relapse after chemotherapy of ovarian cancer. Overall, our results support the hypothesis that preexisting histone modifications at genes in a poised chromatin state may lead to epigenetic silencing during acquired drug resistance.Significance: These results suggest epigenetic targets for intervention to prevent the emergence of cancer drug resistance. Cancer Res; 78(6); 1383-91. ©2018 AACR.

Anaplastic Spindle Cell Squamous Carcinoma Arising from Tall Cell Variant Papillary Carcinoma of the Thyroid Gland: A Case Report and Review of the Literature.

Tall cell variant (TCV) of papillary thyroid carcinoma (PTC), an aggressive form of thyroid cancer, is characterised by 50% of cells with height that is three times greater than the width. Very rarely, some of these cancers can progress to spindle cell squamous carcinoma (SCSC) resulting in cancers with elements of both SCSC and TCV PTC. Here we report a case of SCSC arising from TCV PTC. In addition to this case, we have performed a literature review and compiled all published reports of SCSC arising from TCV PTC, including the nature of treatment and the prognosis for each of the 20 patients recorded. This is intended for use as a guide for clinicians in what the most appropriate treatment options may be for a newly diagnosed patient. Due to the rarity coupled with diagnosis occurring at a very advanced stage of disease progression, performing clinical trials is difficult and therefore drawing conclusions on optimal treatment methods remains a challenge.

Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion.

Endocrine therapies target the activation of the oestrogen receptor alpha (ERα) via distinct mechanisms, but it is not clear whether breast cancer cells can adapt to treatment using drug-specific mechanisms. Here we demonstrate that resistance emerges via drug-specific epigenetic reprogramming. Resistant cells display a spectrum of phenotypical changes with invasive phenotypes evolving in lines resistant to the aromatase inhibitor (AI). Orthogonal genomics analysis of reprogrammed regulatory regions identifies individual drug-induced epigenetic states involving large topologically associating domains (TADs) and the activation of super-enhancers. AI-resistant cells activate endogenous cholesterol biosynthesis (CB) through stable epigenetic activation in vitro and in vivo. Mechanistically, CB sparks the constitutive activation of oestrogen receptors alpha (ERα) in AI-resistant cells, partly via the biosynthesis of 27-hydroxycholesterol. By targeting CB using statins, ERα binding is reduced and cell invasion is prevented. Epigenomic-led stratification can predict resistance to AI in a subset of ERα-positive patients.

Trends in Immediate Postmastectomy Breast Reconstruction in the United Kingdom.

BACKGROUND: The study aimed to evaluate local and national trends in immediate breast reconstruction (IBR) using the national English administrative records, Hospital Episode Statistics. Our prediction was an increase in implant-only and free flap procedures and a decline in latissimus flap reconstructions. METHODS: Data from an oncoplastic center were interrogated to derive numbers of implant-only, autologous latissimus dorsi (LD), LD-assisted, and autologous pedicled or free flap IBR procedures performed between 2004 and 2013. Similarly, Hospital Episode Statistics data were used to quantify national trends in these procedures from 1996 to 2012 using a curve fitting analysis. RESULTS: National data suggest an increase in LD procedures between 1996 (n = 250) and 2002 (n = 958), a gradual rise until 2008 (n = 1398) followed by a decline until 2012 (n = 1090). As a percentage of total IBR, trends in LD flap reconstruction better fit a quadratic (R(2) = 0.97) than a linear function (R(2) = 0.63), confirming a proportional recent decline in LD flap procedures. Conversely, autologous (non-LD) flap reconstructions have increased (1996 = 0.44%; 2012 = 2.76%), whereas implant-only reconstructions have declined (1996 = 95.42%; 2012 = 84.92%). Locally, 70 implant-assisted LD procedures were performed in 2003 -2004, but only 2 were performed in 2012 to 2013. CONCLUSIONS: Implants are the most common IBR technique; autologous free flap procedures have increased, and pedicled LD flap procedures are in decline.

The pioneer factor PBX1 is a novel driver of metastatic progression in ERα-positive breast cancer.

Over 30% of ERα breast cancer patients develop relapses and progress to metastatic disease despite treatment with endocrine therapies. The pioneer factor PBX1 translates epigenetic cues and mediates estrogen induced ERα binding. Here we demonstrate that PBX1 plays a central role in regulating the ERα transcriptional response to epidermal growth factor (EGF) signaling. PBX1 regulates a subset of EGF-ERα genes highly expressed in aggressive breast tumours. Retrospective stratification of luminal patients using PBX1 protein levels in primary cancer further demonstrates that elevated PBX1 protein levels correlate with earlier metastatic progression. In agreement, PBX1 protein levels are significantly upregulated during metastatic progression in ERα-positive breast cancer patients. Finally we reveal that PBX1 upregulation in aggressive tumours is partly mediated by genomic amplification of the PBX1 locus. Correspondingly, ERα-positive breast cancer patients carrying PBX1 amplification are characterized by poor survival. Notably, we demonstrate that PBX1 amplification can be identified in tumor derived-circulating free DNA of ERα-positive metastatic patients. Metastatic patients with PBX1 amplification are also characterized by shorter relapse-free survival. Our data identifies PBX1 amplification as a functional hallmark of aggressive ERα-positive breast cancers. Mechanistically, PBX1 amplification impinges on several critical pathways associated with aggressive ERα-positive breast cancer.

DMXL2 drives epithelial to mesenchymal transition in hormonal therapy resistant breast cancer through Notch hyper-activation.

The acquisition of endocrine therapy resistance in estrogen receptor α (ERα) breast cancer patients represents a major clinical problem. Notch signalling has been extensively linked to breast cancer especially in patients who fail to respond to endocrine therapy. Following activation, Notch intracellular domain is released and enters the nucleus where activates transcription of target genes. The numerous steps that cascade after activation of the receptor complicate using Notch as biomarker. Hence, this warrants the development of reliable indicators of Notch activity. DMXL2 is a novel regulator of Notch signalling not yet investigated in breast cancer. Here, we demonstrate that DMXL2 is overexpressed in a subset of endocrine therapy resistant breast cancer cell lines where it promotes epithelial to mesenchymal transition through hyper-activation of Notch signalling via V-ATPase dependent acidification. Following DMXL2 depletion or treatment with Bafilomycin A1, both EMT targets and Notch signalling pathway significantly decrease. We show for the first time that DMXL2 protein levels are significantly increased in ERα positive breast cancer patients that progress after endocrine therapy. Finally, we demonstrate that DMXL2 is a transmembrane protein with a potential extra-cellular domain. These findings identify DMXL2 as a novel, functional biomarker for ERα positive breast cancer.

A surprising diagnosis: metastatic prostate cancer causing cervical lymphadenopathy.

Cervical lymphadenopathy as an initial presentation for metastatic prostate cancer has been rarely described. Less than 30 cases have been published in medical literature whereby a lymph node biopsy revealed immunoreactivity for prostate-specific antigen (PSA) diagnosing metastatic prostate cancer. We present a unique scenario whereby an asymptomatic patient with previous high-risk gastric cancer presented to clinic with cervical lymphadenopathy. A hunt for a recurrence ensued to no avail and imaging of the head and neck showed no hint of a primary malignancy in those regions. A lymph node biopsy was undertaken which showed elements suggesting metastatic prostate cancer. The patient developed symptoms of urinary outflow obstruction shortly afterwards. Blood tests revealed a very high PSA and a bone scan showed widespread bony metastasis. He was started on androgen deprivation therapy with an improvement of his PSA and symptoms. A regular clinic follow-up has shown stable disease.

Prior exposure to chemotherapy: a marker of sensitivity and selection for antiangiogenic therapy in breast cancer?

The identification of patients who are more likely to derive benefit from antiangiogenic therapy is a key to refine patient selection and so maximize clinical benefit, and reduce unnecessary treatment costs. Improved patient selection will equally be effective in minimizing the exposure of non-eligible patients to ineffectual treatment which could be associated with adverse effects as well as delaying effective treatment. Herein, we review the literature from clinical trials suggesting that the addition of antiangiogenic agents to chemotherapy for the treatment of HER-2 negative metastatic breast cancer in patients previously exposed to chemotherapy may deliver differential therapeutic benefit and may serve as a selection criteria in the current absence of a robust biomarker.

Breast cancer: current and future endocrine therapies.

Endocrine therapy forms a central modality in the treatment of estrogen receptor positive breast cancer. The routine use of 5 years of adjuvant tamoxifen has improved survival rates for early breast cancer, and more recently has evolved in the postmenopausal setting to include aromatase inhibitors. The optimal duration of adjuvant endocrine therapy remains an active area of clinical study with recent data supporting 10 years rather than 5 years of adjuvant tamoxifen. However, endocrine therapy is limited by the development of resistance, this can occur by a number of possible mechanisms and numerous studies have been performed which combine endocrine therapy with agents that modulate these mechanisms with the aim of preventing or delaying the emergence of resistance. Recent trial data regarding the combination of the mammalian target of rapamycin (mTOR) inhibitor, everolimus with endocrine therapy have resulted in a redefinition of the clinical treatment pathway in the metastatic setting. This review details the current endocrine therapy utilized in both early and advanced disease, as well as exploring potential new targets which modulate pathways of resistance, as well as agents which aim to modulate adrenal derived steroidogenic hormones.

Occult bladder injury after laparoscopic appendicectomy.

Minimally invasive procedures have revolutionised surgery by reducing pain and the length of hospital stay for patients. These are not simple procedures and training in laparoscopic surgery is an arduous process. Meticulous preparation prior to surgery is paramount to prevent complications. We report a rare complication involving a 35-year-old patient who underwent a laparoscopic appendicectomy for a perforated appendix. Two days after surgery the patient experienced redness and swelling in the lower abdominal region and oliguria. A delayed computer tomography (CT) scan revealed contrast leakage around the bladder spreading within the peritoneal cavity consistent with an intraperitoneal bladder perforation. She underwent urinary catheterisation for 6 days. A follow-up CT cystogram showed no evidence of leakage into the peritoneal cavity. This case highlights the need for thorough preparation prior to laparoscopic surgery and careful manipulation of instruments during routine procedures to minimise the risk of serious patient complications such as the aforementioned.

New approaches in the management of male breast cancer.

Male breast cancer (MBC) is a rare condition that accounts for 0.1% of all male cancers. Our current evidence base for treatment is derived from female breast cancer (FBC) patients. Risk factors for MBC include age, genetic predisposition, race, sex hormone exposure, and environmental factors. Most patients present later and with more advanced disease than comparable FBC patients. Tumors are likely to be estrogen receptor and progesterone receptor positive, with the most common histologic type being invasive ductal carcinoma. Triple assessment remains the criterion standard for diagnosis. Primary MBC is mostly managed initially by simple mastectomy, with the option of breast conserving surgery, which carries an increased risk of recurrence. Sentinel node biopsy is recommended as the initial procedure for staging the axilla. Reconstructive surgery focuses on achieving primary skin closure, and radiotherapy largely follows treatment protocols validated in FBC. We recommend chemotherapy for men with more advanced disease, in particular, those with estrogen receptor negative histology. MBC responds well to endocrine therapy, although it is associated with significant adverse effects. Third-generation aromatase inhibitors are promising but raise concerns due to their failure to prevent estrogen synthesis in the testes. Fulvestrant remains unproven as a therapy, and data on trastuzumab is equivocal with HER2 receptor expression and functionality unclear in MBC. In metastatic disease, drug-based hormonal manipulation remains a first-line therapy, followed by systemic chemotherapy for hormone-refractory disease. Prognosis for MBC has improved over the past 30 years, with survival affected by disease staging, histologic classification, and comorbidity.

Is the presence of small volume disease in the sentinel node an indication for axillary clearance?

The finding of micrometastases (M(i)) and isolated tumour cells (ITC) within the axillary lymph nodes of patients with breast cancer has raised the question whether either/both have some prognostic significance. Several studies have shown that compared to node-negative patients, prognosis is significantly poorer in patients with M(i) and ITC. The fact that patients with M(i)/ITC in their sentinel lymph nodes have a systemic relapse risk that is higher than that of node-negative patients may be considered as an indication for systemic treatment. Most studies in the literature suggest that in patients with M(i) or ITC in their sentinel nodes who receive systemic therapy and whole breast radiotherapy, the risk of axillary relapse without axillary lymphadenectomy is under 2%. Given the fact that axillary lymphadenectomy is associated with a 5-25% risk of lymphoedema, we propose that a policy of close follow up should be adopted in these patients rather than axillary lymphadenectomy.

Sporadic medullary thyroid carcinoma with a pedunculated intraluminal internal jugular vein recurrence: A case report and literature review.

Medullary thyroid carcinoma (MTC) is an uncommon usually slowly progressing neuroendocrine tumour that arises from calcitonin (CT) producing parafollicular C cells of the thyroid gland. It accounts for approximately 5% of all thyroid cancers. The majority of MTCs are sporadic (75%) whilst 25% are part of the MEN 2 hereditary syndrome (MEN 2A and MEN 2B and familial MTC). Mutations of the proto-oncogene, RET (Rearranged during Transfection), found on chromosome 10q11, are present in more than 95% of hereditary MTCs and about 25% of sporadic MTCs. MTC metastasizes primarily via lymphatic spread, to central, and lateral nodal neck compartments and the anterior and superior mediastinum. Distant haematogenous spread targets the lungs, liver, bone and brain, and is presumed to be secondary to a lymphatic pathway. There are no previously documented reports of a focal pedunculated metastases located within the jugular vein. We present the first reported case of a metastatic MTC lesion found in the right internal jugular vein in a man with recurrent MTC.