Investigating novel mechanisms of metastasis in endocrine resistant breast cancer.

Breast cancer is the commonest solid tumour in European females. Treatment of breast cancer using anti-oestrogenic agents provides a template for the development of targeted therapies, both in breast cancer and other neoplastic diseases. Tamoxifen remains the treatment of choice for pre-menopausal breast cancer patients who express an oestrogen receptor, while a newer class of drug, aromatase inhibitors, are the first-line treatment for post-menopausal patients. In spite of these advances, up to 25% of breast cancer patients will eventually develop a recurrent tumour and metastatic disease. The mechanism by which cancers can overcome this endocrine therapy is poorly understood. Cancer stem cell theory would suggest that there are sub-populations of cells within tumours that are highly tumourigenic and give rise to subsequent, resistant disease. However, this does not fully explain why some tumours may be initially steroid responsive, but can slowly adapt to overcome and even utilise these treatments to drive tumour growth. One of the major players in these adaptive responses is steroid receptor co-activator 1 (SRC-1). Initially described as an ER co-activator, SRC-1 was subsequently shown to interact with a number of transcription factors, including those downstream of an activated MAP kinase pathway, to drive recurrence and metastasis. Furthermore, SRC-1 is central to the metastatic phenomenon. Hypothesis The aim of this work was to use next-generation sequencing techniques such as chromatin immunoprecipitation sequencing and ribonucleic acid seqencing to identify SRC-1 dependent and independent mechanisms by which breast cancer can adapt to and evade therapies such as tamoxifen. Results SRC-1 ChIP sequencing in a tamoxifen resistant cell line identified a disintegrin and metalloproteinase 22 (ADAM22) as a target of SRC-1. Using functional assays and patient data, a role for ADAM22 was established in metastatic, endocrine resistant breast cancer. Expression of ADAM22 may be driven by treatment with tamoxifen. Having established a functional role for ADAM22, a natural ligand (LGI1) which regulates ADAM22 was identified. This was used as a template to develop a peptide mimetic to inhibit the functional role of ADAM22. This was confirmed using in vitro models and has now progressed to in vivo testing. It was noted that SRC-1 may also have a role in repressing gene expression. Analysis of functional assays and patient data showed that SRC-1 may suppress markers of luminal A disease, such as PAWR and CD24 in the resistant setting. This is the first time that SRC-1 has been identified as a co-repressor. Furthermore, it suggests that master-regulatory proteins such as SRC-1 may have a far wider role in both promoting metastasis and suppressing markers of good prognosis than previously realised. Lastly, RNA sequencing on matched patient primary, nodal and distant metastatic tissue was performed to identify alterations in gene expression that may occur following endocrine treatment. It was noted that there was a significantly altered gene expression profile in the metastases as compared with the primary and nodal tumours. There was over-representation of extra-cellular matrix genes the metastases as compared with the primary tumours. In addition, there was a common signature of genes that were up-regulated in metastases as compared with the primary tumours, including the cytokeratin KRT19 and the developmental gene CELSR1. This was confirmed using an in vivo model and in matched patient samples. Conclusion SRC-1 is a master-regulator that can utilise continued treatment with endocrine therapies to promote tumour metastasis. Furthermore, it can actively suppress genes which are striving to maintain a normal cell. The interaction of cancer cells with the ECM is central to metastasis. Understanding this cellular plasticity may allow the development of new therapeutic and diagnostic technologies

Breaking Barriers to Successful Implementation of Day Case Laparoscopic Cholecystectomy.

Laparoscopic cholecystectomy is a common procedure performed in both emergency and elective settings. Our aim was to analyse the trends in laparoscopic surgery in Ireland in the public and private healthcare systems. In particular we studied the trend in day case laparoscopic cholecystectomy. National HIPE data for the years 2010-2012 was obtained. Similar datasets were obtained from the three main health insurers. 19,214 laparoscopic cholecystectomies were carried out in Ireland over the 3-year period. More procedures were performed in the public system than the private system from 2010-2012. There was a steady increase in surgeries performed in the public sector, while the private sector remained static. Although the ALOS was significantly higher in the public sector, there was an increase in the rate of day case procedures from 416 (13%) to 762 (21.9%). The day case rates in private hospitals increased only slightly from 29 (5.1%) in 2010 to 40 (5.9%) in 2012. Day case laparoscopic cholecystectomy has been shown to be a safe procedure, however significant barriers remain in place to the implementation of successful day case units nationwide

ADAM22/LGI1 complex as a new actionable target for breast cancer brain metastasis

Background: Metastatic breast cancer is a major cause of cancer-related deaths in woman. Brain metastasis is a common and devastating site of relapse for several breast cancer molecular subtypes, including oestrogen receptor-positive disease, with life expectancy of less than a year. While efforts have been devoted to developing therapeutics for extra-cranial metastasis, drug penetration of blood–brain barrier (BBB) remains a major clinical challenge. Defining molecular alterations in breast cancer brain metastasis enables the identification of novel actionable targets.Methods: Global transcriptomic analysis of matched primary and metastatic patient tumours (n = 35 patients, 70 tumour samples) identified a putative new actionable target for advanced breast cancer which was further validated in vivo and in breast cancer patient tumour tissue (n = 843 patients). A peptide mimetic of the target's natural ligand was designed in silico and its efficacy assessed in in vitro, ex vivo and in vivo models of breast cancer metastasis.Results: Bioinformatic analysis of over-represented pathways in metastatic breast cancer identified ADAM22 as a top ranked member of the ECM-related druggable genome specific to brain metastases. ADAM22 was validated as an actionable target in in vitro, ex vivo and in patient tumour tissue (n = 843 patients). A peptide mimetic of the ADAM22 ligand LGI1, LGI1MIM, was designed in silico. The efficacy of LGI1MIM and its ability to penetrate the BBB were assessed in vitro, ex vivo and in brain metastasis BBB 3D biometric biohybrid models, respectively. Treatment with LGI1MIM in vivo inhibited disease progression, in particular the development of brain metastasis.Conclusion: ADAM22 expression in advanced breast cancer supports development of breast cancer brain metastasis. Targeting ADAM22 with a peptide mimetic LGI1MIM represents a new therapeutic option to treat metastatic brain disease

Natural orifice transluminal endoscopic surgery (NOTES): the future of surgery

Natural orifice transluminal endoscopic surgery (NOTES) is an exciting and rapidly evolving area of surgery that may eventually provide the previously unattainable goal of scarless, and potentially pain free, surgery. Although a patent detailing the prospective therapy was filed in 1994, it was not until 2004 that interest flourished in this area, progressing quickly from largely investigative techniques in porcine models to the first two human NOTES cholecystectomies, which were performed almost simultaneously in Europe and the USA in April 2007.</p

The safety and acceptability of using telehealth for follow-up of patients following cancer surgery: a systematic review

Introduction: Although virtual consultations have played an increasing role in delivery of healthcare, the COVID-19 pandemic has hastened their adoption. Furthermore, virtual consultations are now being adopted in areas that were previously considered unsuitable, including post-operative visits for patients undergoing major surgical procedures, and surveillance following cancer operations. This review aims to examine the feasibility, safety, and patient satisfaction with virtual follow-up appointments after cancer operations. Methods: A systematic review was conducted along PRISMA guidelines. Studies where patients underwent surgical resection of a malignancy with at least one study arm describing virtual follow-ups were included. Studies were assessed for quality. Outcomes including adverse events, detection of recurrence and patient and provider satisfaction were assessed and compared for those undergoing virtual or in-person post-operative visits. Results: Eleven studies, with 3369 patients were included. Cancer types included were gynecological, colorectal, esophageal, lung, thyroid, breast, prostate and major HPB resections. Detection of recurrence and readmission rates were similar when comparing virtual consultations with in-person visits. Most studies showed high patient and healthcare provider satisfaction with virtual consultations following cancer resection. Concerns were raised about the integration of virtual consultations into workflows in fee-for-service settings, where reimbursement for virtual care may be an issue. Conclusion: Virtual follow-up care can provide timely and safe consultations in surgical oncology. Virtual consultations are as safe as in-person visits for assessing complications and recurrence. Where appropriate, virtual consultations can safely be integrated into the post-operative care pathway for those undergoing resection of malignancy.</p

Omission of intraoperative pyloric procedures in minimally invasive esophagectomy: assessing the impact on patients

Pyloroplasty or pyloromyotomy is often undertaken during esophagectomy to aid gastric emptying postoperatively. Minimally invasive esophagectomy (MIE) frequently omits a pyloric procedure. The impact on perioperative outcomes and the need for subsequent interventions is unclear. This study assesses the requirements for endoscopic balloon dilation of the pylorus (EPD) following MIE. Patients undergoing MIE from 2016 to 2020 were reviewed. Patients undergoing open resection, or an intraoperative pyloric procedure were excluded. Demographic, clinical and pathological data were reviewed. Univariable and multivariable analysis were performed as appropriate. In total, 171 patients underwent MIE. There were no differences in age (median 65 vs. 65 years, P = 0.6), pathological stage (P = 0.10) or ASA status (P = 0.52) between those requiring and not requiring endoscopic pyloric dilation (EPD). Forty-three patients (25%) required EPD, with a total of 71 procedures. Twenty-seven patients (16%) had EPD on their index admission. Seventy-five patients (43%) had a postoperative complication. Higher ASA status was associated with increased requirement for EPD (odds ratio 10.8, P = 0.03). On multivariable analysis, there was no association between the need for a pyloric procedure and overall survival (P = 0.14). Eight patients (5%) required insertion of a feeding jejunostomy in the postoperative period, with no difference between those with or without EPD (P = 0.11). Two patients required subsequent surgical pyloromyotomy for delayed gastric emptying. Although pyloroplasty or pyloromyotomy can safely be excluded during MIE, a quarter of patients will require postoperative EPD procedures. The impact of excluding pyloric procedures on gastric emptying requires further study. </p

PAR-4 – a novel marker of luminal A breast cancer – is down-regulated by the steroid receptor co-activator SRC-1

Introduction: Prostate apoptosis response-4 (PAR-4, PAW-R, PKC apoptosis WT1 regulator) is a gene coding for a tumour suppressor protein involved in the selective apoptosis of cancer cells. Although well described in renal cell carcinomas and prostate cancer, little is known about its role and regulation in breast cancer. Methods: Western blotting techniques looked at the association between PAR-4 expression and breast cancer sub-type, and at the effects of steroid receptor co-activator-1 (SRC-1) on PAR-4 expression. Functional assays (3D cell culture and adhesion independent growth) investigated the role of PAR-4 in breast cancer cells and immunohistochemistry looked at the clinical correlations of PAR-4 positivity in our patient cohort. Results: The results show that PAR-4 is down-regulated by SRC-1 in endocrine-resistant cell lines and they validate its use as a marker of good disease-free survival, both in vitro and in vivo. In addition, the functional assays provide evidence that PAR-4 may play a role in maintaining a well-differentiated phenotype in breast cancer cell lines. Conclusion: The results suggest that PAR-4 expression is a marker of good disease-free survival, or conversely, that the loss of PAR-4 expression would signal tumour progression to a more aggressive phenotype. The identification of such markers is important in the development of more personalised forms of treatments.</p

Nodal yield <15 is associated with reduced survival in esophagectomy and is a quality metric

Background: Surgical resection after neoadjuvant therapy remains the cornerstone of curative management of esophageal adenocarcinoma and is frequently used for squamous cell carcinoma. The optimal extent of lymphadenectomy and whether increasing lymph node yields confer a survival benefit remains unclear. Guidelines suggest resecting and examining a minimum of 15 lymph nodes at esophagectomy. This study assessed the impact of lymph node yield and lymph node ratio (LNR) on survival, identifying factors influencing nodal yield and radicality of resection. Methods: All patients undergoing esophagectomy with curative intent at a single institution (stage 1-4 inclusive) from January 1, 2010, to December 31, 2020, were reviewed. Clinical and pathologic variables were interrogated. LNR was calculated by dividing positive lymph nodes by the total nodes resected. Results: Esophagectomy was performed in 397 patients, with 288 undergoing minimally invasive esophagectomy (MIE). Margin status (hazard ratio [HR], 1.80; 95% CI, 1.15-2.83; P Conclusions: Textbook lymphadenectomy is associated with improved survival. Low lymph node yield and a high LNR are associated with reduced overall survival. A LNR of <0.05 is associated with significant survival benefit. A minimum nodal yield of 15 should remain the standard of care.</p

Nodal yield <15 is associated with reduced survival in esophagectomy and is a quality metric

Background: Surgical resection after neoadjuvant therapy remains the cornerstone of curative management of esophageal adenocarcinoma and is frequently used for squamous cell carcinoma. The optimal extent of lymphadenectomy and whether increasing lymph node yields confer a survival benefit remains unclear. Guidelines suggest resecting and examining a minimum of 15 lymph nodes at esophagectomy. This study assessed the impact of lymph node yield and lymph node ratio (LNR) on survival, identifying factors influencing nodal yield and radicality of resection. Methods: All patients undergoing esophagectomy with curative intent at a single institution (stage 1-4 inclusive) from January 1, 2010, to December 31, 2020, were reviewed. Clinical and pathologic variables were interrogated. LNR was calculated by dividing positive lymph nodes by the total nodes resected. Results: Esophagectomy was performed in 397 patients, with 288 undergoing minimally invasive esophagectomy (MIE). Margin status (hazard ratio [HR], 1.80; 95% CI, 1.15-2.83; P Conclusions: Textbook lymphadenectomy is associated with improved survival. Low lymph node yield and a high LNR are associated with reduced overall survival. A LNR of <0.05 is associated with significant survival benefit. A minimum nodal yield of 15 should remain the standard of care.</p