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When working with patients who have locally advanced rectal cancer (LARC) the ability to undertake minimally invasive procedures becomes more challenging but no less important for patient outcomes. We performed a minimally invasive approach to surgery for LARC invading the posterior vagina and sacrum. The patient was a 75-year-old lady who presented with a locally advanced rectal tumour staged T4N2 with invasion into the posterior wall of the vagina and coccyx/distal sacrum. We introduce a robotic abdominoperineal resection, posterior vaginectomy and abdomino-lithotomy sacrectomy using a purely perineal approach with no robotic adjuncts or intracorporal techniques. Final histology showed moderately differentiated adenocarcinoma invading the vagina and sacrum, ypT4b N0 TRG2 R0 and the patient entered surgical follow-up with no immediate intra- or postoperative complications. A literature review shows the need for more minimally invasive techniques when relating to major pelvic surgery and the benefits of a purely perineal approach include less expensive resource use, fewer training requirements and the ability to utilise this technique in centres that are not robotically equipped.
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AIM: Patient reported outcome measures (PROMs) are self-reported measures of patients' health status or health-related quality of life at a single point in time. We aimed to evaluate the use of a colorectal PROM and conducted a focus group to further explore this and other unmet needs in our patient population treated surgically for colorectal cancer. METHOD: A multidisciplinary research group consisting of colorectal surgeons, nurse specialists, psychologists, sociologists and patient representatives devised a composite tool of new and existing outcome measures which was piloted in our local population (n = 35). Participants were subsequently invited to attend a semi-structured focus group during which the PROM was reviewed and an unmet needs analysis was performed. Thematic analysis of focus group transcripts was undertaken for emergent themes. RESULTS: Initial consensus was for a tool including the EQ-5D, Functional Assessment of Cancer Therapy - Colorectal (FACT-C), the distress thermometer, a validated measure of stigma, an unmet needs analysis, and questions assessing the psychological impact of cancer. Median and interquartile range values suggested that all metrics were discriminatory with the exception of FACT-C. All participants agreed that the tool was acceptable and reflected the current state of their health and emotions. Thematic analysis of focus group transcripts identified four major themes: physical symptoms, emotional response, information provision and coping mechanisms. CONCLUSION: Through expert consensus, local piloting and patient focus groups we have evaluated a novel PROM for colorectal cancer. Furthermore, through our direct engagement with patients we have identified several unmet needs which we are currently exploring within the clinical service.
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Colectomia/psicologia , Neoplasias Colorretais/psicologia , Avaliação das Necessidades , Medidas de Resultados Relatados pelo Paciente , Protectomia/psicologia , Adaptação Psicológica , Adulto , Idoso , Neoplasias Colorretais/cirurgia , Efeitos Psicossociais da Doença , Emoções , Feminino , Grupos Focais , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Anastomotic complications following colorectal surgery are associated with significant morbidity and mortality. For patients in whom systemic sepsis is absent or well controlled, minimal access techniques, such as endoscopic therapies, are being increasingly employed to reduce the morbidity of surgical re-intervention. In this review, we aim to assess the utility of endoscopic management in the acute setting of colorectal anastomotic complications, focusing on anastomotic leak. METHOD: A literature search was performed for published full text articles using the PubMed, Cochrane and Scopus databases using the search criteria string "colorectal anastomotic ("leak" OR "bleed"), "endoscopy", endoscopic management". Additional papers were detected by scanning the references of relevant papers. Data were extracted from each study by two authors onto a dedicated pro-forma. Given the nature of the data extracted, no meta-analysis was performed. RESULTS: A total of 89 papers were identified, 16 of which were included in this review; an additional 14 papers were obtained from reference searches. In patients who are not physiologically compromised, there are promising data regarding the salvage rate of stents, over-the-scope endoscopic clips, vacuum therapy and fibrin glue in the early management of colorectal anastomotic leak. There is no consensus regarding the optimal approach, and data to assist the physician in patient selection are lacking. Whilst data on salvage (i.e. healing and avoidance of surgery) are well understood, no data on functional outcomes are reported. CONCLUSION: Endoscopic therapy in the management of stable patients with colorectal anastomotic leaks appears safe and in selected patients is associated with high rates of technical success. Challenges remain in selecting the most appropriate strategy, patient selection, and understanding the functional and long-term sequelae of this approach. Further evidence from large prospective cohort studies are needed to further evaluate the role of these novel strategies.
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Anastomose Cirúrgica/efeitos adversos , Fístula Anastomótica/cirurgia , Cirurgia Colorretal/efeitos adversos , Endoscopia/métodos , Complicações Pós-Operatórias/cirurgia , Terapia de Salvação/métodos , Fístula Anastomótica/etiologia , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Humanos , Reto/cirurgia , StentsAssuntos
Abdome/cirurgia , Adenocarcinoma/cirurgia , Dissecação/métodos , Recidiva Local de Neoplasia/cirurgia , Neoplasias Retais/cirurgia , Sacro/cirurgia , Procedimentos Cirúrgicos Operatórios/métodos , Adenocarcinoma/diagnóstico , Idoso , Diagnóstico por Imagem/métodos , Feminino , Humanos , Recidiva Local de Neoplasia/diagnóstico , Estadiamento de Neoplasias/métodos , Neoplasias Retais/diagnósticoRESUMO
BACKGROUND: The aim was to establish the feasibility of using a tissue stabilization gel (Allprotect™) as an alternative to liquid nitrogen to facilitate collection of clinical samples for translational research. METHODS: Tumour samples from patients undergoing surgery for primary or metastatic colorectal cancer were either snap-frozen in liquid nitrogen or stored in Allprotect™ under a number of different conditions. Sample integrity was compared across different storage conditions by assessing biomolecule stability and function. DNA quality was assessed spectrophotometrically and by KRas genotyping by pyrosequencing. Total RNA retrieval was determined by nanodrop indices/RNA integrity numbers, and quality assessed by reverse transcription-PCR for two representative genes (high-mobility group box 1, HMGB1; carboxylesterase 1, CES1) and two microRNAs (miR122 and let7d). Western blot analysis of HMGB1 and CES1 was used to confirm protein expression, and the metabolic conversion of irinotecan to its active metabolite, SN-38, was used to assess function. RESULTS: Under short-term storage conditions (up to 1 week) there was no apparent difference in quality between samples stored in Allprotect™ and those snap-frozen in liquid nitrogen. Some RNA degradation became apparent in tissue archived in Allprotect™ after 1 week, and protein degradation after 2 weeks. CONCLUSION: In hospitals that do not have access to liquid nitrogen and -80°C freezers, Allprotect™ provides a suitable alternative for the acquisition and stabilization of clinical samples. Storage proved satisfactory for up to 1 week, allowing transfer of samples without the need for specialized facilities. Surgical relevance Access to clinical material is a fundamental component of translational research that requires significant infrastructure (research personnel, liquid nitrogen, specialized storage facilities). The aim was to evaluate a new-to-market tissue stabilization gel (Allprotect™), which offers a simple solution to tissue preservation without the need for complex infrastructure. Allprotect™ offers comparable DNA, RNA and protein stabilization to tissue snap-frozen in liquid nitrogen for up to 1 week. Degradation of biomolecules beyond this highlights its role as a short-term tissue preservative. Allprotect™ has the potential to increase surgeon participation in translational research and surgical trials requiring tissue collection.
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Géis/farmacologia , Preservação de Tecido/métodos , Pesquisa Translacional Biomédica/métodos , Análise de Variância , Neoplasias Colorretais/cirurgia , DNA/metabolismo , Estudos de Viabilidade , Humanos , RNA/metabolismo , Manejo de Espécimes/métodosRESUMO
INTRODUCTION: Pelvic exenteration (PE) is now the standard of care for locally advanced (LARC) and locally recurrent (LRRC) rectal cancer. Reports of the significant short-term morbidity and survival advantage conferred by R0 resection are well established. However, longer-term outcomes are rarely addressed. This systematic review focuses on long-term oncosurgical and quality of life (QoL) outcomes following PE for rectal cancer. METHODS: A systematic review of the PubMed®, Cochrane Library, MEDLINE® and Embase® databases was conducted, in accordance with the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. Studies were included if they reported long-term outcomes following PE for LARC or LRRC. Studies with fewer than 20 patients were excluded. FINDINGS: A total of 25 papers reported outcomes for 5,489 patients. Of these, 4,744 underwent PE for LARC (57.5%) or LRRC (42.5%). R0 resection rates ranged from 23.2% to 98.4% and from 14.9% to 77.8% respectively. The overall morbidity rates were 17.8-87.0%. The median survival ranged from 12.5 to 140.0 months. None of these studies reported functional outcomes and only four studies reported QoL outcomes. Numerous different metrics and timepoints were utilised, with QoL scores frequently returning to baseline by 12 months. CONCLUSIONS: This review demonstrates that PE is safe, with a good prospect of R0 resection and acceptable mortality rates in selected patients. Morbidity rates remain high, highlighting the importance of shared decision making with patients. Longer-term oncological outcomes as well as QoL and functional outcomes need to be addressed in future studies. Development of a core outcomes set would facilitate better reporting in this complex and challenging patient group.
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INTRODUCTION: Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) is offered in specialist centres as a treatment for peritoneal surface tumours. Despite its demonstrated efficacy, intra-abdominal recurrence occurs in 31-57% of patients. The aim of this study is to review the early and long-term outcomes in patients who undergo repeat CRS/HIPEC. MATERIALS AND METHODS: A retrospective review of a prospectively maintained database of patients who had undergone repeat CRS/HIPEC for appendiceal neoplasms and colorectal peritoneal metastases (CRPM) from 2003 to 2019 was performed at a single specialist centre. Data pertaining to both short term outcomes and survival were evaluated. RESULTS: Of 1259 patients who had undergone CRS/HIPEC, 84(6.7%) underwent repeat surgery: 45(53.6%) had pseudomyxoma peritonei (PMP) secondary to low grade appendiceal mucinous neoplasms (LAMN), 21(25.0%) had appendix carcinoma and 18(21.4%) had CRPM. Demographics, intra-operative findings and short-term outcomes were comparable across tumour types and between procedures. Median (95% CI) interval between procedures was 22.7(18.9-26.6) months and was comparable between tumour types. Median (95%CI) overall survival was not reached for the cohort overall or for those with PMP, but was 61.0(32.6-89.4) months for those with appendix cancer and 76.9(47.4-106.4) months for CRPM (p=<0.001). Survival was favourable in the PMP group (HR [95%CI] 0.044 [0.008-0.262]; p = 0.000) and unfavourable in the CC2-3 at index CRS procedure group (HR [95%CI] 25.612 [2.703-242.703]; p = 0.005). CONCLUSION: Our findings demonstrate that repeat cytoredutive surgery with HIPEC can result in favourable survival, especially for patients with PMP when complete cytoreduction is achieved at index operation. We recommend that detailed patient assessment is performed through an expert multidisciplinary team meeting (MDT).
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Adenocarcinoma Mucinoso/mortalidade , Neoplasias do Apêndice/mortalidade , Neoplasias Colorretais/mortalidade , Procedimentos Cirúrgicos de Citorredução/mortalidade , Hipertermia Induzida/mortalidade , Recidiva Local de Neoplasia/mortalidade , Neoplasias Peritoneais/mortalidade , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Apêndice/patologia , Neoplasias do Apêndice/terapia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Neoplasias Peritoneais/patologia , Neoplasias Peritoneais/terapia , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Electrosurgery for dissection and haemostasis should be associated with minimal thermal spread to surrounding tissues. This study investigated lateral thermal spread following ex vivo application of four commonly utilized instruments. METHODS: Monopolar and bipolar diathermy (power settings 20, 30 and 40 W), the Harmonic Scalpel and Ligasure (power settings 1, 3 and 5) were studied after application to standardized porcine muscle cuts for 5, 10 or 15 s. Temperatures generated at the tips of the instruments, in the tissues adjacent to the tips and 1 cm away were recorded. RESULTS: Following a 5-s application at the highest power setting, the highest mean(s.d.) temperatures recorded at the tips of monopolar and bipolar diathermy, Harmonic Scalpel and Ligasure instruments were 78.9(4.1), 41.9(2.2), 47.6(2.5) and 44.2(2.6) degrees C respectively. Temperatures at the instrument tips after use for 15 s remained above 42 degrees C for 55, 25, 15 and 15 s respectively. Applying monopolar diathermy (10 s at 40 W) resulted in a temperature recording of 59.2(2.2) degrees C in tissues 1 cm away from the tip of the instrument. CONCLUSION: The degree of lateral thermal spread varied with instrument type, power setting and application time. Monopolar diathermy resulted in the highest temperatures and the greatest degree of thermal spread in tissues.
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Diatermia/instrumentação , Eletrocirurgia/instrumentação , Instrumentos Cirúrgicos/normas , Animais , Hemostasia Cirúrgica , Suínos , Temperatura , Condutividade TérmicaRESUMO
INTRODUCTION: Limited knowledge of surgical device and service costs restricts a surgeon's ability to make cost efficient choices and contribute to the efficiency savings required by the NHS to reduce the financial deficit. This study aims to assess how aware surgeons are of surgical equipment and regularly used services. METHODS: A single sided hard copy questionnaire asking for the estimate cost of 24 surgical devices/services was handed out to individuals at two separate UK annual conferences. Items and services which are regularly used and/or clinically significant were selected and, where possible, alternatives to those items were included for comparison. Participants were also asked for their grade and specialty. An estimate was deemed correct if it was within 20% of the actual cost. Planned subgroup analyses for grade and specialty were performed. RESULTS: The 143 participants consisted of 23 (16%) consultants, 39 (27%) registrars, 33 (23%) SHOs and 48 (34%) foundation doctors. Of the 95 participants who were SHO grade or more senior, 67 (71%) work within general surgery. Across all items, only 9.6% of estimates were correct. There was no statistically significant difference between training levels (consultant 11.5%, registrar 10.1%, SHO 8.6%, foundation 8.9%; pâ¯=â¯0.253). Participants were significantly less successful in correctly estimating the cost of high value (>£150 [USD $198; EUR 175]) items (8.5% vs. 11.1%); pâ¯=â¯0.011, and the cost of devices as compared to the cost of services (7.4% vs. 15.0%); pâ¯=â¯0.001. CONCLUSION: Surgeons across all grades and specialties have poor knowledge of device and service costs. It is important that this improves in order to allow surgeons to make a meaningful contribution to NHS efficiency savings by making informed decisions about their use of devices and services.
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Consultores/psicologia , Gastos em Saúde/estatística & dados numéricos , Conhecimentos, Atitudes e Prática em Saúde , Cirurgiões/psicologia , Equipamentos Cirúrgicos/economia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Reino UnidoRESUMO
BACKGROUND: Sphingolipids have been shown to play a key part in cancer cell growth and death and have increasingly become the subject of novel anti-cancer therapies. Acid ceramidase, a sphingolipid enzyme, has an important role in the regulation of apoptosis. In this review we aim to assess the current evidence supporting the role of sphingolipids in cancer and the potential role that acid ceramidase may play in cancer treatment. METHODS: A literature search was performed for published full text articles using the PubMed, Cochrane and Scopus databases using the search criteria string "acid ceramidase", "sphingolipid", "cancer". Additional papers were detected by scanning the references of relevant papers. A summary of the evidence for each cancer subgroup was then formed. Given the nature of the data extracted, no meta-analysis was performed. RESULTS: Over expression of acid ceramidase has been demonstrated in a number of human cancers. In vitro data demonstrate that manipulation of acid ceramidase may present a useful therapeutic target. In the clinical setting, a number of drugs have been investigated with the ability to target acid ceramidase, with the most promising of those being small molecular inhibitors, such as LCL521. CONCLUSION: The role of the sphingolipid pathway in cancer is becoming very clearly established by promoting ceramide accumulation in response to cancer or cellular stress. Acid ceramidase is over expressed in a variety of cancers and has a role as a potential target for inhibition by novel specific inhibitors or off-target effects of traditional anti-cancer agents. Further work is required to develop acid ceramidase inhibitors safe for progression to clinical trials.
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Ceramidase Ácida/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Esfingolipídeos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Humanos , Neoplasias/tratamento farmacológicoRESUMO
INTRODUCTION: Surgical trainees are reporting barriers to training in gastrointestinal (GI) endoscopy. This snapshot survey aimed to gather data on variation in access to quality GI endoscopy training for Colorectal and Upper Gastrointestinal (GI) surgical trainees across the UK and Ireland. MATERIALS AND METHODS: An online 20-point survey was designed and distributed nationally to surgical trainee members of the Association of Surgeons in Training (ASiT), Dukes and The Roux Group (formerly Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland Trainees). The survey was designed in collaboration with The Roux Group for Upper GI trainees and the Dukes' Club for Colorectal trainees. RESULTS: 218 responses were received, most with a Colorectal or Upper GI sub-specialty interest (colorectal 56.0%; upper GI surgery 25.7%). Only 28.6% of trainees attended a dedicated training endoscopy list at least once a week with 28.1% not attending any at all. Less than half of trainees reported having endoscopy formally timetabled on rotas (36.9%). Most trainees (88.0%) encountered difficulties in gaining endoscopy training including lack of available lists (77.2%), conflicting operative commitments (59.4%), preferential allocation of lists to gastroenterology trainees (57.9%) and resistance from endoscopy departmental leads (38.6%). Regarding JAG accreditation, 77.1% respondents felt it should be mandatory prior to CCT with 80.3% believing this would lead to better access to dedicated endoscopy training equivalent to gastroenterology trainees. 93.1% trainees felt that attaining JAG accreditation by surgical trainees was important to patient care. DISCUSSION: This study demonstrates significant barriers in accessing GI endoscopy training for general surgical trainees which urgently needs to be improved. In order to meet JAG training requirements for surgical trainees, a multifaceted collaborative approach from surgical and gastroenterology training bodies, local JAG trainers and the General Surgery SAC and JCST is required. This is to ensure that endoscopy is promoted and a robust model of training is successfully designed and delivered to general surgery trainees.
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Educação Médica/estatística & dados numéricos , Endoscopia Gastrointestinal/educação , Cirurgia Geral/educação , Cirurgiões/educação , Adulto , Competência Clínica , Feminino , Humanos , Irlanda , Masculino , Estudos Prospectivos , Inquéritos e Questionários , Reino UnidoRESUMO
Clostridium difficile induces mucosal inflammation via secreted toxins A and B and initial interactions between the toxins and intestinal epithelial cells (which lead to loss of barrier function) are believed to be important in disease pathogenesis. Secreted toxin-specific antibodies may inhibit such interactions. Using the Caco-2 epithelial cell line, we have investigated the use of an anti-toxin A monoclonal antibody (ATAA) in providing protection against toxin A-mediated disruption of epithelial barrier function (assessed by measurement of transepithelial electrical resistance and luminal to basolateral flux of labelled dextran). In contrast to free antibody, ATAA conjugated to sepharose beads was more effective in neutralizing the activity of purified toxin A. Sepharose bead-conjugated ATAA was subsequently used to investigate the contribution of toxin A in epithelial injury mediated by C. difficile supernatant samples (containing toxins A, B and other products). Loss of barrier function mediated by apical application of supernatant samples of reference and epidemic 027 strains of C. difficile was abrogated by neutralization of toxin A. However, this was not the case when the supernatant samples were applied to the basal surface of epithelial monolayers. In conclusion, our studies have shown that (i) sepharose bead-conjugated ATAA is more effective in neutralizing toxin A than free antibody and (ii) when the apical (luminal) surface of epithelial monolayers is exposed to the secretory products of reference and 027 strains of C. difficile, toxin A is required for the initial injury that leads to loss of barrier function.
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Anticorpos Monoclonais/farmacologia , Clostridioides difficile/patogenicidade , Enterotoxinas/toxicidade , Células Epiteliais/efeitos dos fármacos , Imunotoxinas/farmacologia , Intestinos/efeitos dos fármacos , Animais , Toxinas Bacterianas , Células CACO-2 , Chlorocebus aethiops , Humanos , Mucosa Intestinal/efeitos dos fármacos , Sefarose/farmacologia , Células Vero/imunologiaRESUMO
Excellent surgical trainers play a key role in teaching, mentoring and inspiring the next generation of trainee surgeons. Although there are differences in approach, personality and technique among trainers, common themes exist for those that truly shine as examples of good training. The good surgical trainer has long been the "unsung hero" of patient safety, inspiring and imparting wisdom and skill in trainee surgeons, and instilling a sense of confidence and compassion. In order to recognise exceptional trainers, the Association of Surgeons in Training (ASiT) introduced the Silver Scalpel Award in 2000. The award acknowledges talented trainers who go the "extra mile" for their trainees, and the selection process includes both written nominations and structured interviews with the nominees. We wished to identify what makes the best trainers excellent, to see if these attributes could be used to develop recommendations on how to train and how to support trainers. Here we present an outline of key attributes of an excellent surgical trainer, based on qualitative synthesis of the interview sheets from Silver Scalpel interviews. These results clearly highlight that good trainers are first and foremost good doctors, and that good training goes hand-in-hand with excellent patient care. This symbiotic relationship between training and patient outcomes should be acknowledged, and trainers should be supported by their employers to empower them to carry out their dual roles of training and patient care to the best of their ability. Trainers are key role models to inspire the next generation of surgeons and exceptional trainers should be celebrated.
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Educação Médica/métodos , Mentores , Especialidades Cirúrgicas/educação , Cirurgiões/educação , Distinções e Prêmios , HumanosRESUMO
BACKGROUND: Next generation sequencing technology has facilitated mapping of the colorectal cancer genotype and furthered our understanding of metastogenesis. The aim of this study was to investigate for conserved and different mutations in the exomes of synchronously resected primary colorectal tumour and liver metastases. This information could potentially be utilised to guide the treatment of advanced disease with the help of biological information from the primary tumour. METHODS: We performed exome sequencing of synchronously resected primary colorectal cancer and colorectal liver metastases as well as normal colonic mucosa and liver parenchyma, from four patients who had received neo-adjuvant chemotherapy, at a depth of 50X using the Ion Proton platform. Raw data was mapped to the reference genome prior to variant calling, annotation and downstream analysis. RESULTS: Exome sequencing identified 585 non-synonymous missense single nucleotide variants (SNVs), of which 215 (36.8%) were unique to the primary tumour, 226 (38.6%) unique to the metastasis and 81 (13.8%) present in patient matched pairs. SNVs identified in the ErbB pathway appear to be concordant between primary and metastatic tumours. CONCLUSION: Only 13.8% of the metastatic exome can be predicted by the genotype of the primary tumour. We have demonstrated concordance of a number of SNVs in the ErbB pathway, which may inform selection of therapeutic agents in advanced colorectal cancer.
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Adenocarcinoma/genética , Colectomia/métodos , Neoplasias Colorretais/genética , DNA de Neoplasias/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Hepáticas/genética , Mutação , Adenocarcinoma/secundário , Adenocarcinoma/terapia , Idoso , Quimioterapia Adjuvante , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Terapia Combinada , Exoma , Feminino , Frequência do Gene , Hepatectomia , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Resultado do TratamentoRESUMO
BACKGROUND: Neoadjuvant chemoradiotherapy (CRT) is used in locally advanced rectal cancer when tumours threaten the circumferential resection margin, with varying response to treatment. This experimental study aimed to identify significantly differentially expressed proteins between patients responding and not responding to CRT, and to validate any proteins of interest. METHODS: Mass spectrometry (with isobaric tagging for relative quantification) analysis of rectal cancers pre- and post-CRT, and at resection. Validation of proteins of interest was performed by assessing tissue microarray (TMA) immunohistochemistry expression in a further 111 patients with rectal cancer. RESULTS: Proteomic data are available via ProteomeXchange with identifier PXD008436. Reduced abundance of contributing peptide ions for acid ceramidase (AC) (log fold change -1.526, pâ¯=â¯1.17E-02) was observed in CRT responders. Differential expression of AC was confirmed upon analysis of the TMAs. Cancer site expression of AC in stromal cells from post-CRT resection specimens was observed to be relatively low in pathological complete response (pâ¯=â¯0.003), and relatively high with no response to CRT (pâ¯=â¯0.017). CONCLUSION: AC may be implicated in the response of rectal cancer to CRT. We propose its further assessment as a novel potential biomarker and therapeutic target. SIGNIFICANCE: There is a need for biomarkers to guide the use of chemoradiotherapy in rectal cancer, as none are in routine clinical use. We have determined acid ceramidase may have a role in radiation response, based on novel proteomic profiling and validation in a wider dataset using tissue microarrays. The ability to predict or improve response would positively select those patients who will derive benefit, prevent delays in the local and systemic management of disease in non-responders, and reduce morbidity associated with chemoradiotherapy.
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Ceramidase Ácida/metabolismo , Biomarcadores Tumorais/metabolismo , Quimiorradioterapia , Terapia Neoadjuvante , Proteínas de Neoplasias/metabolismo , Proteômica , Neoplasias Retais , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Retais/metabolismo , Neoplasias Retais/patologia , Neoplasias Retais/terapiaRESUMO
INTRODUCTION: Abdominal wall reconstruction using posterior component separation with transversus abdominis release (AWTAR) produces a unique post-operative CRP profile, when compared to routine elective colorectal operations. Therefore, we aim to establish the normal post-operative C-reactive protein (poCRP) profile following AWRTAR and reduce the unnecessary invasive interventions in patients already at greater risk of septic complications. METHODS: A retrospective analysis of daily poCRP levels was performed both for patients who underwent uncomplicated AWRTAR (n=12), and a comparator group of uncomplicated open right hemicolectomies (RH) matched for age and sex (n=24). All operations in both groups were performed by a single surgeon from 2013 to 2015. RESULTS: The median (IQR) age was 62 (16) and 67 (16) years respectively, with a higher proportion of males to females in both groups (10:2 vs. 17:7). The poCRP profile follows an initial steep rise, peaking at day 2 followed by a gradual washout phase. The poCRP peak is significantly greater in the AWRTAR group compared to the RH group (274 [95%CI ±25] vs. 160 [95%CI±27]; p=0.0001), with a positive correlation between day 2 CRP levels and operative length (r=0.56). CONCLUSIONS: We have demonstrated that uncomplicated AWRTAR provokes a significantly greater poCRP rise (>200) compared to that well described in the literature for uncomplicated open colectomy. As poCRP is an important marker of post-operative recovery with abnormally high levels associated with septic complications, these data should help clinicians interpret the post-operative clinical course after AWRTAR.
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BACKGROUND: Surgical trainees are expected to demonstrate academic achievement in order to obtain their certificate of completion of training (CCT). These standards are set by the Joint Committee on Surgical Training (JCST) and specialty advisory committees (SAC). The standards are not equivalent across all surgical specialties and recognise different achievements as evidence. They do not recognise changes in models of research and focus on outcomes rather than process. The Association of Surgeons in Training (ASiT) and National Research Collaborative (NRC) set out to develop progressive, consistent and flexible evidence set for academic requirements at CCT. METHODS: A modified-Delphi approach was used. An expert group consisting of representatives from the ASiT and the NRC undertook iterative review of a document proposing changes to requirements. This was circulated amongst wider stakeholders. After ten iterations, an open meeting was held to discuss these proposals. Voting on statements was performed using a 5-point Likert Scale. Each statement was voted on twice, with ≥80% of votes in agreement meaning the statement was approved. The results of this vote were used to propose core and optional academic requirements for CCT. RESULTS: Online discussion concluded after ten rounds. At the consensus meeting, statements were voted on by 25 delegates from across surgical specialties and training-grades. The group strongly favoured acquisition of 'Good Clinical Practice' training and research methodology training as CCT requirements. The group agreed that higher degrees, publications in any author position (including collaborative authorship), recruiting patients to a study or multicentre audit and presentation at a national or international meeting could be used as evidence for the purpose of CCT. The group agreed on two essential 'core' requirements (GCP and methodology training) and two of a menu of four 'additional' requirements (publication with any authorship position, presentation, recruitment of patients to a multicentre study and completion of a higher degree), which should be completed in order to attain CCT. CONCLUSION: This approach has engaged stakeholders to produce a progressive set of academic requirements for CCT, which are applicable across surgical specialties. Flexibility in requirements whilst retaining a high standard of evidence is desirable.
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Certificação/normas , Educação de Pós-Graduação em Medicina/normas , Especialidades Cirúrgicas/educação , Instituições de Caridade , Técnica Delphi , Humanos , Irlanda , Sociedades Médicas , Reino UnidoRESUMO
3'-Azido-3'-deoxythymidine (AZT) is used in the management of acquired immunodeficiency syndrome (AIDS) and AIDS-related complex (ARC). The myelotoxic actions of AZT are well known but its effect on platelets is not clear. We studied the effect of AZT at 1 and 2.5 mg/ml in drinking water on platelets in a murine model of AIDS. Three stages of the disease were examined, as determined by the serum IgM levels and other physical features. As early as 15 days after the initiation of drug treatment, AZT was found to significantly increase platelet production. To ascertain that this activity was authentic, a further study was carried out using uninfected mice. Mice were given AZT at both doses for 15 and 30 days. All mice on AZT had significantly increased numbers of platelets. These increases were dose and time dependent. AZT is therefore a potent inducer of thrombocytosis and may be a potential candidate in the treatment of thrombocytopenia in AIDS.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Trombocitopenia/tratamento farmacológico , Zidovudina/uso terapêutico , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Animais , Medula Óssea/efeitos dos fármacos , Feminino , Células-Tronco Hematopoéticas/efeitos dos fármacos , Imunoglobulina M/análise , Vírus da Leucemia Murina , Leucemia Experimental/complicações , Camundongos , Camundongos Endogâmicos C57BL , Contagem de Plaquetas , Trombocitopenia/etiologia , Zidovudina/efeitos adversosRESUMO
In the modern era of surgery, minimally invasive surgery is increasingly applied for excision of gastrointestinal stromal tumors. Site, size and tumor location are important factors that affect the surgical approach and excision. We performed a laparoendoscopic transgastric enucleation of a 4-cm pericardial endophytic gastrointestinal stromal tumor (GIST) using an energy device. The surgery was successful and post-operative recovery uneventful. No tumor recurrence was detected on surveillance gastroscopy. In the safe hands of a well-trained laparoscopic upper gastrointestinal surgeon, pericardial GIST can be enucleated safely by this method. The avoidance of surgical staplers is not only cost-effective, but also reduces the risk of associated complications.