Small bowel neuroendocrine tumours (SBNETs) are neoplasms arising from the neuroendocrine cells of the small intestine. SBNETs are the most common tumours of the small bowel. Their often unspecific symptoms mean that many patients present late with metastatic disease, most commonly to local lymph nodes, small bowel mesentery, and the liver. Although Somatostatin Analogues (SSAs) can relieve symptoms and slow disease progression, surgical resection remains the only curative option. In this case report, a patient undergoes surgical resection of her primary SBNET and several liver metastases. During the operation it becomes apparent that much of the metastatic liver spread is unresectable, and the aim of the surgery becomes tumour de-bulking. This report reveals the limitations of current SBNET imaging, biomarkers and surgical techniques, and explores recent advances.
{"title":"Advances in the diagnosis and management of small bowel neuroendocrine tumours","authors":"A. Nezhentsev","doi":"10.37707/jnds.v3i1.179","DOIUrl":"https://doi.org/10.37707/jnds.v3i1.179","url":null,"abstract":"Small bowel neuroendocrine tumours (SBNETs) are neoplasms arising from the neuroendocrine cells of the small intestine. SBNETs are the most common tumours of the small bowel. Their often unspecific symptoms mean that many patients present late with metastatic disease, most commonly to local lymph nodes, small bowel mesentery, and the liver. Although Somatostatin Analogues (SSAs) can relieve symptoms and slow disease progression, surgical resection remains the only curative option. In this case report, a patient undergoes surgical resection of her primary SBNET and several liver metastases. During the operation it becomes apparent that much of the metastatic liver spread is unresectable, and the aim of the surgery becomes tumour de-bulking. This report reveals the limitations of current SBNET imaging, biomarkers and surgical techniques, and explores recent advances.","PeriodicalId":184356,"journal":{"name":"Journal of the Nuffield Department of Surgical Sciences","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130811514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Breast cancer accounts for the majority of cancers in women worldwide, and the most common cancer overall in the UK. It is typically treated by a combination of surgical and medical therapies, which commonly include neoadjuvant and/or adjuvant chemotherapy. Neoadjuvant chemotherapy in favour of adjuvant chemotherapy alongside surgery in the treatment of breast cancer confers no overall and disease-free survival advantage. Nonetheless, neoadjuvant chemotherapy is commonly favoured as a first line therapy for breast cancer. The case reported illustrates the potential for fertility considerations to delay treatment where neoadjuvant chemotherapy is the first line treatment for an operable, non-metastatic breast cancer. Here, the time taken for the patient to reach a decision on fertility preservation resulted in significant delays to treatment which, had surgery been chosen as the first line treatment, would have been prevented. This report discusses the evidence for neoadjuvant chemotherapy in favour of adjuvant chemotherapy alongside surgery in breast cancer treatment, and concludes that due to the comparable overall and disease-free survival rate, as well as the continuing upward trend in the average age of primigravida in the UK, fertility considerations present a strong argument in favour of surgery as first line therapy for non-metastatic, operable breast cancer, in favour of neoadjuvant chemotherapy.
{"title":"Neoadjuvant chemotherapy and fertility preservation in breast cancer treatment","authors":"Sara Hosseinzadeh","doi":"10.37707/jnds.v3i1.187","DOIUrl":"https://doi.org/10.37707/jnds.v3i1.187","url":null,"abstract":"Breast cancer accounts for the majority of cancers in women worldwide, and the most common cancer overall in the UK. It is typically treated by a combination of surgical and medical therapies, which commonly include neoadjuvant and/or adjuvant chemotherapy. Neoadjuvant chemotherapy in favour of adjuvant chemotherapy alongside surgery in the treatment of breast cancer confers no overall and disease-free survival advantage. Nonetheless, neoadjuvant chemotherapy is commonly favoured as a first line therapy for breast cancer. The case reported illustrates the potential for fertility considerations to delay treatment where neoadjuvant chemotherapy is the first line treatment for an operable, non-metastatic breast cancer. Here, the time taken for the patient to reach a decision on fertility preservation resulted in significant delays to treatment which, had surgery been chosen as the first line treatment, would have been prevented. This report discusses the evidence for neoadjuvant chemotherapy in favour of adjuvant chemotherapy alongside surgery in breast cancer treatment, and concludes that due to the comparable overall and disease-free survival rate, as well as the continuing upward trend in the average age of primigravida in the UK, fertility considerations present a strong argument in favour of surgery as first line therapy for non-metastatic, operable breast cancer, in favour of neoadjuvant chemotherapy. ","PeriodicalId":184356,"journal":{"name":"Journal of the Nuffield Department of Surgical Sciences","volume":"65 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114697698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Welcome from the Editor-in-Chief","authors":"A. Handa","doi":"10.37707/jnds.v2i4.219","DOIUrl":"https://doi.org/10.37707/jnds.v2i4.219","url":null,"abstract":" \u0000 ","PeriodicalId":184356,"journal":{"name":"Journal of the Nuffield Department of Surgical Sciences","volume":"22 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114470070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cross AR, Sansom S, Roberts I, Cerundolo L, Melero I, De Andrea C, Landecho MF, Klenerman P,Hester J, Issa F Acute respiratory distress syndrome (ARDS) is a defining feature of severe infection with theSARS-CoV-2 virus. Approaches to understand the immune response during COVID-19 are largelyconfined to characterisation of circulating leukocytes, however this approach excludes the mostrelevant cells that are active at the site of infection and injury. The aim of this study was to characterise the immune landscape across the lungs of COVID-19patients. Lung samples from three critical COVID-19 patients were assessed for histopathology,viral load, and distribution using qPCR, in situ hybridisation and immunohistochemistry.Leukocyte distribution was then assessed, and the transcript profile of selected areas examinedagainst the >1800 genes in the Cancer Transcriptome Atlas panel on the NanoString GeoMxDigital Spatial Profiling platform. Lung samples exhibited a spectrum of typical COVID-19 pathology with diffuse alveolar damageconsistent with hyaline membrane and type II pneumocyte hyperplasia, interstitialinflammation, organising pneumonia and thrombi. All tissues tested positive for SARS-CoV-2RNA using qPCR, whilst spatially resolved techniques revealed only few and sparsely distributedcells carrying the viral nucleocapsid protein. Multiplexed immunofluorescence for lymphocytes(CD3+) and macrophages (CD68+) was used to select areas of immune enrichment for spatialtranscriptomic profiling. These targeted analyses highlighted functional pathways involved inthe interferon gamma response, TCR activation and antigen presentation. Comparison acrossimmune-enriched areas identified a heterogeneity in lung infiltrates with spatial separation ofchemokine and complement production. Our data identify pathological immune pathways thatare amenable to therapeutic intervention in critical disease.
Cross AR, Sansom S, Roberts I, Cerundolo L, Melero I, De Andrea C, Landecho MF, Klenerman P,Hester J, Issa F。急性呼吸窘迫综合征(Acute respiratory distress syndrome, ARDS)是sars - cov -2病毒严重感染的典型特征。了解COVID-19期间免疫反应的方法主要局限于循环白细胞的特征，然而这种方法排除了在感染和损伤部位活跃的最相关细胞。这项研究的目的是描述covid -19患者肺部的免疫景观。采用qPCR、原位杂交和免疫组织化学方法对3例COVID-19危重患者肺样本进行组织病理学、病毒载量和分布评估。然后评估白细胞分布，并根据NanoString GeoMxDigital Spatial Profiling平台上的癌症转录组图谱面板中的bbbb1800个基因检查选定区域的转录谱。肺样本表现出典型的COVID-19病理谱，弥漫性肺泡损伤与透明膜一致，II型肺细胞增生，间质性炎症，组织性肺炎和血栓。使用qPCR对所有组织检测SARS-CoV-2RNA呈阳性，而空间分辨技术显示只有少数和稀疏分布的细胞携带病毒核衣壳蛋白。淋巴细胞(CD3+)和巨噬细胞(CD68+)的多重免疫荧光用于选择免疫富集区域进行空间转录组分析。这些有针对性的分析强调了涉及干扰素γ反应、TCR激活和抗原呈递的功能途径。跨免疫富集区比较发现肺浸润具有趋化因子和补体产生的空间分离的异质性。我们的数据确定了病理性免疫途径，可适用于危重疾病的治疗干预。
{"title":"Spatial heterogeneity of the immune compartment within the lungs of critical COVID-19 patients","authors":"Amy Cross","doi":"10.37707/jnds.v2i4.214","DOIUrl":"https://doi.org/10.37707/jnds.v2i4.214","url":null,"abstract":"Cross AR, Sansom S, Roberts I, Cerundolo L, Melero I, De Andrea C, Landecho MF, Klenerman P,Hester J, Issa F \u0000Acute respiratory distress syndrome (ARDS) is a defining feature of severe infection with theSARS-CoV-2 virus. Approaches to understand the immune response during COVID-19 are largelyconfined to characterisation of circulating leukocytes, however this approach excludes the mostrelevant cells that are active at the site of infection and injury. \u0000The aim of this study was to characterise the immune landscape across the lungs of COVID-19patients. Lung samples from three critical COVID-19 patients were assessed for histopathology,viral load, and distribution using qPCR, in situ hybridisation and immunohistochemistry.Leukocyte distribution was then assessed, and the transcript profile of selected areas examinedagainst the >1800 genes in the Cancer Transcriptome Atlas panel on the NanoString GeoMxDigital Spatial Profiling platform. \u0000Lung samples exhibited a spectrum of typical COVID-19 pathology with diffuse alveolar damageconsistent with hyaline membrane and type II pneumocyte hyperplasia, interstitialinflammation, organising pneumonia and thrombi. All tissues tested positive for SARS-CoV-2RNA using qPCR, whilst spatially resolved techniques revealed only few and sparsely distributedcells carrying the viral nucleocapsid protein. Multiplexed immunofluorescence for lymphocytes(CD3+) and macrophages (CD68+) was used to select areas of immune enrichment for spatialtranscriptomic profiling. These targeted analyses highlighted functional pathways involved inthe interferon gamma response, TCR activation and antigen presentation. Comparison acrossimmune-enriched areas identified a heterogeneity in lung infiltrates with spatial separation ofchemokine and complement production. Our data identify pathological immune pathways thatare amenable to therapeutic intervention in critical disease.","PeriodicalId":184356,"journal":{"name":"Journal of the Nuffield Department of Surgical Sciences","volume":"2 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115545334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fungai Dengu1; Sadr Shaheed1; Letizia Lo Faro1; Adam Thorne1; Honglei Huang1; Peter Friend1,Rutger Ploeg1. 1. Oxford Organ Perfusion Lab, Nuffield Department of Surgical Sciences and Oxford BiomedicalResearch Centre, University of Oxford, Oxford, UK BackgroundContinuous liver NMP is a novel technology associated with safe extension of organ preservation time, increased organ utilisation and reduced early graft injury1. Increasingly, it is utilised as a ‘back to base’ application with cold storage for organ transport and NMP initiated at the implanting centre prior to transplantation2. We aimed to evaluate the impact of additional cold ischaemia time (CIT) on the proteomic and molecular signature of NMP livers. Methods Liver tissue samples (N= 57) from a prospective clinical trial of ‘back to base’ NMP were analysed. Collection occurred at the end of cold storage (LT1), end of NMP/total preservation (LT2) and after organ reperfusion (LT3). Unbiased, label-free-quantitative (LFQ) proteomic analysis was conducted using liquid chromatography with tandem mass spectrometry and trapped ion mobility spectrometry (TIMS) to time-of-flight (TOF) mass analysis (LC-MS/MS TIMS-TOF). Differential expression and Gene Ontology/Pathway analysis were performed. Results LT2 samples with prolonged CIT (>6hr) prior to NMP had significant differential expression of proteins associated with liver-specific oxidative stress, cellular haemostasis and removal of damaged or misfolded proteins (e.g. CYP3A5, PSMB1). LT3 samples, similarly, had reduced proteins involved in autophagy and cell-cycle regulation (e.g. STBD1, CD2AP, GADD45GIP1,) and increased expression of proteins involved in neutrophil chemotaxis, adhesion and aggregation (e.g. S100A9). Discussion The molecular signature of grafts at LT2 and LT3 varies depending on the length of CIT prior to NMP. Further exploration of the molecular signatures associated with preservation related graft injury is required to determine how best to apply this novel technology clinically. References: 1. Nasralla, D. et al. A randomized trial of normothermic preservation in liver transplantation. Nature 557, 50–56 (2018).2. Ceresa, C. D. L. et al. Transient Cold Storage Prior to Normothermic Liver Perfusion May Facilitate Adoption of a Novel Technology. Liver Transplant. lt.25584 (2019).doi:10.1002/lt.25584
{"title":"Molecular and proteomic signatures associated with preservation related graft injury: insight from human liver normothermic machine perfusion (NMP)","authors":"F. Dengu","doi":"10.37707/jnds.v2i4.203","DOIUrl":"https://doi.org/10.37707/jnds.v2i4.203","url":null,"abstract":"Fungai Dengu1; Sadr Shaheed1; Letizia Lo Faro1; Adam Thorne1; Honglei Huang1; Peter Friend1,Rutger Ploeg1. \u00001. Oxford Organ Perfusion Lab, Nuffield Department of Surgical Sciences and Oxford BiomedicalResearch Centre, University of Oxford, Oxford, UK \u0000 \u0000 \u0000BackgroundContinuous liver NMP is a novel technology associated with safe extension of organ preservation time, increased organ utilisation and reduced early graft injury1. Increasingly, it is utilised as a ‘back to base’ application with cold storage for organ transport and NMP initiated at the implanting centre prior to transplantation2. We aimed to evaluate the impact of additional cold ischaemia time (CIT) on the proteomic and molecular signature of NMP livers. \u0000Methods Liver tissue samples (N= 57) from a prospective clinical trial of ‘back to base’ NMP were analysed. Collection occurred at the end of cold storage (LT1), end of NMP/total preservation (LT2) and after organ reperfusion (LT3). Unbiased, label-free-quantitative (LFQ) proteomic analysis was conducted using liquid chromatography with tandem mass spectrometry and trapped ion mobility spectrometry (TIMS) to time-of-flight (TOF) mass analysis (LC-MS/MS TIMS-TOF). Differential expression and Gene Ontology/Pathway analysis were performed. \u0000Results LT2 samples with prolonged CIT (>6hr) prior to NMP had significant differential expression of proteins associated with liver-specific oxidative stress, cellular haemostasis and removal of damaged or misfolded proteins (e.g. CYP3A5, PSMB1). LT3 samples, similarly, had reduced proteins involved in autophagy and cell-cycle regulation (e.g. STBD1, CD2AP, GADD45GIP1,) and increased expression of proteins involved in neutrophil chemotaxis, adhesion and aggregation (e.g. S100A9). \u0000Discussion The molecular signature of grafts at LT2 and LT3 varies depending on the length of CIT prior to NMP. Further exploration of the molecular signatures associated with preservation related graft injury is required to determine how best to apply this novel technology clinically. References: \u00001. Nasralla, D. et al. A randomized trial of normothermic preservation in liver transplantation. Nature 557, 50–56 (2018).2. Ceresa, C. D. L. et al. Transient Cold Storage Prior to Normothermic Liver Perfusion May Facilitate Adoption of a Novel Technology. Liver Transplant. lt.25584 (2019).doi:10.1002/lt.25584","PeriodicalId":184356,"journal":{"name":"Journal of the Nuffield Department of Surgical Sciences","volume":"9 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114523789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"NDS Virtual Research Away Day Programme 11th February 2021","authors":"NDS away day organising committee","doi":"10.37707/jnds.v2i4.209","DOIUrl":"https://doi.org/10.37707/jnds.v2i4.209","url":null,"abstract":" \u0000 ","PeriodicalId":184356,"journal":{"name":"Journal of the Nuffield Department of Surgical Sciences","volume":"414 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126695035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"NDS Virtual Research Away Day Programme 11th March 2021","authors":"NDS away day organising committee","doi":"10.37707/jnds.v2i4.210","DOIUrl":"https://doi.org/10.37707/jnds.v2i4.210","url":null,"abstract":" \u0000 ","PeriodicalId":184356,"journal":{"name":"Journal of the Nuffield Department of Surgical Sciences","volume":"7 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124850049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fungai Dengu1, Tamsyn Clark1,3, Hussain Abbas1, Etohan Ann Ogbemudia1, Faysal El Gilani1,David Nasralla1, Peter Friend1, James Fildes2 1. Oxford Organ Perfusion Lab, Nuffield Department of Surgical Sciences and Oxford Biomedical ResearchCentre, University of Oxford, Oxford, UK2. The Ex-Vivo Lab, Division of Cell Matrix Biology and Regenerative Medicine, School of BiologicalSciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester AcademicHealth Science Centre, Manchester, UK3. Institute of Biomedical Engineering, University of Oxford, Oxford, UK Background Passenger Leukocytes (PLs) are implicated in both the direct and semi-direct pathways of allorecognition which is the process that underpins acute allograft rejection1. The majority of liver-derived PLs are short lived and predominantly impact early recipient immune responses2. Removal of PLs has been shown in kidney, lung and vascularised composite allografts to reduce early allograft damage and abrogate ejection3. We aimed to assess the use normothermic machine perfusion (NMP) to investigate PL kinetics and explore PL depletion strategies in donor livers. Methods Porcine livers (N=4) procured in a donation after circulatory death (DCD) model were preserved with sequential static cold storage then NMP. During NMP, livers were subjected to repeated 20 min warm ischaemic hits (IH) followed by 30mins of NMP using a leukocyte depleted autologous RBC based perfusate. Leukocytes were quantified using the Sysmex® cell counter system and samples stored for flow cytometric analysis. Results In total, 3.4x106 PLs are effluxed into the circuit immediately after initiation of NMP, this falls rapidly to 1.35x106 by 30 mins. Following the first IH, a further efflux of occurs with a peak of 3.74x106 occurring. The second IH also induced an efflux of cells (1.61x106) with lymphocytes representing the predominant leukocyte sub-type in each efflux. Discussion During NMP, there is an inducible and reproducible efflux of graft derived PLs into the circuit that is composed of predominantly lymphocytes with unexpectedly low numbers of monocytes. Removal of these PLs from the perfusate during NMP may therefore be feasible using an in-line leukocyte-filter. References 1. Alsughayyir, J., Motallebzadeh, R. & Pettigrew, G. J. Are donor lymphocytes a barrier to transplantation tolerance? Curr. Opin. Organ Transplant. 23, 90–96 (2018).2. Mastoridis, S. et al. Impact of donor extracellular vesicle release on recipient cell “cross-dressing” following clinical liver and kidney transplantation. Am. J. Transplant. ajt.16123 (2020). doi:10.1111/ajt.161233. Stone, J. P. et al. Mechanical removal of dendritic cell–generating non-classical monocytes via ex vivo lung perfusion. J. Hear. Lung Transplant. 33, 864–869 (2014).
Fungai Dengu1, Tamsyn clar1,3, Hussain Abbas1, Etohan Ann ogbemudi1, Faysal El Gilani1,David nasrall1, Peter Friend1, James Fildes2牛津大学纳菲尔德外科科学系和牛津生物医学研究中心牛津器官灌注实验室，英国牛津2。曼彻斯特大学生物、医学与健康学院生物科学学院细胞基质生物学和再生医学学部离体实验室，曼彻斯特，英国背景乘客白细胞(PLs)参与同种异体识别的直接和半直接途径，这是支持急性同种异体移植排斥的过程1。大多数肝源性PLs是短命的，主要影响早期受体的免疫反应2。在肾、肺和有血管的复合异体移植物中，去除PLs可以减少早期异体移植物损伤和消除抛射3。我们的目的是评估使用恒温机器灌注(NMP)来研究PL动力学并探索供体肝脏中PL消耗策略。方法采用顺序静态冷库法和NMP法保存循环性死亡(DCD)模型猪肝脏(N=4)。在NMP期间，肝脏接受重复20分钟的热缺血(IH)，然后使用白细胞耗尽的自体红细胞为基础的灌注液进行30分钟的NMP。使用Sysmex®细胞计数系统对白细胞进行定量，并将样品保存用于流式细胞术分析。结果在NMP启动后，总共有3.4 × 106个PLs流入电路，在30分钟内迅速下降到1.35 × 106。在第一次IH之后，发生了进一步的外流，峰值为3.74x106。第二次IH也诱导细胞外流(1.61x106)，淋巴细胞代表每次外流的主要白细胞亚型。在NMP过程中，移植物衍生的PLs可诱导和可重复地流出到主要由淋巴细胞组成的回路中，其中单核细胞的数量出乎意料地少。因此，在NMP期间，使用在线白细胞过滤器从灌注液中去除这些PLs可能是可行的。引用1。Alsughayyir, J, Motallebzadeh, R. & Pettigrew, G. J.供体淋巴细胞是移植耐受的障碍吗?咕咕叫。当今。器官移植，23,90-96(2018)。Mastoridis, S.等。临床肝肾移植后供体细胞外囊泡释放对受体细胞“异装”的影响。点。j .移植。ajt.16123（2020). doi: 10.1111 / ajt.161233。斯通，j.p.等人。通过体外肺灌注机械去除树突状细胞生成的非经典单核细胞。j .听到。肺移植，33,864-869(2014)。
{"title":"Ischaemia reperfusion induces the release of donor derived Passenger Leukocytes (PLs) during normothermic machine perfusion (NMP) of the liver- a new opportunity for ex situ graft leukodepletion?","authors":"F. Dengu","doi":"10.37707/jnds.v2i4.202","DOIUrl":"https://doi.org/10.37707/jnds.v2i4.202","url":null,"abstract":"Fungai Dengu1, Tamsyn Clark1,3, Hussain Abbas1, Etohan Ann Ogbemudia1, Faysal El Gilani1,David Nasralla1, Peter Friend1, James Fildes2 \u00001. Oxford Organ Perfusion Lab, Nuffield Department of Surgical Sciences and Oxford Biomedical ResearchCentre, University of Oxford, Oxford, UK2. The Ex-Vivo Lab, Division of Cell Matrix Biology and Regenerative Medicine, School of BiologicalSciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester AcademicHealth Science Centre, Manchester, UK3. Institute of Biomedical Engineering, University of Oxford, Oxford, UK \u0000 \u0000Background Passenger Leukocytes (PLs) are implicated in both the direct and semi-direct pathways of allorecognition which is the process that underpins acute allograft rejection1. The majority of liver-derived PLs are short lived and predominantly impact early recipient immune responses2. Removal of PLs has been shown in kidney, lung and vascularised composite allografts to reduce early allograft damage and abrogate ejection3. We aimed to assess the use normothermic machine perfusion (NMP) to investigate PL kinetics and explore PL depletion strategies in donor livers. \u0000Methods Porcine livers (N=4) procured in a donation after circulatory death (DCD) model were preserved with sequential static cold storage then NMP. During NMP, livers were subjected to repeated 20 min warm ischaemic hits (IH) followed by 30mins of NMP using a leukocyte depleted autologous RBC based perfusate. Leukocytes were quantified using the Sysmex® cell counter system and samples stored for flow cytometric analysis. \u0000Results In total, 3.4x106 PLs are effluxed into the circuit immediately after initiation of NMP, this falls rapidly to 1.35x106 by 30 mins. Following the first IH, a further efflux of occurs with a peak of 3.74x106 occurring. The second IH also induced an efflux of cells (1.61x106) with lymphocytes representing the predominant leukocyte sub-type in each efflux. \u0000Discussion During NMP, there is an inducible and reproducible efflux of graft derived PLs into the circuit that is composed of predominantly lymphocytes with unexpectedly low numbers of monocytes. Removal of these PLs from the perfusate during NMP may therefore be feasible using an in-line leukocyte-filter. \u0000 \u0000References \u00001. Alsughayyir, J., Motallebzadeh, R. & Pettigrew, G. J. Are donor lymphocytes a barrier to transplantation tolerance? Curr. Opin. Organ Transplant. 23, 90–96 (2018).2. Mastoridis, S. et al. Impact of donor extracellular vesicle release on recipient cell “cross-dressing” following clinical liver and kidney transplantation. Am. J. Transplant. ajt.16123 (2020). doi:10.1111/ajt.161233. Stone, J. P. et al. Mechanical removal of dendritic cell–generating non-classical monocytes via ex vivo lung perfusion. J. Hear. Lung Transplant. 33, 864–869 (2014).","PeriodicalId":184356,"journal":{"name":"Journal of the Nuffield Department of Surgical Sciences","volume":"140 ","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114091051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fungai Dengu1; Sadr Shaheed1; Letizia Lo Faro1; Adam Thorne1; Honglei Huang1; Peter Friend1,Rutger Ploeg1. 1. Oxford Organ Perfusion Lab, Nuffield Department of Surgical Sciences and Oxford BiomedicalResearch Centre, University of Oxford, Oxford, UK BackgroundContinuous liver NMP is a novel technology associated with safe extension of organpreservation time, increased organ utilisation and reduced early graft injury1. Increasingly, it isutilised as a ‘back to base’ application with cold storage for organ transport and NMP initiatedat the implanting centre prior to transplantation2. We aimed to evaluate the impact ofadditional cold ischaemia time (CIT) on the proteomic and molecular signature of NMP livers. MethodsLiver tissue samples (N= 57) from a prospective clinical trial of ‘back to base’ NMP wereanalysed. Collection occurred at the end of cold storage (LT1), end of NMP/total preservation(LT2) and after organ reperfusion (LT3). Unbiased, label-free-quantitative (LFQ) proteomicanalysis was conducted using liquid chromatography with tandem mass spectrometry andtrapped ion mobility spectrometry (TIMS) to time-of-flight (TOF) mass analysis (LC-MS/MS TIMSTOF).Differential expression and Gene Ontology/Pathway analysis were performed. ResultsLT2 samples with prolonged CIT (>6hr) prior to NMP had significant differential expression ofproteins associated with liver-specific oxidative stress, cellular haemostasis and removal ofdamaged or misfolded proteins (e.g. CYP3A5, PSMB1). LT3 samples, similarly, had reducedproteins involved in autophagy and cell-cycle regulation (e.g. STBD1, CD2AP, GADD45GIP1,) andincreased expression of proteins involved in neutrophil chemotaxis, adhesion and aggregation(e.g. S100A9). DiscussionThe molecular signature of grafts at LT2 and LT3 varies depending on the length of CIT prior toNMP. Further exploration of the molecular signatures associated with preservation related graftinjury is required to determine how best to apply this novel technology clinically. References:1. Nasralla, D. et al. A randomized trial of normothermic preservation in livertransplantation. Nature 557, 50–56 (2018).2. Ceresa, C. D. L. et al. Transient Cold Storage Prior to Normothermic Liver Perfusion MayFacilitate Adoption of a Novel Technology. Liver Transplant. lt.25584 (2019).doi:10.1002/lt.25584
{"title":"Molecular and proteomic signatures associated with preservation related graft injury: insight from human liver normothermic achine perfusion (NMP)","authors":"F. Dengu","doi":"10.37707/jnds.v2i4.217","DOIUrl":"https://doi.org/10.37707/jnds.v2i4.217","url":null,"abstract":"Fungai Dengu1; Sadr Shaheed1; Letizia Lo Faro1; Adam Thorne1; Honglei Huang1; Peter Friend1,Rutger Ploeg1. \u00001. Oxford Organ Perfusion Lab, Nuffield Department of Surgical Sciences and Oxford BiomedicalResearch Centre, University of Oxford, Oxford, UK \u0000BackgroundContinuous liver NMP is a novel technology associated with safe extension of organpreservation time, increased organ utilisation and reduced early graft injury1. Increasingly, it isutilised as a ‘back to base’ application with cold storage for organ transport and NMP initiatedat the implanting centre prior to transplantation2. We aimed to evaluate the impact ofadditional cold ischaemia time (CIT) on the proteomic and molecular signature of NMP livers. \u0000MethodsLiver tissue samples (N= 57) from a prospective clinical trial of ‘back to base’ NMP wereanalysed. Collection occurred at the end of cold storage (LT1), end of NMP/total preservation(LT2) and after organ reperfusion (LT3). Unbiased, label-free-quantitative (LFQ) proteomicanalysis was conducted using liquid chromatography with tandem mass spectrometry andtrapped ion mobility spectrometry (TIMS) to time-of-flight (TOF) mass analysis (LC-MS/MS TIMSTOF).Differential expression and Gene Ontology/Pathway analysis were performed. \u0000ResultsLT2 samples with prolonged CIT (>6hr) prior to NMP had significant differential expression ofproteins associated with liver-specific oxidative stress, cellular haemostasis and removal ofdamaged or misfolded proteins (e.g. CYP3A5, PSMB1). LT3 samples, similarly, had reducedproteins involved in autophagy and cell-cycle regulation (e.g. STBD1, CD2AP, GADD45GIP1,) andincreased expression of proteins involved in neutrophil chemotaxis, adhesion and aggregation(e.g. S100A9). \u0000DiscussionThe molecular signature of grafts at LT2 and LT3 varies depending on the length of CIT prior toNMP. Further exploration of the molecular signatures associated with preservation related graftinjury is required to determine how best to apply this novel technology clinically. \u0000 \u0000References:1. Nasralla, D. et al. A randomized trial of normothermic preservation in livertransplantation. Nature 557, 50–56 (2018).2. Ceresa, C. D. L. et al. Transient Cold Storage Prior to Normothermic Liver Perfusion MayFacilitate Adoption of a Novel Technology. Liver Transplant. lt.25584 (2019).doi:10.1002/lt.25584","PeriodicalId":184356,"journal":{"name":"Journal of the Nuffield Department of Surgical Sciences","volume":"78 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132294279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Omair A. Shariq1,2, Kate E. Lines3, Katherine A. English3, Bahram Jafar-Mohammadi3, PhilippaPrentrice3, Ruth Casey5, Benjamin G. Challis5, Andreas Selberherr6, Fiona J. Ryan3, Ultan Healy3,Tom Kurzawinski7, Mehul T Dattani7, Irina Bancos8, Duncan Richards9, Benzon M. Dy2, Melanie L.Lyden2, William F. Young, Jr.8, Travis J. McKenzie2, Rajesh V. Thakker3 1Nuffield Department of Surgical Sciences, University of Oxford, UK2Department of Surgery, Mayo Clinic, Rochester, MN3Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, UK4Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK5Department of Endocrinology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK.6Department of Surgery, Medical University of Vienna, Vienna, Austria.7Centre for Endocrine Surgery, Great Ormond Street Hospital for Children, London, UK8Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN9Oxford Clinical Trials Research Unit, Botnar Research Centre, Oxford, UK Background: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by parathyroid, pituitary and duodenopancreatic neuroendocrine tumours (DP-NETs). Knowledge regarding manifestations and outcomes is largely derived from adult cohorts. Thus, we investigated the occurrence and treatment of MEN1 manifestations in children and adolescents, and also explored potential genotype-phenotype correlations. Methods Eighty MEN1 patients who underwent childhood/adolescent tumour surveillance at 5 international referral centres were included. Fisher’s exact, Wilcoxon rank-sum and Kaplan-Meier tests were used to compare proportions, continuous variables and recurrence-free survival, respectively. Results Fifty-six patients (70%) developed an MEN1 manifestation before 19 years, at a median age of 14 years (range: 6-18 years). Primary hyperparathyroidism occurred in 46/56 patients (82.1%), 33 (72%) of whom underwent parathyroidectomy. Less-than-subtotal (<3-gland) parathyroidectomy resulted in worse recurrence/persistence-free survival vs subtotal (3-3.5-gland) or total (4-gland) parathyroidectomy (median 27 months vs not reached; P=0.005). Twenty-one patients (37.5%) developed DP-NETs (non-functioning [n=15], insulinomas [n=8], and gastrinoma [n=1]), 12 (57.1%) underwent surgery and 3 (14.3%) had metastases (hepatic [n=2] and lymph node [n=1]). Compared to patients without DP-NETs, those with DP-NETs at <19 years were more likely to harbour MEN1 mutations disrupting the menin-JunD interaction domain (80% vs 51.9%; P=0.0459). Pituitary tumours developed in 18/56 patients (32%) and were mostly dopamine agonist-responsive prolactinomas. Conclusions Morbidity from MEN1 manifestations occurs during childhood and adolescence in 70% of patients. Less-than-subtotal parathyroidectomy leads to high failure rates. DP-NETs are the second most common manifestation in this age group and ma
Omair A. shari_1,2, Kate E. Lines3, Katherine A. English3, Bahram Jafar-Mohammadi3, philippaprentric3, Ruth Casey5, Benjamin G. Challis5, Andreas Selberherr6, Fiona J. Ryan3, Ultan Healy3,Tom Kurzawinski7, Mehul T . Dattani7, Irina Bancos8, Duncan Richards9, Benzon M. Dy2, Melanie L.Lyden2, William F. Young, Jr.8, Travis J. McKenzie2, Rajesh V. Thakker3 1英国牛津大学纳菲尔德外科学系2，罗切斯特梅奥诊所外科学系，mn3牛津大学糖尿病、内分泌和代谢中心4伦敦大奥蒙德街儿童医院儿科内分泌科5剑桥大学医院NHS基金会信托内分泌科，剑桥，英国;6奥地利维也纳医科大学外科;7伦敦大奥蒙德街儿童医院内分泌外科;8内分泌、糖尿病、代谢和营养科;背景:多发性内分泌肿瘤1型(MEN1)是一种常染色体显性遗传病，以甲状旁腺、垂体和十二指肠胰腺神经内分泌肿瘤(DP-NETs)为特征。关于表现和结果的知识主要来自成人队列。因此，我们调查了MEN1在儿童和青少年中的发生和治疗，并探讨了潜在的基因型-表型相关性。方法在5个国际转诊中心接受儿童/青少年肿瘤监测的80例MEN1患者。分别使用Fisher精确检验、Wilcoxon秩和检验和Kaplan-Meier检验来比较比例、连续变量和无复发生存率。结果56例(70%)患者在19岁前出现MEN1表现，中位年龄为14岁(范围6-18岁)。56例患者中有46例(82.1%)发生原发性甲状旁腺功能亢进，其中33例(72%)行甲状旁腺切除术。与次全(3-3.5个腺)或全(4个腺)甲状旁腺切除术相比，少于次全(<3个腺)甲状旁腺切除术导致复发/无持久性生存更差(中位27个月vs未达到;P = 0.005)。21例(37.5%)发生DP-NETs(无功能[n=15]，胰岛素瘤[n=8]，胃泌素瘤[n=1])， 12例(57.1%)行手术治疗，3例(14.3%)发生转移(肝脏[n=2]和淋巴结[n=1])。与没有DP-NETs的患者相比，年龄<19岁的DP-NETs患者更有可能携带MEN1突变，破坏menin-JunD相互作用结构域(80% vs 51.9%;P = 0.0459)。56例患者中有18例(32%)发生垂体肿瘤，多数为多巴胺激动剂反应性催乳素瘤。结论70%的MEN1患者发生在儿童期和青春期。甲状旁腺次全切除术失败率高。DP-NETs是这一年龄组中第二常见的表现，可能在破坏menin-JunD结合的突变患者中更为常见。
{"title":"Clinical Features, Genotype-Phenotype Correlations and Treatment Outcomes in Children and Adolescents with Multiple Endocrine Neoplasia Type 1: An International Cohort Study","authors":"O. Shariq","doi":"10.37707/jnds.v2i4.206","DOIUrl":"https://doi.org/10.37707/jnds.v2i4.206","url":null,"abstract":"Omair A. Shariq1,2, Kate E. Lines3, Katherine A. English3, Bahram Jafar-Mohammadi3, PhilippaPrentrice3, Ruth Casey5, Benjamin G. Challis5, Andreas Selberherr6, Fiona J. Ryan3, Ultan Healy3,Tom Kurzawinski7, Mehul T Dattani7, Irina Bancos8, Duncan Richards9, Benzon M. Dy2, Melanie L.Lyden2, William F. Young, Jr.8, Travis J. McKenzie2, Rajesh V. Thakker3 \u00001Nuffield Department of Surgical Sciences, University of Oxford, UK2Department of Surgery, Mayo Clinic, Rochester, MN3Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, UK4Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK5Department of Endocrinology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK.6Department of Surgery, Medical University of Vienna, Vienna, Austria.7Centre for Endocrine Surgery, Great Ormond Street Hospital for Children, London, UK8Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN9Oxford Clinical Trials Research Unit, Botnar Research Centre, Oxford, UK \u0000 \u0000Background: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by parathyroid, pituitary and duodenopancreatic neuroendocrine tumours (DP-NETs). Knowledge regarding manifestations and outcomes is largely derived from adult cohorts. Thus, we investigated the occurrence and treatment of MEN1 manifestations in children and adolescents, and also explored potential genotype-phenotype correlations. \u0000Methods Eighty MEN1 patients who underwent childhood/adolescent tumour surveillance at 5 international referral centres were included. Fisher’s exact, Wilcoxon rank-sum and Kaplan-Meier tests were used to compare proportions, continuous variables and recurrence-free survival, respectively. \u0000Results Fifty-six patients (70%) developed an MEN1 manifestation before 19 years, at a median age of 14 years (range: 6-18 years). Primary hyperparathyroidism occurred in 46/56 patients (82.1%), 33 (72%) of whom underwent parathyroidectomy. Less-than-subtotal (<3-gland) parathyroidectomy resulted in worse recurrence/persistence-free survival vs subtotal (3-3.5-gland) or total (4-gland) parathyroidectomy (median 27 months vs not reached; P=0.005). Twenty-one patients (37.5%) developed DP-NETs (non-functioning [n=15], insulinomas [n=8], and gastrinoma [n=1]), 12 (57.1%) underwent surgery and 3 (14.3%) had metastases (hepatic [n=2] and lymph node [n=1]). Compared to patients without DP-NETs, those with DP-NETs at <19 years were more likely to harbour MEN1 mutations disrupting the menin-JunD interaction domain (80% vs 51.9%; P=0.0459). Pituitary tumours developed in 18/56 patients (32%) and were mostly dopamine agonist-responsive prolactinomas. \u0000Conclusions Morbidity from MEN1 manifestations occurs during childhood and adolescence in 70% of patients. Less-than-subtotal parathyroidectomy leads to high failure rates. DP-NETs are the second most common manifestation in this age group and ma","PeriodicalId":184356,"journal":{"name":"Journal of the Nuffield Department of Surgical Sciences","volume":"164 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124606523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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