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Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy1. The study of large patient cohorts incorporating longitudinal plasma sampling and extended follow-up is required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung cancer (NSCLC). Here we developed ctDNA methods tracking a median of 200 mutations identified in resected NSCLC tissue across 1,069 plasma samples collected from 197 patients enrolled in the TRACERx study2. A lack of preoperative ctDNA detection distinguished biologically indolent lung adenocarcinoma with good clinical outcome. Postoperative plasma analyses were interpreted within the context of standard-of-care radiological surveillance and administration of cytotoxic adjuvant therapy. Landmark analyses of plasma samples collected within 120 days after surgery revealed ctDNA detection in 25% of patients, including 49% of all patients who experienced clinical relapse; 3 to 6 monthly ctDNA surveillance identified impending disease relapse in an additional 20% of landmark-negative patients. We developed a bioinformatic tool (ECLIPSE) for non-invasive tracking of subclonal architecture at low ctDNA levels. ECLIPSE identified patients with polyclonal metastatic dissemination, which was associated with a poor clinical outcome. By measuring subclone cancer cell fractions in preoperative plasma, we found that subclones seeding future metastases were significantly more expanded compared with non-metastatic subclones. Our findings will support (neo)adjuvant trial advances and provide insights into the process of metastatic dissemination using low-ctDNA-level liquid biopsy.
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Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas , DNA Tumoral Circulante , Neoplasias Pulmonares , Mutação , Metástase Neoplásica , Carcinoma de Pequenas Células do Pulmão , Humanos , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Estudos de Coortes , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Metástase Neoplásica/diagnóstico , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Filogenia , Carcinoma de Pequenas Células do Pulmão/patologia , Biópsia LíquidaRESUMO
Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) constituting 85% of cases. Among NSCLCs, squamous cell carcinoma (SqCC) is strongly associated with smoking. However, lung cancer in never smokers (LCINS) represents approximately 25% of lung cancer cases globally and shows increasing incidence, particularly in East Asia. LCINS-SqCC is less well-characterized, especially regarding its genomic alterations and their impact on clinical outcomes. We conducted a retrospective analysis over a 20-year period (July 2003-July 2023) at two major tertiary centers in the UK. The cohort included 59 patients with LCINS-SqCC who underwent radical surgical resection. Data collected included demographic information, comorbidities, histopathological details, and outcome metrics such as disease-free and overall survival. Molecular sequencing of tumor specimens was performed to identify genomic aberrations. The cohort had a median age of 71 years (IQR 62-77) and a median BMI of 25.4 (IQR 22.8-27.8), with a slight male predominance (53%). The majority of patients (93%) had a preoperative MRC of 1-2. Recurrent disease was observed in 23 patients (39%), and 32 patients (54%) had died at a median follow-up of 3 years. Median disease-free survival was 545 days (IQR 132-1496), and overall survival was 888 days (IQR 443-2071). Preoperative creatinine levels were higher in patients who experienced recurrence (p = 0.037). Molecular analysis identified biallelic SMARCB1 loss in two younger patients, associated with rapid disease progression despite R0 resection. These patients' tumors were PDL1-negative, TTF-1-negative, and positive for cytokeratin, CD56, and p40. SMARCB1-deficient SqCC in never smokers represents a highly aggressive variant with poor disease-free survival, highlighting the importance of integrating advanced molecular diagnostics in clinical practice. This study underscores the necessity for personalized treatment strategies, including targeted therapies such as EZH2 inhibitors and immune checkpoint blockade, to address the unique molecular pathways in SMARCB1-deficient cancers. Further clinical trials are essential to optimize therapeutic approaches for this challenging subgroup of lung cancer.
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Carcinoma de Células Escamosas , Neoplasias Pulmonares , Proteína SMARCB1 , Humanos , Masculino , Feminino , Proteína SMARCB1/genética , Proteína SMARCB1/metabolismo , Idoso , Pessoa de Meia-Idade , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Estudos Retrospectivos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , não Fumantes , Biomarcadores Tumorais/genéticaRESUMO
BACKGROUND: Traditional risk stratification tools do not describe the complex principle determinant relationships that exist amongst pre-operative and peri-operative factors and their influence on cardiac surgical outcomes. This paper reports on the use of Bayesian networks to investigate such outcomes. METHODS: Data were prospectively collected from 4776 adult patients undergoing cardiac surgery at a single UK institute between April 2012 and May 2019. Machine learning techniques were used to construct Bayesian networks for four key short-term outcomes including death, stroke and renal failure. RESULTS: Duration of operation was the most important determinant of death irrespective of EuroSCORE. Duration of cardiopulmonary bypass was the most important determinant of re-operation for bleeding. EuroSCORE was predictive of new renal replacement therapy but not mortality. CONCLUSIONS: Machine-learning algorithms have allowed us to analyse the significance of dynamic processes that occur between pre-operative and peri-operative elements. Length of procedure and duration of cardiopulmonary bypass predicted mortality and morbidity in patients undergoing cardiac surgery in the UK. Bayesian networks can be used to explore potential principle determinant mechanisms underlying outcomes and be used to help develop future risk models.
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Procedimentos Cirúrgicos Cardíacos , Insuficiência Renal , Adulto , Humanos , Teorema de Bayes , Ponte Cardiopulmonar/efeitos adversos , Reino Unido , Fatores de Risco , Medição de Risco/métodosRESUMO
BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide. Surgical resection remains the definitive curative treatment for early-stage disease offering an overall 5-year survival rate of 62%. Despite careful case selection, a significant proportion of early-stage cancers relapse aggressively within the first year post-operatively. Identification of these patients is key to accurate prognostication and understanding the biology that drives early relapse might open up potential novel adjuvant therapies. METHODS: We performed an unsupervised interrogation of >1600 serum-based autoantibody biomarkers using an iterative machine-learning algorithm. RESULTS: We identified a 13 biomarker signature that was highly predictive for survivorship in post-operative early-stage lung cancer; this outperforms currently used autoantibody biomarkers in solid cancers. Our results demonstrate significantly poor survivorship in high expressers of this biomarker signature with an overall 5-year survival rate of 7.6%. CONCLUSIONS: We anticipate that the data will lead to the development of an off-the-shelf prognostic panel and further that the oncogenic relevance of the proteins recognised in the panel may be a starting point for a new adjuvant therapy.
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Autoanticorpos/sangue , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Análise Serial de Proteínas/métodos , Idoso , Autoanticorpos/imunologia , Biomarcadores Tumorais/imunologia , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/imunologia , Biologia Computacional/métodos , Feminino , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/imunologia , Masculino , Prognóstico , Curva ROCRESUMO
Tumour-infiltrating immune cells have been widely implicated to play a significant role in carcinogenesis, through both pro- or anti-tumour effects. The multi-faceted effects of lung cancer associated T lymphocytes have been extensively studied, and yet, the role of B lymphocytes remains an area less studied. In this review, we will describe the current understanding of the role of tumour-infiltrating B lymphocytes in NSCLC, discuss their prognostic significance, their functionality within the tumour microenvironment and ultimately how we might harness B-cell biology to develop B-cell therapeutic strategies in cancer.
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Linfócitos B/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Neoplasias Pulmonares/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/patologia , MasculinoRESUMO
OBJECTIVE: To bring together stakeholders in the United Kingdom to establish national priorities for research in single-ventricle heart conditions. METHODS: This study comprised two surveys and a workshop. The initial public online survey asked respondents up to three questions they would like answered for research. Responses were classified as unanswered, already answered, or unable to be answered by scientific research. In the follow-up survey, unanswered questions were divided into categories and respondents were asked to rank categories and questions by priority. A stakeholder workshop attended by patients, parents, healthcare professionals, researchers, and charities was held to determine the final list of research priorities. RESULTS: A total of 128 respondents posed 344 research questions, of which 271 were classified as unanswered, and after removing duplicates, 204 questions remained, which were divided into 20 categories. In the second survey, 56 (49.1%) respondents successfully ranked categories and questions. A total of 39 participants attended the workshop, drawing up a list of 30 research priorities across nine priority categories. The nine priority categories are: Associated co-morbidities; Brain & neurodevelopment; Exercise; Fontan failure; Heart function; Living with a single ventricle heart condition; Management of the well-functioning Fontan circulation; Surgery & perioperative care; and Transplantation, mechanical support & novel therapies. CONCLUSIONS: Through a multi-stage process, we engaged a wide range of interested parties to establish a list of research priorities in single-ventricle heart conditions. This provides a platform for clinicians, researchers, and funders in the United Kingdom and elsewhere to address the most important questions and improve outcomes in these rare but high-impact CHDs.
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Pesquisa Biomédica/organização & administração , Procedimentos Cirúrgicos Cardíacos , Atenção à Saúde/métodos , Cardiopatias Congênitas/cirurgia , Ventrículos do Coração/anormalidades , Cuidados Pré-Operatórios , Inquéritos e Questionários , Adolescente , Adulto , Idoso , Feminino , Cardiopatias Congênitas/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Morbidade/tendências , Estudos Retrospectivos , Reino Unido/epidemiologia , Adulto JovemRESUMO
Lung cancer, a leading cause of cancer-related death, often requires surgical resection for early-stage cases, with recent data supporting less invasive resections for tumors smaller than 2â cm. Central to resection is lymph node assessment, an area of controversy worldwide, compounded by advances in minimally invasive techniques. The review aims to assess current standards for lymph node assessment, recent data from the surgical era, and the immunobiological basis of how lymph node metastases impact patient outcomes. The British Thoracic Society guidelines recommend systematic nodal dissection during lung cancer resection, without specifying node removal or sampling. Historical data on mediastinal lymph node dissection (MLND) survival benefits are inconclusive, although proponents argue for lower recurrence rates. Recent trials such as ACOSOG Z0030 found no survival difference between MLND and nodal sampling, reinforcing the need for robust staging. While lobe-specific dissection strategies have been proposed, they currently lack consensus. JCOG1413 aims to compare the clinical benefits of lobe-specific and systematic dissection. TNM-9 staging revisions emphasize the prognostic significance of single-station N2 involvement. Robotic surgery shows promise, with trials such as RAVAL, which reported comparable outcomes to video-assisted thoracic surgery (VATS) and improved lymph node sampling. Immunobiological insights suggest preserving key immunological sites during lymphadenectomy, especially for patients receiving adjuvant immunotherapy. In conclusion, the standard lymph node resection strategy remains unsettled. The debate between systematic and selective dissection continues, with implications for staging accuracy and patient outcomes. As minimally invasive techniques evolve, robotic surgery emerges as an effective and low-risk approach to delivering optimal lymph node assessment.
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BACKGROUND: Pneumothorax is a non-physiological collection of air in the pleural space. Pneumothoraces can be broadly divided into Primary, Secondary, and Traumatic. Cancer of the lung is a known cause of secondary pneumothorax in both primary and metastatic lesions, however, pneumothorax as the presentation of lung cancer is exceedingly rare. Non-small cell lung carcinoma (NSCLC) has been reported in the literature to present with a pneumothorax, particularly in adeno/squamous cell carcinomas. It is almost completely unheard of for small cell lung carcinoma (SCLC) to present with a pneumothorax. CASE PRESENTATION: We present the case of a 62-year-old male patient, presenting twice in two months with spontaneous pneumothorax. The initial management involved admission and chest drain insertion. The patient has a past medical history of COPD and a significant smoking history. On the second admission, he underwent a video-assisted thoracoscopic (VATS) bullectomy and talc pleurodesis. The pathology report of the resected specimen confirmed SCLC with extensive infiltration. No gross evidence of metastatic spread was present on CT. Due to the R1 resection and significant risk of recurrence, the management plan included four cycles of adjuvant chemotherapy with carboplatin and etoposide, and radiotherapy as a consideration upon completion. CONCLUSIONS: Pneumothorax as the presentation of lung cancer imparts a very poor prognosis, however the reasons for this are largely unknown. Furthermore, the mechanisms underlying spontaneous pneumothorax in lung cancer are also not well understood.
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Neoplasias Pulmonares , Pneumotórax , Carcinoma de Pequenas Células do Pulmão , Humanos , Masculino , Pneumotórax/etiologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/complicações , Pessoa de Meia-Idade , Carcinoma de Pequenas Células do Pulmão/complicações , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Cirurgia Torácica Vídeoassistida , Recidiva , Tomografia Computadorizada por Raios XRESUMO
In this review, we explore the biology of the TIGIT checkpoint and its potential as a therapeutic target in lung cancer. We briefly review a highly selected set of clinical trials that have reported or are currently recruiting in non-small cell and small cell lung cancer, a disease transformed by the advent of PD-1/PD-L1 checkpoint blockade immunotherapy. We explore the murine data underlying TIGIT blockade and further explore the reliance of effective anti-TIGIT therapy on DNAM-1(CD226)-positive activated effector CD8+ T cells. The synergism with anti-PD-1 therapy is also explored. Future directions in the realm of overcoming resistance to checkpoint blockade and extending the repertoire of other checkpoints are also briefly explored.
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INTRODUCTION AND IMPORTANCE: Struma Ovarii is a rare type of monodermal teratoma with at least 50 % of its mass being thyroid tissue. They make up <1 % of all ovarian tumours and 3 to 5 % of all ovarian teratomas. These tumours are usually benign but malignant transformation is seen in <5 % of cases. CASE PRESENTATION: We present the case of a 45-year-old lady with three synchronous primary cancers on a background of Struma Ovarii; primary lung adenocarcinoma, papillary thyroid carcinoma and ovarian teratoma. Over the course of 18 months, this lady underwent full pelvic clearance of malignant Struma Ovarii and lymph nodes, total thyroidectomy, and an anatomical lung resection. CLINICAL DISCUSSION: This case represents an incredibly rare condition of Struma Ovarii for which there is no firm management consensus. Furthermore, the uniqueness of three separate primaries has to the best of our knowledge not previously been reported in the literature. CONCLUSION: This reinforces the notion that in select patients, radical management with curative intent is entirely possible but requires complete multi-disciplinary and multi-modal sub-specialty collaboration.
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BACKGROUND: Behcet's disease is a multi-system inflammatory disorder. A small subset of patients with Behcet's develop relapsing polychondritis which is classified as a separate disease known as Mouth and Genital ulcers with inflamed cartilage (MAGIC syndrome). It has previously been observed that this condition can also affect the cartilaginous tissue in the tracheobronchial tree. CASE PRESENTATION: We present the case of a 44-year-old lady with Behcet's Disease, Mouth and Genital ulcers with inflamed cartilage (MAGIC) syndrome and an aortic Frozen Elephant Trunk (FET) who presented to hospital with recurrent episodes of left lobar collapse of the lung. During bronchoscopy, we found the presence of multiple inflammatory endobronchial webs occluding segments of the left bronchial tree. Repeated examinations showed evidence that these inflammatory webs were progressing in size, density and location. Furthermore, we noticed herniation of her descending aortic FET into her left bronchial tree forming an aorto-bronchial fistula which was complicated by a graft infection. Her descending aortic FET section was surgically replaced with an open procedure and bronchoscopic interventions attempted to remove the occlusions in her bronchial tree. Despite optimisation of medical management and surgical correction, this patient continued to develop progressive occlusion of her left bronchial tree, resulting in a chronically collapsed left lung. CONCLUSIONS: A multi-disciplinary team approach is of paramount importance in order to optimally manage patients with Behcet's disease, balancing immunosuppressive regimens that need close monitoring and titration in the context of potential surgical intervention and the risk for intercurrent infection.
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Síndrome de Behçet , Fístula Brônquica , Humanos , Feminino , Adulto , Síndrome de Behçet/complicações , Úlcera/complicações , Fístula Brônquica/cirurgia , Fístula Brônquica/complicações , Aorta , Complicações Pós-OperatóriasRESUMO
BACKGROUND: Thymic carcinomas are rare and aggressive tumours. They constitute a heterogeneous group of tumours with various histological patterns and subtypes resembling epithelial tumours arising from other organs. CASE PRESENTATION: We hereby represent a case of primary thymic carcinoma with adenoid cystic carcinoma-like features (TCACC) which is an extremely rare variant of thymic adenocarcinoma. To date and to the best of our knowledge, there are nine reported cases in literature and ours is the tenth. Our case was treated surgically but the implementation of adjuvant chemoradiotherapy has been reported in few of the published cases. CONCLUSIONS: TCACC constitutes a rare entity of thymic adenocarcinoma with limited available literature. The current data is derived from few case reports and case series. The histological overlap of these tumours and primary ACC of salivary glands poses a diagnostic challenge. Radiological investigations, immunohistochemical phenotyping and genetic analysis are crucial in establishing the diagnosis.
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Adenocarcinoma , Carcinoma Adenoide Cístico , Timoma , Neoplasias do Timo , Humanos , Carcinoma Adenoide Cístico/diagnóstico por imagem , Carcinoma Adenoide Cístico/cirurgia , Timo , Adenocarcinoma/patologia , Timoma/diagnóstico , Timoma/cirurgia , Neoplasias do Timo/diagnóstico , Neoplasias do Timo/cirurgia , Neoplasias do Timo/patologiaRESUMO
Introduction: B cells, which have long been thought to be minor players in the development of anti-tumor responses, have been implicated as key players in lung cancer pathogenesis and response to checkpoint blockade in patients with lung cancer. Enrichment of late-stage plasma and memory cells in the tumor microenvironment has been shown in lung cancer, with the plasma cell repertoire existing on a functional spectrum with suppressive phenotypes correlating with outcome. B cell dynamics may be influenced by the inflammatory microenvironment observed in smokers and between LUAD and LUSC. Methods: Here, we show through high-dimensional deep phenotyping using mass cytometry (CyTOF), next generation RNA sequencing and multispectral immunofluorescence imaging (VECTRA Polaris) that key differences exist in the B cell repertoire between tumor and circulation in paired specimens from lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). Results: In addition to the current literature, this study provides insight into the in-depth description of the B cell contexture in Non-Small Cell Lung Cancer (NSCLC) with reference to broad clinico-pathological parameters based on our analysis of 56 patients. Our findings reinforce the phenomenon of B-cell trafficking from distant circulatory compartments into the tumour microenvironment (TME). The circulatory repertoire shows a predilection toward plasma and memory phenotypes in LUAD however no major differences exist between LUAD and LUSC at the level of the TME. B cell repertoire, amongst other factors, may be influenced by the inflammatory burden in the TME and circulation, that is, smokers and non-smokers. We have further clearly demonstrated that the plasma cell repertoire exists on a functional spectrum in lung cancer, and that the suppressive regulatory arm of this axis may play a significant role in determining postoperative outcomes as well as following checkpoint blockade. This will require further long-term functional correlation. Conclusion: B and Plasma cell repertoire is very diverse and heterogeneous across different tissue compartments in lung cancer. Smoking status associates with key differences in the immune milieu and the consequent inflammatory microenvironment is likely responsible for the functional and phenotypic spectrum we have seen in the plasma cell and B cell repertoire in this condition.
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Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Plasmócitos/patologia , Adenocarcinoma de Pulmão/genética , Carcinoma de Células Escamosas/genética , Microambiente TumoralRESUMO
Background: Postoperative pneumonia (POP) is a hospital acquired pneumonia that occurs >48 hours after tracheal intubation. The diagnosis of POP should be based on clinical and radiological findings within 30 days after surgery. It is a common complication after thoracoscopic surgery for lung cancer patients. However, the specific impact of preoperative comorbidities on the incidence of POP remains unclear. This study aimed to analyze the preoperative data of patients with lung cancer to help surgeons predict the risk of incidence of POP after thoracoscopic lung resection. Methods: This study is a prospective study that included patients with lung cancer who were scheduled for thoracoscopic surgery in 1 year. All cases came from two medical centers. Preoperative demographic information, tumor information, preoperative comorbidities, quality of life scores, and incidence of POP were collected. Variables were screened by univariate analysis and multivariate regression. Finally, a prediction model was constructed. A total of 53 preoperative factors were included as candidate predictors. The binary outcome variable was defined as the presence or absence of POP. The incidence of POP was the primary outcome variable. The predictive performance of the model was verified internally through 1,000 iterations of bootstrap resampling. Results: A total of 1,229 patients with lung cancer who underwent thoracoscopic surgery were enrolled. In addition, 196 cases (15.95%) had POP; 1,025 (83.40%) patients had comorbid conditions. The total number of comorbidity diagnosed in all samples was 2,929. The prediction model suggested that patients with advanced age, high body mass index (BMI), smoking, poor physical condition, respiratory diseases, diabetes, and neurological diseases were more likely to develop POP. The area under the curve (AUC) and Brier scores were 0.851 and 0.091, respectively. The expected and observed results were in strong agreement, according to the likelihood of POP calibration curve. Conclusions: The constructed model is capable of evaluating the probability of POP occurrence in patients with lung cancer. Seven preoperative factors in patients with lung cancer were found to be associated with increased probability of having pneumonia after thoracoscopic lung resection. This model can help predict the incidence of POP after surgery.
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Tumor-specific MHC class II (tsMHC-II) expression impacts tumor microenvironmental immunity. tsMHC-II positive cancer cells may act as surrogate antigen-presenting cells and targets for CD4+ T cell-mediated lysis. In colorectal cancer, tsMHC-II negativity is common, in cell lines due to CIITA promoter methylation. To clarify mechanisms of tsMHC-II repression in colorectal cancer, we analyzed colorectal cancer organoids which are epigenetically faithful to tissue of origin. 15 primary colorectal cancer organoids were treated with IFNγ ± epigenetic modifiers: flow cytometry was used for tsMHC-II expression. qRT-PCR, total RNA sequencing, nanopore sequencing, bisulfite conversion/pyrosequencing, and Western blotting was used to quantitate CIITA, STAT1, IRF1, and JAK1 expression, mutations and promoter methylation and chromatin immunoprecipitation to quantitate H3K9ac, H3K9Me2, and EZH2 occupancy at CIITA. We define three types of response to IFNγ in colorectal cancer: strong, weak, and noninducibility. Delayed and restricted expression even with prolonged IFNγ exposure was due to IFNγ-mediated EZH2 occupancy at CIITA. tsMHC-II expression was enhanced by EZH2 and histone deacetylase inhibition in the weakly inducible organoids. Noninducibility is seen in three consensus molecular subtype 1 (CMS1) organoids due to JAK1 mutation. No organoid demonstrates CIITA promoter methylation. Providing IFNγ signaling is intact, most colorectal cancer organoids are class II inducible. Upregulation of tsMHC-II through targeted epigenetic therapy is seen in one of fifteen organoids. Our approach can serve as a blueprint for investigating the heterogeneity of specific epigenetic mechanisms of immune suppression across individual patients in other cancers and how these might be targeted to inform the conduct of future trials of epigenetic therapies as immune adjuvants more strategically in cancer. Significance: Cancer cell expression of MHC class II significantly impacts tumor microenvironmental immunity. Previous studies investigating mechanisms of repression of IFNγ-inducible class II expression using cell lines demonstrate epigenetic silencing of IFN pathway genes as a frequent immune evasion strategy. Unlike cell lines, patient-derived organoids maintain epigenetic fidelity to tissue of origin. In the first such study, we analyze patterns, dynamics, and epigenetic control of IFNγ-induced class II expression in a series of colorectal cancer organoids.
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Neoplasias Colorretais , Genes MHC da Classe II , Humanos , Interferon gama/farmacologia , Metilação , Linhagem Celular , Neoplasias Colorretais/genéticaRESUMO
Surgical aortic valve replacement represents a class one indication in the setting of aortic valve endocarditis and decompensated heart failure secondary to aortic regurgitation as per the European Society of Cardiology. However, extreme obesity, whereby the body mass index (BMI) >40 kg/m2, represents a challenging cohort of patients. Performing cardiac surgery in the bariatric population is fraught with challenges pertaining to intraoperative issues of surgical access and approach. We describe the case of a 45-year-old gentleman who had previous been diagnosed with infective endocarditis of the aortic valve and with a BMI of 68.2 (228 kg). Surgical aortic valve replacement in extreme obesity is associated with deep sternal wound infection, requirement and duration of mechanical ventilation, atrial fibrillation and renal failure. The 'obesity paradox' of overweight and class I obesity (BMI <35) has demonstrated favourable long-term results compared with underweight patients or even those with normal BMI undergoing cardiac surgery.
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Mediastinal cysts are commonly an incidental finding simulating a benign or malignant diagnosis. Infection is a recognised complication of mediastinal cyst and therefore early surgical management is essential. Endobronchial ultrasound guided biopsy (EBUS) has been used to diagnose and manage mediastinal cyst. We present a case series of three patients who presented with sepsis following diagnostic EBUS of mediastinal cyst. We would recommend that EBUS guided biopsy be applied cautiously if there is a high suspicion of mediastinal cyst to avoid post procedural infection, which can thus complicate any future therapeutic options.
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BACKGROUND: Percutaneous vascular interventions are performed for the treatment of haemoptysis and involve embolization of bronchial arteries, pulmonary arteries and pulmonary arteriovenous malformations. There are isolated reports of embolization of pseudoaneurysms forming in the pulmonary vasculature. The migration of components of the coils used in the embolization of vascular pulmonary pathologies is rare. CASE PRESENTATION: A 46-year-old man presented to the emergency department with cough, haemoptysis, and expectoration of lengths of metal wire. He had an episode of coughing out a wire about a year prior to his admission to our hospital, which he attributed to be present in the can of coke he had consumed at that time and did not report it to the doctors. His past medical history was significant for stab injury to the right chest 17 years ago, for which he underwent right thoracotomy and exploration for bleeding. Injury to the lung parenchyma was noted and repair was performed by suturing the defect. Post operatively the CT scan demonstrated development of pulmonary artery pseudoaneurysm. We report a case of a patient expectorating coils 17 years after embolization of this traumatic pulmonary artery pseudoaneurysm. Radiological imaging demonstrated coils in the perihilar area of the lung parenchyma and in the tracheobronchial lumen. Operative intervention was used to remove the coils. CONCLUSIONS: Although percutaneous catheter based vascular interventions have emerged as safe and effective procedures, the long-term complications such as coil migration, recanalization and need for further embolization ought to be considered and patients need to be counselled and followed-up accordingly. To the best of our knowledge, this is the first case of migrated coil post embolization of post-traumatic pulmonary artery pseudoaneurysm. Ultimately, the management of endobronchial coil migration post embolization, be it surgical or bronchoscopic, should be decided on a case-by-case basis, considering the patient's symptoms and the risk fatal complications.
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Falso Aneurisma , Embolização Terapêutica , Falso Aneurisma/diagnóstico por imagem , Falso Aneurisma/etiologia , Falso Aneurisma/terapia , Embolização Terapêutica/métodos , Hemoptise/etiologia , Humanos , Pulmão , Masculino , Pessoa de Meia-Idade , Artéria Pulmonar/anormalidades , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/cirurgiaRESUMO
Emergency medical assistance is rare regarding air travel. Pulmonary barotrauma during air travel can occur in asymptomatic patients who have underlying intraparenchymal pulmonary pathology such as bullae or bronchogenic cysts. During aircraft travel the resultant decrease in pressure during the ascent can lead to expansion of cyst volume, culminating in tears and leakage of air into the surrounding vasculature and thus the potential for air embolism. We describe a case of massive cerebral air embolism secondary to pulmonary barotrauma in a previously asymptomatic patient.
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Barotrauma/complicações , Cisto Broncogênico/complicações , Embolia Aérea/complicações , Acidente Vascular Cerebral/etiologia , Adulto , Cisto Broncogênico/etiologia , Embolia Aérea/etiologia , Feminino , HumanosRESUMO
BACKGROUND: Bronchopulmonary sequestration (BPS) is a malformation of the lungs resulting in lung tissue lacking direct communication to the tracheobronchial tree. Most cases demonstrate systemic arterial blood supply from the descending thoracic aorta, the abdominal aorta, celiac axis or splenic artery and venous drainage via the pulmonary veins with occasional drainage into azygos vein. BPS is considered a childhood disease and accounts for 0.15-6.40% of congenital pulmonary malformations. BPS is divided into intralobar sequestrations (ILS) and extralobar sequestrations (ELS) with ILS accounting for 75% of all cases. METHODS: Here we present our 11-year experience of dealing with BPS; all cases presented with recurrent chest sepsis in young-late adulthood regardless of the type of pathological sequestration. The surgical technique employed was a minimally invasive video-assisted thoracoscopic anterior approach (VATS). RESULTS: Between May 2010 and September 2021, we have operated on nine adult patients with bronchopulmonary sequestration who presented late with symptoms of recurrent chest sepsis. Most patients in the cohort had lower lobe pathology, with a roughly even split between right and left sided pathology. Moreover, the majority were life-long never smokers and an equal preponderance in males and females. The majority were extralobar sequestrations (56%) with pathological features in keeping with extensive bronchopneumonia and bronchiectasis. There were no major intra-operative or indeed post-operative complications. Median length of stay was 3 days. CONCLUSIONS: Dissection and division of the systemic feeding vessel was readily achievable through a successful anterior VATS approach, regardless of the type of sequestration and without the use of pre-operative coiling of embolization techniques. This approach gave excellent access to the hilar structures yet in this pathology, judicious and perhaps a lower threshold for open approach should be considered.