The Adaptive Immune Landscape of the Colorectal Adenoma-Carcinoma Sequence.

BACKGROUND: The tumor immune microenvironment exerts a pivotal influence in tumor initiation and progression. The aim of this study was to analyze the immune context of sporadic and familial adenomatous polyposis (FAP) lesions along the colorectal adenoma-carcinoma sequence (ACS). METHODS: We analyzed immune cell counts (CD3+, CD4+, CD8+, Foxp3+, and CD57+), tumor mutation burden (TMB), MHC-I expression and PD-L1 expression of 59 FAP and 74 sporadic colorectal lesions, encompassing adenomas with low-grade dysplasia (LGD) (30 FAP; 30 sporadic), adenomas with high-grade dysplasia (22 FAP; 30 sporadic), and invasive adenocarcinomas (7 FAP; 14 sporadic). RESULTS: The sporadic colorectal ACS was characterized by (1) a stepwise decrease in immune cell counts, (2) an increase in TMB and MHC-I expression, and (3) a lower PD-L1 expression. In FAP lesions, we observed the same patterns, except for an increase in TMB along the ACS. FAP LGD lesions harbored lower Foxp3+ T cell counts than sporadic LGD lesions. A decrease in PD-L1 expression occurred earlier in FAP lesions compared to sporadic ones. CONCLUSIONS: The colorectal ACS is characterized by a progressive loss of adaptive immune infiltrate and by the establishment of a progressively immune cold microenvironment. These changes do not appear to be related with the loss of immunogenicity of tumor cells, or to the onset of an immunosuppressive tumor microenvironment.

Population-based study on surgical care for primary spontaneous pneumothorax.

OBJECTIVES: The optimal surgical strategy for primary spontaneous pneumothorax remains a matter of debate and variation in surgical practice is expected. This variation may influence clinical outcomes, such as postoperative complications and length of stay. This national population-based registry study provides an overview and extent of variability of current surgical practice and outcomes in the Netherlands. METHODS: To identify national patterns of care and between-hospital variability in the treatment of primary spontaneous pneumothorax, patients who underwent surgical pleurodesis and/or bullectomy between 2014 and 2021, were identified from the Dutch Lung Cancer Audit-Surgery database. The type of surgical intervention, postoperative complications, length of stay and ipsilateral recurrences were recorded. RESULTS AND CONCLUSIONS: Out of 4338 patients, 1851 patients were identified to have primary spontaneous pneumothorax. The median age was 25 years (interquartile range 20-31) and 82% was male. The most performed surgical procedure was bullectomy with pleurodesis (83%). The overall complication rate was 12% (Clavien-Dindo grade ≥III 6%), with the highest recorded incidence for persistent air leak >5 days (5%). Median postoperative length of stay was 4 days (interquartile range 3-6) and 0.7% underwent a repeat pleurodesis for ipsilateral recurrence. Complication rate and length of stay differed considerably between hospitals. There were no differences between the surgical procedures. In the Netherlands, surgical patients with primary spontaneous pneumothorax are preferably treated with bullectomy plus pleurodesis. Postoperative complications and length of stay vary widely and are considerable in this young patient group. This may be reduced by optimization of surgical care.

Acute pain management after thoracoscopic lung resection: a systematic review and explorative meta-analysis.

OBJECTIVES: Pain after thoracoscopic surgery may increase the incidence of postoperative complications and impair recovery. Guidelines lack consensus regarding postoperative analgesia. We performed a systematic review and meta-analysis to determine the mean pain scores of different analgesic techniques (thoracic epidural analgesia, continuous or single-shot unilateral regional analgesia and only systemic analgesia) after thoracoscopic anatomical lung resection. METHODS: Medline, Embase and Cochrane databases were searched until 1 October 2022. Patients undergoing at least >70% anatomical resections through thoracoscopy reporting postoperative pain scores were included. Due to a high inter-study variability an explorative meta-analysis next to an analytic meta-analysis was performed. The quality of evidence has been evaluated using the Grading of Recommendations Assessment, Development and Evaluation system. RESULTS: A total of 51 studies comprising 5573 patients were included. Mean 24, 48 and 72 h pain scores with 95% confidence interval on a 0-10 scale were calculated. Length of hospital stay, postoperative nausea and vomiting, additional opioids and the use of rescue analgesia were analysed as secondary outcomes. A common-effect size was estimated with an extreme high heterogeneity for which pooling of the studies was not appropriate. An exploratory meta-analysis demonstrated acceptable mean pain scores of Numeric Rating Scale <4 for all analgesic techniques. CONCLUSIONS: This extensive literature review and attempt to pool mean pain scores for meta-analysis demonstrates that unilateral regional analgesia is gaining popularity over thoracic epidural analgesia in thoracoscopic anatomical lung resection, despite great heterogeneity and limitations of current studies precluding such recommendations. PROSPERO REGISTRATION: ID number 205311.

Pain management after pneumothorax surgery: intercostal nerve block or thoracic epidural analgesia.

OBJECTIVES: In patients undergoing video-assisted thoracoscopic surgery for pneumothorax, the benefits and risks of single-shot intercostal nerve block as loco-regional analgesia are not well known. We retrospectively compared the effectiveness of intercostal nerve blocks as a viable alternative to thoracic epidural analgesia (TEA) regarding pain control and enhanced recovery. METHODS: A retrospective multicentre analysis with single-centre propensity score matching was performed in patients undergoing video-assisted thoracoscopic surgery for pneumothorax receiving either TEA or intercostal nerve block. The primary outcome was a proportion of pain scores ≥4 (scale 0-10) until postoperative day (POD) 3. Secondary outcomes included variation in pain over time, additional opioid use, length of stay, mobility, complications and recurrence rate. RESULTS: In 218 patients, TEA was compared to intercostal nerve block and showed no difference in the proportion of pain scores ≥4 {14.3% [interquartile range (IQR) 0.0-33.3] vs 11.1% (IQR 0.0-27.3) respectively, P = 0.24}, more frequently needed additional opioids on the day of surgery (18% vs 48%) and first POD (20% vs 42%), had a shorter length of stay (4.0 days [IQR 3.0-7.0] vs 3.0 days [IQR 2.8-4.0]) and were significantly more mobile until POD 3, while having similar recurrences. Intercostal nerve block had higher pain scores early in the course whereas TEA had higher late (rebound) pain scores. CONCLUSIONS: In a multimodal analgesic setting with additional opioids, intercostal nerve block shows comparable moments of unacceptable pain from POD 0-3 compared to TEA and is linked to improved mobility. Results require randomized confirmation.

Safety and Efficiency of an Articulating Needle Driver in Advanced Laparoscopic Abdominal Surgery.

Objective: Robotic platforms offer articulating needle drivers but are associated with high costs and lack tactile feedback. The recently developed mechanical Laparoscopic Articulating Needle Driver (LAND) (Flexdex®) for conventional laparoscopy offers enhanced dexterity without these limitations. The goal of this study was to assess safety and efficiency during the implementation of the LAND, and describe its learning curve, in an expert center for laparoscopic surgery. Methods: All LAND-assisted procedures after clinical implementation for a period of 16 months were included into this study. Primary outcome domains were safety (intra- and postoperative complications within 30 days) and efficiency (operative time, suturing, and knot tying time of staple defects of enteroenterostomy). CUmulative SUM (CUSUM) analysis was utilized to describe the enteroenterostomy suturing time learning curve across consecutive cases by plotting the deviation from the series mean. Results: Forty-five procedures (34 Roux-en-Y gastric bypass [of which 7 including diaphragmatic hernia repair], 2 diaphragmatic hernia repair with Nissen fundoplication, and 2 right-sided hemicolectomy) were included into this study. Median (range) operative time and enteroenterostomy suturing time were 68 (46-177) minutes and 161 (112-241) seconds, respectively, comparable with conventional needle driver standards. One procedure was converted to the conventional needle driver due to device malfunctioning and one patients' postoperative course was complicated by a Clavien-Dindo grade 3a complication (intraluminal bleeding requiring gastroscopy). CUSUM chart displays a progression toward the mean from case 22 onward, indicating a limited learning curve. Conclusion: The LAND can be implemented safely and efficiently at a center of excellence for laparoscopic surgery and is associated with a limited learning curve.

Neoadjuvant chemotherapy improves survival in patients with oesophageal mucinous adenocarcinoma: Post-hoc analysis of the UK MRC OE02 and OE05 trials.

BACKGROUND: Adenocarcinoma with more than 50% extracellular mucin is a relatively rare histological subtype of gastrointestinal adenocarcinomas. The clinical impact of extracellular mucin in oesophageal adenocarcinoma (OeAC) has not been investigated in detail. We hypothesised that patients with mucinous OeAC (OeACmucin) do not benefit from neoadjuvant chemotherapy. METHODS: OeAC patients either treated by surgery alone in the OE02 trial (S-patients) or by neoadjuvant chemotherapy followed by surgery (CS-patients) in OE02 or OE05 trials were included. Cancers from 1055 resection specimens (OE02 [test cohort]: 187 CS, 185 S; OE05 [validation cohort]: 683 CS) were classified as either mucinous (more than 50% of the tumour area consists of extracellular mucin, OeACmucin) or non-mucinous adenocarcinoma (OeACnon-mucin). The relationship between histological phenotype, clinicopathological characteristics, survival and treatment was analysed. RESULTS: Overall, 7.3% and 9.6% OeAC were classified as OeACmucin in OE02 and OE05, respectively. In OE02, the frequency of OeACmucin was similar in S and CS-patients. Patients with OeACmucin treated with surgery alone had a poorer overall survival compared with OeACnon-mucin patients (hazard ratio: 2.222, 95% confidence interval: 1.08-4.56, P = 0.025). Patients with OeACmucin treated with neoadjuvant chemotherapy and surgery had similar survival as OeACnon-mucin patients in test and validation cohort. CONCLUSIONS: This is the first study to suggest in a post-hoc analysis of material from two independent phase III clinical trials that the poor survival of patients with mucinous OeAC can be improved by neoadjuvant chemotherapy. Future studies are warranted to identify potential underlying biological, biochemical or pharmacokinetic interactions between extracellular mucin and chemotherapy.

The Influence of the Genetic and Immunologic Context in the Development of Colorectal Adenoma: A Case Series Report.

INTRODUCTION: Overcoming immunosurveillance is a major step in the progression of many types of tumors. Several immune escape strategies have been identified, including immunoediting and the establishment of an immune suppressive microenvironment. The aim of the present study was to determine whether the hereditary or sporadic context has any influence in the relationship between immune surveillance and tumor development, using sporadic and familial adenomatous polyposis related colorectal adenomas as a model. MATERIAL AND METHODS: The immune tumor-infiltrating cells of a total of 58 low-grade and 18 high-grade colorectal adenomas were examined and compared, using immunostaining for CD3, CD4, CD8, CD57, CD68 and FoxP3. RESULTS: FoxP3 and CD68 counts were significantly higher in sporadic low-grade dysplasia (p = 0.0003 and p = 0.0103, respectively),and FoxP3 and CD4 counts were found to be significantly higher in high-grade sporadic dysplasia (p = 0.0008 and p = 0.0018, respectively)when compared with corresponding lesions in patients with familial adenomatous polyposis. DISCUSSION: This study suggests that the immune microenvironment of sporadic and hereditary lesions is different. Sporadic lesions contain a higher number of immune suppressive Treg cells, which suggests a stronger immune selective pressure. In contrast, hereditarylesions seem to benefit from a more tolerant immune microenvironment, allowing for the development of lesions with lower immune cell infiltration. CONCLUSION: This study shows that sporadic lesions harbor higher tumor-infiltrating immune cell counts, which might reflect a higher immune tolerance towards hereditary lesions.

Introdução: A capacidade de contornar a imunovigilância é fundamental na progressão de muitos tumores. Já foram identificadas várias estratégias de escape imunológico, incluindo immunoediting e o estabelecimento de um microambiente imunológico supressivo. O objetivo do presente estudo passa por determinar se o contexto hereditário ou esporádico influencia a relação entre a imunovigilância e o desenvolvimento do tumor, usando adenomas coloretais esporádicos e hereditários, no contexto de polipose adenomatosa familiar, como modelos. Material e Métodos: Os infiltrados imunológicos tumorais de um total de 58 adenomas coloretais de baixo grau e de 18 de alto grau foram avaliados e comparados, usando imunohistoquímica com marcação para CD3, CD4, CD8, CD57, CD68 e FoxP3. Resultados: As contagens celulares com imunorreatividade para FoxP3 e CD68 foram significativamente mais elevadas na displasia esporádica de baixo grau (p = 0,0003 e p = 0,0103, respetivamente), enquanto que as contagens para FoxP3 e CD4 foram significativamente mais elevadas na displasia esporádica de alto grau (p = 0,0008 e p = 0,0018, respetivamente) quando comparadas com lesões correspondentes em doentes com polipose adenomatosa familiar. Discussão: O presente estudo sugere que o microambiente imunológico de lesões esporádicas e hereditárias é diferente. As lesões esporádicas contam com um número superior de células T reguladoras, supressoras da função imunológica, sugerindo-se uma pressão imune seletiva mais forte. Por seu turno, as lesões hereditárias parecem beneficiar de um microambiente imunológico mais tolerante, permitindo o desenvolvimento de lesões com menor infiltrado celular imune. Conclusão: Este estudo demonstra que as lesões esporádicas contam com contagens de infiltrados imunológicos tumorais superiores, o que poderá refletir uma maior tolerância imunológica face a lesões hereditárias.