Search

The role of local ischaemia in the pathogenesis of colorectal anastomotic leakage (AL) is not known. This study investigates the role of local ischaemia caused by sutures in an experimental colonic anastomosis model. 36 mice were assigned to three types of anastomosis, all using running sutures; in the first group 5 stitches were used, in the second group 12 stitches were used, and in the third group at least 30 stitches were used. After 7 days the mice were re-operated, signs of AL were scored, and coronal sections of the anastomosis were histologically analyzed. The distribution of weight was not significantly different between the three groups. Mortality was 44% and not significantly different between the groups (group 1: 5/12, group 2: 4/12, and group 3: 7/12, p = 0.72). Faecal and purulent AL were observed in 6 animals in group 1, 2 in group 2, and 3 in group 3 (group 1: 50%, group 2: 17%, and group 3: 25%, p = 0.19). The distance between the two colonic edges (group 1: 0.51 μm, group 2: 1.34 μm, and group 3: 0.53 μm, p = 0.18), the diameter of the lumen at the site of the anastomosis (group 1: 2.92 μm, group 2: 4.06 μm, and group 3: 3.2 μm, p = 0.9), and the largest diameter of the lumen proximally to the anastomosis (group 1: 2.05 μm, group 2: 3.1 μm, and group 3: 2.6 μm, p = 0.25) were not different between the groups. Histological parameters of wound healing were not significantly different for the three groups. In this study no macroscopic and microscopic differences were observed between colon anastomosis with 5 stitches versus 12 and >30 stitches. This might indicate that local ischaemia does not negatively influence colonic wound healing. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Introduction: Molecular profiling of NSCLC is essential for optimising treatment decisions, but often incomplete. We assessed the efficacy of protocolised molecular profiling in the current standard-of-care (SoC) in a prospective observational study in the Netherlands and measured the effect of providing standardised diagnostic procedures. We also explored the potential of plasma-based molecular profiling in the primary diagnostic setting. Methods: This multi-centre prospective study was designed to explore the performance of current clinical practice during the run-in phase using local SoC tissue profiling procedures. The subsequent phase was designed to investigate the extent to which comprehensive molecular profiling (CMP) can be maximized by protocolising tumour profiling. Successful molecular profiling was defined as completion of at least EGFR and ALK testing. Additionally, PD-L1 tumour proportions scores were explored. Lastly, the additional value of centralised plasma-based testing for EGFR and KRAS mutations using droplet digital PCR was evaluated. Results: Total accrual was 878 patients, 22.0% had squamous cell carcinoma and 78.0% had non-squamous NSCLC. Stage I-III was seen in 54.0%, stage IV in 46.0%. Profiling of EGFR and ALK was performed in 69.9% of 136 patients included in the run-in phase, significantly more than real-world data estimates of 55% (p<0.001). Protocolised molecular profiling increased the rate to 77.0% (p = 0.049). EGFR and ALK profiling rates increased from 77.9% to 82.1% in non-squamous NSCLC and from 43.8% to 57.5% in squamous NSCLC. Plasma-based testing was feasible in 98.4% and identified oncogenic driver mutations in 7.1% of patients for whom tissue profiling was unfeasible. Conclusion: This study shows a high success rate of tissue-based molecular profiling that was significantly improved by a protocolised approach. Tissue-based profiling remains unfeasible for a substantial proportion of patients. Combined analysis of tumour tissue and circulating tumour DNA is a promising approach to allow adequate molecular profiling of more patients. [ABSTRACT FROM AUTHOR]

Background: The tumor immune microenvironment is a heterogeneous entity. Gene expression analysis allows us to perform comprehensive immunoprofiling and may assist in dissecting the different components of the immune infiltrate. As gene expression analysis also provides information regarding tumor cells, differences in interactions between the immune system and specific tumor characteristics can also be explored. This study aims to gain further insights in the composition of the tumor immune infiltrate and to correlate these components to histology and overall survival in non-small cell lung cancer (NSCLC).Methods: Archival tissues from 530 early stage, resected NSCLC patients with annotated tumor and patient characteristics were analyzed using the NanoString nCounter Analysis system.Results: Unsupervised clustering of the samples was mainly driven by the overall level of inflammation, which was not correlated with survival in this patient set. Adenocarcinoma (AD) showed a significantly higher degree of immune infiltration compared to squamous cell carcinoma (SCC). A 34-gene signature, which did not correlate with the overall level of immune infiltration, was identified and showed an OS benefit in SCC. Strikingly, this benefit was not observed in AD. This difference in OS in SCC specifically was confirmed in two independent NSCLC cohorts. The highest correlation between expression of the 34-gene signature and specific immune cell populations was observed for NK cells, but although a plausible mechanism for NK cell intervention in tumor growth could be established in SCC over AD, this could not be translated back to immunohistochemistry, which showed that NK cell infiltration is scarce irrespective of histology.Conclusions: These findings suggest that the ability of immune cell infiltration and the interaction between tumor and immune cells may be different between AD and SCC histology and that a subgroup of SCC tumors seems more susceptible to Natural Killer cell recognition and killing, whereas this may not occur in AD tumors. A highly sensitive technique like NanoString was able to detect this subgroup based on a 34-gene signature, but further research will be needed to assist in explaining the biological rationale of such low-level expression signatures. [ABSTRACT FROM AUTHOR]

Background: At present, transanal advancement flap repair (TAFR) is the treatment of choice for transsphincteric fistulas passing through the upper and middle third of the external anal sphincter. It has been suggested that epithelialization of the fistula tract contributes to the failure of the treatment. The aim of this study was to assess the prevalence of epithelialization of the fistula tract and to study its effect on the outcome of TAFR and TAFR combined with ligation of the intersphincteric fistula tract (LIFT). Methods: Forty-four patients with a high transsphincteric fistula of cryptoglandular origin underwent TAFR. Nine of these patients underwent a combined procedure of TAFR with LIFT. In all patients the fistula tract was excised from the external opening up to the outer border of the external anal sphincter. In patients undergoing TAFR combined with LIFT an additional central part of the intersphincteric fistula tract was excised. A total of 53 specimens were submitted. Histopathological examination of the specimens was carried out by a pathologist, blinded for clinical data. Results: Epithelialization of the distal and intersphincteric fistula tract was observed in only 25 and 22% of fistulas, respectively. There was no difference in outcome between fistulas with or without epithelialization. Conclusions: Epithelialization of high transsphincteric fistulas is rare and does not affect the outcome of TAFR and TAFR combined with LIFT. [ABSTRACT FROM AUTHOR]

• Resection of an oligoprogressive lesion after systemic therapy is feasible. • Oligoprogressive surgery might be considered to achieve long term survival. • M1 disease at initial presentation was predictive for better PFS. • Clinical T4 stage was predictive for PFS. • Superior PFS was seen after resection of the primary lung tumour. Patients with advanced stage non-small cell lung cancer (NSCLC) are generally considered incurable. The mainstay of treatment for these patients is systemic therapy. The addition of local treatment, including surgery, remains controversial. Oligoprogression is defined as advanced stage NSCLC with limited progression of disease after a period of prolonged disease stabilisation or after a partial or complete response on systemic therapy. In this retrospective study we evaluated outcome and survival of patients who underwent a resection for oligoprogression after systemic therapy for advanced stage NSCLC. Patients with oligoprogression after systemic treatment for advanced NSCLC who were operated in the Antoni van Leeuwenhoek Hospital were included. Patient and treatment characteristics were collected in relation to progression free survival (PFS) and overall survival (OS). Between January 2015 and December 2019, 28 patients underwent surgery for an oligoprogressive lesion (primary tumor lung (n = 12), other metastatic site (n = 16)). Median age at time of resection was 60 years (39–86) and 57% were female. Postoperative complications were observed in 2 patients (7%). Progression of disease after resection of the oligoprogressive site was observed in 17 patients (61%). Median PFS was 7 months since date of resection (95% CI 6.0–25.0) and median OS was not reached. Seven patients (25%) died during follow-up. Age was predictive for OS and clinical T4 stage was predictive for PFS. M1 disease at initial presentation was predictive for better PFS compared to patients who were diagnosed with M0 disease initially. Patients who underwent resection because of oligoprogression of the primary lung tumour had a better PFS, when compared to oligoprogression of another metastastic site. Surgical resection of an oligoprogressive lesion in patients with advanced NSCLC treated with systemic treatment is feasible and might be considered in order to achieve long term survival. [ABSTRACT FROM AUTHOR]

• Limited antitumor activity of osimertinib in EGFR exon 20 mutated lung cancer. • Objective response rate was 5 %. • Median progression free survival was 3.6 months. • A subgroup derived durable disease stabilization of five months and beyond. Epidermal growth factor receptor (EGFR) exon 20 insertions comprise 4–10 % of EGFR mutations in non-small cell lung cancer (NSCLC) and are associated with primary resistance to first and second generation EGFR tyrosine kinase inhibitors (TKIs). In vitro and preclinical animal studies have shown that osimertinib exerts antitumor activity against EGFR exon 20 mutation positive NSCLC. We report on a cohort of advanced stage NSCLC patients who harbor an EGFR exon 20 mutation and received osimertinib treatment. Twenty-one patients were treated with osimertinib 80 or 160 mg once daily from April 2016 to June 2018, in four institutions in the Netherlands. Data were obtained retrospectively. Progression free survival (PFS), disease control rate (DCR), overall survival (OS) and objective response rate (ORR) were assessed using RECIST v1.1. Thirteen patients received prior platinum-based chemotherapy, and three patients a first – or second generation EGFR TKI. We observed 1 partial response, 17 patients with stable disease and 3 with progressive disease as best response to osimertinib (ORR 5 %). Median PFS was 3.6 (95 % CI, 2.6–4.5) months. PFS did not differ for patients with co-occurring TP53 mutations (p = 0.937). The DCR at three months was 71 %. Median OS was 8.7 (95 % CI, 1.1–16.4) months. Osimertinib has limited antitumor activity in patients with EGFR exon 20 mutated NSCLC, with an ORR of 5 %. [ABSTRACT FROM AUTHOR]

• Discordant ALK immunohistochemistry positive (IHC) FISH negative NSCLC occurs at low frequency. • Not all locally performed ALK IHC and FISH test were centrally confirmed. • Prognosis of concordant ALK IHC and FISH positive NSCLC is similar as literature. • Prognosis of validated discordant ALK IHC positive FISH negative NSCLC is significantly lower. • In NSCLC a positive ALK IHC screentest should be followed by ALK FISH. Metastasized non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) rearrangement is usually sensitive to a range of ALK-tyrosine kinase inhibitors. ALK-positive NSCLC have been identified in pivotal phase III trials with fluorescence in situ hybridization (ALK FISH+). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC)+). However, discrepant cases occur, including ALK IHC + FISH-. The aim of this study was to collect ALK IHC + cases and compare within this group response to crizotinib treatment of ALK FISH + cases with ALK FISH- cases. In this European prospective multicenter research study patients with Stage IV ALK IHC + NSCLC treated with crizotinib were enrolled. Tumor slides were validated centrally for ALK IHC and ALK FISH. Registration of 3523 ALK IHC tests revealed a prevalence of 2.7% (n = 94) ALK IHC + cases. Local ALK FISH analysis resulted in 48 concordant (ALK IHC+/FISH+) and 16 discordant (ALK IHC+/FISH-) cases. Central validation revealed 37 concordant and 7 discordant cases, 5 of which had follow-up. Validation was hampered by limited amount of tissue in biopsy samples. The PFS at 1 year for ALK concordant and discordant was 58% and 20%, respectively (HR = 2.4; 95% CI: 0.78–7.3; p = 0.11). Overall survival was significantly better for concordant cases than discordant cases after central validation (HR=4.5; 95% CI= 1.2–15.9; p=0.010. ALK IHC + FISH- NSCLC is infrequent and associated with a worse outcome on personalized treatment. A suitable predictive testing strategy may be to screen first with IHC and then confirm with FISH instead of considering ALK IHC equivalent to ALK FISH according to the current guidelines. [ABSTRACT FROM AUTHOR]

Background Immune checkpoint inhibitors have improved survival outcome of advanced non-small-cell lung cancer (NSCLC). However, most patients do not benefit. Therefore, biomarkers are needed that accurately predict response. We hypothesized that molecular profiling of exhaled air may capture the inflammatory milieu related to the individual responsiveness to anti-programmed death ligand 1 (PD-1) therapy. This study aimed to determine the accuracy of exhaled breath analysis at baseline for assessing nonresponders versus responders to anti-PD-1 therapy in NSCLC patients. Methods This was a prospective observational study in patients receiving checkpoint inhibitor therapy using both a training and validation set of NSCLC patients. At baseline, breath profiles were collected in duplicate by a metal oxide semiconductor electronic nose (eNose) positioned at the rear end of a pneumotachograph. Patients received nivolumab or pembrolizumab of which the efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at 3-month follow-up. Data analysis involved advanced signal-processing and statistics based on independent t -tests followed by linear discriminant and receiver operating characteristic (ROC) analysis. Results Exhaled breath data of 143 NSCLC patients (training: 92, validation: 51) were available at baseline. ENose sensors contributed significantly (P  < 0.05) at baseline in differentiating between patients with different responses at 3 months of anti-PD-1 treatment. The eNose sensors were combined into a single biomarker with an ROC-area under the curve (AUC) of 0.89 [confidence interval (CI) 0.82–0.96]. This AUC was confirmed in the validation set : 0.85 (CI 0.75–0.96). Conclusion ENose assessment was effective in the noninvasive prediction of individual patient responses to immunotherapy. The predictive accuracy and efficacy of the eNose for discrimination of immunotherapy responder types were replicated in an independent validation set op patients. This finding can potentially avoid application of ineffective treatment in identified probable nonresponders. [ABSTRACT FROM AUTHOR]

Background: In laparoscopic incisional hernia repair, direct contact between the prosthesis and the abdominal viscera is inevitable, which may lead to an inflammatory reaction resulting in abdominal adhesion formation. This study compared five different synthetic and biologic meshes in terms of adhesion formation, shrinkage, incorporation, and histologic characteristics after a period of 30 and 90 days. Methods: In 85 rats, a mesh was positioned intraperitoneally in direct contact with the viscera. Five different meshes were implanted: Prolene (polypropylene), Parietex composite (collagen-coated polyester), Strattice (porcine dermis, non-cross-linked), Surgisis (porcine small intestine submucosa, non-cross-linked), and Permacol (porcine dermis, cross-linked). The meshes were tested in terms of adhesion formation, shrinkage, and incorporation after a period of 30 and 90 days. Additionally, collagen formation after 90 days was determined. Results: Significantly less adhesion formation was observed with Parietex composite (5 %; interquartile range [IQR], 2-5 %) and Strattice (5 %; IQR, 4-10 %) in the long term. In contrast, organs were attached to Permacol with four of seven meshes (57 %), and adhesion coverage of Surgisis mesh was present in 66 % (IQR, 0-100 %) of the cases. After 90 days, the best incorporation was seen with the Parietex composite mesh (79 %; IQR, 61-83 %). After 90 days, major alterations in adhesion formation were seen compared with 30 days. Histologically, Strattice and Parietex composite showed a new mesothelial layer on the visceral side of the mesh. Microscopic degradation and new collagen formation were seen in the Surgisis group. Conclusions: Parietex composite mesh demonstrated the best long-term results compared with all the other meshes. The biologic non-cross-linked mesh, Strattice, showed little adhesion formation and moderate shrinkage but poor incorporation. Biologic meshes are promising, but varying results require a more detailed investigation and demonstrate that biologic meshes are not necessarily superior to synthetic meshes. The significant changes that take place between 30 and 90 days should lead to careful interpretation of short-term experimental results. [ABSTRACT FROM AUTHOR]