Impact of myopenia and myosteatosis on postoperative outcome and recurrence in Crohn’s disease

PURPOSE: Myopenia and myosteatosis have been proposed to be prognostic factors of surgical outcomes for various diseases, but their exact role in Crohn’s disease (CD) is unknown. The aim of this study is to evaluate their impact on anastomotic leakage, CD recurrence, and postoperative complications after ileocecal resection in patients with CD. METHODS: A retrospective analysis of CD patients undergoing ileocecal resection at our tertiary referral center was performed. To assess myopenia, skeletal muscle index (skeletal muscle area normalized for body height) was measured using an established image analysis method at third lumbar vertebra level on MRI cross-sectional images. Muscle signal intensity was measured to assess myosteatosis index. RESULTS: A total of 347 patients were retrospectively analyzed. An adequate abdominal MRI scan within 12 months prior to surgery was available for 223 patients with median follow-up time of 48.8 months (IQR: 20.0–82.9). Anastomotic leakage rate was not associated with myopenia (SMI: p = 0.363) or myosteatosis index (p = 0.821). Patients with Crohn’s recurrence had a significantly lower SMI (p = 0.047) in univariable analysis, but SMI was not an independent factor for recurrent anastomotic stenosis in multivariable analysis (OR 0.951, 95% CI 0.840–1.078; p = 0.434). Postoperative complications were not associated with myopenia or myosteatosis. CONCLUSION: Based on the largest cohort of its kind with a long follow-up time, we could provide some data that MRI parameters for myopenia and myosteatosis may not be reliable predictors of postoperative outcome or recurrence in patients with Crohn’s disease undergoing ileocecal resection

Novel methods for in vitro modeling of pancreatic cancer reveal important aspects for successful primary cell culture

Background: Pancreatic cancer remains a fatal disease. Experimental systems are needed for personalized treatment strategies, drug testing and to further understand tumor biology. Cell cultures can serve as an excellent preclinical platform, but their generation remains challenging. Methods: Tumor cells from surgically removed pancreatic ductal adenocarcinoma (PDAC) specimens were cultured under novel protocols. Cellular growth and composition were analyzed and culture conditions were continuously optimized. Characterization of cell cultures and primary tumors was performed via hematoxylin and eosin (HE) and immunofluorescence (IF) staining. Results: Protocols for two- and three-dimensional PDAC primary cell cultures could successfully be established. Primary cell culture depended on dissociation techniques, growth factor supplementation and extracellular matrix components containing Matrigel being crucial for the transformation to three-dimensional PDAC organoids. The generated cultures showed to be highly resemblant to established PDAC primary cell cultures. HE and IF staining for cell culture and corresponding primary tumor characterization could successfully be performed. Conclusions: The work presented herein shows novel and effective methods to successfully establish primary PDAC cell cultures in a distinct time frame. Factors contributing to cell growth and differentiation could be identified with important implications for further primary cell culture protocols. The established protocols might serve as novel tools in personalized tumor therapy

Rethinking the TNM Classification Regarding Direct Lymph Node Invasion in Pancreatic Ductal Adenocarcinoma

Mechanisms of lymph node invasion seem to play a prognostic role in pancreatic ductal adenocarcinoma (PDAC) after resection. However, the 8th edition of the TNM classification of the American Joint Committee on Cancer (AJCC) does not consider this. The aim of this study was to analyse the prognostic role of different mechanisms of lymph node invasion on PDAC. One hundred and twenty-two patients with resected PDAC were examined. We distinguished three groups: direct (per continuitatem, Nc) from the main tumour, metastasis (Nm) without any contact to the main tumour, and a mixed mechanism (Ncm). Afterwards, the prognostic power of the different groups was analysed concerning overall survival (OS). In total, 20 patients displayed direct lymph node invasion (Nc = 16.4%), 44 were classed as Nm (36.1%), and 21 were classed as Ncm (17.2%). The difference in OS was not statistically significant between N0 (no lymph node metastasis, n = 37) and Nc (p = 0.134), while Nm had worse OS than N0 (p < 0.001). Direct invasion alone had no statistically significant effect on OS (p = 0.885). Redefining the N0 stage by including Nc patients showed a more precise OS prediction among N stages (p = 0.001 vs. p = 0.002). Nc was more similar to N0 than to Nm; hence, we suggest a rethinking of TNM classification based on the mechanisms of lymph node metastases in PDAC. Overall, this novel classification is more precise

The optimal cut‐off values for tumor size, number of lesions, and CEA levels in patients with surgically treated colorectal cancer liver metastases: An international, multi‐institutional study

Background and Objectives: Despite the long-standing consensus on the importance of tumor size, tumor number and carcinoembryonic antigen (CEA) levels as predictors of long-term outcomes among patients with colorectal liver metastases (CRLM), optimal prognostic cut-offs for these variables have not been established. Methods: Patients who underwent curative-intent resection of CRLM and had available data on at least one of the three variables of interest above were selected from a multi-institutional dataset of patients with known KRAS mutational status. The resulting cohort was randomly split into training and testing datasets and recursive partitioning analysis was employed to determine optimal cut-offs. The concordance probability estimates (CPEs) for these optimal cut offs were calculated and compared to CPEs for the most widely used cut-offs in the surgical literature. Results: A total of 1643 patients who met eligibility criteria were identified. Following recursive partitioning analysis in the training dataset, the following cut-offs were identified: 2.95 cm for tumor size, 1.5 for tumor number and 6.15 ng/ml for CEA levels. In the entire dataset, the calculated CPEs for the new tumor size (0.52), tumor number (0.56) and CEA (0.53) cut offs exceeded CPEs for other commonly employed cut-offs. Conclusion: The current study was able to identify optimal cut-offs for the three most commonly employed prognostic factors in CRLM. While the per variable gains in discriminatory power are modest, these novel cut-offs may help produce appreciable increases in prognostic performance when combined in the context of future risk scores

The optimal cut-off values for tumor size, number of lesions, and CEA levels in patients with surgically treated colorectal cancer liver metastases: An international, multi-institutional study

Background and Objectives Despite the long-standing consensus on the importance of tumor size, tumor number and carcinoembryonic antigen (CEA) levels as predictors of long-term outcomes among patients with colorectal liver metastases (CRLM), optimal prognostic cut-offs for these variables have not been established. Methods Patients who underwent curative-intent resection of CRLM and had available data on at least one of the three variables of interest above were selected from a multi-institutional dataset of patients with known KRAS mutational status. The resulting cohort was randomly split into training and testing datasets and recursive partitioning analysis was employed to determine optimal cut-offs. The concordance probability estimates (CPEs) for these optimal cut offs were calculated and compared to CPEs for the most widely used cut-offs in the surgical literature. Results A total of 1643 patients who met eligibility criteria were identified. Following recursive partitioning analysis in the training dataset, the following cut-offs were identified: 2.95 cm for tumor size, 1.5 for tumor number and 6.15 ng/ml for CEA levels. In the entire dataset, the calculated CPEs for the new tumor size (0.52), tumor number (0.56) and CEA (0.53) cut offs exceeded CPEs for other commonly employed cut-offs. Conclusion The current study was able to identify optimal cut-offs for the three most commonly employed prognostic factors in CRLM. While the per variable gains in discriminatory power are modest, these novel cut-offs may help produce appreciable increases in prognostic performance when combined in the context of future risk scores.publishedVersio

clinical implications and open questions

The research work summarized in this thesis is largely focused on the role of KRAS and BRAF mutation status in determining prognosis and guiding management among patients with resectable CRLM. The decision to focus our investigation on these two biomarkers reflects both their central importance in colorectal carcinogenesis and the availability of relevant data which are collected as part of routine practice in most institutions. The publications presented in this work follow a well-defined continuum that traces the evolution of a number of interconnected ideas on the impact and possible role of available genetic data in the clinical management of patients with CRLM. This intellectual journey begun in 2015 with our first report confirming the prognostic role of KRAS mutation status in CRLM. Subsequently, we proceeded to demystify the impact of BRAF mutations on outcomes which at the time were considered synonymous with poor survival. While we confirmed that BRAF mutation status was indeed a potent predictor of poor prognosis, we were also able to identify distinct subgroups with favorable outcomes (i.e., patients with non-V600E mutations) and ultimately dispel the idea that these patients do not benefit from operative management. Despite these discoveries, when we sought to improve prognostication among patients with CRLM by introducing genetic biomarkers into contemporary risk scores, we found ourselves obligated to employ KRAS, rather than BRAF, due to the much higher incidence of KRAS mutation in CRLM cohorts. The result of this effort was the GAME score, which has gradually emerged as the most robust and accurate of a series of “hybrid” prognostic models that combine genetic and clinicopathologic variables. More so than its successes, the limitations of the GAME score and its predecessors proved of vital importance to future research endeavors by identifying persistent deficits in prognostication among patients with CRLM. One such example was the realization that contemporary survival models offered a static picture of projected outcomes at the time of surgery, failing to reflect clinical developments in a dynamic fashion. Conditional survival analysis helped address this limitation, confirming the prognostic discrepancies between patients with different BRAF codon mutations and highlighting the long-term importance of traditional variables such as surgical margin. The idea that tumor biology could impact tumor growth patterns and thus dictate surgical technique most likely to result in disease control led us to identify the possible utility of anatomical hepatectomy among patients with KRAS mutations. While definitive proof of efficacy will need to await dedicated clinical trials, this work initiated a debate on the potential of “precision surgery,” which remains active to this date. Lastly, having largely explored the prognostic implications of KRAS mutation status among patients with CRLM, we employed this variable to help reconcile disparate reports on the effect of tumor laterality on outcomes, paving the way for the utilization of this powerful prognostic factor in future risk scores

Gene Alterations, Mediators, and Artificial Intelligence in Colorectal Liver Metastases

In this Special Issue of Cells, we seek articles that focus on the study of tumor biology in order to guide the scalpel [...

The anti-inflammatory and anti-oxidative effect of U-74389G and sildenafil in a rat model of TNBS-induced colitis

BACKGROUND: Crohn disease is still incurable. Compounds with anti-inflammatory and/or antioxidativeeffects are tested in various preclinical models of the disease. Our aim was to investigate theeffects of sildenafil and lazaroid U-74389G in an experimental rat model oftrinitrobenzenesulfonic acid-induced colitis.MATERIALS AND METHODS:Trinitrobenzenesulfonic acid was instilled into the colon of all male Wistar rats except for therats belonging to the first group. For 6 days, the animals in group 3 were administered dailysildenafil orally, the rats in group 4 were administered daily U-74389G intravenously, and therats in group 5 were coadministered daily sildenafil orally and intravenous U-74389G. Therats in groups 1 and 2 were not administered any treatment. During the study, the weightswere recorded as a marker of clinical condition. The colon damage was evaluated usingmacroscopic colon mucosal damage index (CMDI), microscopic (Geboes score), andbiochemical methods (tissue tumor necrosis factor [TNF]-αΝandΝmalondialdehydeΝ[εϊχ]ΨέRESULTS:Sildenafil reduced TNF-αΝtissueΝlevelsΝandΝincreasedΝbodyΝweightέΝU-74389G reduced TNF-α,Νthe macroscopic index of mucosal damage score (CMDI) and increased body weight. Thecombined treatment with sildenafil and U-74389G reduced tissue levels of both TNF-αΝandΝMDA, lowered CMDI and microscopic Geboes score, and increased body weight. CONCLUSIONS:U-74389G demonstrated a significant anti-inflammatory activity related to its ability to reducecolonic TNF-α,ΝωεϊIΝscore, and improve weight change. We confirmed that sildenafil hasanti-inflammatory capacity by reducing colonic TNF-αΝandΝbyΝimprovingΝbodyΝweightέΝόinally,Νthe combined treatment showed superior effects by reducing colonic TNF-α,ΝcolonicΝεϊχ,ΝCMDI score, Geboes score, and by improving weight

Staged or Simultaneous Surgery for Colon or Rectal Cancer with Synchronous Liver Metastases: Implications for Study Design and Clinical Endpoints

In patients presenting with colorectal cancer and synchronous liver metastases, the disease burden related to the liver metastasis is the driving cause of limited longevity and, eventually, risk of death. Surgical resection is the potentially curative treatment for colorectal cancer liver metastases. In the synchronous setting where both the liver metastases and the primary tumor are resectable with a relative low risk, the oncological surgeon and the patient may consider three potential treatment strategies. Firstly, a “staged” or a “simultaneous” surgical approach. Secondly, for a staged strategy, a ‘conventional approach’ will suggest removal of the primary tumor first (either colon or rectal cancer) and plan for liver surgery after recovery from the first operation. A “Liver first” strategy is prioritizing the liver resection before resection of the primary tumor. Planning a surgical trial investigating a two-organ oncological resection with highly variable extent and complexity of resection as well as the potential impact of perioperative chemo(radio)therapy makes it difficult to find the optimal primary endpoint. Here, we suggest running investigational trials with carefully chosen composite endpoints as well as embedded risk-stratification strategies to identify subgroups of patients who may benefit from simultaneous surgery