Interpretable artificial intelligence to optimise use of imatinib after resection in patients with localised gastrointestinal stromal tumours: an observational cohort study.

BACKGROUND: Current guidelines recommend use of adjuvant imatinib therapy for many patients with gastrointestinal stromal tumours (GISTs); however, its optimal treatment duration is unknown and some patient groups do not benefit from the therapy. We aimed to apply state-of-the-art, interpretable artificial intelligence (ie, predictions or prescription logic that can be easily understood) methods on real-world data to establish which groups of patients with GISTs should receive adjuvant imatinib, its optimal treatment duration, and the benefits conferred by this therapy. METHODS: In this observational cohort study, we considered for inclusion all patients who underwent resection of primary, non-metastatic GISTs at the Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY, USA) between Oct 1, 1982, and Dec 31, 2017, and who were classified as intermediate or high risk according to the Armed Forces Institute of Pathology Miettinen criteria and had complete follow-up data with no missing entries. A counterfactual random forest model, which used predictors of recurrence (mitotic count, tumour size, and tumour site) and imatinib duration to infer the probability of recurrence at 7 years for a given patient under each duration of imatinib treatment, was trained in the MSKCC cohort. Optimal policy trees (OPTs), a state-of-the-art interpretable AI-based method, were used to read the counterfactual random forest model by training a decision tree with the counterfactual predictions. The OPT recommendations were externally validated in two cohorts of patients from Poland (the Polish Clinical GIST Registry), who underwent GIST resection between Dec 1, 1981, and Dec 31, 2011, and from Spain (the Spanish Group for Research in Sarcomas), who underwent resection between Oct 1, 1987, and Jan 30, 2011. FINDINGS: Among 1007 patients who underwent GIST surgery in MSKCC, 117 were included in the internal cohort; for the external cohorts, the Polish cohort comprised 363 patients and the Spanish cohort comprised 239 patients. The OPT did not recommend imatinib for patients with GISTs of gastric origin measuring less than 15·9 cm with a mitotic count of less than 11·5 mitoses per 5 mm2 or for those with small GISTs (<5·4 cm) of any site with a count of less than 11·5 mitoses per 5 mm2. In this cohort, the OPT cutoffs had a sensitivity of 92·7% (95% CI 82·4-98·0) and a specificity of 33·9% (22·3-47·0). The application of these cutoffs in the two external cohorts would have spared 38 (29%) of 131 patients in the Spanish cohort and 44 (35%) of 126 patients in the Polish cohort from unnecessary treatment with imatinib. Meanwhile, the risk of undertreating patients in these cohorts was minimal (sensitivity 95·4% [95% CI 89·5-98·5] in the Spanish cohort and 92·4% [88·3-95·4] in the Polish cohort). The OPT tested 33 different durations of imatinib treatment (<5 years) and found that 5 years of treatment conferred the most benefit. INTERPRETATION: If the identified patient subgroups were applied in clinical practice, as many as a third of the current cohort of candidates who do not benefit from adjuvant imatinib would be encouraged to not receive imatinib, subsequently avoiding unnecessary toxicity on patients and financial strain on health-care systems. Our finding that 5 years is the optimal duration of imatinib treatment could be the best source of evidence to inform clinical practice until 2028, when a randomised controlled trial with the same aims is expected to report its findings. FUNDING: National Cancer Institute.

Is Precision Surgery Applicable to Colorectal Liver Metastases? A Systematic Review and Meta-analysis of Studies that Investigate the Association of Surgical Technique with Outcomes in the Context of Distinct Tumor Biology.

BACKGROUND: Although some data suggest that patients with mutRAS colorectal liver metastases (CRLM) may benefit from anatomic hepatectomy, this topic remains controversial. We performed a systematic review and meta-analysis to determine whether RAS mutation status was associated with prognosis relative to surgical technique [anatomic resection (AR) vs. nonanatomic resection (NAR)] among patients with CRLM. PATIENTS AND METHODS: A systematic review and meta-analysis of studies were performed to investigate the association of AR versus NAR with overall and liver-specific disease-free survival (DFS and liver-specific DFS, respectively) in the context of RAS mutation status. RESULTS: Overall, 2018 patients (831 mutRAS vs. 1187 wtRAS) were included from five eligible studies. AR was associated with a 40% improvement in liver-specific DFS [hazard ratio (HR) = 0.6, 95% confidence interval (CI) 0.44-0.81, p = 0.01] and a 28% improvement in overall DFS (HR = 0.72, 95% CI 0.54-0.95, p = 0.02) among patients with mutRAS tumors; in contrast, AR was not associated with any improvement in liver-specific DFS or overall DFS among wtRAS patients. These differences may have been mediated by the 40% decreased incidence in R1 resection among patients with mutRAS tumors who underwent AR versus NAR [relative risk (RR): 0.6, 95% CI 0.40-0.91, p = 0.02]. In contrast, the probability of an R1 resection was not decreased among wtRAS patients who underwent AR versus NAR (RR: 0.93, 95% CI 0.69-1.25, p = 0.62). CONCLUSIONS: The data suggest that precision surgery may be relevant to CRLM. Specifically, rather than a parenchymal sparing dogma for all patients, AR may have a role in individuals with mutRAS tumors.

Role of visceral fat on postoperative complications and relapse in patients with Crohn's disease after ileocecal resection: Is it overrated?

INTRODUCTION: The role of visceral fat in disease development, particularly in Crohn´s disease (CD), is significant. However, its preoperative prognostic value for postoperative complications and CD relapse after ileocecal resection (ICR) remains unknown. This study aims to assess the predictive potential of preoperatively measured visceral and subcutaneous fat in postoperative complications and CD recurrence using magnetic resonance imaging (MRI). The primary endpoint was postoperative anastomotic leakage of the ileocolonic anastomosis, with secondary endpoints evaluating postoperative complications according to the Clavien Dindo classification and CD recurrence at the anastomosis. METHODS: We conducted a retrospective analysis of 347 CD patients who underwent ICR at our tertiary referral center between 2010 and 2020. We included 223 patients with high-quality preoperative MRI scans, recording demographics, postoperative outcomes, and CD recurrence rates at the anastomosis. To assess adipose tissue distribution, we measured total fat area (TFA), visceral fat area (VFA), subcutaneous fat area (SFA), and abdominal circumference (AC) at the lumbar 3 (L3) level using MRI cross-sectional images. Ratios of these values were calculated. RESULTS: None of the radiological variables showed an association with anastomotic leakage (TFA p = 0.932, VFA p = 0.982, SFA p = 0.951, SFA/TFA p = 0.422, VFA/TFA p = 0.422), postoperative complications, or CD recurrence (TFA p = 0.264, VFA p = 0.916, SFA p = 0.103, SFA/TFA p = 0.059, VFA/TFA p = 0.059). CONCLUSIONS: Radiological visceral obesity variables were associated with postoperative outcomes or clinical recurrence in CD patients undergoing ICR. Preoperative measurement of visceral fat measurement is not specific for predicting postoperative complications or CD relapse.

Performance of the 7 th and 8 th Editions of the American Joint Committee on Cancer Staging System in Patients with Intraductal Papillary Mucinous Neoplasm-Associated PDAC : A Multi-institutional Analysis.

OBJECTIVE: To validate the 7 th and 8 th editions of the AJCC staging system for patients with invasive carcinomas arising in association with IPMN (IPMN-associated PDAC). BACKGROUND DATA: Although several studies have validated AJCC systems in patients with conventional PDAC, their applicability to IPMN-associated PDAC has not been assessed. METHODS: Two hundred seventy-five patients who underwent resection for IPMN-associated PDAC between 1996 and 2015 at 3 tertiary centers and had data on the size of the invasive component and lymph node status were identified. Concordance probability estimates (CPE) were calculated and recursive partitioning analysis was employed to identify optimal prognostic cutoffs for T and N. RESULTS: The CPE for the 7 th and 8 th editions of the AJCC schema were relatively good (0.64 for both) and similar for colloid and tubular subtypes (0.64 for both). The 8 th edition introduced T1a sub-staging and a new distinction between N1 and N2. The utility of the former was confirmed, although the latter did not improve prognostic discrimination. The successful validation of the 8th edition of the AJCC criteria in patients with tubular and colloid subtypes allowed us to compare these patients in early vs late T and N stages which showed that with advanced disease, the prognostic superiority of colloid tumors over their tubular counterparts diminishes. CONCLUSIONS: Our findings support the use of the AJCC 8 th edition in the IPMN-associated PDAC population, but suggest that certain cutoffs may need to be revisited. In advanced AJCC stages, patients with colloid vs tubular subtypes have comparable prognosis.

Demystifying BRAF Mutation Status in Colorectal Liver Metastases : A Multi-institutional, Collaborative Approach to 6 Open Clinical Questions.

OBJECTIVE: To investigate the clinical implications of BRAF -mutated (mut BRAF ) colorectal liver metastases (CRLMs). BACKGROUND: The clinical implications of mut BRAF status in CRLMs are largely unknown. METHODS: Patients undergoing resection for mut BRAF CRLM were identified from prospectively maintained registries of the collaborating institutions. Overall survival (OS) and recurrence-free survival (RFS) were compared among patients with V600E versus non-V600E mutations, KRAS/BRAF comutation versus mut BRAF alone, microsatellite stability status (Microsatellite Stable (MSS) vs instable (MSI-high)), upfront resectable versus converted tumors, extrahepatic versus liver-limited disease, and intrahepatic recurrence treated with repeat hepatectomy versus nonoperative management. RESULTS: A total of 240 patients harboring BRAF -mutated tumors were included. BRAF V600E mutation was associated with shorter OS (30.6 vs 144 mo, P =0.004), but not RFS compared with non-V600E mutations. KRAS/BRAF comutation did not affect outcomes. MSS tumors were associated with shorter RFS (9.1 vs 26 mo, P <0.001) but not OS (33.5 vs 41 mo, P =0.3) compared with MSI-high tumors, whereas patients with resected converted disease had slightly worse RFS (8 vs 11 mo, P =0.01) and similar OS (30 vs 40 mo, P =0.4) compared with those with upfront resectable disease. Patients with extrahepatic disease had worse OS compared with those with liver-limited disease (8.8 vs 40 mo, P <0.001). Repeat hepatectomy after intrahepatic recurrence was associated with improved OS compared with nonoperative management (41 vs 18.7 mo, P =0.004). All results continued to hold true in the multivariable OS analysis. CONCLUSIONS: Although surgery may be futile in patients with BRAF -mutated CRLM and concurrent extrahepatic disease, resection of converted disease resulted in encouraging survival in the absence of extrahepatic spread. Importantly, second hepatectomy in select patients with recurrence was associated with improved outcomes. Finally, MSI-high status identifies a better prognostic group, with regard to RFS while patients with non-V600E mutations have excellent prognosis.

Diagnostic performance of Node Reporting and Data System (Node-RADS) for regional lymph node staging of gastric cancer by CT.

OBJECTIVES: Diagnostic performance of imaging for regional lymph node assessment in gastric cancer is still limited, and there is a lack of consensus on radiological evaluation. At the same time, there is an increasing demand for structured reporting using Reporting and Data Systems (RADS) to standardize oncological imaging. We aimed at investigating the diagnostic performance of Node-RADS compared to the use of various individual criteria for assessing regional lymph nodes in gastric cancer using histopathology as reference. METHODS: In this retrospective single-center study, consecutive 91 patients (median age, 66 years, range 33-91 years, 54 men) with CT scans and histologically proven gastric adenocarcinoma were assessed using Node-RADS assigning scores from 1 to 5 for the likelihood of regional lymph node metastases. Additionally, different Node-RADS criteria as well as subcategories of altered border contour (lobulated, spiculated, indistinct) were assessed individually. Sensitivity, specificity, and Youden's index were calculated for Node-RADS scores, and all criteria investigated. Interreader agreement was calculated using Cohen's kappa. RESULTS: Among all criteria, best performance was found for Node-RADS scores ≥ 3 and ≥ 4 with a sensitivity/specificity/Youden's index of 56.8%/90.7%/0.48 and 48.6%/98.1%/0.47, respectively, both with substantial interreader agreement (κ = 0.73 and 0.67, p < 0.01). Among individual criteria, the best performance was found for short-axis diameter of 10 mm with sensitivity/specificity/Youden's index of 56.8%/87.0%/0.44 (κ = 0.65, p < 0.01). CONCLUSION: This study shows that structured reporting of combined size and configuration criteria of regional lymph nodes in gastric cancer slightly improves overall diagnostic performance compared to individual criteria including short-axis diameter alone. The results show an increase in specificity and unchanged sensitivity. CLINICAL RELEVANCE STATEMENT: The results of this study suggest that Node-RADS may be a suitable tool for structured reporting of regional lymph nodes in gastric cancer. KEY POINTS: • Assessment of lymph nodes in gastric cancer is still limited, and there is a lack of consensus on radiological evaluation. • Node-RADS in gastric cancer improves overall diagnostic performance compared to individual criteria including short-axis diameter. • Node-RADS may be a suitable tool for structured reporting of regional lymph nodes in gastric cancer.

[Effectiveness of Mucosal Advancement Flaps in Surgery of Perianal Fistulas from Crohn´s Disease and Cryptoglandular Fistulas - a Long-term Follow-up Study]. / Effektivität von Mukosa Muskel Flaps in der Behandlung von perianalen Fisteln bei Morbus Crohn und kryptoglandulären Fisteln ­ eine Langzeit-Follow-up-Studie.

AIM: Surgical treatment of perianal fistulae originating from Crohn's Disease (CD) or cryptoglandular abscess (CGA) remains a challenge. Data on long-term healing rates are scarce. We aimed to evaluate the long-term success rate of mucosal advancement flap (MAF) operations. METHODS: This single centre retrospective analysis was performed at a tertiary referral centre (Charité University Hospital Berlin, Campus Benjamin Franklin) between March 1, 2010 and March 31, 2020. Patients with complex perianal fistulae originating from CD or CGA treated with MAF were included. Long-time healing rates of MAF in CGA and CD were compared. Regression analysis was used to identify predictive factors for definitive healing. RESULTS: 83 patients (24 CD, 59 CGA,) were included. Median follow-up for CD was 5.4 and 1.9 years for CGA. Definitive healing of fistulae was achieved in 19 (79.2%) CD patients (p = 0.682) and in 44 (74.6%) CGA patients. Healing time was significantly shorter in CGA than in CD (9.3 months [standard deviation: SD= 11.3 months] vs. 30.9 months [SD = 23.5 months]; p < 0.001). Treatment with biologicals (hazard ratio: HR = 0.18, 95%-confidence interval: 95%-CI = 0.06-0.59, p = 0.004) and diverting ileostomy (HR = 0.29, 95%-CI = 0.10-0.85, p = 0.023) in CD were independent predictors for MAF success. Simultaneous medication with azathioprine in CD was an independent predictor for MAF failure (HR = 3.20, 95%-CI = 1.05-9.81, p = 0.041). CONCLUSION: This study demonstrates that surgical therapy of perianal fistulae with MAF is successful in about 75% of patients overall. Patients with MC benefit from biologicals and a diverting ileostomy. Treatment with azathioprine had a negative impact on recurrence rates. Repeated MAF operations did not increase the risk of failure in subsequent operations.

Inflammation of the rectal remnant endangers the outcome of ileal pouch-anal anastomosis: a case-control study.

BACKGROUND: Inflammation of the rectal remnant may affect the postoperative outcome of ileal pouch-anal anastomosis (IPAA) in patients with ulcerative colitis (UC). We aimed to determine the extent of inflammation in the anastomotic area during IPAA and to investigate the impact of proctitis on postoperative complications and long-term outcomes. METHODS: Three hundred thirty-four UC patients with primary IPAA were included in this retrospective case-control study. The histopathologic degree of inflammation in the anastomotic area was graded into three stages of no proctitis ("NOP"), mild to medium proctitis ("MIP"), and severe proctitis ("SEP"). Preoperative risk factors, 30-day morbidity, and follow-up data were assessed. Kaplan-Meier analysis was performed in the event of pouch failure. RESULTS: The prevalence of proctitis was high (MIP 40.4%, and SEP 42.8%). During follow-up, the incidence of complications was highest among SEP: resulting in re-intervention (n = 40; 28.2%, p = 0.017), pouchitis (n = 36; 25.2%, p < 0.01), and pouch failure (n = 32; 22.4%, p = 0.032). The time interval to pouch failure was 5.0 (4.0-6.9) years among NOP, and 1.2 (0.5-2.3) years in SEP (p = 0.036). ASA 3, pouchitis, and pouch fistula were independent risk factors for pouch failure. CONCLUSION: Proctitis at the time of IPAA is common. A high degree of inflammation is associated with poor long-term outcomes, an effect that declines over time. In addition, a higher degree of proctitis leads to earlier pouch failure.

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.

The impact of surgical site infection-a cost analysis.

PURPOSE: Surgical site infection (SSI) occurs in up to 25% of patients after elective laparotomy. We aimed to determine the effect of SSI on healthcare costs and patients' quality of life. METHODS: In this post hoc analysis based on the RECIPE trial, we studied a 30-day postoperative outcome of SSI in a single-center, prospective randomized controlled trial comparing subcutaneous wound irrigation with 0.04% polyhexanide to 0.9% saline after elective laparotomy. Total medical costs were analyzed accurately per patient with the tool of our corporate controlling team which is based on diagnosis-related groups in Germany. RESULTS: Between November 2015 and May 2018, 456 patients were recruited. The overall rate of SSI was 28.2%. Overall costs of inpatient treatment were higher in the group with SSI: median 16.685 €; 19.703 USD (IQR 21.638 €; 25.552 USD) vs. median 11.235 €; 13.276 USD (IQR 11.564 €; 13.656 USD); p < 0.001. There was a difference in surgery costs (median 6.664 €; 7.870 USD with SSI vs. median 5.040 €; 5.952 USD without SSI; p = 0.001) and costs on the surgical ward (median 8.404 €; 9.924 USD with SSI vs. median 4.690 €; 5.538 USD without SSI; p < 0.001). Patients with SSI were less satisfied with the cosmetic result (4.3% vs. 16.2%; p < 0.001). Overall costs for patients who were irrigated with saline were median 12.056 €; 14.237 USD vs. median 12.793 €; 15.107 USD in the polyhexanide group (p = 0.52). CONCLUSION: SSI after elective laparotomy increased hospital costs substantially. This is an additional reason why the prevention of SSI is important. Overall costs for intraoperative wound irrigation with saline were comparable with polyhexanide.

Thymidine phosphorylase induction by ionizing radiation antagonizes 5-fluorouracil resistance in human ductal pancreatic adenocarcinoma.

Chemoresistance in pancreatic ductal adenocarcinoma (PDAC) frequently contributes to failure of systemic therapy. While the radiosensitizing properties of 5-fluorouracil (FU) are well known, it is unknown whether ionizing radiation (IR) sensitizes towards FU cytotoxicity. Here, we hypothesize that upregulation of thymidine phosphorylase (TP) by IR reverses FU chemoresistance in PDAC cells. The FU resistant variant of the human PDAC cell line AsPC-1 (FU-R) was used to determine the sensitizing effects of IR. Proliferation rates of FU sensitive parental (FU-S) and FU-R cells were determined by WST-1 assays after low (0.05 Gy) and intermediate dose (2.0 Gy) IR followed by FU treatment. TP protein expression in PDAC cells before and after IR was assessed by Western blot. To analyze the specificity of the FU sensitizing effect, TP was ablated by siRNA. FU-R cells showed a 2.7-fold increase of the half maximal inhibitory concentration, compared to FU-S parental cells. Further, FU-R cells showed a concomitant IR resistance towards both doses applied. When challenging both cell lines with FU after IR, FU-R cells had lower proliferation rates than FU-S cells, suggesting a reversal of chemoresistance by IR. This FU sensitizing effect was abolished when TP was blocked by anti-TP siRNA before IR. An increase of TP protein expression was seen after both IR doses. Our results suggest a TP dependent reversal of FU-chemoresistance in PDAC cells that is triggered by IR. Thus, induction of TP expression by low dose IR may be a therapeutic approach to potentially overcome FU chemoresistance in PDAC.

The Prognostic Impact of Primary Tumor Site Differs According to the KRAS Mutational Status: A Study By the International Genetic Consortium for Colorectal Liver Metastasis.

OBJECTIVE: To examine the prognostic impact of tumor laterality in colon cancer liver metastases (CLM) after stratifying by Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutational status. BACKGROUND: Although some studies have demonstrated that patients with CLM from a right sided (RS) primary cancer fare worse, others have found equivocal outcomes of patients with CLM with RS versus left-sided (LS) primary tumors. Importantly, recent evidence from unresectable metastatic CRC suggests that tumor laterality impacts prognosis only in those with wild-type tumors. METHODS: Patients with rectal or transverse colon tumors and those with unknown KRAS mutational status were excluded from analysis. The prognostic impact of RS versus LS primary CRC was determined after stratifying by KRAS mutational status. RESULTS: 277 patients had a RS (38.6%) and 441 (61.4%) had a LS tumor. Approximately one-third of tumors (28.1%) harbored KRAS mutations. In the entire cohort, RS was associated with worse 5-year overall survival (OS) compared with LS (39.4% vs 50.8%, P = 0.03) and remained significantly associated with worse OS in the multivariable analysis (hazard ratio 1.45, P = 0.04). In wild-type patients, a worse 5-year OS associated with a RS tumor was evident in univariable analysis (43.7% vs 55.5%, P = 0.02) and persisted in multivariable analysis (hazard ratio 1.49, P = 0.01). In contrast, among patients with KRAS mutated tumors, tumor laterality had no impact on 5-year OS, even in the univariable analysis (32.8% vs 34.0%, P = 0.38). CONCLUSIONS: This study demonstrated, for the first time, that the prognostic impact of primary tumor side differs according to KRAS mutational status. RS tumors were associated with worse survival only in patients with wild-type tumors.

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 interplay of KRAS mutational status with tumor laterality in non-metastatic colorectal cancer: An international, multi-institutional study in patients with known KRAS, BRAF, and MSI status.

BACKGROUND: Although the prognostic relevance of KRAS status in metastatic colorectal cancer (CRC) depends on tumor laterality, this relationship is largely unknown in non-metastatic CRC. METHODS: Patients who underwent resection for non-metastatic CRC between 2000 and 2018 were identified from institutional databases at six academic tertiary centers in Europe and Japan. The prognostic relevance of KRAS status in patients with right-sided (RS), left-sided (LS), and rectal cancers was assessed. RESULTS: Of the 1093 eligible patients, 378 had right-sided tumors and 715 had left-sided tumors. Among patients with RS tumors, the 5-year overall (OS) and recurrence-free survival (RFS) for patients with KRASmut versus wild-type tumors was not shown to differ significantly (82.2% vs. 83.2% and 72.1% vs. 76.7%, respectively, all p > .05). Among those with LS tumors, KRAS mutation was associated with shorter 5-year OS and RFS on both the univariable (OS: 79.4% vs. 86.1%, p = .004; RFS: 68.8% vs. 77.3%, p = .005) and multivariable analysis (OS: HR: 1.52, p = .019; RFS: HR: 1.32, p = .05). CONCLUSIONS: KRAS mutation status was independently prognostic among patients with LS tumors, but this association failed to reach statistical significance in RS and rectal tumors. These findings confirm reports in metastatic CRC and underline the possible biologic importance of tumor location.

Survival rates and prognostic factors in right- and left-sided colon cancer stage I-IV: an unselected retrospective single-center trial.

PURPOSE: Colorectal cancer revealed over the last decades a remarkable shift with an increasing proportion of a right- compared to a left-sided tumor location. In the current study, we aimed to disclose clinicopathological differences between right- and left-sided colon cancer (rCC and lCC) with respect to mortality and outcome predictors. METHODS: In total, 417 patients with colon cancer stage I-IV were analyzed in the present retrospective single-center study. Survival rates were assessed using the Kaplan-Meier method and uni/multivariate analyses were performed with a Cox proportional hazards regression model. RESULTS: Our study showed no significant difference of the overall survival between rCC and lCC stage I-IV (p = 0.354). Multivariate analysis revealed in the rCC cohort the worst outcome for ASA (American Society of Anesthesiologists) score IV patients (hazard ratio [HR]: 16.0; CI 95%: 2.1-123.5), CEA (carcinoembryonic antigen) blood level > 100 µg/l (HR: 3.3; CI 95%: 1.2-9.0), increased lymph node ratio of 0.6-1.0 (HR: 5.3; CI 95%: 1.7-16.1), and grade 4 tumors (G4) (HR: 120.6; CI 95%: 6.7-2179.6) whereas in the lCC population, ASA score IV (HR: 8.9; CI 95%: 0.9-91.9), CEA blood level 20.1-100 µg/l (HR: 5.4; CI 95%: 2.4-12.4), conversion to laparotomy (HR: 14.1; CI 95%: 4.0-49.0), and severe surgical complications (Clavien-Dindo III-IV) (HR: 2.9; CI 95%: 1.5-5.5) were identified as predictors of a diminished overall survival. CONCLUSION: Laterality disclosed no significant effect on the overall prognosis of colon cancer patients. However, group differences and distinct survival predictors could be identified in rCC and lCC patients.

Validation of the German Classification of Diverticular Disease (VADIS)-a prospective bicentric observational study.

PURPOSE: The German Classification of Diverticular Disease was introduced a few years ago. The aim of this study was to determine whether Classification of Diverticular Disease enables an exact stratification of different types of diverticular disease in terms of course and treatment. METHODS: This was a prospective, bicentric observational trial. Patients aged ≥ 18 years with diverticular disease were prospectively included. The primary endpoint was the rate of recurrence within 2 year follow-up. Secondary outcome measures were Gastrointestinal Quality of Life Index, Quality of life measured by SF-36, frequency of gastrointestinal complaints, and postoperative complications. RESULTS: A total of 172 patients were included. After conservative management, 40% of patients required surgery for recurrence in type 1b vs. 80% in type 2a/b (p = 0.04). Sixty percent of patients with type 2a (micro-abscess) were in need of surgery for recurrence vs. 100% of patients with type 2b (macro-abscess) (p = 0.11). Patients with type 2a reached 123 ± 15 points in the Gastrointestinal Quality of Life Index compared with 111 ± 14 in type 2b (p = 0.05) and higher scores in the "Mental Component Summary" scale of SF-36 (52 ± 10 vs. 43 ± 13; p = 0.04). Patients with recurrent diverticulitis without complications (type 3b) had less often painful constipation (30% vs. 73%; p = 0.006) when they were operated compared with conservative treatment. CONCLUSION: Differentiation into type 2a and 2b based on abscess size seems reasonable as patients with type 2b required surgery while patients with type 2a may be treated conservatively. Sigmoid colectomy in patients with type 3b seems to have gastrointestinal complaints during long-term follow-up. TRIAL REGISTRATION: https://www.drks.de ID: DRKS00005576.

Risk factors for upper and lower type prolonged postoperative ileus following surgery for Crohn's disease.

PURPOSE: Prolonged postoperative ileus (PPOI) is common after bowel resections, especially in Crohn's disease (CD). The pathophysiology of PPOI is not fully understood. PPOI could affect only the upper or lower gastrointestinal (GI) tract. The aim of this study was to assess risk factors for diverse types of PPOI, particularly to differentiate PPOI of upper and lower GI tract. METHODS: A retrospective analysis of 163 patients with CD undergoing ileocecal resection from 2015 to 2020 in a single center was performed. PPOI of the upper GI tract was predefined as the presence of vomiting or use of nasogastric tube longer than the third postoperative day. Lower PPOI was predefined as the absence of defecation for more than three days. Independent risk factors were identified by multivariable logistic regression analysis. RESULTS: Overall incidence of PPOI was 42.7%. PPOI of the upper GI tract was observed in 30.7% and lower PPOI in 20.9% of patients. Independent risk factors for upper PPOI included older age, surgery by a resident surgeon, hand-sewn anastomosis, prolonged opioid analgesia, and reoperation, while for lower PPOI included BMI ≤ 25 kg/m2, preoperative anemia, and absence of ileostomy. CONCLUSION: This study identified different risk factors for upper and lower PPOI after ileocecal resection in patients with CD. A differentiated upper/lower type approach should be considered in future research and clinical practice. High-risk patients for each type of PPOI should be closely monitored, and modifiable risk factors, such as preoperative anemia and opioids, should be avoided if possible.

Reduction of Postoperative Wound Infections by Antiseptica (RECIPE)?: A Randomized Controlled Trial.

OBJECTIVE: To evaluate whether intraoperative subcutaneous wound irrigation with 0.04% polyhexanide can reduce surgical site infection (SSI) in elective laparotomies compared to saline. BACKGROUND: SSI is a common complication after gastrointestinal surgery. To date, there is a lack of evidence whether subcutaneous wound irrigation is beneficial in terms of reduction of SSI. METHODS: The RECIPE trial was an investigator initiated single-center, single-blind prospective, randomized controlled trial with 2 parallel treatment groups, comparing wound irrigation with 0.9% saline to antiseptic 0.04% polyhexanide solution in elective laparotomies. Primary endpoint was the rate of SSI within 30 days postoperatively according to Centers for Disease Control and Prevention criteria. RESULTS: Between February 02, 2015, and May 23, 2018, 456 patients were randomly assigned to saline (n = 228) or polyhexanide (n = 228). Final cohort for analysis comprised 393 patients (202 in the saline and 191 in the polyhexanide group). Overall rate of SSI was 28.2%, n = 111. Simple analysis with cross tabulation revealed that significantly fewer SSIs occurred in the polyhexanide group: n = 70 (34.7%) versus n = 41 (21.5%); P = 0.004. In a multiple logistic regression model the factor wound irrigation with polyhexanide [odds ratio (OR) 0.44; 95% confidence interval (CI) 0.27-0.72; P = 0.001) was associated with risk reduction of SSI. Preoperative anemia (OR 2.08; 95% CI 1.27-3.40; P = 0.004) and more than 5 prior abdominal operations compared to none (OR 8.51; 95% CI 2.57-28.21; P < 0.001) were associated with SSI. CONCLUSIONS: Intraoperative subcutaneous wound irrigation with antiseptic 0.04% polyhexanide solution is effective in reducing SSI after elective laparotomies.

MRI-Based Use of Neoadjuvant Chemoradiotherapy in Rectal Carcinoma: Surgical Quality and Histopathological Outcome of the OCUM Trial.

BACKGROUND: Preoperative magnetic resonance imaging (MRI) allows highly reliable imaging of the mesorectal fascia (mrMRF) and its relationship to the tumor. The prospective multicenter observational study OCUM uses these findings to indicate neoadjuvant chemoradiotherapy (nCRT) in rectal carcinoma. METHODS: nCRT was indicated in patients with positive mrMRF (≤ 1 mm) in cT4 and cT3 carcinomas of the lower rectal third. RESULTS: A total of 527 patients (60.2%) underwent primary total mesorectal excision, and 348 patients (39.8%) underwent long-term nCRT followed by surgery. The mrMRF was involved in 4.6% of the primary surgery group and 80.7% of the nCRT group. Rates of resections within the mesorectal plane (90.8%), sparing of pelvic nerves on both sides (97.8%), and number of regional lymph nodes (95.3% with ≥ 12 lymph nodes examined) are indicative of high-quality surgery. Resection was classified as R0 in 98.3%, the pathological circumferential resection margin (pCRM) was negative in 95.1%. Patients in the nCRT group had more advanced carcinomas with a significantly higher rate of abdominoperineal excision. Independent risk factors for pCRM positivity were advanced stage (T4), metastatic lymph nodes, resection in the muscularis propria plane, and location in the lower third. CONCLUSIONS: The risk classification of rectal cancer patients by MRI seems to be highly reliable and allows the restriction of nCRT to approximately half of the patients with clinical stage II and III rectal carcinoma, provided there is a high-quality MRI diagnostic protocol, high-quality surgery, and standardized examination of the resected specimen.

Immediate post-interventional contrast-enhanced computed tomography overestimates hepatic microwave ablation - an in vivo animal study.

Objectives: Contrast-enhanced computed tomography (CECT) is used to monitor technical success immediately after hepatic microwave ablation (MWA). However, it remains unclear, if CECT shows the exact extend of the thermal destruction zone, or if tissue changes such as peri-lesionary edema are depicted as well. The objective of this study was to correlate immediate post-interventional CECT with histological and macroscopic findings in hepatic MWA in porcine liver in vivo.Methods: Eleven MWA were performed in porcine liver in vivo with a microwave generator (928 MHz; energy input 24 kJ). CECT was performed post-interventionally. Livers were explanted and ablations were bisected immediately after ablation. Samples were histologically analyzed after vital staining (NADH-diaphorase). Ablation zones were histologically and macroscopically outlined. We correlated histologic findings, macroscopic images and CECT.Results: Three ablation zones were identified in histological and macroscopic findings. Only one ablation zone could be depicted in CECT. Close conformity was observed between histological and macroscopic findings. The ablation zone depicted in CECT overestimated the histological avital central zone and inner red zone (p < = .01). No differences were found between CECT and the histological outer red zone (p > .05).Conclusions: Immediate post-interventional CECT overestimated the clinically relevant zone of complete cell ablation after MWA in porcine liver in vivo. This entails the risk of incomplete tumor ablation and could lead to tumor recurrence.