Neoadjuvant Immunotherapy in Locally Advanced Mismatch Repair-Deficient Colon Cancer.

BACKGROUND: Mismatch repair-deficient (dMMR) tumors can be found in 10 to 15% of patients with nonmetastatic colon cancer. In these patients, the efficacy of chemotherapy is limited. The use of neoadjuvant immunotherapy has shown promising results, but data from studies of this approach are limited. METHODS: We conducted a phase 2 study in which patients with nonmetastatic, locally advanced, previously untreated dMMR colon cancer were treated with neoadjuvant nivolumab plus ipilimumab. The two primary end points were safety, defined by timely surgery (i.e., ≤2-week delay of planned surgery owing to treatment-related toxic events), and 3-year disease-free survival. Secondary end points included pathological response and results of genomic analyses. RESULTS: Of 115 enrolled patients, 113 (98%; 97.5% confidence interval [CI], 93 to 100) underwent timely surgery; 2 patients had surgery delayed by more than 2 weeks. Grade 3 or 4 immune-related adverse events occurred in 5 patients (4%), and none of the patients discontinued treatment because of adverse events. Among the 111 patients included in the efficacy analysis, a pathological response was observed in 109 (98%; 95% CI, 94 to 100), including 105 (95%) with a major pathological response (defined as ≤10% residual viable tumor) and 75 (68%) with a pathological complete response (0% residual viable tumor). With a median follow-up of 26 months (range, 9 to 65), no patients have had recurrence of disease. CONCLUSIONS: In patients with locally advanced dMMR colon cancer, neoadjuvant nivolumab plus ipilimumab had an acceptable safety profile and led to a pathological response in a high proportion of patients. (Funded by Bristol Myers Squibb; NICHE-2 ClinicalTrials.gov number, NCT03026140.).

MRI in addition to CT in patients scheduled for local therapy of colorectal liver metastases (CAMINO): an international, multicentre, prospective, diagnostic accuracy trial.

BACKGROUND: Guidelines are inconclusive on whether contrast-enhanced MRI using gadoxetic acid and diffusion-weighted imaging should be added routinely to CT in the investigation of patients with colorectal liver metastases who are scheduled for curative liver resection or thermal ablation, or both. Although contrast-enhanced MRI is reportedly superior than contrast-enhanced CT in the detection and characterisation of colorectal liver metastases, its effect on clinical patient management is unknown. We aimed to assess the clinical effect of an additional liver contrast-enhanced MRI on local treatment plan in patients with colorectal liver metastases amenable to local treatment, based on contrast-enhanced CT. METHODS: We did an international, multicentre, prospective, incremental diagnostic accuracy trial in 14 liver surgery centres in the Netherlands, Belgium, Norway, and Italy. Participants were aged 18 years or older with histological proof of colorectal cancer, a WHO performance status score of 0-4, and primary or recurrent colorectal liver metastases, who were scheduled for local therapy based on contrast-enhanced CT. All patients had contrast-enhanced CT and liver contrast-enhanced MRI including diffusion-weighted imaging and gadoxetic acid as a contrast agent before undergoing local therapy. The primary outcome was change in the local clinical treatment plan (decided by the individual clinics) on the basis of liver contrast-enhanced MRI findings, analysed in the intention-to-image population. The minimal clinically important difference in the proportion of patients who would have change in their local treatment plan due to an additional liver contrast-enhanced MRI was 10%. This study is closed and registered in the Netherlands Trial Register, NL8039. FINDINGS: Between Dec 17, 2019, and July 31, 2021, 325 patients with colorectal liver metastases were assessed for eligibility. 298 patients were enrolled and included in the intention-to-treat population, including 177 males (59%) and 121 females (41%) with planned local therapy based on contrast-enhanced CT. A change in the local treatment plan based on liver contrast-enhanced MRI findings was observed in 92 (31%; 95% CI 26-36) of 298 patients. Changes were made for 40 patients (13%) requiring more extensive local therapy, 11 patients (4%) requiring less extensive local therapy, and 34 patients (11%) in whom the indication for curative-intent local therapy was revoked, including 26 patients (9%) with too extensive disease and eight patients (3%) with benign lesions on liver contrast-enhanced MRI (confirmed by a median follow-up of 21·0 months [IQR 17·5-24·0]). INTERPRETATION: Liver contrast-enhanced MRI should be considered in all patients scheduled for local treatment for colorectal liver metastases on the basis of contrast-enhanced CT imaging. FUNDING: The Dutch Cancer Society and Bayer AG - Pharmaceuticals.

Hepatic arterial infusion pump chemotherapy combined with systemic chemotherapy for borderline resectable and unresectable colorectal liver metastases: phase II feasibility study.

BACKGROUND: Hepatic arterial infusion pump chemotherapy combined with systemic chemotherapy (HAIP-SYS) for liver-only colorectal liver metastases (CRLMs) has shown promising results but has not been adopted worldwide. This study evaluated the feasibility of HAIP-SYS in the Netherlands. METHODS: This was a single-arm phase II study of patients with CRLMs who received HAIP-SYS consisting of floxuridine with concomitant systemic FOLFOX or FOLFIRI. Main inclusion and exclusion criteria were borderline resectable or unresectable liver-only metastases, suitable arterial anatomy and no previous local treatment. Patients underwent laparotomy for pump implantation and primary tumour resection if in situ. Primary end point was feasibility, defined as ≥70% of patients completing two cycles of HAIP-SYS. Sample size calculations led to 31 patients. Secondary outcomes included safety and tumour response. RESULTS: Thirty-one patients with median 13 CRLMs (i.q.r. 6-23) were included. Twenty-eight patients (90%) received two HAIP-SYS cycles. Three patients did not get two cycles due to extrahepatic disease at pump placement, definitive pathology of a recto-sigmoidal squamous cell carcinoma, and progressive disease. Five patients experienced grade 3 surgical or pump device-related complications (16%) and 11 patients experienced grade ≥3 chemotherapy toxicity (38%). At first radiological evaluation, disease control rate was 83% (24/29 patients) and hepatic disease control rate 93% (27/29 patients). At 6 months, 19 patients (66%) had experienced grade ≥3 chemotherapy toxicity and the disease control rate was 79%. CONCLUSION: HAIP-SYS for borderline resectable and unresectable CRLMs was feasible and safe in the Netherlands. This has led to a successive multicentre phase III randomized trial investigating oncological benefit (EUDRA-CT 2023-506194-35-00). Current trial registration number: clinicaltrials.gov (NCT04552093).

Trends and overall survival after combined liver resection and thermal ablation of colorectal liver metastases: a nationwide population-based propensity score-matched study.

BACKGROUND: In colorectal liver metastases (CRLM) patients, combination of liver resection and ablation permit a more parenchymal-sparing approach. This study assessed trends in use of combined resection and ablation, outcomes, and overall survival (OS). METHODS: This population-based study included all CRLM patients who underwent liver resection between 2014 and 2022. To assess OS, data was linked to two databases containing date of death for patients treated between 2014 and 2018. Hospital variation in the use of combined minor liver resection and ablation versus major liver resection alone in patients with 2-3 CRLM and ≤3 cm was assessed. Propensity score matching (PSM) was applied to evaluate outcomes. RESULTS: This study included 3593 patients, of whom 1336 (37.2%) underwent combined resection and ablation. Combined resection increased from 31.7% in 2014 to 47.9% in 2022. Significant hospital variation (range 5.9-53.8%) was observed in the use of combined minor liver resection and ablation. PSM resulted in 1005 patients in each group. Major morbidity was not different (11.6% vs. 5%, P = 1.00). Liver failure occurred less often after combined resection and ablation (1.9% vs. 0.6%, P = 0.017). Five-year OS rates were not different (39.3% vs. 33.9%, P = 0.145). CONCLUSION: Combined resection and ablation should be available and considered as an alternative to resection alone in any patient with multiple metastases.

Hospital variation and outcomes after repeat hepatic resection for colorectal liver metastases: a nationwide cohort study.

BACKGROUND: Approximately 70% of patients with colorectal liver metastases (CRLM) experiences intrahepatic recurrence after initial liver resection. This study assessed outcomes and hospital variation in repeat liver resections (R-LR). METHODS: This population-based study included all patients who underwent liver resection for CRLM between 2014 and 2022 in the Netherlands. Overall survival (OS) was collected for patients operated on between 2014 and 2018 by linkage to the insurance database. RESULTS: Data of 7479 liver resections (1391 (18.6%) repeat and 6088 (81.4%) primary) were analysed. Major morbidity and mortality were not different. Factors associated with major morbidity included ASA 3+, major liver resection, extrahepatic disease, and open surgery. Five-year OS after repeat versus primary liver resection was 42.3% versus 44.8%, P = 0.37. Factors associated with worse OS included largest CRLM >5 cm (aHR 1.58, 95% CI: 1.07-2.34, P = 0.023), >3 CRLM (aHR 1.33, 95% CI: 1.00-1.75, P = 0.046), extrahepatic disease (aHR 1.60, 95% CI: 1.25-2.04, P = 0.001), positive tumour margins (aHR 1.42, 95% CI: 1.09-1.85, P = 0.009). Significant hospital variation in performance of R-LR was observed, median 18.9% (8.2% to 33.3%). CONCLUSION: Significant hospital variation was observed in performance of R-LR in the Netherlands reflecting different treatment decisions upon recurrence. On a population-based level R-LR leads to satisfactory survival.

Extrahepatic perfusion and incomplete hepatic perfusion after hepatic arterial infusion pump implantation: incidence and clinical implications.

INTRODUCTION: This study investigates the incidence of extrahepatic perfusion and incomplete hepatic perfusion at intraoperative methylene blue testing and on postoperative nuclear imaging in patients undergoing hepatic arterial infusion pump (HAIP) chemotherapy. METHODS: The first 150 consecutive patients who underwent pump implantation in the Netherlands were included. All patients underwent surgical pump implantation with the catheter in the gastroduodenal artery. All patients underwent intraoperative methylene blue testing and postoperative nuclear imaging (99mTc-Macroaggregated albumin SPECT/CT) to determine perfusion via the pump. RESULTS: Patients were included between January-2018 and December-2021 across eight centers. During methylene blue testing, 29.3% had extrahepatic perfusion, all successfully managed intraoperatively. On nuclear imaging, no clinically relevant extrahepatic perfusion was detected (0%, 95%CI: 0.0-2.5%). During methylene blue testing, 2.0% had unresolved incomplete hepatic perfusion. On postoperative nuclear imaging, 8.1% had incomplete hepatic perfusion, leading to embolization in only 1.3%. CONCLUSION: Methylene blue testing during pump placement for intra-arterial chemotherapy identified extrahepatic perfusion in 29.3% of patients, but could be resolved intraoperatively in all patients. Postoperative nuclear imaging found no clinically relevant extrahepatic perfusion and led to embolization in only 1.3% of patients. The role of routine nuclear imaging after HAIP implantation should be studied in a larger cohort.

Initial Impact of National CRC Screening on Incidence and Advanced Colorectal Cancer.

BACKGROUND AND AIMS: Screening for colorectal cancer (CRC) aims to decrease CRC incidence and mortality. Biennial fecal immunochemical test screening started in the Netherlands in 2014 for individuals 55-75 years of age. This study investigated the effect of screening on stage-specific incidence, with focus on stage III and IV CRC. METHODS: Inhabitants diagnosed with CRC in 2009-2018 were included. CRC incidence per stage, year, and detection method (ie, screen-detected vs clinically detected) was evaluated. Patient, tumor, and treatment characteristics, and survival of patients with stage III and IV CRC, were compared according to the detection method. RESULTS: Included were 140,649 CRCs in 136,882 patients. An initial peak of stage I-III CRC diagnoses after initiation of screening was followed by a continuous decrease within screening-eligible ages. Total CRC incidence remained higher than before screening, although stage II and IV CRC incidence decreased below prescreening levels. Screen-detected CRCs were significantly more frequently located in the left-sided colon (stage III; 43.7% vs 30.9%; stage IV: 45.1% vs 36.1%), and the primary tumor resection rate was higher (stage III colon: 99.8% vs 99.0%, rectum: 97.3% vs 89.7%; stage IV colon: 65.4% vs 56.6%, rectum: 47.3% vs 33.5%). Patients with screen-detected stage IV CRC had significantly more often single-organ metastases (74.5% vs 57.0%; P < .001) and more frequently received treatment with curative intent (colon: 41.3% vs 27.4%; rectum: 33.8% vs 24.6%). Overall survival significantly improved for patients with screen-detected CRCs (stage III: P < .001; stage IV: P < .001). CONCLUSIONS: Five years after the start of a nationwide CRC screening program, a decrease in stage II and IV CRC incidence was observed. Patients with screen-detected stage III and stage IV CRC had less extensive disease and improved survival compared with those with clinically detected CRC.

Combined Hepatic Arterial Infusion Pump and Systemic Chemotherapy in the Modern Era for Chemotherapy-Naive Patients with Unresectable Colorectal Liver Metastases.

PURPOSE: Chemotherapy-naive patients with unresectable colorectal liver metastases (CRLM) have been the best responders to hepatic arterial infusion (HAI) therapy. The current treatment paradigm has drifted away from HAI in the first-line setting. We aimed to analyze outcomes of combined first-line systemic therapy with HAI therapy (HAI+SYS) in the modern era. METHODS: We conducted a retrospective study of consecutive chemotherapy-naive patients with unresectable CRLM who received HAI+SYS between 2003 and 2019. Patients were selected from a prospectively maintained database. Outcomes included radiological response rate, conversion to resection (CTR) rate, and overall survival (OS). RESULTS: Fifty-eight chemotherapy-naive patients were identified out of 546 patients with unresectable CRLM managed with HAI. After induction treatment, 4 patients (7%) had a complete radiological response, including two durable responses. In total, 32 patients (55%) underwent CTR. CTR or complete response without resection was achieved after seven cycles of systemic therapy and four cycles of HAI therapy. Median OS for the whole cohort was 53.0 months (95% confidence interval 23.0-82.9). Three- and 5-year OS in patients who achieved CTR or complete response versus patients who did not was 88% and 72% versus 27% and 0% respectively. Of patients who underwent CTR, complete and major pathological response (no and <10% viable tumor cells, respectively) was observed in 7 (22%) and 12 patients (38%). CONCLUSIONS: Combined HAI+SYS in chemotherapy-naive patients resulted in durable and substantial response in a large proportion of patients. Nearly two-thirds of patients achieved a complete response or proceeded to conversion surgery, which was associated with prolonged survival.

Independent validation of CT radiomics models in colorectal liver metastases: predicting local tumour progression after ablation.

OBJECTIVES: Independent internal and external validation of three previously published CT-based radiomics models to predict local tumor progression (LTP) after thermal ablation of colorectal liver metastases (CRLM). MATERIALS AND METHODS: Patients with CRLM treated with thermal ablation were collected from two institutions to collect a new independent internal and external validation cohort. Ablation zones (AZ) were delineated on portal venous phase CT 2-8 weeks post-ablation. Radiomics features were extracted from the AZ and a 10 mm peri-ablational rim (PAR) of liver parenchyma around the AZ. Three previously published prediction models (clinical, radiomics, combined) were tested without retraining. LTP was defined as new tumor foci appearing next to the AZ up to 24 months post-ablation. RESULTS: The internal cohort included 39 patients with 68 CRLM and the external cohort 52 patients with 78 CRLM. 34/146 CRLM developed LTP after a median follow-up of 24 months (range 5-139). The median time to LTP was 8 months (range 2-22). The combined clinical-radiomics model yielded a c-statistic of 0.47 (95%CI 0.30-0.64) in the internal cohort and 0.50 (95%CI 0.38-0.62) in the external cohort, compared to 0.78 (95%CI 0.65-0.87) in the previously published original cohort. The radiomics model yielded c-statistics of 0.46 (95%CI 0.29-0.63) and 0.39 (95%CI 0.28-0.52), and the clinical model 0.51 (95%CI 0.34-0.68) and 0.51 (95%CI 0.39-0.63) in the internal and external cohort, respectively. CONCLUSION: The previously published results for prediction of LTP after thermal ablation of CRLM using clinical and radiomics models were not reproducible in independent internal and external validation. CLINICAL RELEVANCE STATEMENT: Local tumour progression after thermal ablation of CRLM cannot yet be predicted with the use of CT radiomics of the ablation zone and peri-ablational rim. These results underline the importance of validation of radiomics results to test for reproducibility in independent cohorts. KEY POINTS: • Previous research suggests CT radiomics models have the potential to predict local tumour progression after thermal ablation in colorectal liver metastases, but independent validation is lacking. • In internal and external validation, the previously published models were not able to predict local tumour progression after ablation. • Radiomics prediction models should be investigated in independent validation cohorts to check for reproducibility.

Imaging Photoplethysmography for Noninvasive Anastomotic Perfusion Assessment in Intestinal Surgery.

INTRODUCTION: Anastomotic leakage after gastrointestinal surgery has a high impact on patient's quality of life and its origin is associated with inadequate perfusion. Imaging photoplethysmography (iPPG) is a noninvasive imaging technique that measures blood-volume changes in the microvascular tissue bed and detects changes in tissue perfusion. MATERIALS AND METHODS: Intraoperative iPPG imaging was performed in 29 patients undergoing an open segment resection of the small intestine or colon. During each surgery, imaging was performed on fully perfused (true positives) and ischemic intestines (true negatives) and the anastomosis (unknowns). Imaging consisted of a 30-s video from which perfusion maps were extracted, providing detailed information about blood flow within the intestine microvasculature. To detect the predictive capabilities of iPPG, true positive and true negative perfusion conditions were used to develop two different perfusion classification methods. RESULTS: iPPG-derived perfusion parameters were highly correlated with perfusion-perfused or ischemic-in intestinal tissues. A perfusion confidence map distinguished perfused and ischemic intestinal tissues with 96% sensitivity and 86% specificity. Anastomosis images were scored as adequately perfused in 86% of cases and 14% inconclusive. The cubic-Support Vector Machine achieved 90.9% accuracy and an area under the curve of 96%. No anastomosis-related postoperative complications were encountered in this study. CONCLUSIONS: This study shows that noninvasive intraoperative iPPG is suitable for the objective assessment of small intestine and colon anastomotic perfusion. In addition, two perfusion classification methods were developed, providing the first step in an intestinal perfusion prediction model.

Surgical Management of the Primary Tumor in Stage IV Small Intestinal Neuroendocrine Tumors: To Operate or Not to Operate, That Is the Question.

PURPOSE OF REVIEW: Small intestinal neuroendocrine tumors (SI-NET) are rare tumors, often with distant metastases at diagnosis. The objective of this review is to provide an overview of the latest literature regarding surgical management of the primary tumor in stage IV SI-NET. RECENT FINDINGS: Primary tumor resection (PTR) seems to be associated with improved survival in patients with stage IV SI-NET, independent of treatment of distant metastases. A watch and wait approach of the primary tumor increases the risk of needing an emergency resection. PTR improves survival in patients with stage IV SI-NET, decreases the risk of emergency surgery, and should be considered in all patients with stage IV disease and unresectable liver metastasis.

Real-Time Wireless Tumor Tracking in Navigated Liver Resections: An Ex Vivo Feasibility Study.

BACKGROUND: Surgical navigation systems generally require intraoperative steps, such as intraoperative imaging and registration, to link the system to the patient anatomy. Because this hampers surgical workflow, we developed a plug-and-play wireless navigation system that does not require any intraoperative steps. In this ex vivo study on human hepatectomy specimens, the feasibility was assessed of using this navigation system to accurately resect a planned volume with small margins to the lesion. METHODS: For ten hepatectomy specimens, a planning CT was acquired in which a virtual spherical lesion with 5 mm margin was delineated, inside the healthy parenchyma. Using two implanted trackers, the real-time position of this planned resection volume was visualized on a screen, relative to the used tracked pointer. Experienced liver surgeons were asked to accurately resect the nonpalpable planned volume, fully relying on the navigation screen. Resected and planned volumes were compared using CT. RESULTS: The surgeons resected the planned volume while cutting along its border with a mean accuracy of - 0.1 ± 2.4 mm and resected 98 ± 12% of the planned volume. Nine out of ten resections were radical and one case showed a cut of 0.8 mm into the lesion. The sessions took approximately 10 min each, and no considerable technical issues were encountered. CONCLUSIONS: This ex vivo liver study showed that it is feasible to accurately resect virtual hepatic lesions with small planned margins using our novel navigation system, which is promising for clinical applications where nonpalpable hepatic metastases have to be resected with small resection margins.

Primary Tumor Resection is Associated with Improved Disease-Specific Mortality in Patients with Stage IV Small Intestinal Neuroendocrine Tumors (NETs): A Comparison of Upfront Surgical Resection Versus a Watch and Wait Strategy in Two Specialist NET Centers.

INTRODUCTION: Small intestinal neuroendocrine tumors (SI-NETs) often present with metastatic disease. An ongoing debate exists on whether to perform primary tumor resection (PTR) in patients with stage IV SI-NETs, without symptoms of the primary tumor and inoperable metastatic disease. OBJECTIVE: The aim of this study was to compare a treatment strategy of upfront surgical resection versus a surveillance strategy of watch and wait. METHODS: This was a retrospective cohort study of patients with stage IV SI-NETs at diagnosis, between 2000 and 2018, from two tertiary referral centers (Netherlands Cancer Institute [NKI] and Aintree University Hospital [AUH]) who had adopted contrasting treatment approaches: upfront surgical resection and watch and wait, respectively. Patients without symptoms related to the primary tumor were included. Multivariable intention-to-treat (ITT), per-protocol (PP), and instrumental variable (IV) analyses using 'institute' as an IV were performed to assess the influence of PTR on disease-specific mortality (DSM). RESULTS: A total of 557 patients were identified, with 145 patients remaining after exclusion of stage I-III disease or symptoms of the primary tumor (93 from the NKI and 52 from AUH). The cohorts differed in performance status (PS; p = 0.006) and tumor grade (p < 0.001). PTR was independently associated with reduced DSM irrespective of statistical methods employed: ITT hazard ratio [HR] 0.60, p = 0.005; PP HR 0.58, p < 0.001; and IV HR 0.07, p = 0.019. Other factors associated with DSM were age, PS, high chromogranin A, and somatostatin analog treatment. CONCLUSION: Taking advantage of contrasting institutional treatment strategies, this study identified PTR as an independent predictor of DSM. Future prospective studies should aim to validate these results.

Selected stage IV rectal cancer patients managed by the watch-and-wait approach after pelvic radiotherapy: a good alternative to total mesorectal excision surgery?

AIM: The aim of this study was to assess the clinical and oncological outcome of a selected group of stage IV rectal cancer patients managed by the watch-and-wait approach following a (near-)complete response of the primary rectal tumour after radiotherapy. METHOD: Patients registered in the Dutch watch-and-wait registry since 2004 were selected when diagnosed with synchronous stage IV rectal cancer. Data on patient characteristics, treatment details, follow-up and survival were collected. The 2-year local regrowth rate, organ-preservation rate, colostomy-free rate, metastatic progression-free rate and 2- and 5-year overall survival were analysed. RESULTS: After a median follow-up period of 35 months, local regrowth was observed in 17 patients (40.5%). Nine patients underwent subsequent total mesorectal excision, resulting in a permanent colostomy in four patients. The 2-year local regrowth rate was 39.9%, the 2-year organ-preservation rate was 77.1%, the 2-year colostomy-free rate was 88.1%, and the 2-year metastatic progression-free rate was 46.7%. The 2- and 5-year overall survival rates were 92.0% and 67.5%. CONCLUSION: The watch-and-wait approach can be considered as an alternative to total mesorectal excision in a selected group of stage IV rectal cancer patients with a (near-)complete response following pelvic radiotherapy. Despite a relatively high regrowth rate, total mesorectal excision and a permanent colostomy can be avoided in the majority of these patients.

Hospital variation and outcomes of simultaneous resection of primary colorectal tumour and liver metastases: a population-based study.

BACKGROUND: The optimal treatment sequence for patients with synchronous colorectal liver metastases (CRLM) remains uncertain. This study aimed to assess factors associated with the use of simultaneous resections and impact on hospital variation. METHOD: This population-based study included all patients who underwent liver surgery for synchronous colorectal liver metastases between 2014 and 2019 in the Netherlands. Factors associated with simultaneous resection were identified. Short-term surgical outcomes of simultaneous resections and factors associated with 30-day major morbidity were evaluated. RESULTS: Of 2146 patients included, 589 (27%) underwent simultaneous resection in 28 hospitals. Simultaneous resection was associated with age, sex, BMI, number, size and bilobar distribution of CRLM, and administration of preoperative chemotherapy. More minimally invasive and minor resections were performed in the simultaneous group. Hospital variation was present (range 2.4%-83.3%) with several hospitals performing simultaneous procedures more and less frequently than expected. Simultaneous resection resulted in 13% 30-day major morbidity, and 1% mortality. ASA classification ≥3 was independently associated with higher 30-day major morbidity after simultaneous resection (aOR 1.97, CI 1.10-3.42, p = 0.018). CONCLUSION: Distinctive patient and tumour characteristics influence the choice for simultaneous resection. Remarkable hospital variation is present in the Netherlands.

Driver mutations occur frequently in metastases of well-differentiated small intestine neuroendocrine tumours.

AIMS: To investigate the clinicopathological significance of driver mutations in metastatic well-differentiated small intestine neuroendocrine tumours (SI-NETs). METHODS AND RESULTS: Whole genome sequencing (WGS) of 35 metastatic SI-NETs and next-generation sequencing (NGS) of eight metastatic SI-NETs were performed. Biopsies were obtained between 2015 and 2019. Tumours were classified according to the 2019 World Health Organization classification. WGS included assessment of somatic mutations in all cancer-related driver genes, the tumour mutational burden (TMB), and microsatellite status. NGS entailed a cancer hotspot panel of 58 genes. Our cohort consisted of 21% grade 1, 60% grade 2 and 19% grade 3 SI-NETs. Driver mutations were identified in ~50% of SI-NETs. In total, 27 driver mutations were identified, of which 74% were in tumour suppressor genes (e.g. TP53, RB1, and CDKN1B) and 22% were in proto-oncogenes (e.g. KRAS, NRAS, and MET). Allelic loss of chromosome 18 (63%), complete loss of CDKN2A and CDKN1B (both 6%) and CDKN1B mutations (9%) were most common. Potential targetable genetic alterations were detected in 21% of metastasised SI-NETs. All tumours were microsatellite-stable and showed low TMBs (median 1.10; interquartile range 0.87-1.35). The Ki67 proliferation index was significantly associated with the presence of driver mutations (P = 0.015). CONCLUSION: Driver mutations occur in 50% of metastasised SI-NETs, and their presence is associated with a high Ki67 proliferation index. The identification of targetable mutations make these patients potentially eligible for targeted therapy.

Selecting Image-Guided Surgical Technologies in Oncology: A Surgeon's Perspective.

BACKGROUND: To improve surgical performance, image-guided (IG) technologies are increasingly introduced. Yet, it is unknown which oncological procedures yield most value from these technologies. This study aimed to select the most promising IG technology per oncologic indication. METHODS: An Analytic Hierarchical Process was used to evaluate three IG technologies: navigation, optical imaging, and augmented reality, in five oncologic indications compared with usual care. Sixteen decision criteria were selected. The relative importance of the criteria and the expected performance of the technologies were evaluated among surgeons. The combination of these scores gives the expected value per technology. RESULTS: On criteria level, sparing critical tissue (9%-18%) and reducing the risk of local recurrence (11%-27%) were most important. Navigation was preferred in three indications-removal of lymph nodes (42%), liver (47%), and rectal tumors (33%). In removing rectal tumors, optical imaging was equally preferred (34%). In removing breast and tongue tumors, no technology was clearly preferred. CONCLUSIONS: In selecting IG technologies, especially optical and navigation technologies are expected to add value in addition to usual care. Further development of those technologies for the preferred indications seems valuable. Multi-attribute analysis showed to be useful in prioritization of conducting clinical studies and steer research and development initiatives.

Short-term postoperative outcomes after liver resection in the elderly patient: a nationwide population-based study.

BACKGROUND: Liver resection is high-risk surgery in particular in elderly patients. The aim of this study was to explore postoperative outcomes after liver resection in elderly patients. METHODS: In this nationwide study, all patients who underwent liver resection for primary and secondary liver tumours in the Netherlands between 2014 and 2019 were included. Age groups were composed as younger than 70 (70-), between 70 and 80 (septuagenarians), and 80 years or older (octogenarians). Proportion of liver resections per age group and 30-day major morbidity and 30-day mortality were assessed. RESULTS: In total, 6587 patients were included of whom 4023 (58.9%) were younger than 70, 2135 (32.4%) were septuagenarians and 429 (6.5%) were octogenarians. The proportion of septuagenarians increased during the study period (aOR:1.06, CI:1.02-1.09, p < 0.001). Thirty-day major morbidity was higher in septuagenarians (11%) and octogenarians (12%) compared to younger patients (9%, p = 0.049). Thirty-day mortality was higher in septuagenarians (4%) and octogenarians (4%) compared to younger patients (2%, p < 0.001). Cardiopulmonary complications occurred more frequently with higher age, liver-specific complications did not. Higher age was associated with higher 30-day morbidity and 30-day mortality in multivariable logistic regression. CONCLUSION: Thirty-day major morbidity and 30-day mortality are higher after liver resection in elderly patients, attributed mainly to non-surgical cardiopulmonary complications.

Hospital variation in combined liver resection and thermal ablation for colorectal liver metastases and impact on short-term postoperative outcomes: a nationwide population-based study.

BACKGROUND: Combining resection and thermal ablation can improve short-term postoperative outcomes in patients with colorectal liver metastases (CRLM). This study assessed nationwide hospital variation and short-term postoperative outcomes after combined resection and ablation. METHODS: In this population-based study, all CRLM patients who underwent resection in the Netherlands between 2014 and 2018 were included. After propensity score matching for age, ASA-score, Charlson-score, diameter of largest CRLM, number of CRLM and earlier resection, postoperative outcomes were compared. Postoperative complicated course (PCC) was defined as discharge after 14 days or a major complication or death within 30 days of surgery. RESULTS: Of 4639 included patients, 3697 (80%) underwent resection and 942 (20%) resection and ablation. Unadjusted percentage of patients who underwent resection and ablation per hospital ranged between 4 and 44%. Hospital variation persisted after case-mix correction. After matching, 734 patients remained in each group. Hospital stay (median 6 vs. 7 days, p = 0.011), PCC (11% vs. 14.7%, p = 0.043) and 30-day mortality (0.7% vs. 2.3%, p = 0.018) were lower in the resection and ablation group. Differences faded in multivariable logistic regression due to inclusion of major hepatectomy. CONCLUSION: Significant hospital variation was observed in the Netherlands. Short-term postoperative outcomes were better after combined resection and ablation, attributed to avoiding complications associated with major hepatectomy.

Factors associated with failure to rescue after liver resection and impact on hospital variation: a nationwide population-based study.

BACKGROUND: Failure to rescue (FTR) is defined as postoperative complications leading to mortality. This nationwide study aimed to assess factors associated with FTR and hospital variation in FTR after liver surgery. METHODS: All patients who underwent liver resection between 2014 and 2017 in the Netherlands were included. FTR was defined as in-hospital or 30-day mortality after complications Dindo grade ≥3a. Variables associated with FTR and nationwide hospital variation were assessed using multivariable logistic regression. RESULTS: Of 4961 patients included, 3707 (74.4%) underwent liver resection for colorectal liver metastases, 379 (7.6%) for other metastases, 526 (10.6%) for hepatocellular carcinoma and 349 (7.0%) for biliary cancer. Thirty-day major morbidity was 11.5%. Overall mortality was 2.3%. FTR was 19.1%. Age 65-80 (aOR: 2.86, CI:1.01-12.0, p = 0.049), ASA 3+ (aOR:2.59, CI: 1.66-4.02, p < 0.001), liver cirrhosis (aOR:4.15, CI:1.81-9.22, p < 0.001), biliary cancer (aOR:3.47, CI: 1.73-6.96, p < 0.001), and major resection (aOR:6.46, CI: 3.91-10.9, p < 0.001) were associated with FTR. Postoperative liver failure (aOR: 26.9, CI: 14.6-51.2, p < 0.001), cardiac (aOR: 2.62, CI: 1.27-5.29, p = 0.008) and thromboembolic complications (aOR: 2.49, CI: 1.16-5.22, p = 0.017) were associated with FTR. After case-mix correction, no hospital variation in FTR was observed. CONCLUSION: FTR is influenced by patient demographics, disease and procedural burden. Prevention of postoperative liver failure, cardiac and thromboembolic complications could decrease FTR.