Oncological Safety and Potential Cost Savings of Routine vs Selective Histopathological Examination After Appendectomy: Results of the Multicenter, Prospective, Cross-Sectional FANCY Study.

OBJECTIVE: To investigate the oncological safety and potential cost savings of selective histopathological examination after appendectomy. BACKGROUND: The necessity of routine histopathological examination after appendectomy has been questioned, but prospective studies investigating the safety of a selective policy are lacking. METHODS: In this multicenter, prospective, cross-sectional study, inspection and palpation of the (meso)appendix was performed by the surgeon in patients with suspected appendicitis. The surgeon's opinion on additional value of histopathological examination was reported before sending all specimens to the pathologist. Main outcomes were the number of hypothetically missed appendiceal neoplasms with clinical consequences benefiting the patient (upper limit two-sided 95% confidence interval below 3:1000 considered oncologically safe) and potential cost savings after selective histopathological examination. RESULTS: Seven thousand three hundred thirty-nine patients were included. After a selective policy, 4966/7339 (67.7%) specimens would have been refrained from histopathological examination. Appendiceal neoplasms with clinical consequences would have been missed in 22/4966 patients. In 5/22, residual disease was completely resected during additional surgery. Hence, an appendiceal neoplasm with clinical consequences benefiting the patient would have been missed in 1.01:1000 patients (upper limit 95% confidence interval 1.61:1000). In contrast, twice as many patients (10/22) would not have been exposed to potential harm due to re-resections without clear benefit, whereas consequences were neither beneficial nor harmful in the remaining seven. Estimated cost savings established by replacing routine for selective histopathological examination were €725,400 per 10,000 patients. CONCLUSIONS: Selective histopathological examination after appendectomy for suspected appendicitis is oncologically safe and will likely result in a reduction of pathologists' workload, less costs, and fewer re-resections without clear benefit.

Safety and economic analysis of selective histopathology following cholecystectomy: multicentre, prospective, cross-sectional FANCY study.

BACKGROUND: There is ongoing debate concerning the necessity of routine histopathological examination following cholecystectomy. In order to reduce the pathology workload and save costs, a selective approach has been suggested, but evidence regarding its oncological safety is lacking. METHODS: In this multicentre, prospective, cross-sectional study, all gallbladders removed for gallstone disease or cholecystitis were systematically examined by the surgeon for macroscopic abnormalities indicative of malignancy. Before sending all specimens to the pathologist, the surgeon judged whether histopathological examination was indicated. The main outcomes were the number of patients with hypothetically missed malignancy with clinical consequences (upper limit two-sided 95 per cent c.i. below 3:1000 considered oncologically safe) and potential cost savings of selective histopathological examination. RESULTS: Twenty-two (2.19:1000) of 10 041 specimens exhibited malignancy with clinical consequences. In case of a selective policy, surgeons would have held back 7846 of 10041 (78.1 per cent) gallbladders from histopathological examination. Malignancy with clinical consequences would have been missed in seven of 7846 patients (0.89:1000, upper limit 95% c.i. 1.40:1000). No patient benefitted from the clinical consequences, while two were harmed (futile additional surgery). Of 15 patients in whom malignancy with clinical consequences would have been diagnosed, one benefitted (residual disease radically removed), two potentially benefitted (palliative systemic therapy), and four experienced harm (futile additional surgery). Estimated cost savings established by replacing routine for selective histopathological examination were €703 500 per 10 000 patients. CONCLUSION: Selective histopathological examination following cholecystectomy is oncologically safe and could reduce pathology workload, costs, and futile re-resections.

A mouse model for peritoneal metastases of colorectal origin recapitulates patient heterogeneity.

The peritoneum is a common site of dissemination in patients with colorectal cancer. In order to identify high-risk patients and improve therapeutic strategies, a better understanding of the peritoneal dissemination process and the reasons behind the high heterogeneity that is observed between patients is required. We aimed to create a murine model to further elucidate the process of peritoneal dissemination and to provide an experimental platform for further studies. We developed an in vivo model to assess patterns of peritoneal dissemination of 15 colorectal cancer cell lines. Immune deficient mice were intraperitoneally injected with 10,000 human colorectal cancer cells. Ten weeks after injection, or earlier in case of severe discomfort, the mice were sacrificed followed by dissection including assessment of the outgrowth and localization of peritoneal metastases. Furthermore, using a color-based clonal tracing method, the clonal dynamics of peritoneal nodules were observed. The different cell lines showed great variation in the extent of peritoneal outgrowth, ranging from no outgrowth to localized or widespread outgrowth of cells. An association between KRAS pathway activation and the formation of peritoneal metastases was identified. Also, cell line specific tumor location preferences were observed, with similar patterns of outgrowth in anatomically related areas. Furthermore, different patterns regarding clonal dynamics were found, varying from monoclonal or polyclonal outgrowth to extensively dispersed polyclonal lesions. The established murine model recapitulates heterogeneity as observed in human peritoneal metastases, which makes it a suitable platform for future (intervention) studies.

Second and third look laparoscopy in pT4 colon cancer patients for early detection of peritoneal metastases; the COLOPEC 2 randomized multicentre trial.

BACKGROUND: Approximately 20-30% of patients with pT4 colon cancer develop metachronous peritoneal metastases (PM). Due to restricted accuracy of imaging modalities and absence of early symptoms, PM are often detected at a stage in which only a quarter of patients are eligible for curative intent treatment. Preliminary findings of the COLOPEC trial (NCT02231086) revealed that PM were already detected during surgical re-exploration within two months after primary resection in 9% of patients with pT4 colon cancer. Therefore, second look diagnostic laparoscopy (DLS) to detect PM at a subclinical stage may be considered an essential component of early follow-up in these patients, although this needs confirmation in a larger patient cohort. Furthermore, a third look DLS after a negative second look DLS might be beneficial for detection of PM occurring at a later stage. METHODS: The aim of this study is to determine the yield of second look DLS and added value of third look DLS after negative second look DLS in detecting occult PM in pT4N0-2 M0 colon cancer patients after completion of primary treatment. Patients will undergo an abdominal CT at 6 months postoperative, followed by a second look DLS within 1 month if no PM or other metastases not amenable for local treatment are detected. Patients without PM will subsequently be randomized between routine follow-up including 18 months abdominal CT, or an experimental arm with a third look DLS provided that PM or incurable metastases are absent at the 18 months abdominal CT. Primary endpoint is the proportion of PM detected after a negative second look DLS and will be determined at 20 months postoperative. DISCUSSION: Second look DLS is supposed to result in 10% occult PM, and third look DLS after negative second look DLS is expected to detect an additional 10% of PM compared to routine follow-up alone in patients with pT4 colon cancer. Detection of PM at an early stage will likely increase the proportion of patients eligible for curative intent treatment and subsequently improve survival, given the uniformly reported direct association between the extent of peritoneal disease and survival. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03413254 , January 2018.

Transanal Versus Transabdominal Minimally Invasive (Completion) Proctectomy With Ileal Pouch-anal Anastomosis in Ulcerative Colitis: A Comparative Study.

OBJECTIVE: This study aims to compare surgical outcome of transanal ileal pouch-anal anastomosis (ta-IPAA) with transabdominal minimal invasive approach in ulcerative colitis (UC), using the comprehensive complication index (CCI). BACKGROUND: Recent evolutions in rectal cancer surgery led to transanal dissection of the rectum resulting in a better exposure of the distal rectum and presumed better outcome. The same approach was introduced for patients with UC, resulting in decreased invasiveness. METHODS: All patients, undergoing minimally invasive restorative proctocolectomy in 1, 2, or 3 stages between January 2011 and September 2016 in 3 referral centers were included. Only patients who underwent either multiport, single port, single port with 1 additional port, hand-assisted, or robotic (R) laparoscopy were included in the analysis. CCI, registered during 90 days after pouch construction, was compared between the transanal and the transabdominal approach. RESULTS: Ninety-seven patients (male: 52%) with ta-IPAA were compared to 119 (male: 53%) with transabdominal IPAA. Ninety-nine (46%) patients had a defunctioning ileostomy at time of pouch construction. A 2-step model showed that the odds for postoperative morbidity were 0.52 times lower in the ta-IPAA group (95% confidence interval [0.29; 0.92] P = 0.026). In patients with morbidity, mean CCI of the transanal approach was 2.23 points lower than the transabdominal approach (95% confidence interval: [-6.64-3.36] P = 0.13), which was not significant. CONCLUSIONS: Ta-IPAA for UC is a safe procedure, resulting in fewer patients with morbidity, but comparable CCI when morbidity is present. Overall, ta-IPAA led to lower CCI scores.

Molecular characterization of colorectal cancer related peritoneal metastatic disease.

A significant proportion of colorectal cancer (CRC) patients develop peritoneal metastases (PM) in the course of their disease. PMs are associated with a poor quality of life, significant morbidity and dismal disease outcome. To improve care for this patient group, a better understanding of the molecular characteristics of CRC-PM is required. Here we present a comprehensive molecular characterization of a cohort of 52 patients. This reveals that CRC-PM represent a distinct CRC molecular subtype, CMS4, but can be further divided in three separate categories, each presenting with unique features. We uncover that the CMS4-associated structural protein Moesin plays a key role in peritoneal dissemination. Finally, we define specific evolutionary features of CRC-PM which indicate that polyclonal metastatic seeding underlies these lesions. Together our results suggest that CRC-PM should be perceived as a distinct disease entity.

Risk of metachronous peritoneal metastases in patients with pT4a versus pT4b colon cancer: An international multicentre cohort study.

INTRODUCTION: With evolving treatment strategies aiming at prevention or early detection of metachronous peritoneal metastases (PM), identification of high-risk colon cancer patients becomes increasingly important. This study aimed to evaluate differences between pT4a (peritoneal penetration) and pT4b (invasion of other organs/structures) subcategories regarding risk of PM and other oncological outcomes. MATERIALS AND METHODS: From eight databases deriving from four countries, patients who underwent curative intent treatment for pT4N0-2M0 primary colon cancer were included. Primary outcome was the 5-year metachronous PM rate assessed by Kaplan-Meier analysis. Independent predictors for metachronous PM were identified by Cox regression analysis. Secondary endpoints included 5-year local and distant recurrence rates, and 5-year disease free and overall survival (DFS, OS). RESULTS: In total, 665 patients with pT4a and 187 patients with pT4b colon cancer were included. Median follow-up was 38 months (IQR 23-60). Five-year PM rate was 24.7% and 12.2% for pT4a and pT4b categories, respectively (p = 0.005). Independent predictors for metachronous PM were female sex, right-sided colon cancer, peritumoral abscess, pT4a, pN2, R1 resection, signet ring cell histology and postoperative surgical site infections. Five-year local recurrence rate was 14% in both pT4a and pT4b cancer (p = 0.138). Corresponding five-year distant metastases rates were 35% and 28% (p = 0.138). Five-year DFS and OS were 54% vs. 62% (p = 0.095) and 63% vs. 68% (p = 0.148) for pT4a vs. pT4b categories, respectively. CONCLUSION: Patients with pT4a colon cancer have a higher risk of metachronous PM than pT4b patients. This observation has important implications for early detection and future adjuvant treatment strategies.

Routine histopathologic examination of the appendix after appendectomy for presumed appendicitis: Is it really necessary? A systematic review and meta-analysis.

BACKGROUND: Owing to substantial costs and increasing interest in the nonoperative management of appendicitis, the necessity of routine histopathologic examination of appendectomy specimens is being questioned. The aim of this study was to determine whether routine histopathologic examination after appendectomy for suspected appendicitis should still be performed. METHODS: PubMed, Embase, Web of Science, and the Cochrane Library were searched for studies listing the histopathologic diagnoses after appendectomy for suspected appendicitis. Main outcomes were the incidence of histopathologically proven aberrant findings, the ability of surgeons to recognize unexpected appendiceal pathology intraoperatively, and the percentage of aberrant findings resulting in a change of postoperative management. A meta-analysis was performed using a random-effects model. RESULTS: Twenty-five studies with 57,357 patients were included. The pooled percentage of aberrant findings was 2.52% (95% confidence interval 1.81-3.51). Neoplasms were found in 0.71% (95% confidence interval 0.54-0.94). Findings of the intraoperative assessment by the surgeon were reported for 82 of the 2,718 (3.0%) unexpected diagnoses, with great variation between studies. The impact on postoperative management was described for 237 of 2,718 (8.7%) aberrant findings. Of these, 166 (70.0%) resulted in a change of postoperative management. CONCLUSION: Based on current evidence, it remains unclear how many of the unexpected appendiceal pathologies with clinical consequences can be identified intraoperatively by the surgeon. Until reliable data on the safety and potential cost savings of a selective policy becomes available, we advise sending appendectomy specimens routinely for histopathologic examination.

Safety and cost analysis of selective histopathological examination following appendicectomy and cholecystectomy (FANCY study): protocol and statistical analysis plan of a prospective observational multicentre study.

INTRODUCTION: Routine histopathological examination following appendicectomy and cholecystectomy has significant financial implications and comprises a substantial portion of the pathologists' workload, while the incidence of unexpected pathology is low. The aim of the selective histopathological examination Following AppeNdicectomy and CholecystectomY (FANCY) study is to investigate the oncological safety and potential cost savings of selective histopathological examination based on macroscopic assessment performed by the surgeon. METHODS AND ANALYSIS: This is a Dutch multicentre prospective observational study, in which removed appendices and gallbladders will be systematically assessed by the operating surgeon for macroscopic abnormalities suspicious for malignant neoplasms. After visual inspection and digital palpation of the removed specimen, the operating surgeon will report whether macroscopic abnormalities suspicious for a malignant neoplasm are present, and if he or she believes additional microscopic examination by the pathologist is indicated. Regardless of the surgeon's assessment, all specimens will be sent for histopathological examination. In this way, routine histopathological examination can be compared with a hypothetical situation in which specimens are routinely examined by surgeons and only sent to the pathologist on indication. The two main outcomes are oncological safety and potential cost savings of a selective policy. Oncological safety of selective histopathological examination will be assessed by calculating the number of patients in whom a histopathological diagnosis of an appendiceal neoplasm or gallbladder cancer with clinical consequences benefitting the patient would have been missed. A cost analysis will be performed to quantify the potential cost savings. ETHICS AND DISSEMINATION: The study protocol was reviewed by the Institutional Review Board of the Amsterdam UMC, location AMC, which decided that the Dutch Medical Research Involving Human Subjects Act is not applicable. In all participating centres, approval for execution of the FANCY study has been obtained from the local Institutional Review Board before the start of inclusion of patients. The study results will be disseminated through peer-reviewed publications and conference presentations. Guidelines will be revised according to the findings of the study. TRIAL REGISTRATION NUMBER: NCT03510923.