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Karin ATGM Wasmann,1 Charlotte EL Klaver,1 Jarmila DW van der Bilt,1,2 Susan van Dieren,3 Iris D Nagtegaal,4 Cornelis JA Punt,5 Bert van Ramshorst,6 Albert M Wolthuis,2 Johannes HW de Wilt,7 André D’Hoore,2 Hjalmar C van Santvoort,6 Pieter J Tanis11Department of Surgery, Amsterdam University Medical Centre, University of Amsterdam, AZ 1105, Amsterdam, The Netherlands; 2Department of Abdominal Surgery, University Hospital Leuven, Leuven 3000, Belgium; 3Clinical Research Unit, Amsterdam University Medical Centre, University of Amsterdam, AZ 1105, Amsterdam, The Netherlands; 4Department of Pathology, Radboud University Medical Centre, GA 6525, Nijmegen, The Netherlands; 5Department of Medical Oncology, Amsterdam University Medical Centre, University of Amsterdam, AZ 1105, Amsterdam, The Netherlands; 6Department of Surgery, St. Antonius Hospital, CM 3435, Nieuwegein, The Netherlands; 7Department of Surgery, Radboud University Medical Centre, GA 6525, Nijmegen, The NetherlandsPurpose: The aim of this study was to evaluate the impact of a laparoscopic approach on long-term oncological outcomes in curative intent surgery for pT4 colon cancer, in both overall and stratified subgroups with distinct clinical entities.Patients and methods: Patients with a pT4N0-2M0 colon cancer from four centers between 2000 and 2014 were included. Laparoscopic and open approaches were compared according to the intention-to-treat principle. Propensity scores were used to adjust for baseline differences between the groups in three manners: i) as a linear predictor in a Cox regression model, ii) to create a 1:1 matched cohort, and iii) to stratify patients into four groups with an increasing chance of receiving laparoscopy.Results: In total, 424 patients were included. After 1:1 matching, a laparoscopic approach correlated with higher rates of radical resection, lower morbidity, and a higher percentage of patients receiving adjuvant chemotherapy. This translated into better 5-year disease-free survival (52% vs 40%, HR 0.70; 95% CI 0.50–0.96) and 5-year overall survival (68% vs 57%, HR 0.66; 95% CI 0.43–0.99). These results were confirmed in the other two propensity score analyses. In the multivariable models, adjuvant chemotherapy remained independently associated with better survival, whereas surgical approach lost significance.Conclusions: In locally advanced colon cancer, an intentional laparoscopic approach in experienced hands seems to decrease morbidity and to increase the proportion of patients receiving adjuvant chemotherapy. Receiving adjuvant chemotherapy was independently associated with improved survival.Keywords: T4 colon cancer, laparoscopy, lower GI

Background: Changes in the receptor profile of primary breast cancers to their metastases (receptor conversion) have been described for the estrogen receptor α (ERα) and progesterone receptor (PR). The purpose of this study was to evaluate the impact of receptor conversion for ERα and PR on survival in a large group of distant non-bone breast cancer metastases.Methods: Receptor conversion was studied by immunohistochemistry in a group of 233 metastatic breast cancer patients. Kaplan-Meier overall survival curves were plotted, and differences between the curves were analyzed by log-rank analysis. The additional prognostic value of conversion to established prognosticators was studied by Cox regression.Results: Overall survival of patients showing conversion from positive to negative ERα or PR, or from negative to positive ERα or PR, or remaining receptor negative was comparable, and significantly worse than patients remaining receptor positive. ERα or PR receptor conversion from positive in the primary breast tumor to negative in distant metastases has independent negative prognostic value.Conclusions: ERα or PR receptor conversion from positive in the primary breast cancer to negative in distant metastases has negative prognostic value. [ABSTRACT FROM AUTHOR]

Determination of survival time among persons with screen-detected cancer is subject to lead time and length biases. The authors propose a simple correction for lead time, assuming an exponential distribution of the preclinical screen-detectable period. Assuming two latent categories of tumors, one of which is more prone to screen detection and correspondingly less prone to death from the cancer in question, the authors have developed a strategy of sensitivity analysis for various magnitudes of length bias. Here they demonstrate these methods using a series of 25,962 breast cancer cases (1988-2004) from the West Midlands, United Kingdom. [ABSTRACT FROM AUTHOR]

The article discusses the multidisciplinary treatment of rectal cancer. It explains the decision making process for the treatment of rectal cancer, including the preoperative and postoperative evaluation of cancer patients. It offers information on the treatment options for rectal cancer, including neoadjuvant approaches and surgery. The article also emphasizes the role of pathology in the multidisciplinary treatment of rectal cancer.

BACKGROUND: Anti-EGFR monoclonal antibodies in metastatic colorectal cancer (mCRC) treatment are only effective in patients with KRAS wild type tumours. Here we assess the predictive value of other potential relevant markers involved in the epidermal growth factor receptor (EGFR) signalling pathways for response to cetuximab-based treatment. MATERIALS AND METHODS: Formalin-fixed paraffin-embedded colorectal cancer tissue of the primary tumour was obtained from 559 mCRC patients treated with chemotherapy and bevacizumab with or without cetuximab (phase III CAIRO2 study). DNA was isolated for mutation analysis of BRAF (V600E), KRAS (codon 12 and 13) and PIK3CA (exon 9 and 20). Tissue microarray's (TMA's) were constructed for the assessment of EGFR and HER2 gene copy number (GCN), and EGFR and PTEN protein expression. The results of these markers, individually or in combination, were correlated with progression-free survival (PFS) and overall survival (OS) in the subgroup of patients with a KRAS wild type tumour treated in the cetuximab-arm. KRAS wild type patients treated without cetuximab were used as a control group. RESULTS: A total of 208 tumours (39.4%) contained a KRAS mutation, 8.7% a BRAF mutation and 9.9% a PIK3CA mutation. Loss of PTEN expression and the presence EGFR protein expression were observed in 42.0% and 61.7% of the samples, respectively. An increased EGFR GCN was observed in 15.3% of the samples, and 11.5% of the evaluable samples contained an increased HER2 GCN. In KRAS wild type patients treated with cetuximab a BRAF mutation was significantly and independently associated with PFS and OS. In patients treated without cetuximab the PFS and OS were also associated with the BRAF genotype. No prognostic or predictive value was observed for any of the other markers when tested individually or in combination. CONCLUSIONS: BRAF genotype is correlated with PFS and OS in KRAS wild type mCRC patients, which is independent of cetuximab treatment. PIK3CA mutation, loss of PTEN expression, EGFR GCN and HER2 GCN have no predictive value for response to treatment with cetuximab, neither individually nor in combination with other markers. [ABSTRACT FROM AUTHOR]

BACKGROUND: Since the 1990s, treatment of patients with rectal cancer has changed in the Netherlands. Aim of this study was to describe these changes in treatment over time and to evaluate their effects on survival. METHODS: All patients in the Netherlands Cancer Registry with invasive primary rectal cancer diagnosed during the period 1989-2006 were selected. The Cochran-Armitage trend test was used to analyse trends in treatment over time. Multivariate relative survival analyses were performed to estimate relative excess risk (RER) of dying. RESULTS: In total, 40,888 patients were diagnosed with rectal cancer during the period 1989-2006. The proportion of patients with stages II and III disease receiving preoperative radiotherapy increased from 1% in the period 1989-1992 to 68% in the period 2004-2006 for younger patients (<75 years) and from 1% to 51% for older patients (>or=75 years), whereas the use of postoperative radiotherapy decreased. Administration of chemotherapy to patients with stage IV disease increased over time from 21% to 66% for patients younger than 75 years. Both males and females exhibited an increase in five-year relative survival from 53% to 60%. The highest increase in survival was found for patients with stage III disease. In the multivariate analyses survival improved over time for patients with stages II-IV disease. After adjustment for treatment variables, this improvement remained significant for patients with stages III and IV disease. CONCLUSIONS: The changes in therapy for rectal cancer have led to a markedly increased survival. Patients with stage III disease experienced the greatest improvement in survival. [ABSTRACT FROM AUTHOR]

Due to insufficient evidence, tumor budding (TB) is not currently evaluated in colorectal cancer (CRC) biopsies. This study investigates TB in CRC by establishing the value of intratumoral budding (ITB) in resection specimens and assessing the feasibility and clinical value of TB in biopsies. TB was assessed using an algorithm in all cases. In a test cohort of 555 primarily surgically treated CRC patients, we assessed the prognostic impact of ITB compared to peritumoral budding (PTB). The distribution of ITB in the uppermost five millimeters of resection specimens was analyzed to validate TB counting in biopsies. We further validated the prognostic and predictive impact of TB in biopsies of 285 rectal cancer patients, focusing on overall survival and response to neoadjuvant therapy. High-grade TB, whether intratumoral or peritumoral and in biopsies or resections, was associated with advanced pathological stage, lymphatic invasion, infiltrative tumor border, and poor overall survival in the test cohort. Superficial ITBs (0-3 mm from the lumen) accurately predicted the final TB grade based on PTB in 87% of tumors, with 87% of tumors having at least one superficial ITB hotspot. ITB (hazard ratio 3.5, 95% CI 1.1-10.8) was an independent predictor of overall survival, unlike PTB. In the validation cohort, TB presence in biopsies significantly reduced the likelihood of achieving a pathological complete response (odds ratio 0.3, 95% CI 0.1-0.7, p=0.007). ITB is as prognostic as PTB, and evaluating both can improve risk stratification in CRC. TB assessment in biopsies can identify poor prognosis and predict response to neoadjuvant therapy., (Copyright © 2024. Published by Elsevier Inc.)

Background: As a result of recent advances in the development of small microelectromechanical system mirrors, a novel forward-looking optical coherence tomography (OCT) probe with a uniquely large field of view is being commercially developed. The aim of this study is to prospectively assess the feasibility of this advanced OCT probe in interpreting ex vivo images of colorectal polyp tissue and to identify necessary steps for further development., Methods: A total of 13 colorectal lesions from 9 patients, removed during endoscopic resection, were imaged ex vivo with the OCT device and compared with histopathological images that served as the gold standard for diagnostics. Normal tissue from one patient, removed during the endoscopic procedure, was imaged as a negative control. We assessed the presence of features indicative for polyp type and degree of dysplasia, by comparing OCT images to histopathological images and by evaluating the presence of OCT-specific features identified by previous studies, such as effacement (loss of layered tissue structure), a hyperreflective epithelial layer, and irregularity of the surface., Results: As verified by corresponding histological images, tissue structures such as blood vessels and tissue layers could be distinguished in OCT images of the normal tissue sample. Detailed structures on histological images such as crypts and cell nuclei could not be identified in the OCT images. However, we did identify OCT features specific for colorectal lesions, such as effacement and a hyperreflective epithelial layer. In general, the imaging depth was about 1 mm., Conclusion: Some relevant tissue structures could be observed in OCT images of the novel device. However, some adaptations, such as increasing imaging depth using a laser with a longer central wavelength, are required to improve its clinical value for the imaging of colorectal lesions., (© 2024. The Author(s).)

Background: Patients with rectal cancer are often treated with neoadjuvant chemoradiotherapy, followed by a waiting period and surgical resection. Good or complete response to neoadjuvant chemoradiotherapy might enable organ preservation, which highlights the need to increase response rates. Pre-clinical studies suggest that physical activity during neoadjuvant chemoradiotherapy may improve tumor downstaging., Purpose: To investigate whether physical activity and physical functioning of patients with rectal cancer at diagnosis are associated with tumor downstaging after neoadjuvant chemoradiotherapy., Materials and Methods: Patients were included if they participated in the Dutch Prospective ColoRectal Cancer Cohort, a nationwide cohort providing an infrastructure for scientific research, and received neoadjuvant chemoradiotherapy for rectal cancer. Tumor downstaging was dichotomized into good/complete or moderate/poor downstaging. Physical activity (total physical activity, moderate-to-vigorous physical activity (MVPA), and Dutch physical activity guideline adherence) and physical functioning were assessed using questionnaires. Logistic regression analyses were performed to examine associations of physical activity and physical functioning with tumor downstaging, adjusted for relevant confounders., Results: 268 patients (aged 62 ± 11 years, 33 % female) with rectal cancer were included. Patients with moderate (OR = 2.07; 95%CI = 1.07 - 4.07; p = 0.03) or high (OR = 2.05; 95%CI = 1.05 - 4.07; p = 0.04) levels of MVPA were more likely to have good/complete tumor downstaging than patients with low levels. No significant associations with tumor downstaging were found for total physical activity, Dutch physical activity guideline adherence, and physical functioning., Conclusions: We found augmented tumor downstaging in patients with rectal cancer with moderate or high levels of self-reported MVPA before the start of neoadjuvant chemoradiotherapy compared to patients with low levels., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Histopathological growth patterns are one of the strongest prognostic factors in patients with resected colorectal liver metastases. Development of an efficient, objective and ideally automated histopathological growth pattern scoring method can substantially help the implementation of histopathological growth pattern assessment in daily practice and research. This study aimed to develop and validate a deep-learning algorithm, namely neural image compression, to distinguish desmoplastic from non-desmoplastic histopathological growth patterns of colorectal liver metastases based on digital haematoxylin and eosin-stained slides., Methods: The algorithm was developed using digitalized whole-slide images obtained in a single-centre (Erasmus MC Cancer Institute, the Netherlands) cohort of patients who underwent first curative intent resection for colorectal liver metastases between January 2000 and February 2019. External validation was performed on whole-slide images of patients resected between October 2004 and December 2017 in another institution (Radboud University Medical Center, the Netherlands). The outcomes of interest were the automated classification of dichotomous hepatic growth patterns, distinguishing between desmoplastic hepatic growth pattern and non-desmoplatic growth pattern by a deep-learning model; secondary outcome was the correlation of these classifications with overall survival in the histopathology manual-assessed histopathological growth pattern and those assessed using neural image compression., Results: Nine hundred and thirty-two patients, corresponding to 3.641 whole-slide images, were reviewed to develop the algorithm and 870 whole-slide images were used for external validation. Median follow-up for the development and the validation cohorts was 43 and 29 months respectively. The neural image compression approach achieved significant discriminatory power to classify 100% desmoplastic histopathological growth pattern with an area under the curve of 0.93 in the development cohort and 0.95 upon external validation. Both the histopathology manual-scored histopathological growth pattern and neural image compression-classified histopathological growth pattern achieved a similar multivariable hazard ratio for desmoplastic versus non-desmoplastic growth pattern in the development cohort (histopathology manual score: 0.63 versus neural image compression: 0.64) and in the validation cohort (histopathology manual score: 0.40 versus neural image compression: 0.48)., Conclusions: The neural image compression approach is suitable for pathology-based classification tasks of colorectal liver metastases., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Inflammatory bowel disease [IBD] patients are at increased risk of developing colorectal neoplasia [CRN]. In this review, we aim to provide an up-to-date overview and future perspectives on CRN management in IBD. Advances in endoscopic surveillance and resection techniques have resulted in a shift towards endoscopic management of neoplastic lesions in place of surgery. Endoscopic treatment is recommended for all CRN if complete resection is feasible. Standard [cold snare] polypectomy, endoscopic mucosal resection and endoscopic submucosal dissection should be performed depending on lesion complexity [size, delineation, morphology, surface architecture, submucosal fibrosis/invasion] to maximise the likelihood of complete resection. If complete resection is not feasible, surgical treatment options should be discussed by a multidisciplinary team. Whereas [sub]total and proctocolectomy play an important role in management of endoscopically unresectable CRN, partial colectomy may be considered in a subgroup of patients in endoscopic remission with limited disease extent without other CRN risk factors. High synchronous and metachronous CRN rates warrant careful mucosal visualisation with shortened intervals for at least 5 years after treatment of CRN., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Background and Aims: This study aimed to provide evidence on the harm-to-benefit ratio of fecal immunochemical test (FIT)-based colorectal cancer (CRC) screening by previous fecal hemoglobin (f-Hb) concentrations, as reflected in the number needed to screen (NNS) and number needed to scope (NNSc)., Methods: Participants in up to 4 FIT screening rounds of the Dutch CRC screening program were included. The main outcomes of this study were the NNS and NNSc to detect 1 CRC and/or advanced neoplasia (AN) in screening rounds 2, 3, or 4, conditional on previous f-Hb concentrations. Outcomes were compared between participants using chi-square tests and logistic regression., Results: In total, 2,428,883 study participants completed at least 2 consecutive FITs, 1,308,684 completed 3 FITs, and 150,958 completed 4 FITs. There were 31,400, 16,060, and 2007 ANs detected by round, respectively. The NNS for individuals with vs without a history of detectable f-Hb differed significantly irrespective of screening round. Individuals without detectable f-Hb in previous negative FITs had almost 9 times the NNS to detect 1 AN compared with those with detectable f-Hb (odds ratio, 8.71; 95% confidence interval, 8.51-8.92). A similar directional pattern was observed for NNSc, although the differences were smaller (odds ratio, 2.7; 95% confidence interval, 2.7-2.8)., Conclusions: The harm-to-benefit ratio of FIT-based screening is substantially greater in individuals without vs with prior detectable f-Hb. Less intensive screening should be considered for this lower-risk group., (Copyright © 2024. Published by Elsevier Inc.)

Aim: Recommendations for surveillance after colonoscopy are based on risk factors for metachronous advanced colorectal neoplasia (AN) and colorectal cancer (CRC). The value of these risk factors remains unclear in populations enriched by individuals with a positive faecal immunochemical test and were investigated in a modern setting., Methods and Results: This population-based cohort study included all individuals in the Netherlands of ≥55 years old with a first adenoma diagnosis in 2015. A total of 22,471 patients were included. Data were retrieved from the Dutch Nationwide Pathology Databank (Palga). Primary outcomes were metachronous AN and CRC. Patient and polyp characteristics were evaluated by multivariable Cox regression analyses. During follow-up, 2416 (10.8%) patients were diagnosed with AN, of which 557 (2.5% from the total population) were CRC. Adenomas with high-grade dysplasia (hazard ratio [HR] 1.60, 95% confidence interval [CI] 1.40-1.83), villous histology (HR 1.91, 95% CI 1.59-2.28), size ≥10 mm (HR 1.12, 95% CI 1.02-1.23), proximal location (HR 1.12, 95% CI 1.02-1.23), two or more adenomas (HR 1.28, 95% CI 1.16-1.41), and serrated polyps ≥10 mm (HR 1.67, 95% CI 1.42-1.97) were independent risk factors for metachronous AN. In contrast, only adenomas with high-grade dysplasia (HR 2.49, 95% CI 1.92-3.24) were an independent risk factor for metachronous CRC., Conclusions: Risk factors for metachronous AN and CRC were identified for populations with access to a faecal immunochemical test (FIT)-based screening programme. If only risk factors for metachronous CRC are considered, a reduction in criteria for surveillance seems reasonable., (© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.)

Background: The clinical value of different modes of CRM involvement in rectal cancer patients is unclear. This study aims to determine the clinical impact of different modes of circumferential resection margin (CRM) involvement in patients with a locally advanced rectal carcinoma., Patients and Methods: A cohort of patients who were diagnosed with stage III rectal cancer between June 2014 and June 2020 was selected from the prospective Dutch nationwide pathology databank (PALGA). Histopathological and clinical data were analyzed according to the nature of CRM involvement (via primary tumor invasion, lymph node metastasis, tumor deposit, multiple factors) and analyses on recurrence and overall survival (OS) were performed., Results: 3020 patients were included, of whom 12.4 % had a positive CRM. The majority of these patients (63.2 %) had CRM involvement by primary tumor invasion and in 9 % of patients multiple factors caused the positive CRM. The rates of local recurrence and distant metastasis were related to the nature of the CRM involvement, with lowest rate for lymph node metastasis and highest rate for multiple factors. On multivariate analysis, CRM involvement by primary tumor invasion, tumor deposits and multiple factors, but not by lymph node metastasis, were associated with poor OS., Conclusion: This nationwide population based study highlights the clinical importance of reporting the nature of CRM involvement in rectal cancer patients. Lymph node metastasis involving the CRM does not bear the same risks for local recurrence, distant metastases and OS as CRM involvement by primary tumor invasion or CRM involvement by multiple factors., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)