Introduction

​The actual screening of colorectal cancer (CRC) includes people of 45 years old and patients with alcoholic liver cirrhosis (LC) have an elevated risk of developing colon cancer. Curative treatment of CRC in patients with an existing diagnosis of LC can be a challenge, requiring major surgical resection and may include liver-toxic chemotherapy. Postoperative morbidity and mortality are elevated in patients with LC. For improved survival, optimization of liver function is more important than adjuvant chemotherapy.

Aims & Methods

Our study included 149 hospitalized LC patients Classes Child- Pugh A, B and C, meanage 56 years old, during April 2023-March 2024, of which 13 cases presented lower bleeding, iron deficiency anemia, intestinal transit disorders, abdominal pain, and familial history of CRC. Clinical and paraclinical diagnostic of CRC in LC patients were made by digital rectal examination, hematological samples, rectosigmoidoscopy, total colonoscopy, abdominal ultrasound, computed tomography and magnetic resonance imaging.

Results

Biological tests indicated anemia, trombocitopenia, increased ESR, biochemical liver tests increased, occult bleeding (FIT), and the increase of the tumor markers CA19-9, AFP, CEA that is particularly useful for monitoring treated CRC. Flexible rectosigmoidoscopy detected six cases of rectal cancer, three cases of rectosigmoidian tumors, and total colonoscopy was the "gold standard" imaging investigation that detected two cases of descending colon cancer, one case of hepatic flexure tumor and one patient with ascending colon cancer. Of patients with LC Class Child Pugh A, 6 cases were operated by laparotomy, being referred to Oncology Institute with favorable outcomes, and the rest of seven patients with LC Class Child Pugh B and C had advanced CRC, being treated by chemotherapy. Abdominal ultrasound visualizes liver metastases, abdominal lymph nodes and CT, MRI were the main methods used for staging CRC before surgical and oncological treatment.

Conclusion

Colonoscopy is the exploration of choice in CRC detection with 97% sensitivity, providing histopathological examination by tumor biopsy and also diagnosis of synchronous cancer. Early diagnosis of CRC is essential to prevent complications and increase the survival rate in LC. Men with LC are predominantly affected of CRC. Abdominal ultrasound, CT or MRI are the main imaging investigations recommended in CRC staging before the surgical and oncological treatment. Laparotomy should be preferred in patients with LC. Survival rate is strongly associated with the improvements in liver function. Echoendoscopy, immunoscintigraphy with monoclonal antibodies can be useful in CRC and genetic testing of tumor DNA markers in stool can be recommended in families with genetic syndromes (Turcot, FAP).

Introduction

Colorectal cancer (CRC) screening has been implemented in numerous countries within the last two decades¹. There is strong evidence that CRC screening leads to enhanced disease free- and overall survival^2–6. However, there is to the best of our knowledge no studies investigating the effects of CRC screening on treatment in a long-term perspective.

Aims & Methods

The objective of this study was to investigate the effects of the Danish national CRC screening program on long-term treatment and health care contacts for patients diagnosed with CRC.This nationwide retrospective cohort study evaluated surgical- and oncological outpatient visits, treatments with chemo- and radiotherapy, health care contacts and hospitalization for patients with CRC during the first two years after diagnosis comparing patients with and without screen-detected CRC. The population consisted of Danish residents aged 50-75 years and diagnosed with CRC between January 1rst 2014 and March 31rst 2018. Data was collected from national healthcare registers .Duration of hospitalization were analyzed using a multivariate general linear model, metastasectomies and emergency surgeries were analyzed using a multivariate generalized linear model and data on oncological treatments were analyzed using a multivariate Poisson regression. Moreover, analyzes were stratified into UICC stages and adjusted for sex, 5-year age groups, type of cancer (colonic/rectal), and Charlson Comorbidity Index score to reduce healthy user bias.

Results

We included 4,708 and 7,332 patients with screen-detected CRC (SD-CRC) and non-screen-detected CRC (NSD-CRC), respectively. SD-CRC was associated with 38% reduced hospitalization. In a UICC-stratified analysis, hospitalization was shorter in the SD-CRC group across all UICC-stages. The rate of emergency surgery was significantly lower (RR=0.34, 95%-CI:0.28-0.41) in the SD-CRC group. There was no difference between the groups in rates of surgery for lung and liver metastasis. Lower number of oncological outpatient visits (RR=0.35, 95%-CI:0.33-0.37), treatment with chemotherapy (RR=0.57, 95%-CI:0.56-0.59) and radiotherapy (RR=0.50, 95%-CI:0.49-0.52) were found for patients with SD-CRC. UICC-stratified analyses revealed that these differences were consistent for all UICC stages, except for a significantly higher rate of treatment with chemotherapy in SD-CRC UICC stage IV. Overall, there was no difference between the two populations in number of contacts with primary healthcare providers. However, a UICC-stratified analysis revealed significantly fewer contacts with primary healthcare providers for patients with SD-CRC UICC I and III.

Conclusion

Compared with NSD-CRC, SD-CRC was associated with shorter hospitalization, less emergency surgery, and reduced oncological treatment within two years after diagnosis.

References

1. Schreuders EH, Ruco A, Rabeneck L, et al. Colorectal cancer screening: a global overview of existing programmes. 2014;67:643-650.
2. Spolverato G, Capelli G, Battagello J, et al. More favorable short and long-term outcomes for screen-detected colorectal cancer patients. Front Oncol. 2021;11:1-10.
3. Luu XQ, Lee K, Jun JK, Suh M, Jung KW, Choi KS. Effect of colorectal cancer screening on long-term survival of colorectal cancer patients: Results of the Korea National Cancer Screening Program. Int J Cancer. 2022;150:1958-1967.
4. Shaukat A, Mongin SJ, Geisser MS, et al. Long-term mortality after screening for colorectal cancer. N Engl J Med. 2013;369:1106-1114.
5. Cienfuegos JA, Baixauli J, Martínez-Ortega P, et al. Screening-detected colorectal cancers show better long-term survival compared with stage-matched symptomatic cancers. Rev Esp Enfermedades Dig. 2018;110:684-690.
6. Losurdo P, Giacca M, Biloslavo A, et al. Colorectal cancer-screening program improves both short- and long-term outcomes: a single-center experience in Trieste. Updates Surg. 2020;72:89-96.

Introduction

Colonoscopy is the gold standard for diagnosing colorectal cancer (CRC)¹, with post-colonoscopy colorectal cancer (PCCRC) defined by the World Endoscopy Organization (WEO) as CRC diagnosed between 6 and 48 months after a negative colonoscopy². PCCRC rates vary from 2.5% to 7%², and the prognosis of PCCRC is generally poorer than that for CRC detected during colonoscopy³.

Aims & Methods

To evaluate the risk factors associated with PCCRC in a major tertiary medical center.
We analyzed all consecutive colonoscopic procedures conducted between 2001 and 2019. Data was retrieved from electronic medical records (EMR) and cross-referenced with the Israeli Cancer Registry. We defined PCCRC based on the WEO criteria, and two physicians independently confirmed potential PCCRC cases to ensure data accuracy. Root-cause analysis of PCCRC was performed according to the WEO algorithm as follows:
A) possible missed lesion, index examination adequate;
B) possible missed lesion, index examination inadequate;
C) detected lesion, not resected; or
D) likely incomplete resection of previously identified lesion.
We then identified colonoscopy-detected CRCs (CDCRC, controls) and compared them to the PCCRC cases at a ratio of 1:3. We assessed patient median age at the procedure, gender, religion, family history of CRC, diabetes, smoking status, body mass index (BMI), obesity (defined in the EMR or BMI > 30) and endoscopic parameters: colonoscopy indication [surveillance (follow-up colonoscopy according to recommendations), abnormal imaging, patient symptoms], adequate Boston Bowel Preparation Scale (BBPS>6 and >2 in all segments), cecal intubation rate, diverticulosis, rectal retroflection, and tumor location.
Multivariable logistic regression assessed the association of multiple factors (endoscopy indications and obesity) with PCCRC, maintaining a 95% confidence interval (CI).

Results

Out of 54,154 colonoscopies, 2,339 patients were diagnosed with CRC, of which 49 (2.1%) were confirmed PCCRCs, while 2,157 (92.2%) were detected during colonoscopy. Of patients with PCCRC, 65.4% (n=32) had adequate BBPS, and 91.8% (n=45) cecal intubation was documented. The two most common reasons for PCCRC were category A (n=29, 59.1%), and category B (n=17, 34.6%), although in a lesser extent. We then compared PCCRC cases to 150 randomly selected CDCRC cases. Significant differences in patient characteristics included BMI>30 (p = 0.041) and obesity (p=0.015). Statistically significant endoscopic factors included colonoscopy indication (p < 0.001), cecal intubation rate (p < 0.001), and tumor location (p < 0.001). As expected, PCCRC was more commonly detected in the right colon (n=24, 55.8%) or rectum (n=12, 27.9%). Multivariable logistic regression revealed that patients with abnormal imaging as a colonoscopy indication had a lower risk for PCCRC (adjusted odds ratio (aOR) = 0.148, 95% CI: 0.033-0.455), while patients that performed colonoscopy for surveillance had a higher risk (aOR = 7.334, 95% CI: 2.355-25.963). Obesity was also a significant risk factor (aOR = 3.035, 95% CI: 1.326-7.035).

Conclusion

The most frequent cause of PCCRC across various patient populations and colonoscopy indications was a possible missed lesion. Factors such as patient obesity and undergoing colonoscopy for surveillance may increase the likelihood of PCCRC. These findings highlight the importance of physician awareness regarding PCCRC risks during colonoscopy.

References

1. Bretthauer M, Løberg M, Wieszczy P, et al. Effect of Colonoscopy Screening on Risks of Colorectal Cancer and Related Death. N Engl J Med. 2022;387(17):1547-1556.
2. Rutter MD, Beintaris I, Valori R, et al. World Endoscopy Organization Consensus Statements on Post-Colonoscopy and Post-Imaging Colorectal Cancer. Gastroenterology. 2018;155(3):909-925.e3.
3. Govindarajan A, Rabeneck L, Yun L, Tinmouth J, Paszat LF, Baxter NN. Population-based assessment of the outcomes in patients with postcolonoscopy colorectal cancers. Gut. 2016;65(6):971-976.

Introduction

Liver steatosis represents the hepatic manifestation of increased adiposopathy, whose pathogenetic features have been proposed as tumorigenic triggers, specifically in colorectal cancer (CRC) [1]. Fatty liver diagnosis challenges clinicians since it is clinically silent and may be complicated with liver fibrosis. Since liver biopsy is not feasible in all patients, non-invasive and point-of-care indexes have been proposed to detect liver steatosis and fibrosis [2].

Aims & Methods

We performed a retrospective analysis among 1145 metabolic subjects to reveal any condition that may predict and concur to CRC development during a 8-years period. Anthropometric and bio humoral parameters were recorded at time zero. Non-invasive liver fibrosis scores were calculated as follows: AAR=AST/ALT; FIB-4=(age x AST)/(platelet count x √ALT); mFIB-4=(10 x age x AST)/(platelet count x ALT); Forns=7.811 - 3.131 x  ln(platelet count)  + 0.781 x ln(GGT)  + 3.467 x ln(age) - 0.014  x (total cholesterol); APRI= AST/Upper limit of normal values x 100/platelet count; AARPRI=AST/ALT/platelet count x 150. Comparisons were carried out by Student-T test (p-value <0.05 was considered significant) and ROC analysis was performed to assess cut-off values. Chi-square test was used to calculate the associated Odds Ratio (OR) with 95% confidence interval (CI).

Results

During a 8 years period, 28 patients (2.4%) developed CRC. No association between CRC development and visceral and general obesity was detected, while fasting plasma glucose was significantly higher and Vitamin D was significantly lower in patients who later were diagnosed with CRC, compared to those who did not develop cancer. We found that all non-invasive liver fibrosis scores significantly identified CRC-developer at time 0 (see Table). In ROC analysis, these scores also showed good sensitivity and specificity in predicting colon cancer (AAR AUC= 0.59, sensitivity 44% and specificity 78%; FIB-4 AUC= 0.74, sensitivity 84% and specificity 57%; mFIB-4 AUC=0.69, sensitivity 80% and specificity 53%; Forns AUC= 0.67, sensitivity 73% and specificity 54%; APRI AUC= 0.63, sensitivity 57% and specificity 75%; AARPRI AUC =0.64, sensitivity 44% and specificity 83%). We then calculated ORs for values above the ROC cut-offs finding that higher FIB-4 was associated with a 6-fold increased risk of developing CRC (95% CI=2.2-16.5), while mFIB-4 showed a OR=3.6 (95% CI=1.4-8.7), Forns OR was 3.1 (95% CI=1.3-7.9), APRI OR was 3.2 (95% CI=1.4-6.9) and AARPRI OR was 3 (95% CI=1.3-6.4).

Conclusion

These findings support the hypothesis that liver steatosis and fibrosis may play a role in the clinical background of CRC and bring to light the fascinating possibility of a reversed gut-liver axis communication in the pathogenesis of CRC. Thus, the use of non-invasive scores of liver fibrosis may be helpful to predict the risk of CRC and serve as novel prognostic factors for prevention and therapeutic strategies.

References

[1] Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003;348:1625–38. https://doi.org/10.1056/NEJMoa021423.
[2] Hernandez Roman J, Siddiqui MS. The role of noninvasive biomarkers in diagnosis and risk stratification in nonalcoholic fatty liver disease. Endocrinol Diabetes Metab 2020;3:e00127. https://doi.org/10.1002/edm2.127.

Introduction

Colorectal cancer (CRC)-driven liver metastasis formation is one of the main drivers of cancer-related deaths. As CRC development has formerly been identified as a disease of elderly people, recent epidemiological data shows an increasing incidence of CRC in people younger than 50 years of age (early-onset colorectal cancer, EOCRC) while less people are being diagnosed with CRC after the age of 50 years (late-onset CRC, LOCRC). Recent studies have identified disparities between these two forms, with early-onset cases often diagnosed at more advanced stages, including elevated risks for recurrence and metastasis formation, including liver metastasis.

Aims & Methods

Here, we have studied how CRC and CRC-dependent liver metastasis develops in an age-dependent manner by using 8-weeks old and 78-weeks old C57BL/6 mice from the same vendor under the same housing conditions. To this end, we used an orthotopic mouse model of CRC-related liver tumor formation, in which colorectal tumor organoids were engrafted in the liver via injection into the portal circulation, solely leading to liver metastasis formation without any primary colon tumor growth. To study age-dependency of primary CRC growth, we injected CRC organoids into the mucosa of the rectum. We further analyzed the molecular mechanisms of disease development, using antibody depletion, genetic mouse and ex vivo tumor models, as well as spatial transcriptomics approaches.

Results

Interestingly, we could demonstrate that young mice exhibit more and larger liver metastases compared to older counterparts, while the formation of primary CRC was unaffected by the age of the host. Liver metastases in old mice display increased necrosis formation which is accompanied by an elevated abundance of different immune cells such as CD8⁺ T cells. Spatial transcriptomics analysis further revealed a distinct anaplerotic metabolic phenotype in liver metastases of young hosts, showing that tumor-surrounding metabolic factors differ between young and old mice, which highlights important metastatic niche dependencies to control tumor growth. Current investigations therefore are directed towards elucidating the factors driving enhanced metastatic development in young hosts and their interactions within the tumor microenvironment, focusing on spatial metabolomics approaches and human cohorts for early-onset CRC.

Conclusion

Our findings demonstrate more aggressive liver metastasis formation in young hosts, as similarly observed in humans, and offer valuable insights into the pathogenesis of early-onset colorectal cancer.

Introduction

Colorectal cancer’s (CRC) incidence above 50 years old has been decreasing globally in the last decades, but its incidence in patients below 50 years old (early-onset colorectal cancer, EO-CRC) has been increasing, for reasons not yet fully understood.

Aims & Methods

A unicentric cohort study was conducted in a tertiary centre, including all patients admitted for a first diagnosis of CRC and evaluated by the Multidisciplinary Colorectal Cancer Group from 01.01.2017 until 31.12.2018. Patients with a previous diagnosis of a Hereditary Colorectal Cancer Syndrome were excluded.

Results

A total of 438 patients were included, 58.2% males, with a mean age at diagnosis of 67.7±11.1 years old. Mean follow-up time was 41.49 months. There were 25 EO-CRC patients (5.7%), 17 males (68%), mean age 43.1±6.0 years old.
Globally, 32.4% of the patients were current or past smokers, 18.5% had previous non-colorectal cancer, 7.5% and 3.4% were previously exposed to immunosuppressive drugs or abdominal/pelvic radiotherapy, respectively. The majority presented with normal(29.7%) to high Body Max Index (39.7%), median 25.6 (IQR:22.6-28.4) Kg/m². The most common CRC location was the rectum (42.9%) and 56.1% were stage I or II (AJCC 8^th edition).
In the univariate analysis, a significant association was found between EO-CRC and: smoking status (past or current smokers 52% in EO-CRC vs. 31.2% in older cases p=0.009); lymphovascular invasion (40.0% in EO-CRC vs. 17.4% in over 50, p=0.018) No significant differences were found for histological subtype (p=0.447), perineural invasion (p=0.474), or tumor stage at diagnosis, although a relevant proportion of the younger patients had metastatic disease at diagnosis (28.0% vs. 12.8%, p=0.064).
Immunohistochemistry for mismatch-repair proteins showed loss of expression of at least one protein in 1/18 EO-CRC patients and 22/179 of older patients (p=0.728).
From the EO-CRC patients, 16 were evaluated in the Familial Cancer Clinic and 14 underwent germline mutation analysis: 13 patients had inconclusive results, one of them presented a MUTYH heterozygote mutation and another was diagnosed with MUTYH-associated Polyposis (composed heterozygote mutation).

Conclusion

Colorectal cancer showed distinctive features in the younger population, with a higher prevalence of lymphovascular invasion and, possibly, a higher incidence of metastatic disease at diagnosis. Smoking had a significant association with CRC, especially in this younger population. Whether this means there is a biological difference is not yet clear. More evidence is needed in order to clarify EO-CRC aetiology and to develop screening and improve management strategies.

References

Siegel RL, Jakubowski CD, Fedewa SA, Davis A, Azad NS. Colorectal Cancer in the Young: Epidemiology, Prevention, Management. Am Soc Clin Oncol Educ Book. 2020 Mar;40:1-14. doi: 10.1200/EDBK_279901. PMID: 32315236