Role of CRH in colitis and colitis-associated cancer: a combinative result of central and peripheral effects?

Corticotropin-releasing factor family peptides (CRF peptides) comprise corticotropin releasing hormone (CRH), urocortin (UCN1), UCN2 and UCN3. CRH is first isolated in the brain and later with UCNs found in many peripheral cells/tissues including the colon. CRH and UCNs function via the two types of receptors, CRF1 and CRF2, with CRH mainly acting on CRF1, UCN1 on both CRF1 &CRF2 and UCN2-3 on CRF2. Compiling evidence shows that CRH participates in inflammation and cancers via both indirect central effects related to stress response and direct peripheral influence. CRH, as a stress-response mediator, plays a significant central role in promoting the development of colitis involving colon motility, immunity and gut flora, while a few anti-colitis results of central CRH are also reported. Moreover, CRH is found to directly influence the motility and immune/inflammatory cells in the colon. Likewise, CRH is believed to be greatly related to tumorigenesis of many kinds of cancers including colon cancer via the central action during chronic stress while the peripheral effects on colitis-associated-colon cancer (CAC) are also proved. We and others observe that CRH/CRF1 plays a significant peripheral role in the development of colitis and CAC in that CRF1 deficiency dramatically suppresses the colon inflammation and CAC. However, up to date, there still exist not many relevant experimental data on this topic, and there seems to be no absolute clearcut between the central and direct peripheral effects of CRH in colitis and colon cancer. Taken together, CRH, as a critical factor in stress and immunity, may participate in colitis and CAC as a centrally active molecule; meanwhile, CRH has direct peripheral effects regulating the development of colitis and CAC, both of which will be summarized in this review.

[Ascending colon cancer with submucosal tumor-like morphology arising near ileal valve lipohyperplasia:a case report].

An 89-year-old man was diagnosed with a submucosal tumor suspected to be a lipoma and was followed up for 6 years. The patient was admitted to the hospital because of increased tumor size and morphological changes despite negative bioptic findings. The lesion was diagnosed as an advanced adenocarcinoma of the ascending colon (cT3N0M0, cStage IIa). Laparoscopic-assisted right hemicolectomy with D3 lymph node dissection was performed. Pathological diagnosis of a surgically resected specimen revealed adenocarcinoma with lipohyperplasia (pT3N2aM0, pStage IIIb). Reports of colon cancer accompanied by colonic lipomas or lipohyperplasia are limited. This case showed an interesting submucosal tumor-like morphology because the cancer developed at the base of the lipohyperplasia and grew and spread below it.

Switching from FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab based on early tumor shrinkage in RAS wild-type metastatic colorectal cancer: A phase II trial (HYBRID).

BACKGROUND: Long-term anti-EGFR antibody treatment increases the risk of severe dermatologic toxicities. This single-arm, phase II trial aimed to investigate the strategy of switching from cetuximab to bevacizumab in combination with FOLFIRI based on early tumor shrinkage (ETS) in patients with RAS wild-type metastatic colorectal cancer (mCRC). METHODS: Radiologic assessment was performed to evaluate ETS, defined as ≥20% reduction in the sum of the largest diameters of target lesions 8 weeks after the introduction of FOLFIRI plus cetuximab. ETS-negative patients switched to FOLFIRI plus bevacizumab, whereas ETS-positive patients continued FOLFIRI plus cetuximab for eight more weeks, with a switch to FOLFIRI plus bevacizumab thereafter. The primary endpoint was progression-free survival. RESULTS: This trial was prematurely terminated due to poor accrual after a total enrollment of 30 patients. In 29 eligible patients, 7 were ETS-negative and 22 were ETS-positive. Two ETS-negative patients and 17 ETS-positive patients switched to FOLFIRI plus bevacizumab 8 weeks and 16 weeks after initial FOLFIRI plus cetuximab, respectively. Median progression-free and overall survival durations were 13.4 and 34.7 months, respectively. Six (20%) patients experienced grade ≥3 paronychia, which improved to grade ≤2 by 18 weeks. Grade ≥3 acneiform rash, dry skin, and pruritus were not observed in any patients. CONCLUSIONS: Our novel treatment strategy delivered acceptable survival outcomes and reduced severe dermatologic toxicities.

Stressing Out Cancer: Chronic Stress Induces Dysbiosis and Enhances Colon Cancer Growth.

Psychologic stress significantly impacts colorectal cancer, and chronic stress is known to decrease treatment efficacy and survival rates in patients with colorectal cancer. Previous studies have linked psychologic stress to changes in the gut microbiota, and the role of the microbiota in colorectal cancer progression is well characterized. Despite this, the mechanistic link between chronic stress and colorectal cancer remains unclear. In this issue of Cancer Research, Cao and colleagues reveal that chronic stress exacerbates colorectal cancer progression by reducing the presence of Lactobacillus johnsonii (L. johnsonii) and its metabolite protocatechuic acid (PCA). The authors demonstrate an increase in ß-catenin expression as the major mechanism by which chronic stress potentiates cancer stemness and pathogenesis. Administration of L. johnsonii or PCA to stressed mice decreased ß-catenin activity and colorectal cancer progression. This study defines a precise mechanism underlying chronic stress and colorectal cancer progression, emphasizing the relevance of psychologic well-being in colorectal cancer outcome. In addition, the study demonstrates the potential efficacy of L. johnsonii or PCA supplementation as promising therapeutics for colorectal cancer treatment. See related article by Cao et al., p. 771.

Predicting Colonic Neoplasia Surgical Complications: A Machine Learning Approach.

BACKGROUND: A range of statistical approaches have been used to help predict outcomes associated with colectomy. The multifactorial nature of complications suggests that machine learning algorithms may be more accurate in determining postoperative outcomes by detecting nonlinear associations, which are not readily measured by traditional statistics. OBJECTIVE: The aim of this study was to investigate the utility of machine learning algorithms to predict complications in patients undergoing colectomy for colonic neoplasia. DESIGN: Retrospective analysis using decision tree, random forest, and artificial neural network classifiers to predict postoperative outcomes. SETTINGS: National Inpatient Sample database (2003-2017). PATIENTS: Adult patients who underwent elective colectomy with anastomosis for neoplasia. MAIN OUTCOME MEASURES: Performance was quantified using sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve to predict the incidence of anastomotic leak, prolonged length of stay, and inpatient mortality. RESULTS: A total of 14,935 patients (4731 laparoscopic, 10,204 open) were included. They had an average age of 67 ± 12.2 years, and 53% of patients were women. The 3 machine learning models successfully identified patients who developed the measured complications. Although differences between model performances were largely insignificant, the neural network scored highest for most outcomes: predicting anastomotic leak, area under the receiver operating characteristic curve 0.88/0.93 (open/laparoscopic, 95% CI, 0.73-0.92/0.80-0.96); prolonged length of stay, area under the receiver operating characteristic curve 0.84/0.88 (open/laparoscopic, 95% CI, 0.82-0.85/0.85-0.91); and inpatient mortality, area under the receiver operating characteristic curve 0.90/0.92 (open/laparoscopic, 95% CI, 0.85-0.96/0.86-0.98). LIMITATIONS: The patients from the National Inpatient Sample database may not be an accurate sample of the population of all patients undergoing colectomy for colonic neoplasia and does not account for specific institutional and patient factors. CONCLUSIONS: Machine learning predicted postoperative complications in patients with colonic neoplasia undergoing colectomy with good performance. Although validation using external data and optimization of data quality will be required, these machine learning tools show great promise in assisting surgeons with risk-stratification of perioperative care to improve postoperative outcomes. See Video Abstract . PREDICCIN DE LAS COMPLICACIONES QUIRRGICAS DE LA NEOPLASIA DE COLON UN ENFOQUE DE MODELO DE APRENDIZAJE AUTOMTICO: ANTECEDENTES:Se han utilizado una variedad de enfoques estadísticos para ayudar a predecir los resultados asociados con la colectomía. La naturaleza multifactorial de las complicaciones sugiere que los algoritmos de aprendizaje automático pueden ser más precisos en determinar los resultados posoperatorios al detectar asociaciones no lineales, que generalmente no se miden en las estadísticas tradicionales.OBJETIVO:El objetivo de este estudio fue investigar la utilidad de los algoritmos de aprendizaje automático para predecir complicaciones en pacientes sometidos a colectomía por neoplasia de colon.DISEÑO:Análisis retrospectivo utilizando clasificadores de árboles de decisión, bosques aleatorios y redes neuronales artificiales para predecir los resultados posoperatorios.AJUSTE:Base de datos de la Muestra Nacional de Pacientes Hospitalizados (2003-2017).PACIENTES:Pacientes adultos sometidos a colectomía electiva con anastomosis por neoplasia.INTERVENCIONES:N/A.PRINCIPALES MEDIDAS DE RESULTADO:El rendimiento se cuantificó utilizando la sensibilidad, especificidad, precisión y la característica operativa del receptor del área bajo la curva para predecir la incidencia de fuga anastomótica, duración prolongada de la estancia hospitalaria y mortalidad de los pacientes hospitalizados.RESULTADOS:Se incluyeron un total de 14.935 pacientes (4.731 laparoscópicos, 10.204 abiertos). Presentaron una edad promedio de 67 ± 12,2 años y el 53% eran mujeres. Los tres modelos de aprendizaje automático identificaron con éxito a los pacientes que desarrollaron las complicaciones medidas. Aunque las diferencias entre el rendimiento del modelo fueron en gran medida insignificantes, la red neuronal obtuvo la puntuación más alta para la mayoría de los resultados: predicción de fuga anastomótica, característica operativa del receptor del área bajo la curva 0,88/0,93 (abierta/laparoscópica, IC del 95%: 0,73-0,92/0,80-0,96); duración prolongada de la estancia hospitalaria, característica operativa del receptor del área bajo la curva 0,84/0,88 (abierta/laparoscópica, IC del 95%: 0,82-0,85/0,85-0,91); y mortalidad de pacientes hospitalizados, característica operativa del receptor del área bajo la curva 0,90/0,92 (abierto/laparoscópico, IC del 95%: 0,85-0,96/0,86-0,98).LIMITACIONES:Los pacientes de la base de datos de la Muestra Nacional de Pacientes Hospitalizados pueden no ser una muestra precisa de la población de todos los pacientes sometidos a colectomía por neoplasia de colon y no tienen en cuenta factores institucionales y específicos del paciente.CONCLUSIONES:El aprendizaje automático predijo con buen rendimiento las complicaciones postoperatorias en pacientes con neoplasia de colon sometidos a colectomía. Aunque será necesaria la validación mediante datos externos y la optimización de la calidad de los datos, estas herramientas de aprendizaje automático son muy prometedoras para ayudar a los cirujanos con la estratificación de riesgos de la atención perioperatoria para mejorar los resultados posoperatorios. (Traducción-Dr. Fidel Ruiz Healy ).

Farnesoid X receptor mediates macrophage-intrinsic responses to suppress colitis-induced colon cancer progression.

Bile acids (BAs) affect the intestinal environment by ensuring barrier integrity, maintaining microbiota balance, regulating epithelium turnover, and modulating the immune system. As a master regulator of BA homeostasis, farnesoid X receptor (FXR) is severely compromised in patients with inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC). At the front line, gut macrophages react to the microbiota and metabolites that breach the epithelium. We aim to study the role of the BA/FXR axis in macrophages. This study demonstrates that inflammation-induced epithelial abnormalities compromised FXR signaling and altered BAs' profile in a mouse CAC model. Further, gut macrophage-intrinsic FXR sensed aberrant BAs, leading to pro-inflammatory cytokines' secretion, which promoted intestinal stem cell proliferation. Mechanistically, activation of FXR ameliorated intestinal inflammation and inhibited colitis-associated tumor growth, by regulating gut macrophages' recruitment, polarization, and crosstalk with Th17 cells. However, deletion of FXR in bone marrow or gut macrophages escalated the intestinal inflammation. In summary, our study reveals a distinctive regulatory role of FXR in gut macrophages, suggesting its potential as a therapeutic target for addressing IBD and CAC.

Nonoperative management of the primary tumor in patients with unresectable stage IV colon cancer treated with systemic chemotherapy: Higher complication rates for left-sided colon tumors.

INTRODUCTION: Treatment of the primary tumor in asymptomatic patients with unresectable colorectal metastases remains controversial. METHODS: Data from patients with synchronous stage IV colon cancer and an untreated primary tumor who started treatment aimed at metastatic disease at a specialized cancer center between 2014 and 2018 were analyzed retrospectively. Main outcome was primary tumor-related complications comparing left-sided and right-sided colon cancer. A competing-risk regression model was used to identify predictors of complications. RESULTS: Of 523 patients with metastatic colon cancer at presentation, 221 started treatment aimed at metastatic disease; these patients constituted the study cohort. The primary tumor was left-sided in 109 patients (49%) and right-sided in 112 patients (51%). In total, 46 patients (21%) developed a complication that required invasive intervention. Complications occurred more frequently in patients with left-sided tumors than in patients with right-sided tumors (29% vs 13%, P = 0.003). Eighteen patients (8%) underwent non-surgical intervention. Six patients (33%) failed non-surgical management and underwent surgery. Of 34 patients (15%) who underwent surgical intervention, 20 underwent an emergency colectomy and 14 underwent diversion with a permanent stoma. Overall, 10% of patients ended up with a permanent stoma. In competing-risk analysis, only left-sided primary tumor (hazard ratio 2.62; 95% CI 1.40-4.89; P = 0.003) was significantly associated with primary tumor-related complications requiring invasive intervention. CONCLUSIONS: Patients with asymptomatic metastatic left-sided tumors have a higher risk for primary tumor-related complications than patients with right-sided tumors. Close monitoring and early surgical rescue should be considered for patients with left-sided colon cancer who are managed nonoperatively.

Adult Height and Risk of Colorectal Cancer: A Pooled Analysis of 10 Population-based Cohort Studies in Japan.

BACKGROUND: While tall stature has been linked to an increase in the risk of colorectal cancer (CRC), its association with cancer in the colorectum and its subsites remains unclear among Asians. METHODS: We conducted a pooled analysis of 10 population-based cohort studies among adults in Japan. Each study estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC incidence associated with adult height were estimated using Cox proportional hazards regression with adjustment of the same set of covariates were then pooled to estimate summary HRs incidence using random-effect models. RESULTS: We identified 9,470 CRC incidences among 390,063 participants during 5,672,930 person-years of follow-up. Men and women with tall stature had a higher risk of CRC and colon cancer. HRs for CRC, colon cancer, and distal colon cancer for the highest versus lowest height categories were 1.23 (95% CI, 1.07-1.40), 1.22 (95% CI, 1.09-1.36), and 1.27 (95% CI, 1.08-1.49), respectively, in men and 1.21 (95% CI, 1.09-1.35), 1.23 (95% CI, 1.08-1.40), and 1.35 (95% CI, 1.003-1.81), respectively, in women. The association with proximal colon cancer and rectal cancer was less evident in both sexes. CONCLUSION: This pooled analysis confirms the link between tall stature and a higher risk of CRC and colon cancer (especially distal colon) among the Japanese and adds evidence to support the use of adult height to identify those at a higher risk of CRC.

Prognostic role of sodium levels in colorectal cancer patients receiving aflibercept plus FOLFIRI.

Aim: To investigate the impact of natremia in metastatic colorectal cancer (mCRC) patients treated with aflibercept plus folinic acid, 5-fluorouracil, oxaliplatin and irinotecan (FOLFIRI). Patients & methods: A total of 84 mCRC patients receiving aflibercept plus FOLFIRI as second-line treatment were enrolled and divided into two groups based on their median sodium value. Progression-free survival and overall survival were analyzed. Results: Patients with sodium levels ≥140 mEq/l had significantly longer median progression-free survival (4.1 vs 2 months; p < 0.01) and median overall survival (12 vs 7.3 months; p < 0.01) compared with those with lower levels. Conclusion: This study suggests that higher pretreatment serum sodium levels are associated with improved outcomes in mCRC patients receiving aflibercept and FOLFIRI, potentially serving as a prognostic marker to aid treatment management.

What is this article about? Colorectal cancer (CRC) is a common and deadly disease. Despite advances in treatment options, the prognosis remains poor for patients who progress beyond the first-line therapy. Antiangiogenic therapy, which targets blood vessel growth in tumors, has become an important treatment approach for metastatic CRC (mCRC). Aflibercept is a drug used in combination with chemotherapy to treat mCRC patients who have progressed after initial treatment. However, there is limited knowledge about factors that can predict the effectiveness of this treatment. This study aimed to investigate the relationship between sodium levels and treatment outcomes in 84 mCRC patients receiving aflibercept and chemotherapy as second-line therapy. What were the results? The results showed that patients with baseline sodium levels of ≥140 mEq/l had significantly longer progression-free survival and overall survival compared with patients with lower sodium levels. This finding suggests that baseline serum sodium levels could serve as a prognostic factor for survival outcomes in mCRC patients treated with aflibercept and chemotherapy. Other factors associated with better survival outcomes included longer survival without disease progression after first-line chemotherapy, receiving maintenance treatment with aflibercept and completing more treatment cycles. What do the results of the study mean? This study highlights the potential significance of serum sodium levels as a predictor of treatment effectiveness in mCRC patients. Further research is needed to confirm these findings and better understand the underlying mechanisms. Evaluating serum sodium levels could be a useful tool in predicting outcomes and improving treatment strategies for mCRC patients.

Clinical Evidence for the Benefits of Neoadjuvant Chemotherapy and Immunotherapy in Colon Cancer: A Concise Review.

Neoadjuvant chemotherapy (NAC) has long been considered technically difficult in locally advanced colon cancer (LACC). However, the introduction of oxaliplatin-based regimens led to a growing interest in NAC for patients with LACC. Several cohort studies showed that NAC was safe and reduced the rate of incomplete resection in patients with LACC. This was followed by the pivotal phase III FOxTROT trials, which showed significant benefits of NAC in this population. However, in patients with deficient mismatch repair (dMMR), the response to a neoadjuvant fluoropyrimidine regimen may be poor, limiting the benefit of NAC in this subset of patients. Neoadjuvant immunotherapy is a potential alternative for NAC in LACC patients with dMMR. In this concise review, we present the published clinical evidence evaluating the efficacy and safety of NAC and/or neoadjuvant immunotherapy in patients with LACC. Overall, the evidence suggests that NAC can be associated with significant downstaging and tumor regression, which facilitate surgical resection. However, the impact of NAC on long-term survival is still under investigation. Despite the promising results of NAC in LACC, several concerns still exist that necessitate further evidence. On the other hand, LACC patients with dMMR can benefit from neoadjuvant immunotherapy; however, further trials are still needed to confirm its effectiveness, as well as biomarkers that can predict response.

Case report: Interstitial lung disease of XELOEX chemotherapy with cetuximab in advanced colon cancer induced.

INTRODUCTION: This paper presents a case of a Chinese patient with advanced colon cancer who developed drug-induced interstitial lung disease while undergoing treatment with cetuximab combined with XELOX. PATIENT CONCERNS: A 75-year-old man with a history of colon cancer, had metastases in the liver, peritoneum, and lungs, which were initially treated with XELOX and cetuximab (0.4 g) in 2019. However, the lung metastases progressed, and the cetuximab dosage was adjusted to 0.9 g and then readjusted to 0.4 g. DIAGNOSIS: In January 2021, computed tomography revealed developed interstitial lung disease, leading to the discontinuation of chemotherapy and cetuximab. INTERVENTIONS: Receiving methylprednisolone pulse therapy. OUTCOMES: The patient experienced respiratory failure and passed away. The Naranjo Algorithm Assessment score indicated a probable relationship between cetuximab and the adverse event. CONCLUSION: This case highlights the need for regular pulmonary imaging examinations during cetuximab therapy, as drug-induced interstitial lung disease may be associated with the dose and duration of treatment.

Panitumumab plus trifluridine/tipiracil as anti-EGFR rechallenge therapy in patients with refractory RAS wild-type metastatic colorectal cancer: Overall survival and subgroup analysis of the randomized phase II VELO trial.

The randomized phase II VELO trial showed that the addition of panitumumab to trifluridine/tipiracil significantly improves progression-free survival (PFS) as compared to trifluridine/tipiracil in third-line therapy in patients with refractory RAS wild-type (WT) metastatic colorectal cancer (mCRC). With longer follow-up, final overall survival results and posttreatment subgroup analysis are presented. Sixty-two patients with refractory RAS WT mCRC were randomly assigned to receive, as third-line therapy, trifluridine/tipiracil alone (arm A) or in combination with panitumumab (arm B). Primary endpoint was PFS; secondary endpoints included overall survival (OS) and overall response rate (ORR). Median OS was 13.1 months (95% CI 9.5-16.7) in arm A compared to 11.6 months (95% CI 6.3-17.0) in arm B (HR: 0.96, 95% CI 0.54-1.71, P = .9). To evaluate the impact of subsequent lines of treatment, subgroup analysis was performed for the 24/30 patients in arm A, that received fourth-line therapy after disease progression. Median PFS was 4.1 months (95% CI 1.44-6.83) for 17 patients treated with anti-EGFR rechallenge as compared to 3.0 months (95% CI 1.61-4.31) for seven patients that received other therapies (HR: 0.29, 95% CI 0.10-0.85, P = .024). Median OS from the start of fourth-line treatment was 13.6 months (95% CI 7.2-20), and 5.1 months (95% CI 1.8-8.3) for patients treated with anti-EGFR rechallenge vs other therapies, respectively (HR: 0.30, 95% CI 0.11-0.81, P = .019). Final results of the VELO trial support the role of anti-EGFR rechallenge in the continuum of care of patients with RAS/BRAF WT mCRC.

CYP eicosanoid pathway mediates colon cancer-promoting effects of dietary linoleic acid.

Human and animal studies support that consuming a high level of linoleic acid (LA, 18:2ω-6), an essential fatty acid and key component of the human diet, increases the risk of colon cancer. However, results from human studies have been inconsistent, making it challenging to establish dietary recommendations for optimal LA intake. Given the importance of LA in the human diet, it is crucial to better understand the molecular mechanisms underlying its potential colon cancer-promoting effects. Using LC-MS/MS-based targeted lipidomics, we find that the cytochrome P450 (CYP) monooxygenase pathway is a major pathway for LA metabolism in vivo. Furthermore, CYP monooxygenase is required for the colon cancer-promoting effects of LA, since the LA-rich diet fails to exacerbate colon cancer in CYP monooxygenase-deficient mice. Finally, CYP monooxygenase mediates the pro-cancer effects of LA by converting LA to epoxy octadecenoic acids (EpOMEs), which have potent effects on promoting colon tumorigenesis via gut microbiota-dependent mechanisms. Overall, these results support that CYP monooxygenase-mediated conversion of LA to EpOMEs plays a crucial role in the health effects of LA, establishing a unique mechanistic link between dietary fatty acid intake and cancer risk. These results could help in developing more effective dietary guidelines for optimal LA intake and identifying subpopulations that may be especially vulnerable to LA's negative effects.

Causal associations of hyperthyroidism with prostate cancer, colon cancer, and leukemia: a Mendelian randomization study.

Background: Observational studies have shown that hyperthyroidism may increase the risk of cancer, but their causal effects and direction are unclear. We conducted a two-sample Mendelian randomization (MR) study to explore the associations between genetic predisposition to hyperthyroidism and nine common types of cancer, including prostate, lung, breast, colon, leukemia, brain, skin, bladder, and esophagus cancer. Methods: We obtained summary statistics of hyperthyroidism and nine types of cancers from genome-wide association studies (GWAS). MR analysis is performed to investigate the potential causal relationship between hyperthyroidism and cancers. The inverse variance weighted (IVW) as the primary method was carried out. The robustness of the results was evaluated by sensitivity analysis. Results: Genetically predicted hyperthyroidism was associated with a declining risk of occurrence of prostate cancer (odds ratio (OR)IVW= 0.859, P= 0.0004; OR MR-Egger=0.828, P= 0.03; OR weighted median= 0.827, P=0.0009). Additionally, there was a significant association between genetically predicted hyperthyroidism and colon cancer (OR IVW= 1.13, P= 0.011; OR MR-Egger= 1.31, P= 0.004; OR weighted median= 1.18, P= 0.0009). Hyperthyroidism was also suggestively correlated with a higher risk of leukemia based on the result of IVW and weighted median (OR IVW= 1.05, P= 0.01; OR weighted median= 1.08, P= 0.001). Results from a two-sample MR analysis suggested that hyperthyroidism was not associated with the risk of lung cancer, breast cancer, brain cancer, skin cancer, bladder cancer, and esophageal cancer. Conclusion: Our study provides evidence of a causal relationship between hyperthyroidism and the risk of prostate cancer, rectal cancer, and leukemia. Further research is needed to clarify the associations between hyperthyroidism and other cancers.

Survival in relation to time to start of curative treatment of colon cancer: A national register-based observational noninferiority study.

AIM: There are ample discussions regarding the timing of treatment, especially in the era after Covid that caused delay to treatment. The aim of this study was to determine whether a delayed start to curative treatment, within 29-56 days after a diagnosis of colon cancer, was noninferior to starting treatment within 28 days, with regard to all-cause mortality. METHOD: This is a national register-based observational noninferiority study, with a noninferiority margin of hazard ratio (HR) 1.1, including all patients treated with curative intent for colon cancer in Sweden between 2008 and 2016. The primary outcome was all-cause mortality. Secondary outcomes were length of hospital stay, readmissions and reoperations within 1 year after surgery. Exclusion criteria were emergency surgery, disseminated disease at diagnosis, missing diagnosis date and treatment for another cancer 5 years before colon cancer diagnosis. RESULTS: A total of 20 836 individuals were included. A period of 29-56 days from diagnosis to start of curative treatment was noninferior versus starting treatment within 28 days for the primary outcome of all-cause mortality (HR 0.95, 95% CI 0.89-1.00). Starting treatment within 29-56 days was associated with a shorter length of stay (average 9.2 vs. 10 days) but a higher risk of reoperation compared to within 28 days. Post hoc analyses demonstrated that surgical modality was driving survival rather than time to treatment. Overall survival was greater after laparoscopic surgery (HR 0.78, 95% CI 0.69-0.88). CONCLUSION: For patients with colon cancer, a period of up to 56 days from diagnosis to the start of curative treatment did not lead to worse overall survival.

Antibodies to oral pathobionts and colon cancer risk in the CLUE I cohort study.

Periodontitis has been associated with an increased risk for gastrointestinal cancers. The objective of our study was to investigate the association of antibodies to oral bacteria and the risk of colon cancer in a cohort setting. Using the CLUE I cohort, a prospective cohort initiated in 1974 in Washington County, Maryland, we conducted a nested case-control study to examine the association of levels of IgG antibodies to 11 oral bacterial species (13 total strains) with risk of colon cancer diagnosed a median of 16 years later (range: 1-26 years). Antibody response was measured using checkerboard immunoblotting assays. We included 200 colon cancer cases and 200 controls matched on age, sex, cigarette smoking status, time of blood draw and pipe or cigar smoking status. Controls were selected using incidence density sampling. Conditional logistic regression models were used to assess the association between antibody levels and colon cancer risk. In the overall analysis, we observed significant inverse associations for 6 of the 13 antibodies measured (P-trends <.05) and one positive association for antibody levels to Aggregatibacter actinomycetemcomitans (ATCC 29523; P-trend = .04). While we cannot rule out a role for periodontal disease in colon cancer risk, findings from our study suggest that a strong adaptive immune response may be associated with a lower risk of colon cancer. More studies will need to examine whether the positive associations we observed with antibodies to A. actinomycetemcomitans reflect a true causal association for this bacterium.

Health-related quality-of-life trajectories during/after surgery and adjuvant chemotherapy in patients with colon cancer.

PURPOSE: This study aims to evaluate quality of life trajectory during the first year after surgical treatment in patients with resectable primary colon cancer. METHODS: Patients with resectable primary colon cancer diagnosed between 2013 and 2019 who received surgical treatment and adjuvant chemotherapy if indicated were selected from the Prospective Dutch ColoRectal Cancer cohort study (PLCRC). Health-related quality of life (HR-QoL) was assessed using EORTC-QLQ-C30 questionnaire before surgery, and three and twelve months after surgery. HR-QoL scores varied between 0 and 100 and outcomes were compared according to age (< 70 years, ≥ 70 years), comorbidity (yes, no) and treatment type (adjuvant chemotherapy, surgical treatment only). The extent of resilience, defined as a recovery of HR-QoL to baseline level after a clinically relevant decline in HR-QoL at months, was calculated twelve months post-surgery. RESULTS: For all 458 patients, the mean age was 66.4 years (SD 9.5), 40% were aged 70 years and older and 68% were men. Baseline level of HR-QoL summary score was relatively high with a mean of 87.9 (SD 11.5), and did not significantly differ between older and younger patients. The strongest decline of HR-QoL compared to baseline was observed at three months with a gradual recovery over time. Fourteen percent of all patients were non-resilient or showed a late decline at twelve months post-surgery. Compared to younger patients, older patients who received adjuvant chemotherapy were less resilient (respectively, 53 and 32%, p = 0.07) and at risk of a late decline in HR-QoL 1 year post-surgery (respectively, 3% versus 16%, p = 0.02). Comorbidity status had no significant impact on the HR-QoL trajectory. CONCLUSION: Colon cancer treatment was associated with a decline in HR-QoL three months post-surgery, but most patients return to baseline level within twelve months. Still, particularly older patients who received adjuvant chemotherapy were less resilient and at risk of a late decline in HR-QoL. These data could help in patients counselling regarding colon cancer treatment.

Microbiome and Diet in Colon Cancer Development and Treatment.

ABSTRACT: Diet plays critical roles in defining our immune responses, microbiome, and progression of human diseases. With recent progress in sequencing and bioinformatic techniques, increasing evidence indicates the importance of diet-microbial interactions in cancer development and therapeutic outcome. Here, we focus on the epidemiological studies on diet-bacterial interactions in the colon cancer. We also review the progress of mechanistic studies using the experimental models. Finally, we discuss the limits and future directions in the research of microbiome and diet in cancer development and therapeutic outcome. Now, it is clear that microbes can influence the efficacy of cancer therapies. These research results open new possibilities for the diagnosis, prevention, and treatment of cancer. However, there are still big gaps to apply these new findings to the clinical practice.

Cetuximab as third-line rechallenge plus either irinotecan or avelumab is an effective treatment in metastatic colorectal cancer patients with baseline plasma RAS/BRAF wild-type circulating tumor DNA: Individual patient data pooled analysis of CRICKET and CAVE trials.

The rechallenge strategy is based on the concept that a subset of patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC) could still benefit of epidermal growth factor receptor (EGFR) inhibition, after progression to an anti-EGFR based-therapy. We performed a pooled analysis of two-phase II prospective trials to determine the role of rechallenge in third-line mCRC patients with RAS/BRAF WT baseline circulating tumor DNA (ctDNA). Individual data of 33 and 13 patients from CAVE and CRICKET trials that received as third-line therapy cetuximab rechallenge were collected. Overall survival (OS), Progression-free survival (PFS), Overall response rate (ORR), Stable disease (SD) >6 months were calculated. Adverse events were reported. For the whole 46 patient population, median PFS (mPFS) was 3.9 months (95% Confidence Interval, CI 3.0-4.9) with median OS (mOS) of 16.9 months (95% CI 11.7-22.1). For CRICKET patients, mPFS was 3.9 months (95% CI 1.7-6.2); mOS was 13.1 months (95% CI 7.3-18.9) with OS rates at 12, 18, and 24 months of 62%, 23%, and 0%, respectively. For CAVE patients, mPFS was 4.1 months (95% CI 3.0-5.2); mOS was 18.6 months (95% CI 11.7-25.4) with OS rates at 12, 18, 24 months of 61%, 52%, 21%, respectively. Skin rash was more frequently reported in CAVE trial (87.9% vs. 30.8%; p = 0.001), whereas a increased incidence of hematological toxicities was observed in CRICKET trial (53.8%% vs. 12.1%; p = 0.003). Third-line cetuximab rechallenge in combination with either irinotecan or avelumab in RAS/BRAF WT ctDNA mCRC patients represents a promising therapy.