Modulación por Passiflora edulis de triglicéridos y colesterol intracelulares en líneas celulares de cáncer colorrectal SW480 y sus derivadas metastásicas (SW620) / Modulation by Passiflora edulis of intracellular triglycerides and cholesterol in SW480 col orectal cancer cell lines and their metastatic derivatives (SW620)

Cancer cells modify lipid metabolism to proliferate, Passiflora edulis ( P. edulis ) fruit juice (ZuFru) has antitumor activity, but whether a mechanism is through modulation of cell lipids is unknown. T o establish if ZuFru modifies cholesterol and triglycerides in SW480 and SW620. ZuFru composition was studied by phytochemical march; antiproliferative activity by sulforhodamine B, cholesterol , and triglycerides by Folch method. Z ufru contains anthocyanins, flavonoids, alkaloids , and tannins. Cell lines showed differences in their growth rate ( p =0.049). At 39.6 µg/m L of ZuFru, cell viability was decreased: SW480 (45.6%) and SW620 (45.1%). In SW480, cholesterol (44.6%) and triglycerides (46.5%) decreased; In SW620, cholesterol decreased 14.8% and triglycerides increased 7%, with significant differences for both lines. A ntiproliferative activity of ZuFru could be associated with the inhibition of intracellular biosynthesis of cholesterol and triglycerides in SW480. Action mechanisms need to be further investigated.

Las células cancerosas modifican el metabolismo lipídico para proliferar; el zumo de fruta (ZuFru) de Passiflora edulis ( P. edulis ) tiene activida d antitumoral, sin embargo, se desconoce si se involucran los lípidos celulares. E stablecer si ZuFru modifica colesterol y triglicéridos en células SW480 y SW620. C omposición del ZuFru, actividad antiproliferativa, colesterol y triglicéridos. Se encontraro n antocianinas, flavonoides, alcaloides y taninos. Las líneas celulares mostraron diferencias en su tasa de crecimiento ( p =0 . 049); ZuFru 39,6 µg/ml se disminuyó la viabilidad celular; SW480 (45,6%) y SW620 (45,1%); en SW480 colesterol (44,6%) y triglicérid os (46,5%) en SW620, colesterol (14,8%) y los triglicéridos aumentaron 7%, con diferencias significativas para ambas líneas. La actividad antiproliferativa del ZuFru podría estar asociada a la inhibición de la biosíntesis intracelular de colesterol y de tr iglicéridos en SW480, pero no en SW620. Estos mecanismos de acción deben ser fuertemente investigados.

Rheum khorasanicum. Hydroalcoholic root extract induces cell death in human colorectal adenocarcinoma: An in vitro and in silico study.

Colorectal cancer (CRC) is the second greatest cause of cancer-related death in the world and chemotherapy, as an important part of CRC treatment, has some drawbacks, including systemic toxicity. Therefore, it is crucial to discover new and more effective CRC treatment plans. Rheum khorasanicum (R. khorasanicum) is a medicinal plant with high flavonoids, stilbenes, and anthraquinone contents, so it can be a potential source of antioxidants and can be used for therapeutic purposes and trigger apoptosis in cancer cells. In this study, we investigated the effects of hydroalcoholic root extract of R. khorasanicum treatment on inducing mitochondrial apoptosis of HT-29 and Caco-2 human colorectal adenocarcinoma cells. Firstly, the total phenolic and flavonoid content was determined. Then, the cytotoxic effects of R. khorasanicum on cells of three different types, including HT-29 and Caco-2 colon cancer cells as well as normal 3T3 cells were assessed using the MTT assay. To investigate the characteristics of cellular death, flow cytometry, and western blotting were performed. The results of this study indicated considerable phenolic (356.4±9.4 GAE/gDW) and flavonoid (934.55±17.1 QE/gDW) contents in R. khorasanicum. MTT assay's finding indicated that 100, 60, and 30µg/mL concentrations of R. khorasanicum reduce cell viability in HT-29 and Caco-2 cell lines significantly (P<0.05). It has been also revealed that R. khorasanicum extract induces apoptosis rather than necrosis in these cell lines. Moreover, Bcl-2 expression was significantly reduced in both HT-29 and Caco-2 cell lines, while Bax and cleaved caspase-3 expression soared considerably in the groups under R. khorasanicum treatment (P<0.05). In conclusion, our findings have suggested that high phenol and flavonoid contents of R. khorasanicum root extract possibly play an important role in cell cytotoxicity and apoptosis induction in HT-29 and Caco-2 colon cancer cells.

[Contribution of intraperitoneal chemotherapy in the treatment of colorectal peritoneal carcinoma. HIPEC, PIPAC, state of the art and future directions]. / La chimiothérapie intra-péritonéale dans le traitement de la carcinose péritonéale d'origine colorectale. CHIP, PIPAC, état des lieux et perspectives.

After more than a decade of good results using the combination of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal carcinosis of colorectal origin, the PRODIGE7 study, which specifically evaluated the role of HIPEC, failed to show any superiority in terms of overall and disease-free survival for the CRS+HIPEC combination compared with CRS alone. This study constituted a radical change in the knowledge and therapeutic attitudes observed to date. After reviewing the literature and the consensus of national and international experts, a synthesis is provided, together with an outlook on the questions raised and the therapeutic trials and innovations of the near future. An analysis of recent advances due to the advent of a new technique, PIPAC, is also proposed, as well as a review of current therapeutic trials in this field.

[Évaluation de la gravité du cancer colorectal dépisté dans le contexte de la crise sanitaire liée au COVID19 en région Ile-de-France]. / Evaluation of the severity of screened colorectal cancer in the context of the health crisis linked to COVID19 in Ile-de-France region.

BACKGROUND: After the announcement in March 2020 of the COVID-19 pandemic, colorectal cancer (CRC) screening programs were suspended in several countries. Compared to the lesions detected during previous campaigns, this study aims to assess the severity of CRC detected during the 2020 screening campaign in Île-de-France, the French region most affected by the 1st wave of the pandemic. METHODS: The descriptive and etiological study included all faecal immunochemical test (FIT) results carried out between January 2017 and December 2020 on people aged 50-74, living in Île-de-France. First, the proportion of colonoscopies performed within one month (One-month-colo) following FIT; the yield of colonoscopy (proportion of colonoscopies with a neoplasm lesion among those performed) and CRC severity (TNM Classification, Level-0: T0/N0/M0, Level-1: T1/T2/N0/M0, Level-2: T3/T4/N0/M0; Level-3: T3/T4/N1/M0; Level-4: M1) were described in 2020 compared to previous campaigns (2017, 2018, and 2019). Subsequently, the link between the level of CRC severity and the predictive factors, including campaign year and time to colonoscopy, was analysed using polytomous multivariate regression. RESULTS: The one-month-colo (2017: 9.1% of 11,529 colonoscopies; 2018: 8.5% of 13,346; 2019: 5.7% of 7,881; 2020: 6.7% of 11,040; p < 0.001), the yield (65.2%, 64.1%, 62.4%, 60.8% respectively, p < 0.001) were significantly different between campaigns. The proportion of CRC level-4 (4.8% in 2017 (653 CRC); 7.6% in 2018 (674 CRC); 4.6% in 2019 (330 CRC) and 4.7% in 2020 (404 CRC); p < 0.29) was not significantly different between campaigns. The probability of having CRC with a high severity level was inversely related to the time to colonoscopy but not to the campaign year. Compared to patients having undergone colonoscopy within 30 days, the odds were significantly reduced by 60% in patients having undergone colonoscopy after 7 months (adjusted Odds-Ratio: 0.4 [0.3; 0.6]; p < 0.0001). CONCLUSIONS: The French indicators were certainly degraded before the first wave of the COVID-19. The delay in access to colonoscopy as well as its extension induced by the COVID-19 crisis had no impact in terms of cancer severity, due to a discriminatory approach prioritizing patients with evident symptoms.

[Targeting HER2 in colorectal cancer]. / Cibler HER2 dans le cancer colorectal.

Among the molecular subgroups of interest in metastatic colorectal cancer (mCRC), innovations are underway for tumors with overexpression of HER2 (Human Epidermal Growth Factor Receptor 2). Overexpression of the HER2 protein concerns 2 to 5% of CRC at any stage mainly located in the distal colon and rectum. Diagnosis is based on immunohistochemistry, in situ hybridization with appropriate criteria for colorectal localization, and molecular biology (NGS: next-generation sequencing). Overexpression of HER2 is a predictive factor for resistance to treatments targeting EGFR which are indicated in the case where the tumor is wild-type RAS. It seems to be associated with a poor prognosis of mCRC with a higher risk of brain metastasis. Regarding treatments targeting HER2, no randomized controlled phase III has been published to date. However, several combinations have been evaluated in phase II with clinically meaningful objective response rates: trastuzumab-deruxtecan (45%), trastuzumab-tucatinib (46%), trastuzumab-pyrotinib (45%), trastuzumab-pertuzumab (30%) ou trastuzumab-lapatinib (30%). In this literature review, we present here the current state of knowledge on the diagnostic methods of HER2 overexpression in CRC, the main clinical, molecular and prognostic characteristics, and the efficacy results of the different therapeutic combinations for the patients with HER2 overexpressed mCRC. This justifies, despite the lack of marketing authorization in France and in Europe for agents targeting HER2 in CRC, the systematic evaluation of the HER2 status, as recommended in particular by the NCCN (National Comprehensive Cancer Network).

Tetraspanin-29 activates Notch signaling by interacting with ADAM10 to enhance its activity in colorectal cancer.

ADAM10 acts upstream of Notch signaling and plays oncogenic roles in various cancers. Tetraspanin family proteins regulate ADAM10 trafficking and activity. Here, we aimed to investigate whether and how tetraspanin-29 modulates ADAM10 in colorectal cancer (CRC). We found that ADAM10 expression was upregulated in CRC tissues and this was cross-validated in the TCGA COAD data set. The ADAM10 protein level and its α-secretase activity were enhanced in CRC cell lines compared with control cell lines. Co-immunoprecipitation showed ADAM10 interacted with tetraspanin-29 in the LoVo cell line. Tetraspanin-29 knockdown reduced the cell surface trafficking and α-secretase activity of ADAM10. In addition, tetraspanin-29 knockdown inhibited Notch activity in a luciferase reporter assay and reduced the levels of cleaved Notch1 and Notch target genes such as HES2, c-MYC, and cyclin D3. Consistently, tetraspanin-29 overexpression increased cleaved Notch1 and this effect was blocked by ADAM10 inhibitors. The TCGA COAD data set confirmed the positive correlations of tetraspanin-29 with HES2, c-MYC, and cyclin D3. Thus, the tetraspanin-29/ADAM10/Notch pathway plays an important role in CRC.

Stereotactic body radiation therapy for colorectal liver metastases.

Multidisciplinary case discussion of patients with colorectal liver metastases (CRLM) has led to improved selection of more complex patients with the oligometastatic disease for treatment with surgical resection, locally ablative therapy or a combination of local modalities to improve the therapeutic ratio in patients with CRLM. Stereotactic body radiation therapy (SBRT) is a noninvasive local therapy with a potential role in the management of oligometastatic CRLM and may be considered as an alternate choice to other locally ablative therapies like radiofrequency ablation, radioembolization, chemoembolization or surgery or after the failure of other local treatment or in combination with surgery. Existing evidence reports for highly selected patients with CRLM, one to five fractions SBRT can be delivered safely, with satisfactory long-term local control, overall survival and quality of life. This review article will present the evidence of SBRT in this setting.

[Medical oncological treatment of colorectal cancer in the elderly]. / Traitement chirurgical du cancer colorectal chez la personne âgée.

Approximately a quarter of patients undergoing colorectal cancer surgery are over 75 years of age. Their care must therefore be adapted to minimise his functional consequences, which can be more significant in an elderly patient.

[Medical oncological treatment of colorectal cancer in the elderly]. / Traitement oncologique médical du cancer colorectal chez la personne âgée.

Medical treatment with chemotherapy is discussed in several situations in the treatment of colon cancer. In the adjuvant setting, chemotherapy with 5FU±oxaliplatin for six months should be considered in the case of lymph node involvement. In the metastatic setting, several protocols exist. The choice of treatments should be based on the expected objectives in terms of response and survival gain, but also of tolerance and quality of life for the patient. A thorough oncogeriatric assessment helps to better define the therapeutic programme. The continuation of geriatric follow-up throughout the treatment process shows a benefit for the patient in terms of quality of life and tolerance of treatments.

Colorectal cancer screening knowledge and uptake in lebanon: a national survey.

OBJECTIVE: The main aim of this national survey was to identify the levels of colorectal cancer screening knowledge and uptake in Lebanon. METHODS: A total of 1200 participants were enrolled in this cross-sectional household survey targeting the Lebanese population aged 50 years and above. The sample was recruited using a two-stage stratified cluster sampling approach. RESULTS: Of the total sample, 38.3% knew about any screening test for colorectal cancer but only 7.5% had ever used any. Thirty-nine percent of the participants rated their risk of getting colorectal cancer as very low or low, and only 53.5% were confident in their ability to undertake a screening test. Almost all participants agreed that medical advice and test reimbursement would encourage them to do a screening test. At the multivariate analysis level, hearing of an awareness campaign in the last two years showed the strongest association with the knowledge of a colorectal cancer screening test with an estimated ORadj = 5.12 (95%CI: 3.67 - 7.15). Other factors that were significantly associated with this knowledge variable included: a family history of colorectal cancer, a personal history of colorectal illness, having a health coverage, and knowledge of colorectal cancer signs and symptoms. DISCUSSION: This national study highlights an alarming lack of uptake and low levels of knowledge of colorectal cancer screening tests even though it is among the most prevalent cancers in Lebanon and its prevalence has been continuously increasing in the past years. The evidence suggests that people who had an experience with colorectal cancer diagnostic tests, either personally or through a family member, and those who have heard of an awareness campaign about colorectal cancer in the last two years are more likely to know its screening tests. CONCLUSION: Colorectal cancer screening knowledge and uptake in Lebanon are limited and justify the need for public health interventions. This study gives evidence that awareness campaigns, coupled with the involvement of medical providers and the reimbursement of screening test fees, would alleviate the burden of colorectal cancer in Lebanon.

[Pathological complete response of a metastatic MisMatch Repair deficient/MicroSatellite Instable colon cancer after immunotherapy: A case report]. / Réponse histologique complète d'un cancer colique métastatique de phénotype MisMatch Repair déficient/MicroSatellite Instable après immunothérapie : à propos d'un cas.

Immunotherapies are part of the therapeutic strategy in many cancers and are indicated for metastatic colorectal adenocarcinoma with loss of expression of MisMatch Repair system proteins or with microsatelite instability (dMMR/MSI) in the United States. The rate of pathological response to immunotherapy remains poorly documented, but several cases of complete or major pathological response have recently been described. We decided to report the case of a complete pathological response to immunotherapy of a dMMR/MSI colorectal adenocarcinoma in a 74-year-old patient, initially inoperable due to duodenal invasion. Three months after the introduction of immunotherapy, the patient developed drug-induced colitis that contraindicated further treatment. Histological examination of the subtotal colectomy specimen revealed no residual tumour cells. The patterns of tumour regression were mainly represented by colloid regression, infarctoid-type necrosis and a resorptive inflammatory reaction. Although the operative indications for patients with metastatic dMMR/MSI colorectal cancer treated by immunotherapy are still very limited, the number of such specimens is expected to increase rapidly. The management of these specimens, as well as the possibility of a complete histological response, must be known by pathologists who play a key role in the pathophysiological knowledge of these lesions.

[Tumour deposition (TD), a probably underestimated poor prognostic criterion, to be taken into account in the therapeutic management of patients with stage III colon cancer]. / Les dépôts tumoraux (DT), un critère pronostique péjoratif probablement sous-estimé, à prendre en compte dans la prise en charge thérapeutique des malades atteints de cancer colique de stade III.

The management of colorectal cancer (CRC) relies heavily on TNM staging. In order to improve this staging, it is essential to identify all histological markers bearing a significant prognostic value. Among these, tumor deposits (TDs), defined as tumor foci in the pericolonic or perirectal adipose tissue with no residual lymph node tissue, have been shown to be associated with poor prognosis in cohort studies leading to their individualization in the TNM7 classification as pN1c. However, TDs are only considered in the absence of lymph node metastases. There is no consensus on this particular way of integrating TDs in the TNM classification. Indeed, at the time when the choice of the type of adjuvant treatment and its duration in stage III colon cancers (i.e. with lymph node metastases) is based on pT and pN criteria, taking into account TDs only in the absence of concomitant lymph node metastases is potentially responsible for a misclassification of some patients and wrong therapeutic decisions. In addition, many questions concerning the true definition of TDs, their origin, their prognostic value and the optimization of their consideration remain open. The objective of this review is to provide a synthesis of current knowledge on TDs in CRC, in view of their prognostic importance, their biological complexity and the scientific interest they are currently the subject of.

[Colorectal cancer screening program : Test completion rate and follow-up results after selective mailing of the test kit, based on likelihood of participation]. / Dépistage organisé du cancer colorectal : taux de réalisation du test et résultats du suivi après un envoi postal sélectif du kit de test, basé sur la probabilité de participation.

BACKGROUND: Even though theinterest of a Colorectal-Cancer Screening Program has been amply demonstrated, in French departments the participation rate (PR) seldom reaches 45%. In the absence of mass mailing, a strategy (S-1) consisting in mailing a test kit to people having made a request was implemented in 2015. In 2017, another mailing strategy (S-2), which consisted in sending the test kit only to people likely to take the test, was programmed. This study assesses the respective impact of these two strategies as compared to the standard approach (S-0). METHODS: The study included 254,113 (S-0), 4,130 (S-1) and 10,887 (S-2) people aged 50-74, targeted during the 2016-2017 campaign in Seine-Saint-Denis (France). S-0 persons received a 2nd reminder without a test-kit, while S-1 persons received, at their request, a mailed test kit. Without having made a request, S-2 persons the mailed test kit according to probability of participation (Proba) which was estimated a priori by the ratio between the sum total of index values (frequency of previous participation, date of most recent participation, age) and a theoretical maximum. Completion rates (test/colonoscopy) were compared 18 months after the last S-2 kit was sent. RESULTS: PR was highest in S-1 (S-0: 5.8%, S-1: 74.9%, S-2: 31.3%; p < 0.0001). In S-2, PR rose as Proba increased (Proba: ]0-30%], ]30-50%], ]50-75%], ]75-100%]; PR: 21.1%, 23.3%, 36.2%, 52.8% respectively; p < 0.05). Compared to the ≥70 years age-group, the 50-54 years age-group presented a lower PR in S-1 (65.9% vs. 85.1%; p < 0.05) whereas it presented a higher PR in S-0 (4.3% vs. 7.1%; p < 0.05) and in S-2 (23.2% vs. 54.5%; p < 0.05). All in all, colonoscopy completion rates were highest in S-1 (S-0: 62.2%, S-1: 80.0%, S-2: 65.0%; p < 0.001). CONCLUSION: Test-kit mailing without spontaneous request does not lead to an optimal level of participation, thereby highlighting a need to give thought to new and improved mobilization methods. The relatively pronounced participation of younger persons, who are not favored by present-day testing specifications, underscores the interest of a specific approach addressed to active people, who are less inclined than elderly individuals to regularly consult their attending physicians.

[Role of stereotactic radiotherapy in the treatment of oligometastatic colorectal cancer]. / Place de la radiothérapie (cancer primitif, métastases) dans la prise en charge des patients atteints d'un cancer oligométastatique : cancer colorectal.

Stereotactic radiotherapy is used for patients with oligometastases from colorectal cancer. It results in good local tumour control, especially for hepatic and pulmonary metastases, subject to a sufficiently high biologically effective dose, and is well-tolerated. It can be associated with other local treatments such as surgery or radiofrequency as part of combined treatments, in order to increase patient survival.

[Benefit-risk balance of hormone replacement therapy: Cancers and mortality. Postmenopausal women management - CNGOF and GEMVi clinical practice guidelines]. / La balance bénéfice­risque du traitement hormonal de la ménopause : cancers et mortalité. RPC Les femmes ménopausées CNGOF ­ GEMVi.

The use of hormone replacement therapy (HRT) for menopausal women has been the subject of much controversy in recent years, particularly concerning the carcinologic risks. The purpose of this review is to evaluate the impact of the use of HRT on the risk of gynecological but also extra-gynecological cancers. The effect of the type and the duration of use of HRT in menopausal women will also be discussed. The beneficial impact of HRT on overall mortality is also an element that will be discussed and must be taken into account when evaluating the benefit-risk balance of HRT for menopausal women.

Long-term outcome of Stereotactic Body Radiation Therapy for patient with unresectable liver metastases from colorectal cancer.

PURPOSE: To investigate clinical outcome and predicting factors of local failures in patients with colorectal cancer treated for unresectable liver metastases with stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: We restrospectively reviewed the medical records of 67 patients treated with the Cyberknife SBRT system for 99 hepatic metastases between January 2007 and December 2015 in our center. In total, 37.5 to 54.0Gy in 3 to 5 fractions were prescribed to the 80% isodose line. Local control (LC), intrahepatic progression incidence, Progression-Free Survival (PFS), Overall Survival (OS) and toxicity were evaluated. RESULTS: The median follow-up was 47 months (IQR, 28-59 months). The median OS was 53 months, the 2-year OS and PFS rates were 81.4% and 54.0%. The 1- and 2-year LC rates were 86.6% and 72.4%. In the multivariate analysis, the degree of differentiation was the only prognostic factor for LC (HR 0.31, 95% CI, 0.10-0.98, P=0.046). Margin expansion>5mm was not associated with a better LC (HR 0.72, 95% CI, 0.38-1.37, P=0.317). Performans Status≥2 (HR 3.27, 95% CI, 1.07-9.98, P=0.038), chemotherapy for metastases before SBRT (HR 0.36, 95% CI, 0.18-0.75, P=0.006) and regional lymph node at diagnosis (HR 2.19, 95% CI, 1.09-4.43, P=0.029) were independent prognostic factors for OS. We report 2 cases of grade≥3 toxicity (3.0%) - one grade 3 acute nausea and one grade 3 late gastric ulcer. CONCLUSION: Stereotactic body radiation therapy is an effective and well-tolerated treatment that allow high LC for liver metastases from colorectal cancer during the first two years. A prescription dose of 45Gy in 3 fractions to the 80% isodose line with a risk adapted schedule to respect Organ At Risk constraints allows a low rate of toxicity.

Weight loss with exercise improves muscle architecture and progenitor cell populations compared with weight loss alone in mice with preneoplastic colorectal lesions.

Weight loss and exercise reduce colorectal cancer (CRC) risk in persons with obesity. Whether weight loss and exercise effect myofiber characteristics and muscle stem/progenitor cell populations in mice with preneoplastic colorectal lesions, a model of CRC risk, is unknown. To address this gap, male C57Bl/6J mice were fed a high-fat diet (HFD) to induce obesity or a control (CON) diet prior to azoxymethane injection to induce preneoplastic colorectal lesions. The HFD group was then randomized to weight loss conditions that included (1) switching to the CON diet only (HFD-SED) or switching to the CON diet with treadmill exercise training (HFD-EX). Average myofiber cross-sectional area was not different between groups. There were more smaller-sized fibres in HFD-EX (p < 0.05 vs. CON), and more fibrosis in HFD-SED (p < 0.05 vs. HFD-EX and CON). There was a trend for more committed (Pax7+MyoD+) myoblasts (p = 0.059) and more fibro-adipogenic progenitors in HFD-EX (p < 0.05 vs. CON). Additionally, the canonical pro-inflammatory marker p-NF-κB was markedly reduced in the interstitium of HFD-EX (p < 0.05 vs. CON and HFD-SED). Our findings suggest that in mice with preneoplastic colorectal lesions, HFD followed by weight loss with exercise reduces muscle fibrosis and results in a higher content of muscle stem/progenitor cells. Novelty: Exercise improves muscle architecture in mice with preneoplastic colorectal lesion Exercise increases fibro/adipogenic progenitors and reduces inflammatory signaling in mice with preneoplastic colorectal lesions.