Prognostic Impact of Tumor Budding on Moroccan Colon Cancer Patients.

BACKGROUND: Tumor budding is now emerging as one of the robust and promising histological factors that play an important role in colon cancer. In this study, we aimed to investigate the association between tumor budding and tumor clinicopathological factors, tumor molecular signature, and patient survival for the first time in a Moroccan population. METHODS: We collected data of 100 patients operated from colon adenocarcinoma. Tumor budding was assessed on HES slides, according to the International Tumor Budding Consensus Conference 2016 recommendations. The expression of MMR proteins was performed by immunohistochemistry. KRAS and NRAS mutations testing was performed by Sanger sequencing and pyrosequencing. RESULTS: High tumor budding grade (BUD 3) was found to be significantly associated with adverse clinicopathological features including older age (P=0.03), presence of perineural invasion (P=0.02), presence of vascular invasion (P=0.05), distant metastases (P < 0.001), advanced TNM stage (P=0.001), the occurrence of relapse (P=0.04), and the high number of deceased cases (P=0.02). Interestingly, we found that tumors with high-grade tumor budding were more likely to be microsatellite stable (MSS) (P=0.005) and harbor more KRAS mutations (P=0.02). Tumors with high-grade tumor budding were strongly associated with KRAS G12D mutation (P=0.007). In all stages, high tumor budding was correlated with poorer overall survival (P=0.04) and decreased relapse-free survival with a difference close to significance ((P=0.09). We concluded that high tumor budding was strongly associated with unfavorable clinicopathological features and special molecular biomarkers and effectively affects the overall survival of CC patients. CONCLUSIONS: Based on these findings and the ITBCC group recommendations, tumor budding should be taken into account along with other clinicopathologic factors in the risk assessment of colorectal cancer.

Mutation status and prognostic value of KRAS and NRAS mutations in Moroccan colon cancer patients: A first report.

This study aimed to estimate the incidence of KRAS, NRAS, and BRAF mutations in the Moroccan population, and investigate the associations of KRAS and NRAS gene mutations with clinicopathological characteristics and their prognosis value. To achieve these objectives, we reviewed medical and pathology reports for 210 patients. RAS testing was investigated by Sanger sequencing and Pyrosequencing technology. BRAF (exon 15) status was analyzed by the Sanger method. The expression of MMR proteins was evaluated by Immunohistochemistry. KRAS and NRAS mutations were found in 36.7% and 2.9% of 210 patients, respectively. KRAS exon 2 mutations were identified in 76.5% of the cases. RAS-mutated colon cancers were significantly associated with female gender, presence of vascular invasion, classical adenocarcinoma, moderately differentiated tumors, advanced TNM stage III-IV, left colon site, higher incidence of distant metastases at the time of diagnostic, microsatellite stable phenotype, lower number of total lymph nodes, and higher means of positive lymph nodes and lymph node ratio. KRAS exon 2-mutated colon cancers, compared with KRAS wild-type colon cancers were associated with the same clinicopathological features of RAS-mutated colon cancers. NRAS-mutated patients were associated with lower total lymph node rate and the presence of positive lymph node. Rare RAS-mutated tumors, compared with wild-type tumors were more frequently moderately differentiated and associated with lower lymph node rate. We found that KRAS codon 13-mutated, tumors compared to codon 12-mutated tumors were significantly correlated with a higher death cases number, a lower rate of positive lymph, lower follow-up time, and poor overall survival. Our findings show that KRAS and NRAS mutations have distinct clinicopathological features. KRAS codon 13-mutated status was the worst predictor of prognosis at all stages in our population.

The Effect of Lymph Nodes' Histologic Response on Survival Outcomes in Moroccan Patients with Rectal Cancer.

Prognosis for patients with locally advanced rectal cancer remains controversial. The purpose of this study was to elucidate possible association between therapeutic effect on lymph nodes (LNs) and patient prognosis. Overall, 149 patients with rectal cancer received preoperative radiotherapy in concomitance with chemotherapy or exclusive radiotherapy before rectal excision. Microscopic examination of formalin-fixed lymph nodes was assessed for therapeutic effect. The establishment of groups combined reaction tissue types of fibrosis, colloid, and necrosis after neoadjuvant treatment was assigned. The average age was 56.38 years, ranged between 22 and 88 years, 53% were female, and 47% were men, with a sex ratio of 1 : 12. In the present study, we noticed that after a median follow-up time of 40.67 months (0-83; SD: 21.1), overall survival was statistically significant depending on age groups. Kaplan-Meier analysis showed significant differences in the rate of patients with an age under 65 years (70.64%) versus those with an age over 85 years (36.5%) (p < 0.001). Also, the OS was statistically significant depending on therapeutic effect groups composed of 0TE (No Therapeutic effect), C+ (presence of only colloidal effect), F+ (presence of only fibrosis tissue), and ME+ (mixture of 2 or 3 types of therapeutic effect) group. Indeed, we observed a significantly higher OS rate in the ME + group (86%) compared with the OS rate of LNs group with no therapeutic effect (57%) (p=0.028). Additionally, there was a significant association between the presence of fibrosis on LNs and an extended delay of more than 8 weeks to neoadjuvant treatment completion and surgery. Our study indicates that the best patient prognosis could be predicted based on tumor presenting a best pathologic effect on lymph nodes, and that delaying surgery for more than 8 weeks to neoadjuvant treatment completion improves therapeutic response on LNs.

Analysis of Molecular Pretreated Tumor Profiles as Predictive Biomarkers of Therapeutic Response and Survival Outcomes after Neoadjuvant Therapy for Rectal Cancer in Moroccan Population.

Pathologic features depending on tumor response to preoperative chemoradiotherapy are important to determine the outcomes in patients with rectal cancer. Evaluating the potential predictive roles of biomarker expression and their prognostic impact is a promising challenge. We reported here the immunohistochemical staining of a panel marker of mismatch repair protein (MMR), Ki67, HER-2, and p53. Additionally, identification of somatic mutations of KRAS, NRAS, and BRAF genes were performed by direct sequencing and pyrosequencing in pretreated biopsy tissues from 57 patients diagnosed for rectal cancer. Clinical features and pathological criteria for postneoadjuvant treatment surgical resection specimen's data were collected. Immunohistochemical expression and mutational status were correlated with therapeutic response, overall survival, and disease progression. The mean age of patients was 56 years. Seven (12.3%) out of 57 patients had a complete therapeutic response. Our analysis showed that when using complete therapeutic response (Dworak 4) and incomplete therapeutic response (Dworak 3, 2, and 1) as grouping factor, high p53 expression at the pretreatment biopsy was significantly associated to an incomplete response (p = 0.002). For 20 and 2 out of 57, KRAS and NRAS mutations were detected, respectively. The majority of these mutations affected codon 12. KRAS mutations detected at codon 146 (A146T, A146V) was associated with the appearance of recurrence and distant metastasis (p = 0.019). A high expression of HER-2 corresponding to score 3+ was observed in 3 pretreatment biopsy specimens. This class was significantly associated with a short relapse-free survival (p = 0.002). Furthermore, the high expression of Ki67 was moderately correlated with an older age (p = 0.016, r = 0.319). In addition, this shows that high p53 expression in the pretreatment biopsy was associated with an incomplete response in surgical resection specimens after neoadjuvant treatment, and a HER-2 score 3+ can be a predictive factor of distant metastasis and local recurrence. Larger, prospective, and more studies are needed.

Consumption of meat, traditional and modern processed meat and colorectal cancer risk among the Moroccan population: A large-scale case-control study.

The current study aimed to investigate the relationship between red and white meat subtypes, processed meat (divided into traditional "Khlii, Kaddid" and industrially processed meat) and colorectal cancer (CRC) risk, considering CRC subsites, in Moroccan adults. A case-control study was conducted including 2,906 matched case-control pairs recruited from the five largest university hospitals in Morocco. Dietary data were collected through a validated Food Frequency Questionnaire (FFQ). Multivariable odds ratios (OR) and 95% confidence intervals (CI), for the association of CRC risk with meat consumption (high vs. low intake), were estimated using conditional logistic regression models, adjusted for relevant confounding variables. Overall, consumption of red meat was positively associated with colon cancer and CRC risk (OR = 1.23, 95% CI = 1.05-1.44; OR = 1.14, 95% CI = 1.02-1.27), respectively. In contrast, no significant association was observed between the consumption of red meat and rectal cancer risk (OR = 1.05, 95% = 0.90-1.23). Interestingly, while processed meat from industrial processes was positively associated with colon cancer, rectal cancer and CRC (OR = 1.61, 95% CI = 1.27-2.04; OR = 1.73, 95% CI = 1.34-2.23; OR = 1.67, 95% CI = 1.41-1.98), processed meat prepared using traditional methods was inversely associated with colon cancer and CRC risk (OR = 0.74, 95% CI = 0.57-0.98; OR = 0.77, 95% CI = 0.64-0.93), respectively. Furthermore, positive associations were observed between poultry intake and colon cancer risk among men (OR = 1.27, 95% CI = 1.01-1.59). Our study showed similar associations between the consumption of red meat and CRC risk in Morocco as in developed countries, while inverse associations were found for traditionally processed meat products. This is the first study to investigate the differential effects of traditional vs. westernized processed meat products in a developing country. Other studies are needed to confirm these findings and to understand the physiological pathways underlying these associations.

Prevalence of Helicobacter pylori and its recurrence after successful eradication in a developing nation (Morocco).

INTRODUCTION: In developed countries, reinfection after successful eradication of Helicobacter pylori appears unusual. High prevalences of H. pylori in developing countries may result in high reinfection rates. In Morocco, published studies regarding the prevalence of H. pylori are limited, and to our knowledge, there are no data regarding the reinfection rate of H. pylori after successful treatment. AIM: The aim of this study was to determine the prevalence of H. pylori in our area, and the reinfection rate at 6 months and 1 year of follow-up after successful eradication. METHODS: Consecutive patients with investigated ulcer or non-ulcer dyspepsia were prospectively enrolled in the Hassan II University Hospital of Fez. Patients with H. pylori infection were treated with a 1-week triple therapy or 10 day sequential therapy. Those tested urea breath test negative after 3 months of treatment were followed prospectively with repeated urea breath test at 6 months and 1 year. H. pylori status at endoscopic examination was determined by rapid urease test, histology, and culture. RESULTS: Four hundred and twenty-nine patients were enrolled in the study, among them 324 patients (75.5%) presented with H. pylori infection. Two hundred and fifty-six (83.3%) patients had successfully eradicated H. pylori following treatment, among them, two patients (0.8%) were reinfected with H. pylori over 12 months. The rate of reinfection was 0.42% in the first 6 months and of 0.45% in the first year of the study. CONCLUSION: The results of the present study demonstrate that firstly, prevalence of H. pylori is high (75.5%) in our area, secondly as in developed countries, there is a low (0.8%) but continuous risk of H. pylori infection in adulthood. A different approach for follow-up after H. pylori eradication is probably needed in patients of developing countries, since reinfection prevalence is different between countries.

Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: result of the HPFEZ randomised study.

OBJECTIVE: The aim of this study was to assess and compare the efficacy and safety of sequential treatment with standard triple therapies in a located population in Morocco. METHODS: Consecutive H. pylori-positive patients with endoscopy-proven ulcer or non ulcer dyspepsia were prospectively randomized in the trial into one of three groups: AM and AC group were administered a tri-therapy for 7 days including PPI + amoxicillin + metronidazole (AM group)/clarithromycin (AC group) and SQ group was administered a sequential regimen consisting of PPI + amoxicillin for 5 days followed by PPI + clarithromycin + metronidazole for the remaining 5 days. Eradication was confirmed by 13C-urea breath test 3 months after the end of the treatment. RESULTS: Groups AM, AC and SQ included respectively 104, 115 and 104 patients. They were comparable in terms of age, sex, clinical and endoscopic presentation. The rate of H. pylori eradication with sequential therapy was found at 94.2% (n=98) in ITT and 96% (n=98) in PP. It was higher than those found in the AM group: 70% (n=73) in ITT and 70.8% (n=73) in PP and the AC group: 78.2% (n=90) in ITT and 79.6% (n=90) in PP (0.001). The prevalence of side effects following the sequential treatment was 9.6% (n=10) versus 22% (n=22) and 27.8% (n=32) in the AM and AC groups, respectively, (P=0.006). CONCLUSIONS: Sequential treatment was better tolerated and achieved a significantly higher eradication rate of H. pylori compared with standard triple therapies in this population.

Mutation analysis of BRAF exon 15 and KRAS codons 12 and 13 in Moroccan patients with colorectal cancer.

BACKGROUND: The RAS/RAF/MEK/MAP kinase cascade transduces signals from the cell surface to the nucleus in order to control cellular responses including proliferation, differentiation and survival. We investigated the occurrence of BRAF exon 15 and KRAS codon 12 and 13 mutations in Moroccan patients with colorectal cancer. METHODS: Sixty-two samples from patients with sporadic colorectal adenocarcinomas were studied for BRAF exon 15 and KRAS codon 12 and 13 mutations. DNA from paraffin-embedded tissue specimens was analyzed by a combination of polymerase chain reaction-high resolution melting and direct sequencing. RESULTS: Of the analyzed specimens, 29% exhibited KRAS codon 12 or 13 mutations and only 1.6% carried a BRAF codon 600 mutation. KRAS mutations were more often observed in women (35.5%) than in men (22.6%). Patients in the age range between 41 and 60 years were more likely to be carriers of this mutation. No KRAS mutations were detected in patients aged >60 years. CONCLUSION: Despite the limited study sample, our data suggest that KRAS mutations arise more frequently than BRAF mutations in Moroccan patients with colorectal carcinomas. The KRAS mutation status must be assessed in a large cohort of Moroccan patients to confirm these findings and to determine whether this mutation in combination with extrinsic, environmental or microenvironmental factors might be involved in the high frequency of colorectal cancer in middle-aged Moroccans.

Peritoneal tuberculosis in the Fes University Hospital (Morocco). Report of 123 cases.

AIMS: Peritoneal tuberculosis is an important public health issue in Morocco. Our aim was to describe the clinical, biological, and therapeutic features of peritoneal tuberculosis treated in a University Hospital in Morocco. PATIENTS AND METHODS: We retrospectively included 123 patients with peritoneal tuberculosis diagnosed at the gastroenterology unit of the Fes University Hospital between January 2001 and August 2003. RESULTS: The mean age was 28 years with a clear female predominance (sex ratio 2.61). Ascites associated with fever were the most frequent signs found in 80.5% of patients. The ascitic fluid was exsudative in 90% of cases and lymphocytic in 88%. The diagnosis was based on laparoscopy or laparotomy with peritoneal biopsy demonstrating caseating granulomatous lesions in 92.4% of patients. Patients were given antituberculous therapy for 6 months, and the outcome was favourable in 90%. CONCLUSION: Peritoneal tuberculosis is very frequent in Morocco, where the diagnosis is based exclusively on peritoneal biopsies obtained during laparoscopy. With an adapted treatment, the course of the disease is favourable in most cases.