RAS/RAF/MAPK Pathway Mutations as Predictive Biomarkers in Middle Eastern Colorectal Cancer: A Systematic Review.

Background: This review article aims to investigate the prevalence and spectrum of rat sarcoma (RAS) and V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) mutations, and their connection with geographical location, clinicopathological features, and other relevant factors in colorectal cancer (CRC) patients in the Middle East. Methods: A systematic literature review, employing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework, was conducted to investigate the association between the frequency of relevant mutations and the descriptive clinicopathological characteristics of CRC patients. Multiple electronic databases, including PubMed, Science Direct, Web of Science, Scopus, and Google Scholar, were searched to analyze the relevant literature. Results: A total of 19 eligible studies comprising 2960 patients with CRC were included in this review. A comprehensive analysis of the collected literature data as well as descriptive and methodological insights is provided. Men were predominant in reviewed studies for the region, accounting for 58.6%. Overall, RAS mutation prevalence was 38.1%. Kirsten RAS Viral Oncogene Homolog (KRAS) mutations were the most common, accounting for 37.1% of cases and distributed among different exons, with the G12D mutation being the most frequent in exon 2 (23.2%) followed by G12V (13.7%), G13D (10.1%), G12C (5.1%), G12A (5.04%), and G12S (3.6%). Neuroblastoma RAS Viral Oncogene Homolog (NRAS) mutations were identified in 3.3% of tumor samples, with the most common mutation site located in exons 2, 3, and 4, and codon 61 being the most common location for the region. The total mutation frequency in the BRAF gene was 2.6%, with the V600E mutation being the most common. Conclusion: The distribution patterns of RAS and BRAF mutations among CRC patients exhibit notable variations across diverse ethnic groups. Our study sheds light on this phenomenon by demonstrating a higher prevalence of KRAS mutations in CRC patients from the Middle East, as compared with those from other regions. The identification of these mutations and geographical differences is important for personalized treatment planning and could potentially aid in the development of novel targeted therapies. The distinct distribution patterns of RAS and BRAF mutations among CRC patients across different ethnic groups, as well as the regional variability in mutation prevalence, highlight the need for further research in this area.

Prevalence and patterns of mutations in RAS/RAF/MEK/ERK/MAPK signaling pathway in colorectal cancer in North Africa.

BACKGROUND: Our review discuss (i) the findings from analyzed data that have examined KRAS, NRAS and BRAF mutations in patients with colorectal cancer (CRC) in North Africa and to compare its prevalence with that shown in other populations and (ii) the possible role of dietary and lifestyle factors with CRC risk.  METHODS: Using electronic databases, a systematic literature search was performed for the KRAS, NRAS, and BRAF mutations in CRC patients from Morocco, Tunisia, Algeria and Lybia.  RESULTS: Seventeen studies were identified through electronic searches with six studies conducted in Morocco, eight in Tunisia, two in Algeria, and one in Libya. A total of 1843 CRC patients were included 576 (31.3%) in Morocco, 641 (34.8%) in Tunisia, 592 (32.1%) in Algeria, and 34 (1.8%) in Libya. Overall, the average age of patients was 52.7 years old. Patients were predominantly male (56.6%). The mutation rates of KRAS, NRAS and BRAF were 46.4%, 3.2% and 3.5% of all patients, respectively. A broad range of reported KRAS mutation frequencies have been reported in North Africa countries. The KRAS mutation frequency was 23.9% to 51% in Morocco, 23.1% to 68.2% in Tunisia, 31.4% to 50% in Algeria, and 38.2% in Libya. The G12D was the most frequently identified KRAS exon 2 mutations (31.6%), followed by G12V (25.4%), G13D (15.5%), G12C (10.2%), G12A (6.9%), and G12S (6.4%). G12R, G13V, G13C and G13R are less than 5%. There are important differences among North Africa countries. In Morocco and Tunisia, there is a higher prevalence of G12D mutation in KRAS exon 2 (≈50%). The most frequently mutation type in KRAS exon 3 was Q61L (40%). A59T and Q61E mutations were also found. In KRAS exon 4, the most common mutation was A146T (50%), followed by K117N (33.3%), A146P (8.3%) and A146V (8.3%). CONCLUSION: KRAS mutated CRC patients in North Africa have been identified with incidence closer to the European figures. Beside established anti-CRC treatment, better understanding of the causality of CRC can be established by combining epidemiology and genetic/epigenetic on CRC etiology. This approach may be able to significantly reduce the burden of CRC in North Africa.

Clinical Significance of Somatic Mutations in RAS/RAF/MAPK Signaling Pathway in Moroccan and North African Colorectal Cancer Patients.

BACKGROUND: Mutations in RAS (KRAS, NRAS) and BRAF genes are the main biomarker predicting response to anti-EGFR monoclonal antibodies in targeted therapy in colorectal cancer (CRC). OBJECTIVE: Our study aims to evaluate the frequencies of KRAS, NRAS and BRAF mutations and their possible associations with clinico-pathological features in CRC patients from Morocco. METHODS: DNA was extracted from 80 FFPE samples using the QIAamp DNA FFPE-kit. RAS and BRAF mutations were assessed by pyrosequencing assays using Qiagen, KRAS Pyro®kit 24.V1, Ras-Extension Pyro®kit 24.V1 and BRAF Pyro®Kit 24.V1, respectively, and carried out in the PyroMark-Q24. RESULTS: RAS mutations were identified in 57.5% (56.2% in KRAS, 8.8% in NRAS). In KRAS gene, exon 2 mutations accounted for 93.3% (68.9% in codon 12, 24.4% in codon 13). Within codon 12, G12D was the most prevalent mutation (37.7%), followed by G12C (13.4%), G12S (8.9%) and G12V (6.6%). Within codon 13, the most frequently observed mutation was G13D (22.3%). The mutation rates of exon 3 and 4 were 15.6% and 13.3%, respectively. In exon 3 codon 61, 2.3% patients were detected with two concurrent mutations (Q61R, Q61H), and 4.4% with three concurrent mutations (Q61R, Q61H, Q61L). In NRAS gene, the mutation rates of exon 2, 3 and 4 were 57.1%, 28.6%, and 14.3%, respectively. G13A and Q61H were the most common mutations, accounting for 42.9% and 28.5%, respectively. There were 13% patients with concurrent KRAS/NRAS mutation and 4.3% wt KRAS with NRAS mutations. No mutations were identified in BRAF gene. In both sexes, KRAS codon 12 mutations were associated with higher stage III/IV tumors. Moreover, Patients whose tumor is in the proximal colon (56.3%) are more likely to harbor KRAS mutations than those tumor located in rectum (25%). CONCLUSION: RAS mutations could be useful in future target anti-EGFR therapy and molecular CRC screening strategy in Morocco.

Synchronous Primary Renal Cell Carcinoma and Pancreatic Ductal Adenocarcinoma: Case Report and Literature Review.

Synchronous primary cancers involving the pancreas and kidney are extremely rare and poorly documented. We report the first case of this association treated with chemotherapy and tyrosine kinase inhibitor. A 70-year-old woman presented with a 2-month history of epigastric pain with weight loss of 12 kg. Two weeks previously, she had presented with jaundice and pelvic pain. A computed tomography (CT) scan of the body revealed the presence of an irregular mass in the body of the pancreas, encasing the celiac trunk, with dilatation of the biliary tract. CT also revealed a heterogeneously right renal mass with bone metastasis in the left acetabular cup and the left iliac wing. A biliary metallic prosthesis was performed with a pancreatic mass biopsy. Histology revealed a moderately differentiated pancreatic ductal adenocarcinoma. Another biopsy was performed in the right iliac wing. Pathological examination with immunohistochemistry confirmed the diagnosis of bone metastasis from clear cell renal cell carcinoma. The patient was treated with a combination of gemcitabine, sunitinib, and denosumab. She had a stabilization disease and a prolonged progression-free survival of 9 months. Side effects were manageable and included grade 2 fatigue and grade 2 hypertension. The patient died at 13 months from diagnosis after disease progression. This report suggests that the appropriate treatment for this association in metastatic or unresectable disease is chemotherapy for pancreatic cancer and tyrosine kinase inhibitor for kidney cancer. We also review the appropriate literature concerning that association.

Triple malignancy in a single patient including a squamous cell carcinoma of the cervix, a colloid adenocarcinoma of the colon and a lung adenocarcinoma: A case report and literature review.

INTRODUCTION: The association of two cancers in the same patient is unusual but has been widely reported in the literature, while triple malignancy in the same patient is exceptional. Indeed, only very rare cases have been described. CASE PRESENTATION: A 70-year-old woman treated in our institute in 2006 for a tumor of the cervix. She underwent extrafascial hysterectomy. Pathology revealed a well differentiated squamous cell carcinoma of the cervix (pT1N0M0). No external pelvic radiation or brachytherapy were done. The patient remained in good control until 2013 when she presented a tumor of the ascending colon. A right hemicolectomy was made. Pathology confirmed a colloid adenocarcinoma (pT3N0M0). No adjuvant chemotherapy was given. Three years later, a Computed tomography scan of the chest revealed a nodule of the lower lobe of the left lung. Biopsy was made. Histology with immunochemistry revealed the diagnosis of lung adenocarcinoma. Positron emission tomography scan showed abnormal fluorodeoxyglucose uptake in the lung nodule with no anomaly in mediastinal nodes and no metastasis. A left lower lobectomy was performed with lymph node dissection. Pathology confirmed the diagnosis of 2.5 cm lung adenocarcinoma without node invasion (pT1N0M0). No chemotherapy was given. After 14 months, the patient remained in good control. CONCLUSIONS: Triple malignancy in a single patient is exceptional. The management depend on stages. Surgery is the standard of care in localized cancers.

Toxicities of docetaxel: original drug versus generics-a comparative study about 81 cases.

INTRODUCTION: Docetaxel is a chemotherapy drug widely prescribed in oncology that recognizes a variety of manufactured generics whose toxicity is increasingly reported. The aim of this study was to compare the toxicities between the original and a generics docetaxel in a Moroccan center. METHODS: In a cross sectional study, we enrolled patients treated with docetaxel from the oncology department of the military hospital of Rabat over a period of 2 years (2013-2014). We compared the prevalence of hypersensitivity reactions, febrile neutropenia, peripheral neuropathy, gastrointestinal, cutaneous, and hematologic toxicities, between four different presentations of docetaxel including the original drug. Only grade II or worse adverse events related to chemotherapy were considered. Treatments discontinuations due to toxicity were also compared. Unusual skin toxicities were included. RESULTS: 81 patients were eligible for analysis [43/generics arm vs. 38/original drug arm. Hematological toxicity was significantly more frequent in the generic arm than in the original drug (32.6 vs. 13.2 %; p = 0.04)]. Also, a signifying higher rate of treatment discontinuation was observed in the generic arm (39.5 vs. 7.9 %, p = 0.001). The use of specific generic increase numerically the skin toxicities (17.6 vs. 0 %, p = 0.026). CONCLUSION: Our data suggest that generics of docetaxel are associated with an increase of hematological and cutaneous toxicities, an increase of treatment discontinuation rate and emphasize the need of a regulation of generics' manufacture.

Tolerability profile of bevacizumab in metastatic colorectal cancer: about a Medical Department experience.

Colorectal cancer is one of the most common cancers worldwide, and associated with high mortality rates in our country. The prognosis of patients diagnosed with metastatic colorectal cancer (mCRC) has improved markedly over the last 12 years, increasing from 5 months with best supportive care to almost 2 years with combination chemotherapy plus bevacizumab. Bevacizumab is well suited for use in combination with first or second line chemotherapy in the treatment of mCRC because its side effects are predictable and appear not to add to the incidence or severity of the side effects of chemotherapy. The aim of our small study is to explore the tolerability profile of bevacizumab used in daily clinical practice in patients with metastatic colorectal cancer (mCRC) in our department.

Three weekly irinotecan and bolus 5-fluorouracil combination in the first line treatment of advanced gastric cancer - a single institution experience

Background: The goal of this study is to determine the efficacy and toxicity of a non-platinum based chemotherapy combination using irinotecan associated to bolus 5-FU as first line treatment in advanced gastric cancer. Materiel and methods: Retrospective analysis of a population of patients treated for metastatic and locally advanced gastric cancer with irinotecan and 5-FU as upfront chemotherapy. Results: Thirteen patients were enrolled. The median age was 56 years. Seven patients were males and six were of females. Ten patients had a metastatic disease and three patients had a locally advanced disease. Patients received a total number of 43 cycles of chemotherapy. Overall response rate was 38,4%, median time to progression (TTP) was 3 months, and median overall survival was 4 months. Three patients (23,1%) presented grade 3 /4 neutropenia complicated with an infectious episode with fever in two cases, three patients (23,1%) required blood transfusion for a grade 4 anemia, and one patient (7,6%) was hospitalized for a severe episode of diarrhea. Conclusion: Three weekly irinotecan and bolus 5-FU is an interesting combination as first line treatment of advanced gastric cancer; designed clinical trials are needed to confirm the activity of this combination

Cardiac metastases of renal cell carcinoma revealed by syncope: diagnosis and treatment.

INTRODUCTION: Cardiac metastases from renal cell carcinoma are very rare. In this report, we describe a case of ventricular metastases in the absence of vena cava or right atrial involvement. CASE REPORT: We report the case of a 60-year-old man who had a past history of heavy tobacco intake and well-controlled arterial hypertension. He experienced sudden-onset palpitations, lost consciousness and, as a result, was involved in an accident on the public highway. Cardiac arrhythmia was suspected and, therefore, transthoracic echocardiography was suggested, which revealed a large right ventricular mass. Chest and abdominal computed tomography demonstrated a mass in the right ventricle, but without contiguous vena cava involvement, and a right renal mass related to the probable neoplasm. An ultrasound-guided renal biopsy showed a clear-cell renal cell carcinoma. A bone scan revealed a metastatic bone disease. The patient was started on sunitinib treatment, which was well tolerated. However, approximately 8 months later, reevaluation showed pulmonary metastases. The patient was subsequently started on treatment with everolimus, which, however, was poorly tolerated. Two months later, the patient died due to terminal respiratory insufficiency. DISCUSSION: Based on the literature and our observations in this case, targeted antiangiogenic therapy should be considered as a viable therapeutic alternative to metastasectomy for patients with inoperable cardiac metastatic disease as long as there is no baseline systolic or diastolic dysfunction. The case also emphasizes the importance of a thorough history review and physical examination in the workup of patients with syncope.

Flagellate erythema secondary to bleomycin: a new case report and review of the literature.

Bleomycin is an antibiotic with antineoplastic properties. It is used in the treatment of different tumors in oncology. The mucocutaneous side effects of this drug include ulcers, scaly erythematous and bullous lesions, sclerosis, stomatitis, and pigmentary alterations. Flagellate erythema is a characteristic hyperpigmentation of bleomycin. We report a case of flagellate erythema following the administration of bleomycin in a 34-year-old woman with ovarian teratoma. She developed linear lesions two weeks after the first injection of bleomycin. Flagellate erythema is a specific reaction to bleomycin therapy, which occurs in susceptible individuals independently of dose, route of administration, and type of malignant disease treated.

Primary non-Hodgkin's lymphoma of the bladder: case report and literature review.

Primary non-Hodgkin's lymphoma (NHL) of the bladder is a very rare entity. The clinical, radiological and endoscopic signs are not specifics. The diagnosis is exclusively histological. Chemotherapy, radiotherapy and surgery are the different therapeutic options used either alone or in combination. We report a 57 years old patient treated with chemotherapy (6 cycles of R-CHOP) for primary NHL of the bladder with a complete response while discussing the different specificities of this disease.

Bevacizumab 5 or 7.5 mg/kg in metastatic colorectal cancer can be infused safely over 10 minutes.

BACKGROUND: Bevacizumab is a humanized monoclonal antibody that blocks vascular endothelial factor. It demonstrated an efficacy in many cancer types. The standard recommendation of administration is the 90-, 60-, and 30-min infusion sequence for all doses. We evaluated in this study the possibility of reducing infusion time to 10 min for bevacizumab given at 5 or 7.5 mg/kg in metastatic colorectal cancer (MCRC). PATIENTS AND METHODS: All patients who received bevacizumab for MCRC were analyzed. Patients were divided into two groups: Group A (bevacizumab was given in the 90-, 60-, and 30-min infusion sequence) and group B (bevacizumab was given over 10 min). Patients' medical records were used to identify any hypersensitivity reactions (HSR) possibly related to bevacizumab. RESULTS: There were 38 patients in group A and 43 in group B. In group A, 459 doses of bevacizumab were given (286 doses at 5 mg/kg and 173 doses at 7.5 mg/kg). No HSR occurred in this group. In group B, 527 doses of bevacizumab were given (335 doses at 5 mg/kg and 192 doses at 7.5 mg/kg). Only two events of HSR grade 2 were reported in the 7.5 mg/kg infusions. Both of them were easily resolved with symptomatic treatment. CONCLUSIONS: Bevacizumab 5 or 7.5 mg/kg in MCRC can be infused safely over 10 min.

Triple malignancy in a single patient including a cervical carcinoma, a basal cell carcinoma of the skin and a neuroendocrine carcinoma from an unknown primary site: A case report and review of the literature.

INTRODUCTION: The occurrence of multiple primary cancers is rare. Only a few cases and patient reviews of an association of triple malignancy have been reported. CASE PRESENTATION: We report here a case of a 78-year-old Moroccan woman presenting initially with a synchronous double malignancy, the first in her cervix and the second in her skin. Our patient was treated with radiation therapy for both tumors and remained in good control for 17 years, when she developed a metastatic disease from a neuroendocrine carcinoma of an unknown primary site. CONCLUSIONS: Although the association of multiple primary cancers can be considered a rare occurrence, improving survival in cancer patients has made this situation more frequent.

Surface plasmons reveal spin crossover in nanometric layers.

Nano-objects and thin films displaying molecular spin-crossover phenomena have recently attracted much attention. However, the investigation of spin crossover at reduced sizes is still a big challenge. Here we demonstrate that surface plasmon polariton waves propagating along the interface between a metal and a dielectric layer can be used to detect the spin-state changes in the latter with high sensitivity, even at the nanometer scale.

A Synchronous undifferentiated nasopharyngeal carcinoma and infiltrating ductal carcinoma of the breast successfully treated with induction chemotherapy followed by local control of both tumours: a case report.

BACKGROUND: Multiple primary cancers have a low incidence particularly when cancers are synchronous. Few cases of synchronous head and neck cancer and breast carcinoma are reported in the literature. CASE PRESENTATION: We report here an exceptional case of a 47 years old Moroccan woman presenting two synchronous cancers, the first in the nasopharynx and the second in the breast. The patient was treated successfully with a combined strategy associating chemotherapy, radiation therapy, and surgery. She remains disease free after 27 months of follow up. CONCLUSIONS: Treatment strategy in the case of multiple primary cancers remains controversial because of the variety of presentations; initial aggressive treatment reports good results.

Electric-field-induced charge-transfer phase transition: a promising approach toward electrically switchable devices.

Much research has been directed toward the development of electrically switchable optical materials for applications in memory and display devices. Here we present experimental evidence for an electric-field-induced charge-transfer phase transition in two cyanometalate complexes: Rb(0.8)Mn[Fe(CN)(6)](0.93).1.62H(2)O and Co(3)[W(CN)(8)](2)(pyrimidine)(4).6H(2)O, involving changes in their magnetic, optical, and electronic properties as well. Application of an electric field above a threshold value and within the thermal hysteresis region leads to a transition from the high- to the low-temperature phase in these compounds. A model is proposed to explain the main observations on the basis of a para-ferroelectric transition. Our observations suggest that this new concept of electrical switching, based on materials exhibiting charge-transfer phase transitions with large thermal hysteresis loops, may open up doors for novel electro-optical devices.