Insights on the Biomarker Potential of Exosomal Non-Coding RNAs in Colorectal Cancer: An In Silico Characterization of Related Exosomal lncRNA/circRNA-miRNA-Target Axis.

Colorectal cancer (CRC) is one of the most common cancer types, ranking third after lung and breast cancers. As such, it demands special attention for better characterization, which may eventually result in the development of early detection strategies and preventive measures. Currently, components of bodily fluids, which may reflect various disease states, are being increasingly researched for their biomarker potential. One of these components is the circulating extracellular vesicles, namely, exosomes, which are demonstrated to carry various cargo. Of importance, the non-coding RNA cargo of circulating exosomes, especially long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and micro RNAs (miRNAs), may potentially serve as significant diagnostic and prognostic/predictive biomarkers. In this review, we present existing evidence on the diagnostic and prognostic/predictive biomarker value of exosomal non-coding RNAs in CRC. In addition, taking advantage of the miRNA sponging functionality of lncRNAs and circRNAs, we demonstrate an experimentally validated CRC exosomal non-coding RNA-regulated target gene axis benefiting from published miRNA sponging studies in CRC. Hence, we present a set of target genes and pathways downstream of the lncRNA/circRNA-miRNA-target axis along with associated significant Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, which may collectively serve to better characterize CRC and shed light on the significance of exosomal non-coding RNAs in CRC diagnosis and prognosis/prediction.

Frequency and mutational spectrum of PIK3CA gene mutations in breast cancer patients: Largest and first report from Lebanon.

The PIK3CA pathway is one of the most frequently altered pathways in human cancers, especially in breast cancer with approximately 40% of HR+/HER2- advanced breast cancer cases exhibiting mutations in the PIK3CA gene. While the mutations can occur across the entire gene, the most common are observed in exon 9 corresponding to the helical domain, and in exon 20 encompassing the kinase domain. This study constitutes the first attempt at determining the frequency and mutational spectrum in Lebanese breast cancer patients. For this purpose, DNA samples from 280 breast cancer patients from across Lebanon were screened for PIK3CA mutations using the Therascreen® PIK3CA RGQ Real-time PCR assay. In line with previous reports, 38.57% of cases were positive for at least one PIK3CA mutation, among which approximately 59% were in exon 9 and 37% in exon 20. However, PIK3CA mutations are breast cancer are heterogeneous whereby 20% of known PIK3CA mutants might not be detected by compact PCR based assays. Thus, the adoption of comprehensive Next Generation Sequencing based panels to decipher the complete clinical, molecular and immunohistochemical profile of breast cancer tumor requires further investigation.

Prospective, open-label, and observational study of cetuximab for metastatic colorectal carcinoma: The OPTIM1SE study.

AIM: The OPTIM1SE study observed long-term real-world outcomes of cetuximab-based infusional 5-fluorouracil (5-FU) regimens for first-line treatment of metastatic colorectal cancer (mCRC) across Asia-Pacific and Middle East regions, aiming to characterize their use, effectiveness, and safety in routine practice. METHODS: OPTIM1SE was a prospective, open-label, observational study. Patients with untreated KRAS wild-type mCRC and distant metastases were treated per locally approved labels and monitored for 3 years via electronic medical records. The primary endpoint was the overall response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS). RESULTS: From November 19, 2013, to June 30, 2016, 520 patients were enrolled in 51 sites. Patients were mostly male (61.2%), with a mean age of 58.5 (±12.0) years; 420 patients received leucovorin, 5-FU, and irinotecan-based regimens and 94 received leucovorin, 5-FU, and oxaliplatin. The most common primary tumor site was the rectum (38.8%), with liver metastases (65.0%). ORR was 45.4% (95% CI, 41.1%-49.7%), including 26 patients (5.0%) with a complete response. Median PFS was 9.9 months (95% CI, 8.2-11.0); median OS (mOS) was 30.8 months (95% CI, 27.9-33.6). Higher mOS was associated with tumors of left compared with right-sided origin (hazard ratio, 0.69 [95% CI, 0.49-0.99]); higher ORR was also associated with liver metastases compared with all other metastases (55.4% vs. 40.2%). Adverse events were consistent with the known safety profile of cetuximab. CONCLUSION: Cetuximab-based 5-FU regimens were effective first-line treatments for mCRC in routine practice, particularly in patients with left-sided disease and liver metastases only.

Well-differentiated gastro-entero-pancreatic neuroendocrine tumors with positive FDG-PET/CT: a retrospective chart review.

PURPOSE: Rarely, well-differentiated gastro-entero-pancreatic neuroendocrine tumors (GEP NETs) can have positive uptake on 18F-fluorodeoxyglucose-PET/computerized tomography ( 18 F-FDG-PET/CT), with or without a positive 68 Ga-PET/CT. We aim to evaluate the diagnostic role of 18 F-FDG-PET/CT in patients with well-differentiated GEP NETs. METHODS: We retrospectively reviewed a chart of patients diagnosed with GEP NETs between 2014 and 2021, at the American University of Beirut Medical Center, who have low (G1; Ki-67 ≤2) or intermediate (G2; and Ki-67 >2-≤20) well-differentiated tumors with positive findings on FDG-PET/CT. The primary endpoint is progression-free survival (PFS) compared to historical control, and the secondary outcome is to describe their clinical outcome. RESULTS: In total 8 out of 36 patients with G1 or G2 GEP NET met the inclusion criteria for this study. The median age was 60 years (range 51-75 years) and 75% were male. One patient (12.5%) had a G1 tumor whereas 7 (87.5%) had G2, and seven patients were stage IV. The primary tumor was intestinal in 62.5% of the patients and pancreatic in 37.5%. Seven patients had both 18 F-FDG-PET/CT and 68 Ga-PET/CT positive and one patient had a positive 18 F-FDG-PET/CT and negative 68 Ga-PET/CT. Median and mean PFS in patients positive for both 68 Ga-PET/CT and 18 F-FDG-PET/CT were 49.71 months and 37.5 months (95% CI, 20.7-54.3), respectively. PFS in these patients is lower than that reported in the literature for G1/G2 NETs with positive 68 Ga-PET/CT and negative FDG-PET/CT (37.5 vs. 71 months; P = 0.0217). CONCLUSION: A new prognostic score that includes 18 F-FDG-PET/CT in G1/G2 GEP NETs could identify more aggressive tumors.

Can plasma vitamin C predict survival in stage IV colorectal cancer patients? Results of a prospective cohort study.

Background and Aims: In light of the inconclusive evidence on the association between vitamin C status and colorectal cancer (CRC) outcome, this study assessed the prognostic value of vitamin C in participants with metastatic CRC (mCRC). Methods: Adults with mCRC and cancer-free controls were recruited in this prospective cohort study to allow for comparison of vitamin C levels with healthy individuals from the same population. Sociodemographic, lifestyle, medical variables, BRAF and KRAS mutations, as well as Vitamin C plasma level and food intake were evaluated. Predictors of diminished vitamin C level were assessed via multivariate logistic regression. Mortality and progression free survival (PFS) among mCRC participants were analyzed based on plasma vitamin C level. Results: The cancer group (n = 46) was older (mean age: 60 ± 14 vs. 42 ± 9.6, p = 0.047) and included more males (29% vs. 19%, p < 0.001) than the cancer-free group (n = 45). There was a non-significant difference in the vitamin C intake between the two groups; however, the mean plasma vitamin C level was lower in the cancer group (3.5 ± 3.7 vs. 9.2 ± 5.6 mg/l, p < 0.001). After adjusting for age and gender, the cancer group was more likely to be deficient compared to the cancer-free group [Adjusted Odds Ratio (95%CI): 5.4 (2.1-14)]. There was a non-significant trend for higher mortality in the vitamin C deficient cancer group (31% vs. 12%, p = 0.139). PFS did not differ based on vitamin C deficiency and patients with BRAF and KRAS mutations did not have significant differences in vitamin C levels. Conclusion: mCRC patients have lower plasma vitamin C levels than healthy controls. The trend toward higher mortality in the vitamin C deficient cancer group was not statistically significant. Whether this phenomenon affects survival and response to treatment warrants further exploration in phase III clinical trials.

Overcoming EGFR Resistance in Metastatic Colorectal Cancer Using Vitamin C: A Review.

Targeted monoclonal antibody therapy against Epidermal Growth Factor Receptor (EGFR) is a leading treatment modality against metastatic colorectal cancer (mCRC). However, with the emergence of KRAS and BRAF mutations, resistance was inevitable. Cells harboring these mutations overexpress Glucose Transporter 1 (GLUT1) and sodium-dependent vitamin C transporter 2 (SVCT2), which enables intracellular vitamin C transport, leading to reactive oxygen species generation and finally cell death. Therefore, high dose vitamin C is proposed to overcome this resistance. A comprehensive search strategy was adopted using Pubmed and MEDLINE databases (up to 11 August 2022). There are not enough randomized clinical trials to support its use in the clinical management of mCRC, except for a subgroup analysis from a phase III study. High dose vitamin C shows a promising role in overcoming EGFR resistance in mCRC with wild KRAS mutation with resistance to anti-epidermal growth factor inhibitors and in patients with KRAS and BRAF mutations.

The Ketogenic Diet in Colorectal Cancer: A Means to an End.

Some diets, such as high lipid and high glucose diets, are known to increase the risk of colorectal cancer. On the other hand, little is known about diets that prevent colonic carcinogenesis. The ketogenic diet, which is characterized by high fat and very low carbohydrate content, is one such diet. The ketogenic diet decreases the amount of available glucose for tumors and shifts to the production of ketone bodies as an alternative energy source for healthy cells. Cancer cells are unable to use the ketone bodies for energy thus depriving them of the energy needed for progression and survival. Many studies reported the beneficial effects of the ketogenic diet in several types of cancers. Recently, the ketone body ß-hydroxybutyrate has been found to possess anti-tumor potential in colorectal cancer. Despite its beneficial effects, the ketogenic diet also has some drawbacks, some of which are related to gastrointestinal disorders and weight loss. Thus, studies are being directed at this time towards finding alternatives to following a strict ketogenic diet and supplementing patients with the ketone bodies responsible for its beneficial effects in the hope of overcoming some potential setbacks. This article discusses the mechanism by which a ketogenic diet influences growth and proliferation of tumor cells, it sheds the light on the most recent trials regarding its use as an adjunctive measure to chemotherapy in patients with metastatic colorectal cancer, and it explains the limitations of its usage in metastatic patients and the promising role of exogenous ketone supplementation in this setting.

Maintenance chemotherapy in advanced and metastatic pancreatic cancer, a narrative review and case series.

Limited data exist on the management of patients with locally advanced (aPC) or metastatic pancreatic (mPC) cancer who achieve stable disease/response after first-line chemotherapy. In this setting, maintenance therapy is important to minimize toxicity while preserving survival benefits. The aim of this study is to conduct a narrative review of the evidence available on the topic and present the results of a retrospective case series of patients with aPC or mPC who received maintenance therapy following a good response to induction chemotherapy. Olaparib is the only drug approved for maintenance therapy in patients with metastatic pancreatic cancer and germline Breast Cancer gene mutation. Data from several trials, including the phase II PANOPTIMOX-PRODIGE35 trial, showed clinical benefit from the use of 5-fluorouracil (5-FU) as maintenance. We also conducted a case series including 12 patients who received FOLFIRINOX as induction chemotherapy for aPC or mPC followed by fluorouracil (5-FU) or FOLFIRI maintenance therapy. Median progression-free survival is 22.13 months which is higher than that reported in the literature, which ranges between 5 and 10.6 months. Although further conclusions cannot be drawn because of the small sample size, the results are promising and encourage further exploration of this topic in larger prospective trials.

A phase II single arm study of Nivolumab with stereotactic Ablative radiation Therapy after induction chemotherapy in CHOlangiocarcinoma (NATCHO).

BACKGROUND: Intrahepatic cholangiocarcinoma (CCA) is amongst the most common primary liver tumors worldwide. CCA carries a bad prognosis prompting research to establish new treatment modalities other than surgery and the current chemotherapeutic regimens adopted. Hence, this trial explores a new therapeutic approach, to combine stereotactic body radiation therapy (SBRT) and immunotherapy (Nivolumab), and asses its clinical benefit and safety profile after induction chemotherapy in CCA. METHODOLOGY: This is a Phase II open-label, single-arm, multicenter study that investigates Nivolumab (PD-1 inhibitor) treatment at Day 1 followed by SBRT (30 Gy in 3 to 5 fractions) at Day 8, then monthly Nivolumab in 40 patients with non-resectable locally advanced, metastatic or recurrent intrahepatic or extrahepatic CCA. Eligible patients were those above 18 years of age with a pathologically and radiologically confirmed diagnosis of non-resectable locally advanced or metastatic or recurrent intrahepatic or extrahepatic CCA, following 4 cycles of cisplatin-based chemotherapy with an estimated life expectancy of more than 3 months, among other criteria. The primary endpoint is the progression free survival (PFS) rate at 8 months and disease control rate (DCR). The secondary endpoints are overall survival (OS), tumor response rate (TRR), duration of response, evaluation of biomarkers: CD3 + , CD4 + and CD8 + T cell infiltration, as well as any change in the PD-L1 expression through percutaneous core biopsy when compared with the baseline biopsy following 1 cycle of Nivolumab and SBRT. DISCUSSION: SRBT alone showed promising results in the literature by both inducing the immune system locally and having abscopal effects on distant metastases. Moreover, given the prevalence of PD-L1 in solid tumors, targeting it or its receptor has become the mainstay of novel immunotherapeutic drugs use. A combination of both has never been explored in the scope of CCA and that is the aim of this study. TRIAL REGISTRATION: ClinicalTrials.gov NCT04648319 , April 20, 2018.

Liquid biopsy derived circulating tumor cells and circulating tumor DNA as novel biomarkers in hepatocellular carcinoma.

INTRODUCTION: The diagnosis of hepatocellular carcinoma (HCC) is made at a relatively advanced stage resulting in poor prognosis. Alpha-fetoprotein and liver ultrasound have limited accuracy as biomarkers in HCC. Liver biopsy provides information on tumor biology; however, it is invasive and holds high threat of tumor seeding. Thus, more accurate and less invasive approaches are needed. AREAS COVERED: Highly sensitive liquid biopsy assays have made possible the detection and analysis of cells or organelles such as circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and tumor-derived exosomes. Here, we focus on CTCs and ctDNA components of liquid biopsy and their clinical application as diagnostic, prognostic, and predictive biomarkers in HCC. Unlike tissue biopsy, liquid biopsy involves attaining a sample at several time frames in an easy and a non-invasive manner. They have been efficacious in detecting and classifying cancer, in predicting treatment response, in monitoring disease relapse and in identifying mechanisms of resistance to targeted therapies. EXPERT OPINION: Although interesting and highly promising, liquid biopsy techniques still have many obstacles to overcome before their wide spread clinical application sees the light. It is expected that these techniques will be incorporated into traditional methodologies for better diagnostic, predictive and prognostic results.

Tumor profiling of KRAS, BRAF, and NRAS gene mutations in patients with colorectal cancer: A Lebanese major center cohort study.

BACKGROUND: In the era of precision medicine, treatment schemes for advanced Colorectal (CRC) disease include monoclonal antibodies which block the epidermal growth factor receptor (EGFR) implicated in tumor proliferation, invasion, migration and neovascularization. Resistance to these agents has been correlated with activating downstream mutations in KRAS, BRAF and NRAS genes, among others, leading to constitutive activation of the EGFR axis bypassing EGFR blockade. The assessment of tumor RASandBRAFmutational status has thus become standard clinical practice. While multiple investigations reported roughly mutations rates of 40% in KRAS, 7% in NRAS and 5-15 % in BRAF, numbers vary across different populations with limited data specifically from the Middle East. METHODS: This is a retrospective observational Laboratory information system (LIS) chart review of all the patients with pathologically confirmed colorectal carcinoma (CRC) or metastatic CRC who underwent KRAS, NRAS and/or BRAF mutational analysis testing at the Molecular Diagnostics Laboratory of the American University of Beirut Medical Center (AUBMC) from January 2012 to December 2018, inclusive. Data retrieved included the results of mutation testing performed for KRAS, NRAS and BRAF genes, the age, gender, and tumor location for each patient. Analysis of the mutations was performed using polymerase chain reaction (PCR) hybridization StripAssay® (ViennaLab, Vienna, Austria). RESULTS: 130 (47.6%) out of 273 histologically confirmed CRC cases, had positive KRAS mutations, namely in codons 12 (82%), 13 (17%), 146 (1.5%), 117 (0.75%), or 61 (0.75%). Two patients had two concomitant mutations: 12 + 12 (different mutations) and 12 + 146. Of 203 CRC cases tested for NRAS mutations, 16 (7.8%) were found to be positive for a mutation in codon 12 (37.5%), 61 (37.5%), or 13 (12.5%). Two patients had two concomitant mutations: 12 + 13 and 59 + 61. Of 172 CRC cases tested for BRAF mutations, 2 (1.2 %) were positive for the V600E -. CONCLUSION: This retrospective study is the first to report the frequencies of KRAS, NRAS and BRAF gene mutations in a Lebanese CRC cohort diagnosed and managed at a tertiary care center. The frequencies of the studied somatic gene mutations were similar to previously reported cohorts in other populations however the rate of BRAF mutation was lower in this cohort than expected.

Comparison Between Liver Stiffness Measurement by Fibroscan and Splenic Volume Index as NonInvasive Tools for the Early Detection of Oxaliplatin-induced Hepatotoxicity.

Background: Oxaliplatin remains an essential component of many chemotherapy protocols for gastrointestinal cancers; however, neurotoxicity and hepatotoxicity may be dose-limiting. The gold standard for the diagnosis of oxaliplatin-induced hepatotoxicity is liver biopsy, which is invasive and costly. Splenomegaly has also been used as a surrogate for liver biopsy in detecting oxaliplatin-induced sinusoidal obstruction syndrome (SOS), but splenic measurement is not routine and can be inaccurate and complex. We investigated the correlation between increased liver elasticity assessed by Fibroscan and the increase in spleen volume on cross-sectional imaging after oxaliplatin as a noninvasive technique to assess liver stiffness associated with oxaliplatin-induced SOS. Methods: Forty-six patients diagnosed with gastrointestinal cancers and planned to take oxaliplatin containing regimens were included in this prospective study at the American University of Beirut Medical Center (AUBMC). Measurement of spleen volume using cross-sectional imaging and of liver elasticity using Fibroscan was performed at baseline, 3 and 6 months after starting oxaliplatin. Mean liver elasticity measurements were compared between patients stratified by the development of splenomegaly using the Student t-test. Splenomegaly was defined as 50% increase in spleen size compared with baseline. Results: Patients who developed splenomegaly after oxaliplatin use had significantly higher mean elasticity measurements as reported by Fibroscan at 3 (16.2 vs. 7.8 kPa, P = 0.036) and 6 (9.3 vs. 6.7 kPa, P = 0.03) months. Conclusion: Measurement of elasticity using Fibroscan could be potentially used in the future as a noninvasive test for predicting oxaliplatin-induced hepatotoxicity.

Neo-adjuvant FOLFIRINOX in borderline resectable and locally advanced pancreatic adenocarcinoma.

BACKGROUND: Surgery and systemic therapy provide the best option for long-term cancer control in localized resectable pancreas cancer. The present study assessed the efficacy and safety of neoadjuvant treatment with FOLFIRINOX in patients with borderline resectable (BR) and locally advanced (LA) pancreas cancer (PDAC). METHODS: This was a prospective noninterventional observational trial of neoadjuvant FOLFIRINOX in BR and LA PDAC. The primary objective was the R0/R1 surgical resection rate. Secondary objectives included progression free survival (PFS) and overall survival (OS), tolerability, and toxicity. RESULTS: Forty-nine patients were enrolled between 2013 and 2019; the majority had LA disease (59.2%). Median age was 61 years, and median Ca 19-9 level pretreatment was 523.4 µmol/L. Following neoadjuvant FOLFIRINOX, 11 patients (22.5%) underwent surgical resection, the majority of which were BR at diagnosis (72.7%). Median OS and PFS for the entire group were 25 (95% CI: 17.2-32.8) and 12 months (95% CI: 9.7-13.3), respectively. Median PFS in BR patients was 14 (95% CI: 10.5-17.5) compared to 12 months (95% CI: 5.2-18.8) in patients with LA patients. Median OS and PFS were not reached in patients who underwent surgical resection as compared to 22 (95% CI: 18.6-25.4) and 9 months (95% CI: 4.2-13.9) in those who did not, respectively. Grade 3/4 neutropenia, leukopenia, neuropathy, nausea/vomiting, and diarrhea occurred in 6.3%, 2.1%, 10.4%, 4.2%, and 8.3%, respectively. CONCLUSION: Neoadjuvant FOLFIRINOX is an active regimen for patients with LA/BR PDAC with a resection rate of 22.5%. These results are in line with prior data.

Oxaliplatin-induced thrombotic microangiopathy: a case report.

BACKGROUND: Oxaliplatin-based chemotherapy represents a standard of care in the treatment of metastatic colorectal cancer. We report a rare case of fulminant oxaliplatin-induced thrombotic microangiopathy, clinically suggestive of hemolytic-uremic syndrome, occurring in a female patient with a prolonged history of exposure to oxaliplatin for the treatment of metastatic colon cancer. CASE PRESENTATION: A 73-year-old Caucasian female with a treatment history including several lines of chemotherapy for the management of metastatic colon cancer was reinitiated on chemotherapy with oxaliplatin, fluorouracil, and leucovorin with bevacizumab for disease progression. She presented to the emergency department with malaise, headache, vomiting, and decreased urine output appearing a few hours after chemotherapy administration. Clinical symptoms and laboratory findings were suggestive of thrombotic microangiopathy, with a triad of microangiopathic hemolytic anemia, pronounced thrombocytopenia, and acute renal failure. The predominance of the severe renal failure was evocative of hemolytic-uremic syndrome. The rapid development of the thrombotic microangiopathy was linked to exposure to oxaliplatin. The patient was promptly managed with daily plasma exchange and high-dose corticosteroids, platelet, and red blood cell transfusions in conjunction with intermittent hemodialysis, and she recovered progressively. CONCLUSION: Our case confirms the risk of hemolytic-uremic syndrome as a rare and life-threatening complication of oxaliplatin-based chemotherapy. A dose-dependent, drug-induced toxicity mechanism is suggested. Physicians need to maintain a high level of clinical suspicion to diagnose and treat this acute life-threatening disorder.

A Non-Interventional Multicenter Study of First-Line Bevacizumab in Combination with Chemotherapy in Patients with Metastatic Colorectal Cancer in Lebanon.

PURPOSE: When combined with chemotherapy, bevacizumab improves progression-free survival (PFS) in metastatic colorectal cancer (mCRC). This observational trial was designed to assess the safety and efficacy of bevacizumab plus first-line chemotherapy in a real-world setting in Lebanon. PATIENTS AND METHODS: A non-interventionaL multicenter study of first-LIne AVastin® (bevacizumab) in combination with chEmotherapy in patients with metastatic colorectal cancer (LLIVE) is a multicenter, prospective, Lebanon-based, observational study that enrolled mCRC patients who received first-line bevacizumab plus chemotherapy combination. The primary end point of the study was PFS. Secondary endpoints comprised the overall response rate (ORR) and the safety and tolerability of bevacizumab. RESULTS: A total of 196 patients were enrolled between July 2010 and August 2013. The median duration of follow-up was 11 months. Median duration of bevacizumab treatment was 4 months with FOLFOX being the chiefly chemotherapy regimen used in the first-line setting (26%). Median PFS was 8.22 months (95% confidence interval (CI): 7.005-9.443). The ORR was 50.3% (complete response 7.5%, partial response 42.8%). The most common adverse event encountered was hypertension (28%) followed by epistaxis (4.8%), diarrhea (4%), anemia (4%) and headache (4%). Grade 3/4 adverse events occurred in 15.2% of patients. CONCLUSION: The trial further substantiated the efficacy and safety of bevacizumab and chemotherapy in the first-line treatment of mCRC patients in Lebanon.

The impact of young age (< 40 years) on the outcome of a cohort of patients with primary non-metastatic breast cancer: analysis of 10-year survival of a prospective study.

BACKGROUND: The role of young age (< 40 years) at diagnosis as an independent risk factor for adverse outcomes in female patients with breast cancer has been highlighted in several studies. In this prospective study, we assessed the difference in 10-year survival between two groups of patients diagnosed with non-metastatic breast cancer based on an age cutoff of 40 years. We also assessed the impact of factors including tumor characteristics, molecular markers and immunohistochemical markers on survival outcomes, highlighting the interaction of those variables with age. METHODS: A total of 119 female patients with newly diagnosed non-metastatic breast cancer were recruited at the American University of Beirut Medical Center (AUBMC) between July 2011 and May 2014. Patients were recruited and divided into 2 age groups (< 40 and ≥ 40 years). In addition to clinical characteristics, we assessed immunohistochemistry including estrogen, progesterone and HER2 receptors, p53, cyclin B1, vascular endothelial growth factor receptor (VEGFR), and ki-67. Germline BRCA mutations were also performed on peripheral blood samples. Patient and tumor characteristics were compared between the age groups. 10-year overall survival (OS) and disease-free survival (DFS) were estimated accordingly. Cox regression analysis was performed in order to assess the effect of the different variables on clinical outcomes. RESULTS: After a median Follow-up of 96 (13-122) months, the estimated 10-year OS was 98.6% for patients ≥40 as compared to 77.6% in patients < 40 (p = 0.001). A similar trend was found for 10-year DFS reaching 90% for patients ≥40 and 70.4% for those < 40 (p = 0.004). On multivariate analysis for DFS and OS, only younger age (< 40 years), higher stage and triple negative phenotype among other parameters assessed significantly affected the outcome in this cohort. CONCLUSION: This prospective study confirms the association between younger age and adverse survival outcomes in patients with non-metastatic breast cancer. Future studies of the whole genome sequences may reveal the genomic basis underlying the clinical differences we have observed.

High rates of advanced prostate cancer in the Middle East: Analysis from a tertiary care center.

OBJECTIVES: Prostate cancer incidence is increasing in the Middle East (ME); however, the data of stage at the diagnosis and treatment outcomes are lacking. In developed countries, the incidence of de novo metastatic prostate cancer ranges between 4% and 14%. We hypothesized that the rates of presentation with advanced disease are significantly higher in the ME based on clinical observation. This study aims to examine the stage at the presentation of patients with prostate cancer at a large tertiary center in the ME. METHODS: After Institutional Review Board approval, we identified the patients diagnosed with prostate adenocarcinoma and presented to a tertiary care center between January 2010 and July 2015. Clinical, demographic, and pathological characteristics were abstracted. Patients with advanced disease were stratified according to tumor volume based on definitions from practice changing clinical trials. Descriptive and Kaplan-Meier survival analysis was used. RESULTS: A total of 559 patients were identified, with a median age at the diagnosis of 65 years and an age range of 39-94 years. Median prostate-specific antigen (PSA) at the presentation was 10 ng/ml, and almost a quarter of the men (23%) presented with metastatic disease. The most common site of metastasis was the bone (34/89, 38%). High-volume metastasis was present in 30.3%, 9%, and 5.2% of the cohort based on STAMPEDE, CHAARTED, and LATITUDE trial criteria, respectively. CONCLUSION: This is the first report showing the high proportion of men from ME presenting with de novo metastasis. This could be due to many factors, including the highly variable access to specialist multidisciplinary management, lack of awareness, and lack of PSA screening in the region. There is a clear need to raise the awareness about prostate cancer screening and early detection and to address the rising burden of advanced prostate cancer affecting men in the ME region.

COVID-19 vaccination immune response in patients with solid organ and haematologic malignancies: call for active monitoring.

Vaccines against COVID-19 have demonstrated a remarkable efficacy in decreasing hospitalisations and deaths; however, clinical trials leading to vaccine approvals did not include immunocompromised individuals such as patients receiving antineoplastic therapies. Emerging data suggest that patients on active anti-cancer therapy may have a reduced immune response to COVID-19 vaccination compared to the general population and may be at greater risk of COVID-19 infection as measures to reduce transmission in the community are relaxed. We report preliminary data from the American University of Beirut Medical Center in Lebanon demonstrating relatively low seroconversion rates. Of 36 patients on active anti-cancer therapy who had received two doses of vaccine, 17% were negative for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) anti-spike IgG. These results highlight the importance of maintaining strict precautionary measures against COVID-19 in patients on immunosuppressive treatment. There is an urgent need for active monitoring of immune response post-vaccination in prospective studies involving populations from diverse resource settings.

Anticoagulation for COVID-19 Patients: A Bird's-Eye View.

Coronavirus disease 2019 (COVID-19) is a systemic disease that can be life-threatening involving immune and inflammatory responses, and that can result in potentially lethal complications, including venous thrombo-embolism (VTE). Forming an integrative approach to thrombo-prophylaxis and coagulation treatment for COVID-19 patients ensues. We aim at reviewing the literature for anticoagulation in the setting of COVID-19 infection to provide a summary on anticoagulation for this patient population. COVID-19 infection is associated with a state of continuous inflammation, which results in macrophage activation syndrome and an increased rate of thrombosis. Risk assessment models to predict the risk of thrombosis in critically ill patients have not yet been validated. Currently published guidelines suggest the use of prophylactic intensity over intermediate intensity or therapeutic intensity anticoagulant for patients with critical illness or acute illness related to COVID-19 infection. Critically ill COVID-19 patients who are diagnosed with acute VTE are considered to have a provoking factor, and, therefore, treatment duration should be at least 3 months. Patients with proximal deep venous thrombosis or pulmonary embolism should receive parenteral over oral anticoagulants with low-molecular-weight heparin or fondaparinux preferred over unfractionated heparin. In patients with impending hemodynamic compromise due to PE, and who are not at increased risk for bleeding, reperfusion may be necessary. Internists should remain updated on new emerging evidence regarding anticoagulation for COVID-19 patients. Awaiting these findings, we invite internists to perform individualized decisions that are unique for every patient and to base them on clinical judgment for risk assessment.

Overview in Breast Cancer Screening in Lebanon.

Breast cancer (BC) is the most common cancer in women and men combined, and it is the second cause of cancer deaths in women after lung cancer. In Lebanon, the same epidemiological profile applies where BC is the leading cancer among Lebanese females, representing 38.2% of all cancer cases. As per the Center for Disease Control, there was a decline in BC mortality rate from 2003 to 2012 reflecting the adoption of national mammographic screening as the gold standard for BC detection by Western countries. The aim of this review study is to summarize current recommendations for BC screening and the available modalities for detecting BC in different countries, particularly in Lebanon. It also aims at exploring the impact of screening campaigns on BC early stage diagnosis in Lebanon. Despite the considerable debates whether screening mammograms provides more harm than benefits, screening awareness should be stressed since its benefits far outweigh its risks. In fact, the majority of BC mortality cases in Western countries are non-preventable by the use of screening mammograms alone. As such, Lebanon adopted a public focus on education and awareness campaigns encouraging early BC screening. Several studies showed the impact of early detection that is reflected by an increase in early stage disease and a decrease in more aggressive stages. Further studies should shed the light on the effect of awareness campaigns on early breast cancer diagnosis and clinical down staging at a national scope; therefore, having readily available data on pre- and post-adoption of screening campaigns is crucial for analyzing trends in mortality of breast cancer origin and reduction in advanced stages diseases. There is still room for future studies evaluating post-campaigns knowledge, attitudes, and practices of women having participated, emphasizing on the barriers refraining Lebanese women to contribute in BC screening campaigns.