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.

Short-course radiation followed by mFOLFOX-6 plus avelumab for locally-advanced rectal adenocarcinoma.

BACKGROUND: Current standard practice for locally advanced rectal cancer (LARC) entails a multidisciplinary approach that includes preoperative chemoradiotherapy, followed by total mesorectal excision, and then adjuvant chemotherapy. The latter has been accompanied by low compliance rates and no survival benefit in phase III randomized trials, so the strategy of administering neoadjuvant, rather than adjuvant, chemotherapy has been adapted by many trials, with improvement in pathologic complete response. Induction chemotherapy with oxaliplatin has been shown to have increased efficacy in rectal cancer, while short-course radiation therapy with consolidation chemotherapy increased short-term overall survival rate and decreased toxicity levels, making it cheaper and more convenient than long-course radiation therapy. This led to recognition of total neoadjuvant therapy as a valid treatment approach in many guidelines despite limited available survival data. With the upregulation (PDL-1) expression in rectal tumors after radiotherapy and the increased use of in malignant melanoma, the novel approach of combining immunotherapy with chemotherapy after radiation may have a role in further increasing pCR and improving overall outcomes in rectal cancer. METHODS: The study is an open label single arm multi- center phase II trial. Forty-four recruited LARC patients will receive 5Gy x 5fractions of SCRT, followed by 6 cycles of mFOLFOX-6 plus avelumab, before TME is performed. The hypothesis is that the addition of avelumab to mFOLFOX-6, administered following SCRT, will improve pCR and overall outcomes. The primary outcome measure is the proportion of patients who achieve a pCR, defined as no viable tumor cells on the excised specimen. Secondary objectives are to evaluate 3-year progression-free survival, tumor response to treatment (tumor regression grades 0 & 1), density of tumor-infiltrating lymphocytes, correlation of baseline Immunoscore with pCR rates and changes in PD-L1 expression. DISCUSSION: Recent studies show an increase in PD-L1 expression and density of CD8+ TILs after CRT in rectal cancer patients, implying a potential role for combinatory strategies using PD-L1- and programmed-death- 1 inhibiting drugs. We aim through this study to evaluate pCR following SCRT, followed by mFOLFOX-6 with avelumab, and then TME procedure in patients with LARC. TRIAL REGISTRATION: Trial Registration Number and Date of Registration: ClinicalTrials.gov NCT03503630, April 20, 2018.

The Unmasking of Cytomegalovirus as an Accomplice to Helicobacter pylori-Induced Severe Acute Gastroenteritis in a Healthy Host.

Cytomegalovirus (CMV) belongs to the Herpesviridae family, and it is considered the largest virus to infect humans. Primary CMV infection frequently targets immunodeficient patients and is often symptomatic. However, it may remain latent or clinically unapparent for years in immunocompetent individuals. CMV infection rarely presents as an invasive disease in the latter group of individuals, in which case, the most common site of involvement in the gastrointestinal tract. When CMV affects the gastrointestinal tract, the colon and stomach are the 2 frequently involved sites. This case report describes a unique case of an immunocompetent patient who presented with acute excruciating periumbilical pain and was diagnosed with acute gastritis secondary to CMV infection and possible Helicobacter pylori-associated chronic active gastritis. Symptoms resolved entirely soon after treatment with antimicrobials that cover for both infections. The diagnosis was based on histopathologic findings from biopsies taken from the stomach during the endoscopic evaluation combined with positive CMV serology and positive CMV-deoxyribonucleic acid.

Statin Use in Patients With Chronic Liver Disease and Cirrhosis: Current Evidence and Future Directions.

Chronic liver disease (CLD) and its complications constitute a significant cause of mortality and morbidity worldwide. Most deaths are secondary to the decompensation of cirrhosis and evolution of portal hypertension (PHTN). Since disease progression reversal is hardly attainable after decompensated cirrhosis develops, it is essential to intervene early with a therapeutic agent or regimen that could prevent or slow disease evolution. Thus far, there has been no agreed-upon medication to help in the fight against the development of cirrhosis or its decompensation. While early data depicted statins as harmful agents for the liver, current evidence from preclinical and clinical studies suggests that they might have positive impact on CLD. Low-quality evidence supports the fact that statins reduce mortality in CLD. Moderate-quality evidence suggests that statins reduce the risk of hepatic decompensation, variceal bleeding, and mortality, especially among patients with compensated cirrhosis. Combining this data with the long track-record of safety and tolerability of statins and their potential benefits in hepatocellular carcinoma (HCC) risk reduction, hepatologists might soon rely on statins to achieve better outcomes in their CLD and cirrhotic patients without significant additional costs. This review describes the rationale behind the use of statins in patients with CLD and cirrhosis. It sheds light on the current preclinical and clinical studies that reflect beneficial effects of the use of different types and doses of statins in the treatment of patients with different types and stages of CLD and cirrhosis. It also emphasizes the need for designing and developing additional large prospective interventional randomized control trials (RCTs) to better evaluate the association between statin exposure and the risk of fibrosis progression and development of cirrhosis in patients with non-cirrhotic CLDs, the risk of progression of PHTN in patients with cirrhosis, and the mortality rates in patients with cirrhotic or non-cirrhotic CLDs.

Proton Pump Inhibitors Use and Increased Risk of Spontaneous Bacterial Peritonitis in Cirrhotic Patients: A Retrospective Cohort Analysis.

Background: Since their introduction in the early 1980s, proton pump inhibitors (PPIs) have been used worldwide for a broad range of indications. Unfortunately, however, PPIs have become overly prescribed by healthcare providers, sometimes in the absence of clear indications. Although PPIs were initially presumed to have an excellent safety profile, emerging studies have shed light on the association between their long-term use and a myriad of side effects, including the possibility of an increased risk of spontaneous bacterial peritonitis (SBP). Data available to date regarding the association between PPI use and SBP development in cirrhotic patients is conflicting. While some observational studies provide no association between PPI use in cirrhotic patients and an increased risk of SBP development, many others support this association. As a result of the conflicting conclusions from case controls, cohorts, and meta-analyses, we aimed to carry out this retrospective cohort analysis of data from cirrhotic patients included in the electronic medical record-based commercial database, EXPLORYS (IMB-WATSON, Cleveland, Ohio). Our aim was to evaluate for a possible association between PPIs use and the risk of SBP development in cirrhotic patients and to compare the prevalence of SBP development between cirrhotic patients who were actively using PPIs and those who were not. Methods: A retrospective cohort analysis with chart review was conducted on patients with cirrhosis who were included in the electronic medical record-based commercial database, EXPLORYS (IMB-WATSON, Cleveland, Ohio). Using this database, records were reviewed between December 2017 and 2020. Included patients were adults aged 30 to 79 years with a Systematized Nomenclature of Medicine-Clinical Terms (SNOMED-CT) diagnosis of liver cirrhosis. Included patients with a SNOMED-CT diagnosis of liver cirrhosis were divided into two groups: the first group included all cirrhotic patients who did not use PPIs and the second group included all cirrhotic patients who were on PPIs at home. Results: In our analysis, SBP occurred in 1.7% (1,860 patients) of the included cirrhotic patients whether they were actively taking PPIs or not. Among the 40,670 cirrhotic patients who were on PPIs at home, 1,350 (3.3%) patients developed SBP. On multivariate analysis, PPI use was the strongest predictor for SBP in cirrhotic patients (odds ratio (OR) = 4.24; 95% confidence interval (CI): 3.83 - 4.7, P value < 0.0001), with cirrhotic patients taking PPIs being 4.24 more likely to develop SBP than those not on PPIs. In addition, PPI use, history of bleeding varices, age, race, and gender were found to be independent predicting factors for SBP, in descending order of importance. Conclusions: Our retrospective cohort analysis has shown that the use of PPIs in patients with liver cirrhosis is an independent predicting risk factor for SBP development. It solidified the argument that cirrhotic patients receiving this form of therapy seem to have a higher risk of developing SBP. In the setting of the emerging evidence that PPIs might impose health risks in cirrhotic patients, further studies are needed to settle the current debate between supporters and opponents of this proposition. In addition, future studies may help clarify the relationship between the occurrence of SBP in cirrhotic patients and the type, dose, and duration of PPIs used. We recommend that unless it is clearly indicated, PPI therapy should be avoided or administered with caution in patients with cirrhosis.

The Incidence of Venous Thromboembolism and Practice of Deep Venous Thrombosis Prophylaxis Among Hospitalized Cirrhotic Patients.

Background: Patients with liver cirrhosis have altered hepatic synthetic functions which theoretically result in reduced levels of pro-and anti-coagulant factors as well as thrombocytopenia. Initially, cirrhotic patients were thought to be at an increased risk of bleeding and a reduced risk of thrombosis. Several studies have recently reported an increased occurrence of venous thromboembolism (VTE) in cirrhotic patients. In this study, we aimed to assess the current practice of deep venous thrombosis (DVT) prophylaxis, the incidence and predictors of VTE, and the associated bleeding sequelae in patients with liver cirrhosis. Methods: A retrospective cohort study was performed. We included all adult patients with a diagnosis of liver cirrhosis from January 2010 to June 2019 admitted to the hospital. Our cohort patients were divided into two groups, cirrhotic patients with pharmacological VTE prophylaxis and those with mechanical or no VTE prophylaxis. Results: We included 601 cirrhotic patients in our study. The incidence of VTE occurring within the first 6 months of their admission was 1.5%. Seven patients (1.49%) developed VTE with the majority being DVTs while not on pharmacologic prophylaxis, and two patients developed VTE despite being on pharmacologic prophylaxis; however, there was no statistical difference. Alcohol use was the most common underlying cause of liver cirrhosis (40.4%), followed by chronic hepatitis C (21.1%), and nonalcoholic steatohepatitis (11.3%). Out of the 601 patients included, 69 patients received neither pharmacologic nor mechanical VTE prophylactic agent (11.48%), while the remaining majority received either pharmacological or mechanical prophylaxis (88.52%). Conclusions: Our study did not show a statistically significant association between the use of pharmacological VTE prophylactic agents and a reduction in the risk of VTE in cirrhotic patients. The rates of usage of DVT prophylactic agents among our Northwell hospitals during the study period appeared to be no longer suboptimal when compared to prior studies. Low albumin appears to be a predictor factor to develop VTE. There was a statistically significant increase in bleeding risk and transfusion requirement in cirrhotic patients receiving no pharmacological VTE prophylactic agents. Further prospective trials are needed to shed more light on this subject and identify the group of cirrhotic patients who could safely benefit from pharmacologic VTE prophylaxis.

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.

Total neoadjuvant therapy in patients with locally advanced rectal cancer: A tertiary medical center experience.

The current standard of care for locally advanced rectal cancer (LARC) includes preoperative chemoradiation, followed by total mesorectal excision and adjuvant chemotherapy. This multimodality treatment improves local control but is associated with low compliance rates without clear beneficial effects on overall survival (OS) and distant metastasis. In this retrospective study, the charts of patients diagnosed with cT3/4 or cT2-node-positive rectal cancer between January 2011 and June 2019 were reviewed. The chemoradiation therapy (CRT) group received a long course of CRT with capecitabine followed by surgery and adjuvant chemotherapy. The total neoadjuvant therapy (TNT) group received 6 cycles mFOLFOX and a short course of radiation therapy followed by surgery. A total of 81 patients were included, among which 55 (67.9%) received CRT and 26 (32.1%) received TNT. In the CRT group, 15 (27.3%) patients achieved pathologic complete response (pCR) compared with 10 (38.5%) in the TNT group (P=0.22). A total of 19 (35.8%) cases in the CRT group downstaged to pT0N0 or pT1N0 compared with 11 (42.3%) in the TNT group (P=0.33). The 2-year disease-free survival (DFS) rate was 81.0% in the TNT group and 84.0% in the CRT group (P=0.15). Out of 55 patients in the CRT group, 30 patients received adjuvant chemotherapy, 22 (40.0% of CRT cases) of which completed a full course. All 26 patients in the TNT group received neoadjuvant chemotherapy, where 22 (84.6%) patients took a full course (P<0.001). In conclusion, the present study revealed that patients treated with TNT were more compliant to chemotherapy than those treated with CRT. A numerically higher pCR rate, and nodal and tumor downstaging were noted in the TNT group without significance. No difference was noted in the 2-year DFS. Longer follow-up is required.

Expanding the Scope of Immunotherapy in Colorectal Cancer: Current Clinical Approaches and Future Directions.

The success of immune checkpoint inhibitors (ICIs) in an increasing range of heavily mutated tumor types such as melanoma has culminated in their exploration in different subsets of patients with metastatic colorectal cancer (mCRC). As a result of their dramatic and durable response rates in patients with chemorefractory, mismatch repair-deficient-microsatellite instability-high (dMMR-MSI-H) mCRC, ICIs have become potential alternatives to classical systemic therapies. The anti-programmed death-1 (PD-1) agents, Pembrolizumab and Nivolumab, have been granted FDA approval for this subset of patients. Unfortunately, however, not all CRC cases with the dMMR-MSI-H phenotype respond well to ICIs, and ongoing studies are currently exploring biomarkers that can predict good response to them. Another challenge lies in developing novel treatment strategies for the subset of patients with the mismatch repair-proficient-microsatellite instability-low (pMMR-MSI-L) phenotype that comprises 95% of all mCRC cases in whom treatment with currently approved ICIs has been largely unsuccessful. Approaches aiming at overcoming the resistance of tumors in this subset of patients are being developed including combining different checkpoint inhibitors with either chemotherapy, anti-angiogenic agents, cancer vaccines, adoptive cell transfer (ACT), or bispecific T-cell (BTC) antibodies. This review describes the rationale behind using immunotherapeutics in CRC. It sheds light on the progress made in the use of immunotherapy in the treatment of patients with dMMR-MSI-H CRC. It also discusses emerging approaches and proposes potential strategies for targeting the immune microenvironment in patients with pMMR-MSI-L CRC tumors in an attempt to complement immune checkpoint inhibition.

Resistance Mechanisms to Anti-angiogenic Therapies in Cancer.

Tumor growth and metastasis rely on tumor vascular network for the adequate supply of oxygen and nutrients. Tumor angiogenesis relies on a highly complex program of growth factor signaling, endothelial cell (EC) proliferation, extracellular matrix (ECM) remodeling, and stromal cell interactions. Numerous pro-angiogenic drivers have been identified, the most important of which is the vascular endothelial growth factor (VEGF). The importance of pro-angiogenic inducers in tumor growth, invasion and extravasation make them an excellent therapeutic target in several types of cancers. Hence, the number of anti-angiogenic agents developed for cancer treatment has risen over the past decade, with at least eighty drugs being investigated in preclinical studies and phase I-III clinical trials. To date, the most common approaches to the inhibition of the VEGF axis include the blockade of VEGF receptors (VEGFRs) or ligands by neutralizing antibodies, as well as the inhibition of receptor tyrosine kinase (RTK) enzymes. Despite promising preclinical results, anti-angiogenic monotherapies led only to mild clinical benefits. The minimal benefits could be secondary to primary or acquired resistance, through the activation of alternative mechanisms that sustain tumor vascularization and growth. Mechanisms of resistance are categorized into VEGF-dependent alterations, non-VEGF pathways and stromal cell interactions. Thus, complementary approaches such as the combination of these inhibitors with agents targeting alternative mechanisms of blood vessel formation are urgently needed. This review provides an updated overview on the pathophysiology of angiogenesis during tumor growth. It also sheds light on the different pro-angiogenic and anti-angiogenic agents that have been developed to date. Finally, it highlights the preclinical evidence for mechanisms of angiogenic resistance and suggests novel therapeutic approaches that might be exploited with the ultimate aim of overcoming resistance and improving clinical outcomes for patients with cancer.

Efficacy and safety-in analysis of short-course radiation followed by mFOLFOX-6 plus avelumab for locally advanced rectal adenocarcinoma.

BACKGROUND: Neoadjuvant chemotherapy and short-course radiotherapy followed by resection has been gaining recognition in the treatment of rectal cancer. Avelumab is a fully human immunoglobulin that binds Programmed Death-Ligand 1 (PD-L1) and prevents the suppression of the cytotoxic T cell immune response. This phase II trial evaluates the safety and pathologic response rate of short-course radiation followed by 6 cycles of mFOLFOX6 with avelumab in patients with locally advanced rectal cancer (LARC). METHODS: This study is prospective single-arm, multicenter phase II trial adopting Simon's two-stage. Short-course radiation is given over 5 fractions to a total dose of 25 Gy. mFOLFOX6 plus avelumab (10 mg/kg) are given every 2 weeks for 6 cycles. Total mesorectal excision is performed 3-4 weeks after the last cycle of avelumab. Follow up after surgery is done every 3 months to a total of 36 months. Adverse event data collection is recorded at every visit. RESULTS: 13 out of 44 patients with LARC were enrolled in the first stage of the study (30% from total sample size). All patients met the inclusion criteria and received the full short-course radiation course followed by 6 cycles of mFOLFOX6 plus avelumab. 12 out of the 13 patients completed TME while one patient had progression of disease and was dropped out of the study. The sample consisted of 9 (69%) males and 4 (31%) females with median age of 62 (33-73) years. The first interim analysis revealed that 3 (25%) patients achieved pathologic complete response (pCR) (tumor regression grade, TRG 0) out of 12. While 3 (25%) patients had near pCR with TRG 1. In total, 6 out of 12 patients (50%) had a major pathologic response. All patients were found to be MMR proficient. The protocol regimen was well tolerated with no serious adverse events of grade 4 reported. CONCLUSION: In patients with LARC, neoadjuvant radiation followed by mFOLFOX6 with avelumab is safe with a promising pathologic response rate. Trial Registration Number and Date of Registration ClinicalTrials.gov NCT03503630, April 20, 2018. https://clinicaltrials.gov/ct2/show/NCT03503630?term=NCT03503630&draw=2&rank=1 .

The Combination of Stereotactic Body Radiation Therapy and Immunotherapy in Primary Liver Tumors.

Treatment recommendations for primary liver malignancies, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are complex and require a multidisciplinary approach. Despite surgical options that are potentially curative, options for nonsurgical candidates include systemic therapy, radiotherapy (RT), transarterial chemoembolization (TACE), and radiofrequency ablation (RFA). Stereotactic Body Radiation Therapy (SBRT) is now in routine use for the treatment of lung cancer, and there is growing evidence supporting its use in liver tumors. SBRT has the advantage of delivering ablative radiation doses in a limited number of fractions while minimizing the risk of radiation-induced liver disease (RILD) through highly conformal treatment plans. It should be considered in a multidisciplinary setting for the management of patients with unresectable, locally advanced primary liver malignancies and limited treatment options. Recently, the combination of immunotherapy with SBRT has been proposed to improve antitumor effects through engaging the immune system. This review aims at shedding light on the novel concept of the combination strategy of immune-radiotherapy in liver tumors by exploring the evidence surrounding the use of SBRT and immunotherapy for the treatment of HCC and CCA.