Thrombotic Microangiopathy in the Setting of Colorectal Cancer: A Therapeutic Challenge with a Bad Prognosis.

While most cases of thrombotic microangiopathic hemolytic anemias are idiopathic, some can occur in the setting of a malignancy. Differentiating both conditions is crucial to initiate the appropriate treatment. In this case report and literature review, we discuss the occurrence of a thrombotic microangiopathy in a 61-year-old male patient with a treatment-refractory metastatic colorectal cancer invading his bone marrow. Plasmapheresis does not constitute the mainstay of treatment in this setting, as targeting the primary disease is the ultimate management. Treating the condition of our patient has been challenging as multiple lines of treatments of his primary disease had been exhausted. The discrepancy in KRAs status obtained between PCR and later NGS offered a new treatment line with Cetuximab. In this article, we will discuss the different factors that differentiate between idiopathic and cancer-induced microangiopathy. We will emphasize on the fact that the treatment of the primary disease constitutes the most important step in the treatment of cancer-induced thrombotic microangiopathy. We will also raise several explanations to target the disagreement in KRAS status obtained by the different technical modalities.

From Tumor Cells to Endothelium and Gut Microbiome: A Complex Interaction Favoring the Metastasis Cascade.

Metastasis is a complicated process through which tumor cells disseminate to distant organs and adapt to novel tumor microenvironments. This multi-step cascade relies on the accumulation of genetic and epigenetic alterations within the tumor cells as well as the surrounding non-tumor stromal cells. Endothelial cells constitute a major player in promoting metastasis formation either by inducing the growth of tumor cells or by directing them towards dissemination in the blood or lymph. In fact, the direct and indirect interactions between tumor and endothelial cells were shown to activate several mechanisms allowing cancer cells' invasion and extravasation. On the other side, gastrointestinal cancer development was shown to be associated with the disruption of the gut microbiome. While several proposed mechanisms have been investigated in this regard, gut and tumor-associated microbiota were shown to impact the gut endothelial barrier, increasing the dissemination of bacteria through the systemic circulation. This bacterial dislocation allows the formation of an inflammatory premetastatic niche in the distant organs promoting the metastatic cascade of primary tumors. In this review, we discuss the role of the endothelial cells in the metastatic cascade of tumors. We will focus on the role of the gut vascular barrier in the regulation metastasis. We will also discuss the interaction between this vascular barrier and the gut microbiota enhancing the process of metastasis. In addition, we will try to elucidate the different mechanisms through which this bacterial dislocation prepares the favorable metastatic niche at distant organs allowing the dissemination and successful deposition of tumor cells in the new microenvironments. Finally, and given the promising results of the studies combining immune checkpoint inhibitors with either microbiota alterations or anti-angiogenic therapy in many types of cancer, we will elaborate in this review the complex interaction between these 3 factors and their possible therapeutic combination to optimize response to treatment.

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.

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.

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.

Complete Radiological Response of Recurrent Metastatic Adrenocortical Carcinoma to Pembrolizumab and Mitotane.

Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. Treatment options for ACC are limited, with resection the main intervention. Most cases present in late metastatic cases, and data regarding effective therapies is limited. We report a case of ACC in a 40-year-old woman with history of ACC postadrenalectomy, who presented with recurrent metastatic ACC in the left perinephric space. She was started on pembrolizumab which was added to her mitotane maintenance therapy. Complete radiological response was achieved after 4 cycles of pembrolizumab. As far as we know, this is the first case to achieve complete radiological response with mitotane and pembrolizumab in recurrent metastatic ACC, with negative prognostic markers and no prior radiotherapy. As our findings are in the setting of one clinical case, we suggest the need to perform a trial to assess the benefit of combining mitotane and pembrolizumab in treating metastatic ACC.

Management of colorectal cancer in the era of COVID-19: Challenges and suggestions.

The Coronavirus (COVID-19) pandemic had a huge impact on all sectors around the world. In particular, the healthcare system has been subject to an enormous pressure that has surpassed its ability in many instances. Additionally, the pandemic has called for a review of our daily medical practices, including our approach to colorectal cancer management where treatment puts patients at high risk of virus exposure. Given their higher median age, patients are at an increased risk for severe symptoms and complications in cases of infection, especially in the setting of immunosuppression. Therefore, a review of the routine colorectal cancer practices is needed to minimize risk of exposure. Oncologists should weigh risk of exposure versus the patient's oncologic benefits when approaching management. In addition, treatment protocols should be modified to minimize hospital visits and admissions while maintaining the same treatment efficacy. In this review, we will focus on challenges that colorectal cancer patients face during the pandemic, while highlighting the priority in each case. We will also discuss the evidence for potential modifications to existing treatment plans that could reduce infectious exposure without compromising care. Finally, we will discuss the impact of the socio-economic difficulties faced by Lebanese patients due to a poor economy toppled by an unexpected pandemic.

Metabolic Factors Affecting Tumor Immunogenicity: What Is Happening at the Cellular Level?

Immunotherapy has changed the treatment paradigm in multiple solid and hematologic malignancies. However, response remains limited in a significant number of cases, with tumors developing innate or acquired resistance to checkpoint inhibition. Certain "hot" or "immune-sensitive" tumors become "cold" or "immune-resistant", with resultant tumor growth and disease progression. Multiple factors are at play both at the cellular and host levels. The tumor microenvironment (TME) contributes the most to immune-resistance, with nutrient deficiency, hypoxia, acidity and different secreted inflammatory markers, all contributing to modulation of immune-metabolism and reprogramming of immune cells towards pro- or anti-inflammatory phenotypes. Both the tumor and surrounding immune cells require high amounts of glucose, amino acids and fatty acids to fulfill their energy demands. Thus, both compete over one pool of nutrients that falls short on needs, obliging cells to resort to alternative adaptive metabolic mechanisms that take part in shaping their inflammatory phenotypes. Aerobic or anaerobic glycolysis, oxidative phosphorylation, tryptophan catabolism, glutaminolysis, fatty acid synthesis or fatty acid oxidation, etc. are all mechanisms that contribute to immune modulation. Different pathways are triggered leading to genetic and epigenetic modulation with consequent reprogramming of immune cells such as T-cells (effector, memory or regulatory), tumor-associated macrophages (TAMs) (M1 or M2), natural killers (NK) cells (active or senescent), and dendritic cells (DC) (effector or tolerogenic), etc. Even host factors such as inflammatory conditions, obesity, caloric deficit, gender, infections, microbiota and smoking status, may be as well contributory to immune modulation, anti-tumor immunity and response to immune checkpoint inhibition. Given the complex and delicate metabolic networks within the tumor microenvironment controlling immune response, targeting key metabolic modulators may represent a valid therapeutic option to be combined with checkpoint inhibitors in an attempt to regain immune function.

Cystectomy vs. bladder preservation after neoadjuvant chemotherapy in muscle-invasive bladder cancer: A tertiary medical center experience.

BACKGROUND: Radical cystectomy (RC) remains the standard of care for muscle-invasive bladder cancer (MIBC). Because of the higher overall risks associated with RC, particularly in the elderly patients with multiple comorbidities, other less invasive bladder preservation strategies have been considered. METHODS: This is a retrospective chart review of patients diagnosed with MIBC, pT2-4N0-2M0, at the American University of Beirut Medical Center between 2007 and 2017. RESULTS: 98 patients, 85 (86.7%) males and 13 (13.3%) females, were included. Of the 98 patients, 19 (19.3%) patients were treated with upfront CRT, 35 (35.7%) were treated with upfront RC and 44 (45%) were treated with NAC. 26 (26.5%) patients underwent RC after NAC and 18 (18.4%) received CRT after NAC. The mean overall survival (OS) for the different treatment modalities was 69.4, 60.4, 56.1 and 44.2 months for RC, CRT, RC post-NAC and CRT post-NAC, respectively (p = 0.83). The median disease-free survival (DFS) was 29, 22, 21 and 16 months for RC, CRT, RC post-NAC and CRT post-NAC, respectively (p = 0.49). Patients with pT3/T4 had a higher risk of death by 3.335 folds compared to pT2 (95% CI [1.321-8.422], p<0.05). CONCLUSIONS: No difference was noted in the OS and DFS between the groups who underwent RC post-NAC and CRT post-NAC. These findings further support the possibility of bladder preservation after the treatment with NAC for MIBC. The pathologic T stage at diagnosis is an important prognostic factor regardless of treatment modality.

Resisting Resistance to Immune Checkpoint Therapy: A Systematic Review.

The treatment landscape in oncology has witnessed a major revolution with the introduction of checkpoint inhibitors: anti-PD1, anti-PDL1 and anti-CTLA-4. These agents enhance the immune response towards cancer cells instead of targeting the tumor itself, contrary to standard chemotherapy. Although long-lasting durable responses have been observed with immune checkpoints inhibitors, the response rate remains relatively low in many cases. Some patients respond in the beginning but then eventually develop acquired resistance to treatment and progress. Other patients having primary resistance never respond. Multiple studies have been conducted to further elucidate these variations in response in different tumor types and different individuals. This paper provides an overview of the mechanisms of resistance to immune checkpoint inhibitors and highlights the possible therapeutic approaches under investigation aiming to overcome such resistance in order to improve the clinical outcomes of cancer patients.

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.

Female oncologists in the Middle East and North Africa: progress towards gender equality.

BACKGROUND: Female doctors are increasingly choosing oncology as a career while they are still under-represented in leadership positions globally. The European Society of Medical Oncology has recently surveyed its members regarding gender equality in the work place. Limited data are available from the Middle East. The aim of our study was to survey female oncologists practicing in the Middle East to identify common challenges and suggest areas for improvement. METHODS: A cross-sectional survey was distributed among female participants attending the annual Lebanese Society of Medical Oncology meeting in March 2018, and in the Pan-Arab annual meeting in April 2018. The questionnaire used included questions assessing sociodemographic characteristics, involvement in leadership and academic positions and the impact of career on family life. RESULTS: Overall, 88 questionnaires were collected from women practicing all over the Middle East. 59% reported that a male doctor was responsible for the work team; however, 57% covered a managerial or leadership role within their job. 64% of the female oncologists believed that their gender had at least moderate, significant and even major impact on their career. Participants reported that their careers have a considerable impact on their relationship with friends and social networking (49%) and their family and marriage (44%). 58% report having problems with finding balance between work and family, and 50% find barriers to attend international meetings. Several ways to improve were suggested, 56% voted for offering development and leadership training specifically women, 45% suggested implementing a flexible work schedule. CONCLUSION: In what is considered a male dominant environment, gender equality according to female oncologists working in the Middle East, is very comparable to the world data provided. Several strategies have been identified to continue progress in this domain with the aim to improve academic leadership opportunities and work-life balance for all.

Maximizing response: a case report of salvage chemotherapy after immune checkpoint inhibition in a patient with previous chemo-refractory metastatic esophageal carcinoma.

Esophageal carcinoma is an aggressive malignancy and outcomes remain poor. Immune checkpoint inhibitors are a standard-of-care in the third-line and beyond settings, although benefit is modest. Herein, we report the case of a patient who achieved a partial response to salvage chemotherapy following treatment with an immune checkpoint inhibitor despite having chemo-refractory disease. A 41-year-old male, with a history of Crohn's disease, was diagnosed with Her2-positive metastatic esophageal adenocarcinoma to lungs and lymph nodes. The patient received multiple lines of systemic therapy including: first-line modified DCF (docetaxel/cisplatin/5-fluorouracil) with trastuzumab, second-line trastuzumab/afatinib on a clinical study, third-line carboplatin/irinotecan/ramucirumab and fourth-line treatment with a Her2 antibody-drug conjugate, DS-8201A, on a phase I study. While the patient was not a candidate for clinical trials evaluating immune checkpoint inhibitors due to his history of Crohn's disease, the latter was well controlled. Thus, the patient commenced pembrolizumab as fifth-line of treatment 2 years since diagnosis. After 3 cycles of therapy, the patient developed grade 3 immune-related colitis and treatment was discontinued. The patient maintained a good performance status and commenced a sixth-line of carboplatin/irinotecan/ramucirumab. Subsequent imaging demonstrated a partial response which was maintained over a 6-month period. This case demonstrates a response to previously administered chemotherapy following immune checkpoint inhibitor therapy, despite prior progression on this chemotherapy regimen. To our knowledge, this has not been previously reported in esophagogastric carcinoma (EGC). Post-immune checkpoint inhibitor chemotherapy may be a feasible treatment strategy. Research is needed to evaluate the role of post-immune checkpoint inhibitor chemotherapy in patients with metastatic EGC.

The unveiling of a new risk factor associated with bladder cancer in Lebanon.

BACKGROUND: No accurate evaluation of smoking and water pollution on bladder cancer has been conducted in the Lebanese population. Our aim is to examine the significance of smoking and one of the main water pollutants Trihalomethanes (THM) on bladder cancer risk. METHODS: Population Attributable Fraction (PAF) was used to quantify the contribution of the risk factors smoking and THMs on bladder cancer in Lebanon. To calculate PAF for each risk factor, we used the proportion of the population exposed and the relative risk for each risk factor. Relative risks for each risk factor were obtained from published meta-analyses. The population at risk values were obtained from a report on chronic disease risk factor surveillance in Lebanon which was conducted by the World Health Organization between 2008 and 2009 and a national study by Semerjian et al. that conducted a multipathway exposure assessment of selected public drinking waters of Lebanon for the risk factors smoking and THMs, respectively. RESULTS: Bladder cancer cases that were the result of smoking in Lebanon among males and females are 33.4 and 18.6%, respectively. Cases attributed to mid-term exposure to THM contamination of drinking water is estimated at 8.6%. CONCLUSION: This paper further highlights the negative impact of smoking on bladder cancer risk and adds an overlooked and often underestimated risk that THMs have on this type of cancer. Thus, it is imperative that a national based study which assesses THM exposure by gender and smoking status be implemented to determine the real risk behind this byproduct.

Prevalence and Correlates of Complementary and Alternative Medicine Use among Patients with Lung Cancer: A Cross-Sectional Study in Beirut, Lebanon.

Patients with lung cancer are increasingly seeking complementary and alternative medicine (CAM) to improve their physiological and psychological well-being. This study aimed to assess CAM use among lung cancer patients in Lebanon. Using a cross-sectional design, 150 lung cancer patients attending the Basile Cancer Institute at the American University of Beirut Medical Center were interviewed. Participants completed a questionnaire addressing sociodemographic characteristics, lung cancer condition, and use of CAM. The main outcome of interest was "use of any CAM therapy since diagnosis." Prevalence of CAM use was 41%. The most commonly used CAM modality among study participants was "dietary supplements/special foods." Results of the multiple logistic regression analyses showed that CAM use was positively associated with Lebanese nationality and paying for treatment out of pocket and was negatively associated with unemployment and having other chronic diseases. About 10% of patients used CAM on an alternative base, 58% did not disclose CAM use to their physician, and only 2% cited health professionals as influencing their choice of CAM. This study revealed a prevalent CAM use among lung cancer patients in Lebanon, with a marginal role for physicians in guiding this use. Promoting an open-communication and a patient-centered approach regarding CAM use is warranted.