Genome Engineering as a Therapeutic Approach in Cancer Therapy: A Comprehensive Review.

Cancer is one of the foremost causes of mortality. The human genome remains stable over time. However, human activities and environmental factors have the power to influence the prevalence of certain types of mutations. This goes to the excessive progress of xenobiotics and industrial development that is expanding the territory for cancers to develop. The mechanisms involved in immune responses against cancer are widely studied. Genome editing has changed the genome-based immunotherapy process in the human body and has opened a new era for cancer treatment. In this review, recent cancer immunotherapies and the use of genome engineering technology are largely focused on.

Mesenchymal stem cells-derived secretome and extracellular vesicles: perspective and challenges in cancer therapy and clinical applications

Stem cell-based therapies have been foreshowed as a promising therapeutic approach for the treatment of several diseases. However, in the cancer context, results obtained from clinical studies were found to be quite limited. Deeply implicated in inflammatory cues, Mesenchymal, Neural, and Embryonic Stem Cells have mainly been used in clinical trials as a vehicle to deliver and stimulate signals in tumors niche. Although these stem cells have shown some therapeutical promises, they still face several challenges, including their isolation, immunosuppression potential, and tumorigenicity. In addition, regulatory and ethical concerns limit their use in several countries. Mesenchymal stem cells (MSC) have emerged as a gold standard adult stem cell medicine tool due to their distinctive characteristics, such as self-renewal and potency to differentiate into numerous cell types with lower ethical restrictions. Secreted extracellular vesicles (EVs), secretomes, and exosomes play a crucial role in mediating cell-to-cell communication to maintain physiological homeostasis and influence pathogenesis. Due to their low immunogenicity, biodegradability, low toxicity, and ability to transfer bioactive cargoes across biological barriers, EVs and exosomes were considered an alternative to stem cell therapy through their immunological features. MSCs-derived EVs, exosomes, and secretomes showed regenerative, anti-inflammatory, and immunomodulation properties while treating human diseases. In this review, we provide an overview of the paradigm of MSCs derived exosomes, secretome, and EVs cell-free-based therapies, we will focus on MSCs-derived components in anti-cancer treatment with decreased risk of immunogenicity and toxicity. Astute exploration of MSCs may lead to a new opportunity for efficient therapy for patients with cancer (AU)

Mesenchymal stem cells-derived secretome and extracellular vesicles: perspective and challenges in cancer therapy and clinical applications.

Stem cell-based therapies have been foreshowed as a promising therapeutic approach for the treatment of several diseases. However, in the cancer context, results obtained from clinical studies were found to be quite limited. Deeply implicated in inflammatory cues, Mesenchymal, Neural, and Embryonic Stem Cells have mainly been used in clinical trials as a vehicle to deliver and stimulate signals in tumors niche. Although these stem cells have shown some therapeutical promises, they still face several challenges, including their isolation, immunosuppression potential, and tumorigenicity. In addition, regulatory and ethical concerns limit their use in several countries. Mesenchymal stem cells (MSC) have emerged as a gold standard adult stem cell medicine tool due to their distinctive characteristics, such as self-renewal and potency to differentiate into numerous cell types with lower ethical restrictions. Secreted extracellular vesicles (EVs), secretomes, and exosomes play a crucial role in mediating cell-to-cell communication to maintain physiological homeostasis and influence pathogenesis. Due to their low immunogenicity, biodegradability, low toxicity, and ability to transfer bioactive cargoes across biological barriers, EVs and exosomes were considered an alternative to stem cell therapy through their immunological features. MSCs-derived EVs, exosomes, and secretomes showed regenerative, anti-inflammatory, and immunomodulation properties while treating human diseases. In this review, we provide an overview of the paradigm of MSCs derived exosomes, secretome, and EVs cell-free-based therapies, we will focus on MSCs-derived components in anti-cancer treatment with decreased risk of immunogenicity and toxicity. Astute exploration of MSCs may lead to a new opportunity for efficient therapy for patients with cancer.

Management of Multiple Myeloma in the Middle East: Unmet Needs, Challenges and Perspective.

Multiple myeloma (MM) is a prevalent hematological malignancy. Resource-constrained settings such as the Middle East are particularly burdened by the increasing trends in MM morbidity and mortality in addition to challenges in the management of MM. It thus becomes necessary to identify and address debatable areas of current practice and gaps in the management of MM in the Middle East. With a special focus on the Lebanese situation, the first-line treatment of the very elderly (> 80 years old) is discussed, in addition to the impact of relapse type (biochemical or clinical relapse) on maintenance therapy, the choice of first relapse therapy in relation to maintenance therapy, and the role of MRD in the MM treatment landscape. The need for realistic management guidelines accounting for local resources and expertise, in addition to the reflection of drug accessibility and cost on clinical practice are recognized.

Impact and Cost-Effectiveness of Oncotype DX for Guiding Adjuvant Chemotherapy Decisions in Early Breast Cancer.

INTRODUCTION: Oncotype DX is approved in multiple countries but its cost-effectiveness is a matter of considerable health debate. Lebanon is high-middle income country according to the World Bank classification however it is facing a mounting financial and health care burden from cancer. Therefore, we conducted a costeffectiveness analysis of Oncotype DX based Lebanese on real-life data. METHODS: We updated a Canadian cost-effectiveness model of Oncotype DX by incorporating Lebanese data. The patient population was a real-life cohort of 82 women diagnosed with hormone receptor - positive and HER2 - negative early breast cancer. RESULTS: Overall, providing Oncotype DX to only intermediate Adjuvant! Online risk patients costs an additional $83 CAD (93,883 LBP) per additional QALY. From this point, extending provision to also cover high Adjuvant! Online risk patients costs an additional $736 CAD (831,578 LBP) per additional QALY. From this point, extending provision further to also cover low Adjuvant! Online risk patients (such that Oncotype DX is provided to all patients) costs an additional $14,562 CAD (16.46m LBP) per additional QALY. Given that most women in our population-based sample were classified as intermediate Adjuvant! Online risk patients, our study focused on this subset in the second analysis. Providing Oncotype DX to intermediate Adjuvant! Online risk patients has a relatively small additional cost compared to not providing Oncotype DX, and results in a relatively large QALY gain. The incremental cost per QALY is $2,022 CAD (2.29m LBP), implying that Oncotype DX is cost-effective for intermediate Adjuvant! Online risk patients if the willingness-to-pay for a QALY is greater than 2.29m LBP. CONCLUSION: As one of the few economic evaluations to date conducted using Lebanese data, this evaluation provides information to decision makers regarding the cost-effectiveness of providing Oncotype DX to Lebanese patients.

Should we screen patients with hematologic malignancies for COVID-19?

The coronavirus disease (COVID-19) pandemic has posed several challenges to the hematology community to re-organize the medical care of patients with hematologic malignancies. Whereas the oncology societies favored a more or less conservative approach which considered the possibility of delaying treatment administration on a case-by-case basis, the hematology community guidelines were less stringent and recommended adequate individualized regimens. As countries are de-escalating the lockdown and the medical community is unable to foresee the end of the current outbreak will and whether the pandemic would eventually come back as a seasonal infection, there is interest in screening of patients with hematology malignancies with COVID-19 instead of limiting access to curative treatments. The rapidly accumulating knowledge about COVID-19 allows a better understanding of the diagnostic tools that may be potentially used in screening. Herein, we briefly review the pathophysiology of COVID-19, the rationale of screening of patients with hematologic malignancies, tools for screening, and available guidelines.

Comprehensive tumor profiling-guided therapy in rare or refractory solid cancer: A feasibility study in daily clinical practice.

Tumor profiling has been shown to benefit patients with rare or refractory metastatic cancer, but several limitations hamper its use in daily clinical practice. We aim to assess the added benefit of a comprehensive tumor profiling, including factors predictive of response to targeted and cytotoxic therapy, in the treatment of refractory or rare solid tumors outside of a formal clinical trial. Patients were included between 2013 and 2017. Multiplatform comprehensive tumor profiling (CTP) was performed on FFPE specimens. Tumor response was evaluated by imaging using the RECIST criteria version 1.1. The PFS ratio was defined as PFS under CTP-guided therapy (PFS2)/PFS under previous standard therapy (PFS1). A clinical benefit was identified if the PFS ratio exceeded the 1.3 threshold value. In total, 184 patients were enrolled among whom 104 were evaluable for the PFS ratio. Objective response rates (ORR) were equal to 25% (CI95: 16.6-33.4%) and 36.5% (CI95: 27.2-45.8%) on the last therapy before CTP and on the CTP-guided therapy respectively (P-value=0.058 on paired proportion comparison test). The proportion of patients achieving a PFS2/PFS1 ratio≥1.3 was equal to 50%. The median PFS1 was statistically lower than PFS2 (120 days compared to 184 days respectively, P-value log rank 0.01). These results confirm the feasibility and the added benefit of a CTP in patients with refractory tumors in daily clinical practice especially in patients not able to enter a clinical trial.

Efficacy and safety of everolimus in hormone receptor positive breast cancer in a developing country: Real-life single institutional experience.

INTRODUCTION: Breast cancer is the second leading cause of cancer-related mortality despite the staggering improvement in cancer therapeutics. So far, published data illustrate endocrine therapy as the cornerstone treatment for patients with hormone receptor-positive metastatic breast cancer. Unfortunately, most patients eventually develop resistance to this treatment. METHODS: The purpose of this study is to evaluate the efficacy of mammalian target of rapamycin inhibition in reversing hormone resistance in the Lebanese breast cancer patients. Efficacy of the intervention according to the independent factors and notable side effects encountered were the primary points of the evaluation. RESULTS: In total, fifty patients received the combination of everolimus and exemestane. The mean age of the study population was 61 ± 11 years. Sensitivity to hormonal therapy before the start of the combination treatment was estimated at 64%. Response rate was 14%, and all patients were partial responders. After regular interval evaluation, the median progression-free survival was 5.2 months since the initiation of therapy. The main toxicities associated with the combination were stomatitis (22%), myalgia (22%), skin toxicity (8%), and hyperglycemia (4%), all Grades 1 and 2. CONCLUSION: Everolimus has been shown to be effective in overcoming hormonal resistance in Lebanese breast cancer patients with results inferior to those reported in the BOLERO-2 population. The particular differences in molecular and pathological aspects of breast cancer in our region should stimulate the extensive research for a better understanding of the particular pattern of the disease.

Trends in hematopoietic stem cell transplant activity in Lebanon.

Hematopoietic stem cell transplantation (HSCT) has been accessible to the population residing in Lebanon and surrounding countries since 1997. HSCT programs were developed in two major hospitals in Beirut: American University of Beirut Medical Center (AUBMC) and Makassed General Hospital. Mount Lebanon Hospital initiated an autologous HSCT activity later. Between 2012 and 2016, the HSCT activity in Lebanon reached a total of 897 transplants, among which 303 (33.8%) were allogeneic HSCT and 594 (66.2%) were autologous HSCT. Overall, autologous HSCT activity has remained stable over the past 5years, whereas allogeneic HSCT activity has seen a steep increase between 2012 and 2013 followed by a modest increase later. Haploidentical transplantation has mushroomed and represented almost half of allogeneic HSCT activity in 2016. AUBMC and Makassed General Hospital are members of the European Blood and Marrow Transplantation (EBMT) and East Mediterranean Blood and Marrow Transplantation groups, and AUBMC has been accredited by JACIE (Joint Accreditation Committee - ISCT & EBMT) since 2016. The past 5years have seen an increase in HSCT-related research and publications, mainly from AUBMC. These research activities were predominantly focused on personalized conditioning for allogeneic HSCT and post-transplant maintenance therapy.

Immune checkpoint inhibitors renal side effects and management.

The choice of immunotherapy in the treatment of cancer has improved the prognosis of many patients affected by various malignancies. The high expectations foreseen with immunotherapy have led to fast approvals despite the incomplete understanding of the toxicity profiles in the different organs, including the kidneys. The high prevalence of chronic kidney disease in cancer patients complicates the issue further and requires a better knowledge of the renal safety profile to ensure an optimal safe treatment. This review summarizes the present knowledge of renal adverse events secondary to immune checkpoint inhibitors and discusses their pathophysiology, clinical presentation and adequate management. We also advocate the need for a multidisciplinary approach in patients with immune-related toxic adverse events.

Where does chemotherapy stands in the treatment of ampullary carcinoma? A review of literature.

Ampullary carcinoma (AC) is a rare gastrointestinal tumor without clear treatment recommendations. The management of this tumor is usually extrapolated from the treatment of pancreatic, biliary duct and intestinal cancers. Few papers have studied the AC as an independent entity and yet succombs to several limitations. These studies were retrospective single institutional experiences with limited sample sizes recruited over a long period of time. Unlike metastatic ACs where chemotherapy is the only recommended option, localized AC once excised may be approached by either chemotherapy alone or concomitant chemoradiation therapy. In this review, we report the overall survival and recurrence factors of more than 1000 patients from all the studies treating exclusively ACs. We also review the medical treatment of this tumor and conclude to the necessity of multi-institutional randomized controlled studies for AC exclusively.

Optimum chemotherapy for the management of advanced biliary tract cancer.

Biliary tract cancers (BTCs) are highly fatal malignancies, which are often diagnosed at an advanced stage and have relatively poor prognosis. The treatment of patients with advanced BTC is systemic, based on chemotherapy or best supportive care, depending on their performance status. Despite clinical trials studying many chemotherapeutic regimens and targeted therapies for the treatment of BTC, the standard of care for advanced BTC remains the combination of gemcitabine with cisplatin. Many new molecules targeting proliferation and survival pathways, the immune response and angiogenesis are currently undergoing phase I and II trials for the treatment of advanced BTC with promising results.

Optimum chemotherapy in the management of metastatic pancreatic cancer.

Pancreatic cancer is one of the most devastating solid tumors, and it remains one of the most difficult to treat. The treatment of metastatic pancreatic cancer (MPC) is systemic, based on chemotherapy or best supportive care, depending on the performance status of the patient. Two chemotherapeutical regimens have produced substantial benefits in the treatment of MPC: gemcitabine in 1997; and FOLFIRIONOX in 2011. FOLFIRINOX improved the natural history of MPC, with overall survival (OS) of 11.1 mo. Nab-paclitaxel associated with gemcitabine is a newly approved regimen for MPC, with a median OS of 8.6 mo. Despite multiple trials, this targeted therapy was not efficient in the treatment of MPC. Many new molecules targeting the proliferation and survival pathways, immune response, oncofetal signaling and the epigenetic changes are currently undergoing phase I and II trials for the treatment of MPC, with many promising results.

Myeloid sarcoma of the nasopharynx mimicking an aggressive lymphoma.

BACKGROUND: Myeloid sarcoma (MS) is a rare extra-medullary tumour of the myeloid lineage, which can be a difficult diagnosis to make. CASE PRESENTATION: We report the case of a 73-year-old male with a right-sided nasopharyngeal mass revealed on CT scan and MRI. RESULTS: An initial cytological and histological examination suggested a high-grade lymphoma. Nevertheless, the final diagnosis was a MS with an unusual involvement of the nasopharynx that was treated with a conventional induction leukemia therapy. Eight months later, the patient had persistent thrombocytopenia and a bone marrow aspiration showed the dysplasia of a high grade myelodysplastic syndrome and cytogenetics detected t(3;21). The patient was treated with a 5-Azacitidine (Vidaza) protocol until overt progression and disease evolution. CONCLUSION: In conclusion few cases of MS involving the nasopharynx have been reported. Its diagnosis is often difficult and should be considered especially when a high index of suspicion is present and the immunophenotype of the malignant haematological cells is not clearly in favour of a lymphoma.

Low-dose radiation treatment in pulmonary mucosa-associated lymphoid tissue lymphoma: a plausible approach? A single-institution experience in 10 patients.

PURPOSE: To propose an alternative approach for treatment of pulmonary marginal zone lymphoma, using a very small radiation dose (2 × 2 Gy) delivered exclusively to tumor sites. METHODS AND MATERIALS: Patients had localized pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma according to the World Health Organization classification. The 6-MV radiation treatments were delivered using tumor-limited fields, except in cases of diffuse bilateral involvement. Two daily fractions of 2 Gy were delivered to tumor-limited fields using a 6-MV linear accelerator. RESULTS: Ten patients with pulmonary MALT lymphoma entered the study. All but 1 had localized tumor masses. The median follow-up was 56 months (range, 2-103 months). Complete remission or an unconfirmed complete remission was obtained in 60% of patients within the first 2 months, and two additional partial responses were converted into a long-term unconfirmed complete remission. All patients are well and alive, no local progression was observed, and the 5-year progression-free survival rate was 87.5% (95% confidence interval 49%-97%). CONCLUSIONS: Our results suggest that extremely low radiation doses delivered exclusively to tumor sites might be a treatment option in pulmonary MALT lymphoma.