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Immunotherapy has improved the prognosis of many cancers, yet a large number of patients have demonstrated resistance to current immune checkpoint inhibitors. LAG-3 is an immune checkpoint expressed on tumor-infiltrating lymphocytes CD4+ and CD8+, Tregs and other immune cells. Coexpression of PD-1 and LAG-3 in solid or hematological cancers is generally associated with a poor prognosis and may be responsible for immunotherapy resistance. Dual inhibition therapy in the RELATIVITY-047 trial significantly improved progression-free survival in metastatic melanoma. This article discusses the presence of a possible synergistic interaction between LAG-3 and PD-1 in the tumor microenvironment and the utility of targeting both immune checkpoint inhibitors as an effective way to bypass resistance and increase treatment efficacy.

Talazoparib is an oral PARP inhibitor approved for locally advanced/metastatic breast cancer. There is no consensus, however, as to whether it is better used as a first-line treatment or after other therapies in patients with gBRCA mutations. In fact, talazoparib showed its superiority compared with chemotherapy in the survival and quality of life of patients with BRCA mutations, with an acceptable toxicity profile. While its role in this indication is not debated, its cost as well as the availability of other effective new agents, particularly immune checkpoint inhibitors, may encourage the movement of this drug to later treatment lines. Until more robust data are available, the best treatment sequence for BRCA-mutated breast cancer must be personalized on a case-by-case basis.

Aim: HER2 is a proto-oncogene expressed in 10–30% of gastric adenocarcinomas and is an ideal target for inhibition in malignancy with high recurrence and dismal survival rates. Materials & methods: A systematic search was conducted via PubMed, Google Scholar and the clinicaltrials.gov database to report the results of ongoing and past studies investigating HER2 inhibitors in gastric cancer. Results: Twenty-five studies were included; ToGA trial is the pivotal trial approving the use of trastuzumab in metastatic gastric cancer, followed by more studies investigating other HER2 inhibitors in this setting, as well as in local and locoregional malignancy. Conclusion: Anti-HER2 molecules are proving efficacy and safety in gastric cancer; the evidence is growing and association with other cancer agents is under investigation.

Locoregional, as well as metastatic renal cell carcinoma, tends to relapse after nephrectomy or metastasectomy. Adjuvant therapy seems to be an effective strategy to reduce the risk of recurrence. All anti-VEGF tyrosine kinase inhibitors except sunitinib have failed to show any benefit in the adjuvant setting in patients with locally advanced disease and an intermediate-to-high chance of recurrence. On the other hand, immune checkpoint inhibitors, which are now used in the first-line in the metastatic setting, are being tested in the adjuvant setting. Pembrolizumab has shown benefit in the adjuvant setting in patients with a high risk of recurrence or with resected metastatic disease with no evidence of disease. Results for other checkpoint inhibitors are still awaited.Advanced and metastatic kidney cancer often tend to relapse after surgery. Treatment maintenance after surgery could be an effective strategy to reduce the risk of recurrence. Anti-VEGF tyrosine kinase inhibitors are the standard of care in the treatment of metastatic kidney cancer. However, they have all (but one) failed to prevent the occurrence of metastases in advanced nonmetastatic kidney cancer. On the other hand, immunotherapy is now being tested as a postsurgery treatment to prevent disease recurrence. Pembrolizumab has shown efficacy in preventing recurrence and is now approved as a postsurgery drug in advanced kidney cancer.

PD-L1 is an important predictive biomarker for treatment by immune checkpoint inhibitors (ICIs). ICIs are now indicated for the treatment of various cancer depending on the level of expression of PD-L1 on tumor cells. PD-L1 testing is done using immunohistochemistry with five different assays approved as companion diagnostic for ICIs. However, these assays have different score reporting methods and do not accurately measure PD-L1 expression. Exosomal PD-L1 testing has recently emerged as an alternative for cell-surface PD-L1 testing however studies are still premature and more extensive knowledge about this new potential biomarker is needed.Lay abstract Immunotherapy is a new strategy for cancer treatment that aims to reactivate the body’s own immune system, originally disabled by the tumor, to fight the malignancy. Immune checkpoint inhibitors are compounds developed for this purpose. However, their efficacy is subject to the abundance of their target, PD-L1, on the surface of cancer cells. Conventional PD-L1 testing through tumor biopsy has multiple technical drawbacks. Another form of PD-L1 secreted by the tumor into the circulation has emerged as a potential target for assessing immune checkpoint inhibitors efficacy but studies are still in their preliminary stages and further testing is required.

The first ‘advanced course on biomarkers in molecular and immuno-oncology’ in the Middle East took place in Beirut, Lebanon, as a hybrid meeting on 11 December 2020. The aim of this seminar was to discuss biomarker development, implications and detection modalities and to highlight advances in molecular technologies as well as the clinical applicability of biomarkers in oncology. The seminar consisted of five sessions, each discussing a special topic in the biomarker field. It also included a competition in the form of a quiz following each session. This was followed by a plenary session presented by well-known national and international speakers, highlighting various aspects of biomarkers in immuno-oncology.

The general population is increasingly using YouTube as a source of information on breast cancer, the most frequent cancer among women. Arabs are the most interested population in breast cancer on YouTube. The transmission of accurate information is important to reduce mortality rates. This cross-sectional study aims to evaluate breast cancer videos on YouTube in the Arab world. A YouTube search for “breast cancer” in Arabic was performed. The most viewed 60 videos included were evaluated for global quality (GQS score), reliability (modified DISCERN score), content (content score), and misleading claims. Recorded and calculated data included views, duration, videos power index, and viewers’ interaction. Sources from legal persons (governments, universities, TV channels, physicians’ groups), and blogs (online health channels, individuals) were categorized. The median global quality (3/5), reliability (2/5), and content scores (4/11) were overall low. Misleading information was found in 42% of the videos. Although videos uploaded by legal persons were less popular (163,454 vs 327,488 views), they hosted more physicians (52% vs 15%), were less misleading (15% vs 64%), covered more content, and were of higher global quality and reliability than videos uploaded by blogs [p

Bladder cancer (BC) is the most common cancer involving the urinary system and the ninth most common cancer worldwide. Tobacco smoking is the most important environmental risk factor of BC. Several single nucleotide polymorphisms have been validated by genome-wide association studies as genetic risk factors for BC. However, the identification of DNA mismatch-repair genes, including MSH2 in Lynch syndrome and MUTYH in MUTYH-associated polyposis, raises the possibility of monogenic hereditary forms of BC. Moreover, other genetic mutations may play a key role in familial and hereditary transmissions of BC. Therefore, the aim of this review is to focus on the major hereditary syndromes involved in the development of BC and to report BC genetic susceptibilities established with genome-wide significance level.

IntroductionBladder cancer (BC) is a highly prevalent malignancy worldwide and particularly in Lebanon. Several studies have reported genetic risk factors in GSTM1 and NAT2, as well as many modifiable and non-modifiable risk factors, associated with BC.MethodsThis is a retrospective study that includes 51 Lebanese patients with BC. Peripheral blood samples were collected from patients and DNA extraction was performed using the standard salting-out method. Whole exome sequencing (WES) was performed and was followed by a thorough analysis of GSTM1, NAT2 and a panel of 127 genes known to be implicated in different hereditary cancers, for the detection of pathogenic germline mutations in the studied individuals.ResultsOur cohort included 42 men (82.4%) and 9 women (17.6%), with a mean age at diagnosis equal to 67 years. Of all participants, 10.8% had a family member diagnosed with BC and 17.3% with other cancer types. Our WES analysis allowed the detection of a high-risk variant found in APC (rs1801155) and a variant in BRIP1 (rs28903098) that are frequent in our cohort and more prevalent in our Lebanese in-house database compared to other international databases. Furthermore, two actionable variants, one in PALB2 (rs864622498) and another in ERCC2 (rs121913016) were detected in 2 different individuals from our cohort, paving the way to personalized therapies in these patients. A variant in NAT2 (rs1799931), shown to be associated with BC in other populations, was detected in 4 patients from our cohort.ConclusionThis is the first study in Lebanon and one of very few international studies carried out by NGS in patients with BC. Further studies in larger cohorts are required to confirm our findings in the Lebanese population.

Acute myeloid leukemia (AML) is a heterogeneous neoplasm characterized by the monoclonal proliferation of immature progenitors. It is the most common acute leukemia in adults and its incidence increases with age. The standard traditional treatment in fit patients was the ‘3 + 7’ regimen and cytarabine consolidation followed or not with allogeneic stem cell transplantation. Recently, several targeted therapies such as gemtuzumab ozogamicin targeting the CD33+ AML, midostaurin, gilteritinib and crenolanib inhibiting FLT3-positive AML and ivosidenib and enasidenib blocking IDH-mutated AML have been approved. These new drugs led to the change of the landscape of the treatment of AML and transforming this disease to a targetable one. We aimed in this paper to review the implications of each new target, the mechanisms of action of these new drugs and we discuss all the studies leading to the approval of these new drugs in their indications according to each target.

Talazoparib is an oral PARP inhibitor approved for locally advanced/metastatic breast cancer. There is no consensus, however, as to whether it is better used as a first-line treatment or after other therapies in patients with

Gastric cancer (GC) is the fourth most common cancer worldwide, characterized by multifactorial pathogenesis and a heterogeneous geographic distribution. The complexity of this malignancy has evolved, with environmental and genetic factors and treatment strategies being more studied.We aimed to group and organize the clinicopathological and epidemiological features of GC in the Arab World and compare with data from Western countries.To obtain the highest number of topic-related articles, an extensive electronic search was conducted in the PubMed MEDLINE and Cochrane databases up to March 2022 using Boolean operators with a combination of keywords and MeSH terms. A total of 42 articles were retained after screening in accordance with the objectives of the study. The estimated age-standardized incidence rates in the Arab World were collected from the GLOBOCAN 2020 database.A total of 46 articles were retrieved from 11 countries in the Arab World. Epidemiological elements were collected, especially tumour attributes, risk factors and population characteristics, in addition to some therapeutic strategies. Results were regrouped by theme and then organized in tables and charts, allowing a global and regional approach to the subject.This review shows that the Arab World is considered a low-rate GC incidence region, presenting almost the same tumour characteristics as the Western countries. The lack of GC data in the Arab World should trigger a rise in research on this type of malignancy to better understand the subject.سرطان المعدة في العالم العربي: استعراض منهجي.مارك عودة، مارك مسلم، مجد عبده، براين يوسف، هامبيك رفايل كوريه، حميد عبيد الشامسي.يُعدُّ سرطان المعدة رابع أكثر أنواع السرطانات شيوعًا في العالم، ويتميز بأنه ينشأ عن عوامل متعددة، وله توزيع جغرافي غير متجانس. وقد تطور تعقيد هذا الورم الخبيث، مع خضوع العوامل البيئية والجينية واستراتيجيات العلاج لمزيد من الدراسة.هدفت هذه الدراسة الى تجميع وتنظيم السمات السريرية الباثولوجية والوبائية لسرطان المعدة في العالم العربي ومقارنتها ببيانات من بلدان غربية.للحصول على أكبر عدد من المقالات المتعلقة بالموضوع، أُجريَ بحث إلكتروني موسع في قاعدتََي بيانات PubMed MEDLINE وCochrane حتى مارس 2022 باستخدام عوامل منطقية (Boolean) مع مزيج من الكلمات المفتاحية ومصطلحات العناوين الرئيسية للموضوعات الطبية (MeSH). وجرى الاحتفاظ بما مجموعه 42 مقالًًا بعد الفرز وفقًا لأهداف الدراسة. وجُُمعت معدلات الإصابة المقدَّرة المُوحَّدة حسب السن في العالم العربي من قاعدة بيانات GLOBOCAN 2020.جرى الحصول على ما مجموعه 46 مقالًًا من 11 بلدًا في العالم العربي. وجرى جمع العناصر الوبائية، ولا سيما خصائص الأورام، وعوامل الخطر، وخصائص السكان، بالإضافة إلى بعض الاستراتيجيات العلاجية. وأُعيد تجميع النتائج حسب الموضوع، ثم نُظِّمت في جداول ومخططات، الأمر الذي أتاح اتباعَ نهجٍ عالمي وإقليمي إزاء الموضوع.يُبيِِّّن هذا الاستعراض أن العالم العربي يُعدُّ منطقة ذات معدل منخفض للإصابة بسرطان المعدة، إذ تُظهِر خصائصَ الأورام نفسها تقريبًا التي تظهر في الدول الغربية. وينبغي أن يؤدي نقص بيانات سرطان المعدة في العالم العربي إلى زيادة الأبحاث المتعلقة بهذا النوع من الأورام الخبيثة، من أجل التوصل إلى فهم أفضل للموضوع.Cancer de l'estomac dans le monde arabe : une analyse systématique.Le cancer de l'estomac est le quatrième cancer le plus fréquent dans le monde. Il se caractérise par une pathogenèse multifactorielle et une distribution géographique hétérogène. La complexité de cette tumeur maligne a évolué, les facteurs environnementaux et génétiques ainsi que les stratégies de traitement étant davantage étudiés.Notre objectif consistait à regrouper et organiser les caractéristiques clinicopathologiques et épidémiologiques du cancer de l'estomac dans le monde arabe et les comparer aux données provenant des pays occidentaux.Afin d'obtenir le plus grand nombre d'articles liés au sujet, une recherche en ligne approfondie a été menée dans les bases de données PubMed/MEDLINE et Cochrane jusqu'en mars 2022 en utilisant des opérateurs booléens avec une combinaison de mots-clés et de termes MeSH. Au total, 42 articles ont été retenus après une sélection conforme aux objectifs de l'étude. Les taux d'incidence standardisés selon l'âge dans le monde arabe ont été recueillis à partir de la base de données GLOBOCAN 2020.Au total, 46 articles provenant de 11 pays du monde arabe ont été extraits. Des données épidémiologiques ont été recueillies, notamment les caractéristiques des tumeurs, les facteurs de risque et les caractéristiques de la population, ainsi que certaines stratégies thérapeutiques. Les résultats ont été regroupés par thème, puis organisés sous forme de tableaux et de graphiques, de telle sorte qu'ils permettent de traiter le sujet à l'échelle mondiale et régionale.Cette analyse montre que le monde arabe est considéré comme une région à faible incidence de cancer de l'estomac, où les caractéristiques des tumeurs sont sensiblement les mêmes que dans les pays occidentaux. Le manque de données sur le cancer de l'estomac dans le monde arabe devrait susciter une augmentation des recherches concernant ce type de tumeur maligne afin de mieux comprendre le sujet.

Poly-(ADP-ribose) polymerase (PARP) inhibitors act in cells with defects in homologous recombination DNA repair (HRR) caused by genomic aberrations such as BRCA mutations. This phenomenon called synthetic lethality is known now to be more common in prostate cancer than previously thought. Olaparib and rucaparib, two PARP inhibitors, were successfully tested in clinical trials for HRR-deficient metastatic castration-resistant prostate cancer. They received a breakthrough US FDA approval in HRR altered metastatic castration-resistant prostate cancer in May 2020. Consequently, the combination of PARP inhibitors with other agents such as androgen receptor pathway inhibitors, immune checkpoint inhibitors or DNA damage inducing chemotherapy are being currently largely studied. In our review, we aim to summarize the key PARP inhibitors published and ongoing trials in prostate cancer.

In December 2019, a new emerging virus causing mild-to-severe pneumonia was detected in China. The virus was described as a variant of SARS-CoV and was called SARS-CoV-2, then declared a pandemic by the WHO on 11 March 2020. Millions of people contracted the virus and presented with a symptomatology of variable severity, including upper respiratory tract symptoms, systemic symptoms and diarrhea. We herein report a rare skin presentation in a 33-year-old female that occurred both during COVID-19 infection and after receiving the first dose of COVID-19 vaccine.

Introduction/Background* Borderline ovarian tumors (BOT) are low malignant potential lesions with a good prognosis that represent around 15% of all epithelial tumors of the ovary. In addition to that, 30% of patients with BOT are less than 40 years old which makes the preservation of fertility a key point in management. Molecular studies in ovarian cancer have shown a correlation between the genetic profile of the tumor and the patient‘s prognosis Methodology We report the case of a 25-year-old patient, G0P0A0, diagnosed with a mucinous borderline right ovarian tumor back in 2005. In 2009, during a routine control ultrasound, another ovarian cyst was identified on the right side. She was operated again of a cystectomy and peritoneal staging and histopathology confirmed the mucinous nature of the tumor. FIGO stage was IA in both cases. The two blocs of tumors underwent a full exome sequencing technique in order to identify possible key mutations. Result(s)* Both tumors had variations of EGFR, FGFR3, BRCA1, STK11, NTKR1 and PIK3CA genes. However, the first tumor also had a KRAS mutation that wasn’t found in the second lesion four years later. KRAS variants have been shown to be present in low grade ovarian cancer and well-differentiated tumors. Conclusion* Borderline tumors often recurs in form of borderline tumor but the genetic profile should not be the same as the primary tumor, as shown in our case report. Loss of KRAS could explain the recurrence of the disease. Seeing that the molecular profile of the tumor is in constant change, a continuity in the spectrum normal-benign-borderline-malignant could be hypothesized.

In a study of 105 patients with cancer and 536 without, all with confirmed COVID-19, cancer was predictive of more severe disease, with stage IV cancer, hematologic cancer, and lung cancer being associated with worse outcomes., The novel COVID-19 outbreak has affected more than 200 countries and territories as of March 2020. Given that patients with cancer are generally more vulnerable to infections, systematic analysis of diverse cohorts of patients with cancer affected by COVID-19 is needed. We performed a multicenter study including 105 patients with cancer and 536 age-matched noncancer patients confirmed with COVID-19. Our results showed COVID-19 patients with cancer had higher risks in all severe outcomes. Patients with hematologic cancer, lung cancer, or with metastatic cancer (stage IV) had the highest frequency of severe events. Patients with nonmetastatic cancer experienced similar frequencies of severe conditions to those observed in patients without cancer. Patients who received surgery had higher risks of having severe events, whereas patients who underwent only radiotherapy did not demonstrate significant differences in severe events when compared with patients without cancer. These findings indicate that patients with cancer appear more vulnerable to SARS-CoV-2 outbreak. Significance: Because this is the first large cohort study on this topic, our report will provide much-needed information that will benefit patients with cancer globally. As such, we believe it is extremely important that our study be disseminated widely to alert clinicians and patients. This article is highlighted in the In This Issue feature, p. 747

The evolution of precision medicine in the field of oncology has led to a radical change in the course of malignancies. PARP inhibitors are drugs that block the activity of the PARP enzyme responsible for base excision repair and have shown significant positive response when used for tumors lacking homologous recombination, namely high efficacy among BRCA-mutated tumors. Since 2014, when olaparib received an accelerated US FDA approval in ovarian cancer, we witnessed many other FDA approvals for olaparib, rucaparib, niraparib and talazoparib. Additionally, many Phase I, II and III trials were published presenting revolutionizing results. Other ongoing trials combined PARP inhibitors with checkpoint inhibitors. We aimed in this review to state the FDA approvals for PARP inhibitors in breast, ovarian, fallopian tube and primary peritoneal cancers, report the major published trials in high impact medical journals, and mention the ongoing trials combining these drugs with checkpoint inhibitors.

The use of immune checkpoint inhibitors has been approved in the advanced and metastatic setting for many types of solid tumors. Nonetheless, their role in the adjuvant setting is limited to the treatment of surgically resected melanoma. Ipilimumab was the first immune checkpoint inhibitor approved for this indication, followed by nivolumab and pembrolizumab. Many ongoing trials are evaluating these molecules in the postoperative setting, alone or in combination with other therapies. Preliminary results are promising regarding the treatment of other cutaneous tumors, lung cancers, head and neck squamous cell carcinomas, bladder cancer and renal cell carcinomas. Some data assessing their use for the adjuvant treatment of esophageal, colorectal, ovarian cancer and other solid tumors are similarly emerging.

Triple-negative breast cancer (TNBC) is known to have a poor prognosis and limited treatment options, namely chemotherapy. Different molecular studies have recently classified TNBC into different subtypes opening the door to potential new-targeted treatment options. In this review, we discuss the current standard of care in the treatment of TNBC in the neoadjuvant, adjuvant and metastatic settings. In addition, we summarize the ongoing phase III clinical trials evaluating different associations between the 3 pillars of anticancer treatment: chemotherapy, targeted therapy and immunotherapy.