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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.

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.

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.

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.

Aim: Assess the knowledge and behavior of Lebanese parents when it comes to melanoma and its prevention in children. Methods: A survey, to be completed by parents, was sent through children from three schools. Results: During sun exposure only 23.5% of 1012 respondents were always covering enough areas of their children's skin and 74.1% did not always apply sunscreen to their children. Parents of private school children were three times more likely to apply sunscreen to their children when exposed to sun, four times more likely to reapply sunscreen every 2–3 h and 21 times more likely to use a higher sun protection factor. Conclusion: Sun protection in children is insufficient and sunburns are frequent, illustrating the need for melanoma awareness campaigns.

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.

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.

Bladder cancer (BC) is the most frequent cancer affecting the urinary tract. With the growing era of targeted therapies around the 2000s, many trials evaluated the efficacy of targeted therapy in advanced BC. However, no approval was given yet to any form of targeted therapy when it comes to BC. The aim of this paper was to report the most pivotal trials that evaluated different families of targeted therapy in the treatment of BC, according to their biomarkers (FGFR3, EGFR, HER2, VEGF and PI3K/AKT/mTOR). The ongoing trials testing targeted therapies in advanced BC were then summarized. Finally, the different immunotherapies approved for this disease and their potential combination with targeted therapy were addressed.

Aim: To describe the activity in the ‘breast unit’ at the department of radiology during the coronavirus disease 19 lockdown in a university hospital treating coronovirus disease 19 patients in a Middle-Eastern developing country. Materials: This was a retrospective study conducted from March 9 until 11 May 2020, in the breast unit at the department of radiology of a central university hospital in a Middle-Eastern developing country. Data were collected from 205 patients visiting the breast unit during the lockdown period and compared with the activity in the same period in the previous year. Results: Reduction of the breast unit activity was estimated at 73%. In addition, 153 mammograms, 205 ultrasounds, and 16 breast MRIs were done. Indications for mammogram were screening (41.5%), follow-up (22%), clinical symptoms (20%) and breast cancer surveillance (16.5%). MRI was performed mostly for preoperative surgical management. The rate of positive biopsies was 41%. All staff members and patients have accommodated to new adjustments. Conclusion: Activity in the breast unit dropped during the lockdown period. Staff should continue to seek their own and their patient’s safety without diminishing the quality of healthcare.

Aim: Report the epidemiologic and histologic characteristics of CNS lesions in the Lebanese population. Methods: We conducted a retrospective study evaluating 2025 CNS lesions diagnosed between 1998 and 2017 in the pathology laboratory of a Lebanese tertiary center. Results: 52.2% of patients were men with a median age of 50 years. The most frequent symptoms were epilepsy (22.5%), headache (20.6%) and motor impairment (19.9%). 90.7% of tumors were primary. Lung (35.6%) and breast (16.5%) were the most frequent primaries of metastases. 46.2% of primary CNS tumors were glial, predominantly astrocytic (56.4%), and (42.5%) were nonglial, predominantly meningeal tumors (58%). Conclusion: Compared with Western literature, the Lebanese population is characterized by a younger age of onset of brain tumors, a lower rate of meningiomas and a higher rate of gliomas.

Aim: As no meta-analyses have evaluated tyrosine kinase inhibitors in the adjuvant setting of high-risk renal cell carcinoma (RCC), the aim was to evaluate the benefit of sunitinib and pazopanib in the adjuvant setting. Methods: This meta-analysis included all Phase III randomized controlled trials evaluating adjuvant sunitinib and pazopanib in high-risk RCC. Primary outcome was the comparison of disease-free survival (DFS) between tyrosine kinase inhibitors and placebo. Results: There was a tendency for significant overall effect of both sunitinib and pazopanib on DFS (hazard ratio: 0.85; 95% confidence interval: 0.72–1.01; p = 0.06). There was no significant difference between the effect of sunitinib and pazopanib on DFS (p = 0.51; I2 = 0%). Conclusion: Pazopanib and sunitinib could prolong DFS in the adjuvant treatment of high-risk RCC and seem equally effective in this setting.

Driving molecular mutations such as rearrangement of ALK and EGFR mutation is present in 5–10% of non-small-cell lung cancer. Tyrosine kinase inhibitors have shown good efficacy and thus become the standard of care. However, tumors have developed several resistance mechanisms against tyrosine kinase inhibitors, including transformation to small-cell lung carcinoma (SCLC). Transformation to SCLC after administration of anti-EGFR in EGFR-mutated adenocarcinoma has been well documented. Similarly, it appears that the same transformation happens in ALK-rearranged adenocarcinoma after the use of anti-ALK. In fact, to date eight cases have been reported in the literature. We aimed in this paper to focus on the characteristics, prognosis and treatment of these transformed SCLC.

Aim: We aimed to understand the biology of chronic lymphocytic leukemia (CLL) patients in Lebanon. Materials & methods: We applied conventional cytogenetic and FISH studies on Lebanese patients diagnosed with CLL and undergoing a watch and wait approach. Results: Our study disclosed 53.6% of patients with aberrant karyotypes among which 26.7% were complex karyotypes. Genetic aberrations included del(13q14) 46.4%, 14q32 translocation in 25%, trisomy 12 in 14.3%, del(17p13) and del(11q22) in 7.1% each. The deletion of 6q21/6q23 was not found in any of our patients. Conclusion: The higher prevalence of del(13q14) as a sole abnormality could be the primary event in inducing CLL. The del(17p13) and del(11q22) followed as potential drivers for progression in CLL patients with a watch and wait approach.

Brain metastases (BMs) are representing a new challenge for the oncologist; their incidence is increasing due to the better overall survival and systemic disease control in many malignancies, consequent to new potent cytotoxic and targeted therapies. In the era of immunotherapies, checkpoint inhibitors are representing a new therapeutic option in different solid tumors and settings; preliminary results showed potential activity of these agents in patients with BM, when administered as single agent or in combination with radiation therapy. After presenting the arguments in favor of this new strategy, we reported the preliminary results of the trials evaluating these agents in BM, we described the ongoing trials and we discussed the potential role of these agents in the BM treatment.

Immune checkpoint inhibitors (ICI) represent a new revolutionary weapon in the armamentarium of anti-cancer therapies. The side effects of these new agents represent a new challenge for oncologists; they are usually unpredictable and sometimes life threatening, if not managed rapidly and adequately. The most frequent side effects are the dermatologic, but they are usually low grade side effects and consequently easily manageable. Rash, pruritus and vitiligo are the most frequent dermatologic side effects. We aimed in this review to describe first all the dermatologic side effects of ICI according to the subtype of ICI and combination therapies in the clinical trials, then to report all the rare case reports dermatologic side effects, and finally to present the management algorithm of these side effects.

The next decade in cancer therapy will be marked by the expansion of immunotherapies, namely immune checkpoint inhibitors. The increasing number and combination of checkpoint inhibitors and the variety of their mechanisms of action and indications will most likely multiply the side effects associated with these therapies and make their management more complicated and diversified. Given the growing rate of approval of different checkpoint inhibitors in different cancers in multiple settings, a review summarizing the major side effects of the new agents in use today and their management seems to be appropriate. Highlighting these adverse events and their management in a single review might help the daily practice of the physicians and consequently contribute the patient's safety and quality of life.

Aim: This study aims to recognize the distribution of different seizures etiologies in cancer patients, the most common primary tumors responsible for brain metastases, the most epileptogenic primary tumors and the therapeutic modalities. Methods: A retrospective study was conducted at Hotel-Dieu de France Hospital targeting patients admitted to hematology–oncology department between 2005 and 2016 who presented a seizure. Results: Of the 153 included patients, mean age was 57 years (standard deviation = 16 years) and a male predominance (66%). The majority of seizures were due to a primary tumor (49%) or brain metastases (32%). Other reversible (metabolic and drug) or nonreversible causes (carcinomatous meningitis, radiation and cardiovascular complications) formed the remaining causes. Regarding antiepileptic treatments, sodium valproate was mostly used, followed by levetiracetam and phenytoin. Conclusion: Numerous reversible causes are involved in the onset of epileptic seizures, including metabolic disorders, antibiotics and chemotherapies.