Management of biliary tract cancers in early-onset patients: A nested multicenter retrospective study of the ACABI GERCOR PRONOBIL cohort.

BACKGROUND & AIMS: Accumulating data has shown the rising incidence and poor prognosis of early-onset gastrointestinal cancers, but few data exist on biliary tract cancers (BTC). We aimed to analyse the clinico-pathological, molecular, therapeutic characteristics and prognosis of patients with early onset BTC (EOBTC, age ≤50 years at diagnosis), versus olders. METHODS: We analysed patients diagnosed with intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder adenocarcinoma between 1 January 2003 and 30 June 2021. Baseline characteristics and treatment were described in each group and compared. Progression-free survival, overall survival and disease-free survival were estimated in each group using the Kaplan-Meier method. RESULTS: Overall, 1256 patients were included, 188 (15%) with EOBTC. Patients with EOBTC demonstrated fewer comorbidities (63.5% vs. 84.5%, p < .0001), higher tumour stage (cT3-4: 50.0% vs. 32.3%, p = .0162), bilobar liver involvement (47.8% vs. 32.1%, p = .0002), and metastatic disease (67.6% vs. 57.5%, p = .0097) compared to older. Patients with EOBTC received second-line therapy more frequently (89.5% vs. 81.0% non-EOBTC, p = .0224). For unresectable patients with BTC, median overall survival was 17.0 vs. 16.2 months (p = .0876), and median progression-free survival was 5.8 vs. 6.0 months (p = .8293), in EOBTC vs. older. In advanced stages, fewer actionable alterations were found in EOBTC (e.g., IDH1 mutations [7.8% vs. 16.6%]; FGFR2-fusion [11.7% vs. 8.9%]; p = .029). CONCLUSIONS: Patients with EOBTC have a more advanced disease at diagnosis, are treated more heavily at an advanced stage but show similar survival. A distinctive molecular profile enriched for FGRF2 fusions was found.

Targetable Molecular Alterations in the Treatment of Biliary Tract Cancers: An Overview of the Available Treatments.

Biliary tract cancers (BTCs) are rare tumours, most often diagnosed at an unresectable stage, associated with poor prognosis, with a 5-year survival rate not exceeding 10%. Only first- and second-line treatments are well codified with the combination of cisplatin-gemcitabine chemotherapy and immunotherapy followed by 5-FU and oxaliplatin chemotherapy, respectively. Many studies have shown that BTC, and more particularly intrahepatic cholangiocarcinoma (iCCA), have a high rate of targetable somatic alteration. To date, the FDA has approved several drugs. Ivosidenib targeting IDH1 mutations, as well as futibatinib and pemigatinib targeting FGFR2 fusions, are approved for pre-treated advanced CCA. The combination of dabrafenib and trametinib are approved for BRAFV600E mutated advanced tumours, NTRK inhibitors entrectinib and larotrectinib for tumours bearing NTRK fusion and prembrolizumab for MSI-H advanced tumours, involving a small percentage of BTC in these three settings. Several other potentially targetable alterations are found in BTC, such as HER2 mutations or amplifications or KRASG12C mutations and mutations in genes involved in DNA repair mechanisms. This review aims to clarify the specific diagnostic modalities for gene alterations and to summarize the results of the main trials and developments underway for the management of advanced BTC with targetable alterations.

Precision Medicine in Pancreatic Ductal Adenocarcinoma: The Impact of Targeted Therapies on Survival of Patients Harboring Actionable Mutations.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of death by cancer worldwide. Mostly diagnosed with locally advanced or metastatic disease, patients lack treatment options. Gene alterations (GAs) are frequently observed in PDAC, some of which are considered for molecular targeted therapies (MTTs), with potential clinical benefits and improved outcomes. However, the applicability of molecular profiling (MP) for precision medicine in PDAC remains to be demonstrated. METHODS: We conducted a retrospective analysis of all patients, aged ≥18 years with histologically confirmed PDAC, who underwent tumor MP between 2010 and 2020 in our institution as part of personalized medicine trials. The primary study endpoint was overall survival (OS), and (minimal follow-up was 6 months after MP). RESULTS: Of 115 eligible patients, MP was successful in 102 patients (89%). KRAS mutations were the most frequent GAs, mostly G12D. Based on ESCAT classification, actionable GAs were found in 29 patients (28%), involving mainly BRCA1 or BRCA2 (5 (18%)), HER2 (5 (18%)), MTAP (5 (18%)), and FGFR (3 (11%)). Only 12 of these 29 patients (41%, or 10% of the whole population) received MTTs, with a median progression-free survival of 1.6 months. Median OS was 19 months in patients with actionable GAs treated with MTTs (n = 12 (11.8%)), 14 months in patients with actionable GAs treated with standard therapies (n = 17 (16.7%)), and 17 months in patients without actionable GAs treated with standard therapies (n = 73 (71.5%); p = 0.26). The absence of liver metastases was associated with better OS (HR = 0.471, p = 0.01). The highest OS following MTT was observed in patients with BRCA mutations treated with olaparib. INTERPRETATION: Actionable GAs were found in more than a quarter of patients with advanced PDAC. Overall, targeting actionable GAs with MTTs was not associated with improved OS in this retrospective study with limited patient numbers. However, selected GA/MTT combinations (e.g., BRCA mutations/olaparib) were associated with a better outcome.

Non Hodgkin lymphoma in Lebanon: a retrospective epidemiological study between 1984 and 2019.

BACKGROUND: Lymphomas are ranked as the fifth most common cancer in Lebanon. There is concern about the need of information regarding the prevalence of lymphoid neoplasm particularly Non-Hodgkin lymphoma (NHL) subtypes in the Lebanese population. This study intended to establish a descriptive status of NHL histological subtypes distribution in Lebanon thus identifying the most common types, knowing that the literature is poor regarding the distribution of lymphoid malignancies particularly NHLs in Lebanon. METHODS: A bicenter retrospective descriptive study was performed. Patients aged above 18, diagnosed with NHL between January 1984 and March 2019 and registered in two Lebanese Medical centers were included in this study; 699 medical files were reviewed and the baseline characteristics of the disease were collected. Histological classification was based on the Working Formulation (WF) and World Health Organization (WHO) classification systems, whereas staging was based on the Ann Arbor system. Disease status was monitored with imaging studies. RESULTS: The mean age at diagnosis was 53.52 ± 17.46 years in the studied population, with 380 (54.4%) males and 319 (45.6%) females. B-cell lymphoma (BCL) accounted for 86.3% while T-cell neoplasms accounted for 13.7%. The most common subtype was diffuse large B-cell lymphoma (DLBCL) (54%) followed by follicular lymphoma (FL) (17.2%). Mantle cell lymphoma (MCL) represented 3% of all BCL and small lymphocytic lymphoma (SLL) comprised less than 2%. Mucosa-associated lymphoid tissue (MALT) and Burkitt's lymphomas represented 3 and 1.7% respectively. 36.5% of the patients had extranodal disease at diagnosis. High-grade tumor represented 80.1% with 33.1% stage IV disease. CONCLUSION: These observations indicate that the epidemiological patterns of NHLs in Lebanon were comparable to Western countries. Aggressive lymphomas account for the majority of NHLs in Lebanon.

Molecular Landscape of Therapy-related Myeloid Neoplasms in Patients Previously Treated for Gynecologic and Breast Cancers.

Definition of therapy-related myeloid neoplasms (TRMN) is only based on clinical history of exposure to leukemogenic therapy. No specific molecular classification combining therapy-related acute myeloid leukemia and therapy-related myelodysplastic syndromes has been proposed. We aimed to describe the molecular landscape of TRMN at diagnosis, among 77 patients with previous gynecologic and breast cancer with a dedicated next-generation sequencing panel covering 74 genes. We investigated the impact of clonal hematopoiesis of indeterminate potential-associated mutations (CHIP-AMs defined as presence at TRMN stage of mutations described in CHIP with a frequency >1%) on overall survival (OS) and the clinical relevance of a modified genetic ontogeny-based classifier that categorized patients in 3 subgroups. The most frequently mutated genes were TP53 (31%), DNMT3A (19%), IDH1/2 (13%), NRAS (13%), TET2 (12%), NPM1 (10%), PPM1D (9%), and PTPN11 (9%). CHIP-AMs were detected in 66% of TRMN patients, with no impact on OS. Yet, patients with CHIP-AM were older and had a longer time interval between solid tumor diagnosis and TRMN. According to our modified ontogeny-based classifier, we observed that the patients with TP53 or PPM1D mutations had more treatment lines and complex karyotypes, the "MDS-like" patients were older with more gene mutations, while patients with "De novo/pan-AML" mutations were younger with more balanced chromosomal translocations. Median OS within each subgroup was 7.5, 14.5, and 25.2 months, respectively, with statistically significant difference in multivariate analysis. These results support the integration of cytogenetic and molecular markers into the future TRMN classification to reflect the biological diversity of TRMN and its impact on outcomes.

Duchenne Smile is Associated with Quality of Life and Survival in Hemodialysis Patients.

Objectives: Hemodialysis is the most used renal replacement modality for end-stage renal disease patients. Dialysis patients are usually assessed for quality of life (QoL) but smiling was never studied. Duchenne smile is a genuine expression of joy, associated with better survival in some groups of the general population. In this study, we aimed to evaluate whether the smile of dialysis patients can predict their QoL and mortality. Methods: All hemodialysis patients in Saint-George Hospital were included in this prospective study. Patients were interviewed using the Health-Related QoL questionnaire and followed for 10 days for smile screening. Those who smiled more than 34% of time were considered as smiling, then followed for death over 2 years. Results: Overall, 71 patients were studied. Duchenne smile was associated with death at 1 and 2 years (HR = 0.194 [95% CI 0.039-0.958], p = .044) but not with sex or diabetes. Smiling showed a statistically significant correlation with older age, fewer hospitalizations, vitality, physical component score, several QoL scores and general health. Conclusions: A simple observation of patients' Duchenne smile by nephrologists in hemodialysis units can give an idea about their QoL and 2-year survival.

Iron deficiency across chronic kidney disease stages: Is there a reverse gender pattern?

In non-dialysis chronic kidney disease patients, looking for iron deficiency is highly variable in practice and there is a great variability regarding the cutoffs used to treat iron deficiency. The aim of this study is to investigate the degree of iron deficiency in non-dialysis chronic kidney disease patients on erythropoiesis-stimulating agents. We included all non-dialysis chronic kidney disease patients that applied to the Lebanese Ministry of Public Health for erythropoiesis-stimulating agents' coverage during a 5-month period. Iron requirement was assessed based on two guidelines' target-to-treat cutoffs: 1-ferritin <100 ng/ml and/or TSAT < 20% (KDOQI 2006), 2- ferritin ≤500 ng/ml and TSAT ≤30% (KDIGO 2012). A total of 238 CKD patients were included over 5 months. All patients had a ferritin level in their record and 64% had an available TSAT. Median age was 71.0 (59.8-79.3) years and 61.8% were female. All had an eGFR<60 ml/min. The proportion of patients found to require iron therapy ranged between 48 and 78% with a trend towards higher values when using KDIGO-based criteria. Using ANCOVA test, inverse normal transformations of ferritin and TSAT showed a reverse pattern between men and women with women being more iron deficient in the early stage. Iron deficiency is highly prevalent in non-dialysis chronic kidney disease patients on erythropoiesis-stimulating agents' therapy. These findings reflect a lack in effective iron supplementation when managing anemia in pre-dialysis patients, especially in men at advanced stages. Renal societies should spread awareness about iron deficiency screening in those patients.

Reduction of intracerebral hemorrhage in hemodialysis patients after reducing aspirin use: A quality-assurance observational study.

There is so far no international consensus concerning the prescription of antithrombotic agents in hemodialysis patients. It is not clear yet why they cause more bleeding in some patients and are beneficial in others. We therefore tried to find out what triggers bleeding in this population. This is an observational before-and-after study that included all patients undergoing hemodialysis in our center between 2005 and 2015. We divided the study into two phases: phase one (125 patients) where aspirin was used without restrictions and phase two (110 patients) where aspirin was avoided in severe hypertension and primary prevention. We aimed to assess the differential occurrence of intracerebral hemorrhage between the two phases and the cardiovascular mortality of patients whether on aspirin or not. Bleeding events occurred in 12.8% of patients in phase one and 13.6% in phase two (p = 0.85). Seven out of 125 patients (6%) in phase one experienced intracerebral hemorrhage and none in phase two. Intracerebral hemorrhage was significantly increased in those with the combination of aspirin and severe hypertension (p = 0.003). Aspirin and acenocoumadin were significantly associated with total bleeding (OR = 3.81 and 4.85 with p = 0.005 and 0.001 respectively). Cardiovascular mortality did not differ between phase one and two whether patients were on aspirin or not (p = 0.45 and 0.31 respectively). Minimizing aspirin use in hemodialysis patients with severe hypertension reduced intracerebral bleeding without a significant difference in cardiovascular mortality.

Brucellosis: A lymphoma-like presentation.

Brucellosis is one of the most common zoonotic infections worldwide caused by gram negative bacilli of the genus Brucella. It is transmitted to humans by contact with infected animals or derived food products such as unpasteurized milk. Brucellosis' clinical presentation varies widely from multi-systemic involvement to asymptomatic infection. We present the case of a 52-year-old Lebanese male who was admitted to our hospital with a 3-week history of fever (up to 40 °C), chills, night sweats and abdominal pain. Abdominal CT scan revealed the presence of several mesenteric lymphadenopathies and some retroperitoneal lymphadenopathies. Blood cultures came back positive for Brucella melitensis, and a follow-up CT of the abdomen done after treatment revealed complete resolution of the lymphadenopathies. To our knowledge, this is the first case in the literature of brucellosis presenting as retroperitoneal and mesenteric lymphadenopathies. In endemic areas, the diagnosis of brucellosis should always be raised in front of any long duration fever even in the absence of a typical clinical presentation.