Disclosure of Diagnosis and Prognosis to Cancer Patients in Traditional Societies: A Qualitative Assessment from Lebanon

Background: The issue of when, how, and whether to disclose full information about cancer diagnosis and prognosis to patients is still debated in some parts of the world, including Lebanon. Despite formal academic emphasis on a larger autonomy for Lebanese patients in deciding the course of their disease, there has been no apparent impact on either clinical practices nor public expectations.  The topic of full disclosure is rarely if ever discussed in open fora, or in mass media channels in Lebanon. Subjects and Method: Seven key stakeholders were identified and interviewed regarding obstacles to spelling out clear guidelines within our national context. The interviews were transcribed and subsequently analyzed for recurrent patterns and concepts.Results: Senior oncologists interviewed generally favored gradual disclosure and most perceived a changing trend among both patients and physicians towards more disclosure. They also agreed on a need for the formal training of residents and fellows to better communicate bad news to patients. All the interviewed physicians attested to the benefits of candid disclosure in terms of patient psychology and overall wellbeing. They also mentioned that psychological services, which may facilitate the disclosure process, are greatly under-utilized in oncology. Lawyers highlighted the vagueness of the current Lebanese legislation regarding the obligation of truthful disclosure in comparison to laws in developed countries and the implications on patient autonomy. Conclusion: The study identified the need for improvements at various levels, including interventions to modify the expectations of the Lebanese public regarding cancer disclosure and to clarify existing legislative texts.Keywords: Ethics; Legislation; Middle-East; DisclosureCorrespondence: James Feghali. Faculty of Medicine, American University of Beirut (AUB), Lebanon, 1101 North Calvert Street, 610, Baltimore, Maryland, 21202. E-mail: [email protected]. Telephone: +1-(267)-595-9995.Journal of Epidemiology and Public Health (2019), 4(2): 109-116https://doi.org/10.26911/jepublichealth.2019.04.02.0

Knowledge, Perception, Attitudes and Behavior on Influenza Immunization and the Determinants of Vaccination

BACKGROUND: We sought to determine the knowledge of, perception, attitudes, and behaviors toward influenza virus and immunization, and the determinants of vaccination among students, patients, and Healthcare Workers (HCWs) at the American University of Beirut and its affiliated Medical Center. METHODS: We conducted a cross-sectional study between October 2016 and January 2017 utilizing a self-administered questionnaire that was provided to 247 randomly selected adult participants. Data collected included socio-demographic characteristics, prior vaccination against influenza, knowledge, perception, attitudes, and behaviors toward influenza and influenza immunization. A multivariable regression model was used to evaluate for independent associations between the different variables and regular or yearly vaccination as a primary outcome. RESULTS: The overall survey response rate was 77%. A substantial proportion of respondents (47.4%) had never received the influenza vaccine. Only 10.2% of students, 19.1% of patients, and 35.6% of HCWs reported regular or yearly influenza vaccine uptake. HCWs had the lowest knowledge score about influenza and its vaccine despite high self-reported levels of knowledge. Barriers to vaccinations included lack of information (31%), fear of adverse effects (29%), and a perception of not being at risk (23%). Several factors were independently associated with regular or yearly vaccination uptake including having children (adjusted OR = 3.8; 95% CI 1.2-12.5), a "very good" self-reported level of knowledge (OR = 16.3; 95% CI 1.4-194.2) and being afraid of the consequences of influenza (OR = 0.2; 95% CI 0.1-0.6). CONCLUSION: Adherence rates with regular or yearly vaccination against influenza remain low across all study groups. We were able to identify predictors as well as barriers to vaccination. Future awareness and vaccination campaigns should specifically aim at correcting misconceptions about vaccination, particularly among HCWs, along with addressing the barriers to vaccination. Predictors of vaccination should be integrated in the design of future campaigns

Molecular characterization and clinical outcomes of pancreatic neuroendocrine tumors (pNENs) harboring PAK4-NAMPT alterations

Background: The mTOR inhibitor, Everolimus (EVE), is FDA-approved for the treatment of advanced PNENs on the basis of delay of progression. The RADIANT-3 trial showed an increase in PFS from 4.6 to 11 months compared to placebo with an ORR of only 5%. Prior studies suggest that targeting the aberrant expression of mTOR regulators p21 activated kinase 4 (PAK4) and nicotinamide adenine dinucleotide biosynthesis enzyme nicotinamide phosphoribosyltransferase (NAMPT) in PNENs sensitizes these tumors to EVE. To further qualify these observations, we queried a large real-world dataset of PNENs, characterizing the molecular and immune landscapes, as well as the clinical outcomes associated with aberrant PAK4 and NAMPT expression. Methods: 294 cases of PNENs were analyzed using Next Generation Sequencing (NextSeq) and Whole Exome and Whole Transcriptome Sequencing (NovaSeq) at Caris Life Sciences (Phoenix, AZ). For our analyses, we stratified our study cohort into four groups based on the median expression of PAK4 and NAMPT: PAK4-low/NAMPT-low, PAK4-low/ NAMPT-high, PAK4-high/NAMPT-low and PAK4-high/NAMPT-high. Significance was determined using chi-square, Fisher-Exact or Mann-Whitney U, and p-values were adjusted for multiple comparisons (q , 0.05). Results: High prevalence of mutations in PTEN (10.71% vs 1.18%; p \u3c 0.05, q \u3e 0.05), a tumor suppressor of the mTOR pathway and high expression of genes activated in response to mTOR activation such as SLC2A1 (3.07-fold), PFKP (3.32-fold), SCD (2.70-fold), MVK (2.92-fold) and G6PD (2.58-fold) were observed in PAK4-high/NAMPT-high compared to the PAK4-low/NAMPTlow tumors (all q , 0.05). A congruent enrichment of PI3K/AKT/mTOR and glycolysis pathways by single-sample gene set enrichment analysis was observed in these tumors (all q , 0.05). When querying the immune landscape, we observed enrichment in inflammatory response, IL6/JAK/STAT3, IL2/STAT5 signaling pathways and immune checkpoint genes such as PDCD1 (5.14-fold), CD274 (2.84-fold), PDCD1LG2 (2.44-fold), CD80 (3.00-fold), CD86 (2.82-fold), IDO1 (1.92-fold), LAG3 (3.09-fold), HAVCR2 (2.66-fold) and CTLA4 (4.49-fold) in the PAK4-high/NAMPT-high tumors (all q,0.05). Immune cell infiltration estimates revealed an increase in Neutrophils, NK cells and Tregs in the PAK4-high/NAMPT-high tumors (p \u3c 0.05, q \u3e 0.05). Conclusions: Our study demonstrates that PAK4-high/NAMPT-high PNENs are associated with distinct molecular and immune profiles. While the dual blockade of PAK4 and NAMPT has been reported to enhance the efficacy of EVE in PNENs, whether such a blockade would enhance the efficacy of immunotherapeutics warrants further investigation

Interleukin 10-Mediated Response and Correlated Anemia in a Patient with Advanced Non-Small Cell Lung Carcinoma

Anemia in cancer patients is associated with poor quality of life, reduced response to therapy, and decreased overall survival. We describe a case of a 56-year old woman with advanced metastatic non-small cell lung carcinoma who demonstrated marked response to a novel combinational immunotherapy approach involving a long-acting PEGylated construct of recombinant human Interleukin-10 with Nivolumab, an anti-PD-L1 checkpoint inhibitor. While on treatment, the patient developed severe anemia and hyper-ferritinemia requiring RBC transfusion support. Here we discuss a possible novel immune mechanism of IL10-mediated anemia in correlation with tumor response

The clinical implications of the survival pathway in prostate cancer

Prostate Cancer (PCa) is the second leading cause of cancer death in North Americanmen. The heterogeneity of the disease, along with the imperfection of the current prognostic determinants is a challenge to physicians who are unable to discriminate indolent cancers from those that will become life-threatening. Previous work has identified 3 molecular subtypes of PCa that correlated with clinical behaviour, and found the PI/AKT pathway genes to be up-regulated in metastatic samples compared to primary ones. Copy number alteration analysis on this group of patients showed frequent 16p13(PDPK1) genomic amplification and the 10q23 (PTEN) deletion. PDK1 activates thePI/AKT survival pathway, while PTEN inhibits it. In this study, we report for the first time the detection of the 16p13.3 (PDPK1) genomic gain in lymph node metastasis and their matched primary samples, in castration- resistant prostate cancer, and in unmatched primary prostate cancer samples. This localized gain was enriched in advanced disease compared to primary prostate cancer, and associated with high Gleason grade and high preoperative PSA levels, pointing its potential prognostic value. In vitro, we characterized a role for PDK1 in PCa cells motility, a crucial process in metastasis. This finding supports the idea of a role for the 16p13.3 (PDPK1) gain in PCa progression towards a more aggressive disease, and makes PDK1 a potential therapeutic target in patients with aggressive PCaLe cancer de la prostate (CaP) est la deuxième cause de décès par cancer chez les hommes nord-américains. L'hétérogénéité de la maladie, ainsi que l'imperfection des déterminants pronostiques actuels, constitue un défi pour les médecins qui sont incapables de distinguer les cancers indolents de ceux qui progresseront pour devenir mortels. Une étude antérieure a identifié 3 sous-types moléculaires de cancer de la prostate qui corrèlent avec le comportement clinique, et a rapporté une augmentation dans l'expression des gènes de la voie de signalisation PI/AKT dans les échantillons métastatiques, comparé aux cancers primaires. L'analyse des altérations génomiques dans ce groupe de patients a montré que l'amplification génomique 16p13 (PDPK1)et la délétion 10q23 (PTEN) sont fréquentes. PDK1 active la voie de survie PI /AKT, tandis que PTEN l'inhibe. Dans cette étude, nous rapportons pour la première fois la détection du gain génomique 16p13.3 (PDPK1) dans les métastases et de leurs échantillons appariés primaires, dans des spécimens de cancer de la prostate résistants à la castration, et dans des tumeurs primaire non-métastatiques. Le niveau de gain augmente dans les échantillons de stade avancé, soulignant ainsi une possible valeur pronostique. In vitro, nous avons caractérisé le rôle de PDK1 dans la motilité des cellules du cancer de la prostate, un processus essentiel à la métastase. Cette constatation appuie l'idée d'un rôle joué par le gain génomique 16p13 (PDPK1) dans la progression du cancer de la prostate vers une maladie létale, et rend PDK1 une cible thérapeutique potentielle chez les patients avec un cancer agressif

Clonal Neoantigen: Emerging “Mechanism-based” Biomarker of Immunotherapy Response

Clonal mutations represent the initiating molecular defects related to cellular transition of a normal phenotype to a malignant phenotype. Molecular genomic assessment utilizing next generation and whole exome sequencing is now being increasingly applied to biomarker determination to refine the use of targeted immune therapies. Case examples followed by retrospective study assessment have convincingly demonstrated clonal neoantigens provide a relevant predictor of response to checkpoint inhibition. A meta-analysis, by Litchfield et al., of over 1000 cancer patients from 12 landmark trials demonstrated no clinical benefit to checkpoint inhibitor (CPI) therapy in correlation to high subclonal tumor mutational burden (TMB), whereas high clonal TMB was found to be significantly correlated with better overall survival (p = 0.000000029). We discuss the mechanism of clonal vs. subclonal neoantigen targeting relationship to homologous recombination proficient (HRP) profile, evidence of preclinical and clinical benefit related to clonal neoantigens, and review a novel developing therapy called Vigil®, designed to expand the clonal neoantigen targeting effector cell populations. Vigil® is an autologous cellular immunotherapy which is designed to carry the full set of personal clonal neoantigens. Phase 2b results demonstrate a durable recurrence-free survival (RFS) and overall survival (OS) advantage for Vigil® in a subset ovarian cancer population with an HRP cancer profile

Disclosure of Diagnosis and Prognosis to Cancer Patients in Traditional Societies: A Qualitative Assessment from Lebanon

Background: The issue of when, how, and whether to disclose full information about cancer diagnosis and prognosis to patients is still debated in some parts of the world, including Lebanon. Despite formal academic emphasis on a larger autonomy for Lebanese patients in deciding the course of their disease, there has been no apparent impact on either clinical practices nor public expectations. The topic of full disclosure is rarely if ever discussed in open fora, or in mass media channels in Lebanon. Subjects and Method: Seven key stakeholders were identified and interviewed regarding obstacles to spelling out clear guidelines within our national context. The interviews were transcribed and subsequently analyzed for recurrent patterns and concepts. Results: Senior oncologists interviewed generally favored gradual disclosure and most perceived a changing trend among both patients and physicians towards more disclosure. They also agreed on a need for the formal training of residents and fellows to better communicate bad news to patients. All the interviewed physicians attested to the benefits of candid disclosure in terms of patient psychology and overall wellbeing. They also mentioned that psychological services, which may facilitate the disclosure process, are greatly under-utilized in oncology. Lawyers highlighted the vagueness of the current Lebanese legislation regarding the obligation of truthful disclosure in comparison to laws in developed countries and the implications on patient autonomy. Conclusion: The study identified the need for improvements at various levels, including interventions to modify the expectations of the Lebanese public regarding cancer disclosure and to clarify existing legislative texts

Intrigue: Phase III study of ripretinib versus sunitinib in advanced gastrointestinal stromal tumor after imatinib

Ripretinib (DCC-2618) is a novel, type II tyrosine switch control inhibitor designed to broadly inhibit activating and drug-resistant mutations in KIT and PDGFRA. Ripretinib has emerged as a promising investigational agent for the treatment of gastrointestinal stromal tumor owing to targeted inhibition of secondary resistance mutations that may develop following treatment with prior line(s) of tyrosine kinase inhibitors. Here we describe the rationale and design of intrigue (NCT03673501), a global, randomized (1:1), open-label, Phase III study comparing the safety and efficacy of ripretinib versus sunitinib in patients with advanced gastrointestinal stromal tumor following imatinib. The primary end point is progression-free survival and key secondary objectives include objective response rate and overall survival. Clinical Trial Registration: NCT03673501.status: publishe