Cannabinoid exposure as a major driver of pediatric acute lymphoid Leukaemia rates across the USA: combined geospatial, multiple imputation and causal inference study

Background Acute lymphoid leukaemia (ALL) is the commonest childhood cancer whose incidence is rising in many nations. In the USA, between 1975 and 2016, ALL rates (ALLRs) rose 93.51% from 1.91 to 3.70/100,000 < 20 years. ALL is more common in Caucasian-Americans than amongst minorities. The cause of both the rise and the ethnic differential is unclear, however, prenatal cannabis exposure was previously linked with elevated childhood leukaemia rates. We investigated epidemiologically if cannabis use impacted nationally on ALLRs, its ethnic effects, and if the relationship was causal. Methods State data on overall, and ethnic ALLR from the Surveillance Epidemiology and End Results databank of the Centre for Disease Control (CDC) and National Cancer Institute (NCI) were combined with drug (cigarettes, alcoholism, cannabis, analgesics, cocaine) use data from the National Survey of Drug Use and Health; 74.1% response rate. Income and ethnicity data was from the US Census bureau. Cannabinoid concentration was from the Drug Enforcement Agency Data. Data was analyzed in R by robust and spatiotemporal regression. Results In bivariate analyses a dose-response relationship was demonstrated between ALLR and Alcohol Use Disorder (AUD), cocaine and cannabis exposure, with the effect of cannabis being strongest (β-estimate = 3.33(95%C.I. 1.97, 4.68), P = 1.92 × 10− 6). A strong effect of cannabis use quintile on ALLR was noted (Chi.Sq. = 613.79, P = 3.04 × 10− 70). In inverse probability weighted robust regression adjusted for other substances, income and ethnicity, cannabis was independently significant (β-estimate = 4.75(0.48, 9.02), P = 0.0389). In a spatiotemporal model adjusted for all drugs, income, and ethnicity, cannabigerol exposure was significant (β-estimate = 0.26(0.01, 0.52), P = 0.0444), an effect increased by spatial lagging (THC: β-estimate = 0.47(0.12, 0.82), P = 0.0083). After missing data imputation ethnic cannabis exposure was significant (β-estimate = 0.64(0.55, 0.72), P = 3.1 × 10− 40). 33/35 minimum e-Values ranged from 1.25 to 3.94 × 1036 indicative of a causal relationship. Relaxation of cannabis legal paradigms had higher ALLR (Chi.Squ.Trend = 775.12, P = 2.14 × 10− 112). Cannabis legal states had higher ALLR (2.395 ± 0.039 v. 2.127 ± 0.008 / 100,000, P = 5.05 × 10− 10). Conclusions Data show that ALLR is associated with cannabis consumption across space-time, is associated with the cannabinoids, THC, cannabigerol, cannabinol, cannabichromene, and cannabidiol, contributes to ethnic differentials, demonstrates prominent quintile effects, satisfies criteria for causality and is exacerbated by cannabis legalization.

Cancer in Lahore, Pakistan, 2010–2019: an incidence study

ObjectivesTo study the cancer incidence rates over 10 years (2010–2019), in Lahore, Pakistan.DesignAn incidence study.SettingThe population-based Punjab Cancer Registry was established in 2005 in Lahore, which is the provincial metropolis of the province of Punjab (five rivers), and is located in the northeast region of Pakistan. The coordinating office of the Registry is located within Shaukat Khanum Memorial Cancer Hospital and Research Center. Both the active and passive forms of data collection are used.ParticipantsResidents of the district of Lahore diagnosed with cancer. The average annual population of Lahore was estimated at 11.1 million.Outcome measuresCancer counts and incidence rates per 100 000 population, by age-group, sex and cancer site/type, over 10 years.ResultsIn Lahore, from 2010 to 2019, 58 394 incident cases were reported, with the majority seen in females (57.1%). Adults accounted for 92.2%, adolescents 2.2% and children 5.6% of the total cases. Per 100 000 population, the age-standardised incidence rate was 103.4 for females and 65.6 for males. Among females, the highest incidence rates were recorded for breast cancer (76.7) in adults, bone tumour (1.2) in adolescents and lymphoid leukaemia (1.6) in children, and among males, prostate cancer (10.7) in adults, bone tumour (2.2) in young adults and lymphoid leukaemia (2.4) in children. The age-specific incidence rates peaked in the 60–70 year group, reaching a high of 420 per 100 000 in women and 330 per 1 00 000 men.ConclusionsIn Lahore, the incidence rates for cancers of the breast, prostate, lymphoid leukaemia and bone were among the highest documented. More cases were recorded in females than in males. The results reported could be used as a reference point for assessing the effectiveness of future interventions.

A mixed method study design to explore the adherence of haematological cancer patients to oral anticancer medication in a multilingual and multicultural outpatient setting: The MADESIO protocol

Background Patients with haematologic malignancies are increasingly treated by oral anticancer medications, heightening the challenge of ensuring optimal adherence to treatment. However, except for chronic myelogenous leukaemia or acute lymphoid leukaemia, the extent of non-adherence has rarely been investigated in outpatient settings, particularly for migrant population. With growing numbers of migrants in Belgium, identifying potential differences in drug use is essential. Also, previous research regarding social determinants of health highlight important disparities for migrant population. Difficulties in communication between health caregivers and patients from different cultural and ethnic backgrounds has been underlined. Methods Using a sequential mixed method design, the MADESIO protocol explores the adherence to oral anticancer medications in patients with haematological malignancies and among first and second generation migrants of varied origin. Conducted in the ambulatory setting, a first quantitative strand will measure adherence rates and associated risk factors in two sub-groups of patients with haematological malignancies (group A: first and second generation migrants and group B: non-migrants). The second qualitative strand of this study uses semi-structured interviews to address address the patients’ subjective meanings and understand the statistical associations observed in the quantitative study (strand one). MADESIO aims to provide a first assessment of whether and why migrants constitute a population at risk concerning adherence to oral anticancer medications. Discussion Our protocol is designed to provide a comprehensive understanding of adherence in a specific population. The methodological choices applied allow to explore adherence among patients from diverse linguistic and cultural backgrounds. A particular emphasis has been paid to minimize the biases and increase the reliability of the data collected. Easily reproductible, the MADESIO design may help healthcare services to screen adherence to Oral anticancer medications and to guide providers in choosing the best strategies to address medication adherence of migrants or minority diverse population.

Learning mutational signatures and their multidimensional genomic properties with TensorSignatures

We present TensorSignatures, an algorithm to learn mutational signatures jointly across different variant categories and their genomic localisation and properties. The analysis of 2778 primary and 3824 metastatic cancer genomes of the PCAWG consortium and the HMF cohort shows that all signatures operate dynamically in response to genomic states. The analysis pins differential spectra of UV mutagenesis found in active and inactive chromatin to global genome nucleotide excision repair. TensorSignatures accurately characterises transcription-associated mutagenesis in 7 different cancer types. The algorithm also extracts distinct signatures of replication- and double strand break repair-driven mutagenesis by APOBEC3A and 3B with differential numbers and length of mutation clusters. Finally, TensorSignatures reproduces a signature of somatic hypermutation generating highly clustered variants at transcription start sites of active genes in lymphoid leukaemia, distinct from a general and less clustered signature of Polη-driven translesion synthesis found in a broad range of cancer types. In summary, TensorSignatures elucidates complex mutational footprints by characterising their underlying processes with respect to a multitude of genomic variables.

1,3-Butadiene, styrene and lymphohaematopoietic cancers among North American synthetic rubber polymer workers: exposure–response analyses

ObjectiveTo evaluate exposure–response between 1,3-butadiene, styrene and lymphohaematopoietic cancers in an updated cohort of workers at six North American plants that made synthetic rubber polymers.MethodsEmployees were followed from 1943 through 2009 to determine mortality outcomes. Cox regression analyses estimated rate ratios (RRs) and 95% CIs by quartile of cumulative exposure to butadiene or styrene, measured in parts per million-years (ppm-years), and exposure–response trends for all leukaemia, lymphoid leukaemia, myeloid leukaemia, acute myeloid leukaemia, non-Hodgkin’s lymphoma (NHL), multiple myeloma and all B-cell malignancies.ResultsAmong 21 087 workers, adjusted RRs for butadiene and all leukaemia (132 deaths) rose with increasing exposure, with an RR of 2.53 (95% CI 1.37 to 4.67) in the highest exposure quartile (≥363.64 ppm-years), and the exposure–response trend was statistically significant for all leukaemia (p=0.014) and for lymphoid leukaemia (52 deaths, p=0.007). Styrene exposure–response trends for all leukaemia and lymphoid leukaemia were less consistent than those for butadiene. Cumulative exposures to butadiene and styrene were not associated consistently with myeloid leukaemias or the B-cell malignancies, NHL and multiple myeloma.ConclusionsWe confirmed a positive exposure–response relationship between butadiene and all leukaemia among workers, most of whom had coexposure to styrene. Results supported an association between butadiene and lymphoid leukaemia, but not myeloid leukaemia, and provided little evidence of any association of butadiene or styrene exposures with major subtypes of B-cell malignancies other than lymphoid leukaemia, including NHL and multiple myeloma.

Orbital Swelling and Ptosis as an Initial Presentation of Childhood Acute Lymphoblastic Leukaemia: A Case Report and Review of the Literature

We are reporting the case of a 3-year-old-girl who initially presented with unilateral eyelid swelling and ptosis. A diagnosis of acute lymphoblastic leukaemia (ALL) was eventually made based on an orbital incisional biopsy and a bone marrow examination. Historically, orbital involvement had been linked to myeloid leukaemia; however, in lymphoid leukaemia, they are increasingly being implicated and had been reported as the sole presentation of the disease. These findings stress the importance of conducting ophthalmologic assessments in cases diagnosed with ALL in order to prevent delays in proper assessment and treatment. Management options in orbital disease are fortunately not significantly different than well-established treatment protocols.

Haematological Malignancies: Overview of the Recent Progresses in Genetics

Genetic defects play a major role in pathogenesis of the most of haematological malignancies, including cytogenetic abnormalities, gene mutations, and abnormal gene expression. Our knowledge about the genetics of haematological disorders has been dramatically improved during the past decade, due to revolution of sequencing technologies which have played a crucial role. In this chapter, we describe the techniques commonly employed for elucidating chromosomal aberrations, prognostic impact of recurrent chromosomal abnormalities, and recently updated risk stratification systems. We will summarise the chromosomal abnormalities recently identified on many of haematological diseases such acute myeloid leukaemia, acute lymphoid leukaemia, myelodysplasic syndrome, multiple myeloma, meyloproliferative disease and clarify their impacts on clinical phenotype and prognosis, as well as their role in the pathogenesis of these diseases. The aim of this chapter is to provide a brief overview of the recent progresses in haematological diseases genetics.

Steroids—has the time come to extend their use to AML?

Background In 2018, leukaemia accounted for 2.6% of all new cancers, it being the 13th most common cause of cancer and the 10th most common cause of cancer death. Glucocorticoids are commonly used in lymphoid leukaemia treatment, where they are cytotoxic. The aim of this review is to highlight ongoing research of steroid use in myeloid leukaemias. Main text Glucocorticoids increase infection risks in acute myeloid leukaemia, but with adequate antifungal cover, they can help in hyperleucocytic disease. They also show some benefits in sensitising multidrug-resistant AML cell lines to cytotoxic agents, induce differentiation marker expression and can also induce CD38 expression, making AML cells possible targets of daratumumab. Cardiotonic steroids, like digitalis, are being recognised as sensitising AML cells to the chemotherapeutic effects of many cytotoxic agents, primarily by inhibiting efflux pumps, thus minimising AML resistance. Ecdysteroids enhance sensitivity in multidrug-resistant AML, but also in non-resistant AML cell lines, through pathways including the activation of mitochondrial apoptosis. Their anti-apoptotic effects on non-malignant cell lines help their target specificity. Sensitisation is chemotherapy-specific, enhancing the effects of doxorubicin and tubulin inhibitors but increasing resistance to cisplatinum. Short conclusion Cardiotonic steroids and ecdysteroids both show chemosensitisation to the cytotoxic effects of chemotherapy on AML cell lines. It is likely time to consider clinical trials to assess whether these, as well as traditional glucocorticoids, can contribute to the AML armamentarium, particularly in chemo-resistant disease.

A krónikus lymphoid leukaemia mai kezelésének interdiszciplináris kérdései

Összefoglaló. A Bruton-féle tirozin-kinázt gátló ibrutinib és a B-sejtes lymphoma-2-t gátló venetoklax a krónikus lymphoid leukaemia (CLL) kezelésének egyre korábbi vonalában alkalmazható, és ezek mellett a progressziómentes túlélés növekedése figyelhető meg. A célzott kismolekulákkal végzett kezelés nemcsak a CLL lefolyását, de a betegek gondozását is alapvetően megváltoztatta. A tartósan adagolt orális szerek mellett a betegek nagyobb valószínűséggel jelennek meg a panaszaiknak megfelelő szakrendeléseken. Az új típusú szerek hatásai és mellékhatásai mellett az alapvető gyógyszer-interakciókra is fel kell hívni a figyelmet. Kiemelt fontosságú az ibrutinib hypertoniát provokáló hatása, illetve a 6–16%-ban megjelenő pitvarfibrilláció. Ez utóbbi ellátását a gyógyszer-interakciókon túl az ibrutinib vérzékenységet okozó hatása is nehezíti. A CLL-lel, illetve annak kezelésével kapcsolatos ismeretek a másodlagos daganatok, néhány gastrointestinalis és bőrgyógyászati betegség megközelítése szempontjából is fontosak. A venetoklax mellett potenciálisan kialakuló tumorlízis-szindróma alkalmanként a nefrológusok bevonását igényli. A betegek gondozása, megfelelő szakszerű ellátása és a betegutak optimalizálása érdekében a háziorvosok, a sürgősségi ellátók és az egyéb szakellátó helyek szoros együttműködése szükséges szakorvosi konzultáció keretei között. Orv Hetil. 2021; 162(9): 336–343. Summary. Chronic lymphocytic leukemia (CLL) is ubiquitously treated with novel agents. The Bruton’s tyrosine kinase inhibitor ibrutinib and the B-cell lymphoma 2 inhibitor venetoclax can be used increasingly in earlier lines of treatment with improved progression-free survival. Treatment with targeted small molecules fundamentally changed not only the course of CLL but also the care of patients. With the administration of long-term oral medications, patients are more likely to show up at specialist clinics that match their complaints. In addition to the effects and side effects of the new drugs, attention should also be drawn to basic drug interactions. The effect of ibrutinib on blood pressure and the ability to provoke atrial fibrillation in 6–16% of cases are of paramount importance. In addition to drug interactions, the treatment of the latter is also complicated by the hemorrhagic effect of ibrutinib. Knowledge on CLL and its treatment is also important in the approach to secondary tumors, some gastrointestinal and dermatological diseases. The potential for tumor lysis syndrome of venetoclax requires close collaboration with nephrologists. In order to provide appropriate professional care and optimize patient pathways, close co-operation between GPs, emergency care providers and other specialist care facilities is required within the framework of professional consultation. Orv Hetil. 2021; 162(9): 336–343.