Cancer Risk Studies and Priority Areas for Cancer Risk Appraisal in Uganda.

Background: Research into aetiologies and prevention of the commonest cancers and implementation of primary and secondary prevention can reduce cancer risk and improve quality of life. Moreover, monitoring the prevalence of cancer risk factors in a specific population helps guide cancer prevention and early detection efforts and national cancer control programming. Objective: This article aims to provide the scope and findings of cancer risk studies conducted in Uganda to guide researchers, health-care professionals, and policymakers. Methods: Between November 2019 to January 2020, we searched peer-reviewed published articles in Pubmed, EMBASE and Cochrane Library (Cochrane central register of controlled trials-CENTRAL). We followed the recommendation of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses - the PRISMA. The primary focus was to identify cancer risk and prevention studies conducted in Uganda and published in peer-reviewed journals from January 2000 and January 2020. We used key Boolean search terms with their associated database strings. Results: We identified 416 articles, screened 269 non-duplicate articles and obtained 77 full-text articles for review. Out of the 77 studies, we identified one (1%) randomized trial, two (2.5%) retrospective cohort studies and 14 (18%) case-control studies, 46 (60%) cross-sectional studies, five (6.4%) ecological studies, three panel studies (4%) and six (8%) qualitative studies. Cervical cancer was the most studied type of cancer in Uganda (23.4%, n = 18 studies), followed by lymphomas - both Hodgkin and Non-Hodgkin sub-types (20.7%), n = 16 studies) and breast cancer (15.6%, n = 12 studies). In lymphoma studies, Burkitt lymphoma was the most studied type of lymphoma (76%, n = 13 studies). The studies concentrated on specific cancer risk awareness, risk perceptions, attitudes, uptake of screening, uptake of human papillomavirus vaccination, the prevalence of some of the known cancer risk factors and obstacles to accessing screening services. Conclusion: The unmet need for comprehensive cancer risk and prevention studies is enormous in Uganda. Future studies need to comprehensively investigate the known and putative cancer risk factors and prioritize the application of the higher-hierarchy evidence-generating epidemiological studies to guide planning of the national cancer control program.

The promise of a prophylactic Epstein-Barr virus vaccine.

The worldwide burden of disease due to Epstein-Barr virus (EBV) infection is enormous. Diseases include endemic Burkitt lymphoma, infectious mononucleosis, cancers after transplantation, Hodgkin lymphoma, and nasopharyngeal carcinoma. A prophylactic EBV vaccine has the potential to significantly reduce the incidence and/or the severity of all these diseases. Infectious mononucleosis can be nasty and prolonged with a median duration of 17 days. Patients, especially children, undergoing bone marrow or solid organ transplantation may develop post-transplant lymphoproliferative disorder (PTLD). Preventing or modifying primary EBV infection could reduce the incidence PTLD, and also certain lymphomas and nasopharyngeal carcinoma. EBV is a major environmental risk factor for multiple sclerosis (MS). Contracting EBV is essential to getting MS, and having a childhood case of infectious mononucleosis increases that risk. Vaccinating against EBV could be vaccinating against MS.

Prevention and treatment of relapse after stem cell transplantation in lymphoid malignancies.

Relapse is now the major cause of treatment failure after allogeneic HSCT (alloHSCT). Many novel strategies to address this critical issue are now being developed and tested. At the 3rd International Workshop on Biology, Prevention, and Treatment of Relapse held in Hamburg, Germany in November 2016, international experts presented and discussed recent developments in the field. Some approaches may be applicable to a wide range of patients after transplant, whereas some may be very disease-specific. We present a report from the session dedicated to issues related to prevention and treatment of relapse of lymphoid malignancies after alloHSCT. This session included detailed reviews as well as forward-looking commentaries that focused on Hodgkin lymphoma, chronic lymphocytic leukemia and mantle cell lymphoma, diffuse large cell and follicular lymphoma, and multiple myeloma.

Targeting Cancer Cells and Tumor Microenvironment in Preclinical and Clinical Models of Hodgkin Lymphoma Using the Dual PI3Kδ/γ Inhibitor RP6530.

PURPOSE: Tumor-associated macrophages (TAMs) and the hyperactivation of the PI3K/AKT pathway are involved in the pathogenesis of Hodgkin lymphoma and affect disease outcome. Because the δ and γ isoforms of PI3K are overexpressed in Hodgkin/Reed-Sternberg (HRS) cells and the tumor microenvironment (TME), we propose that the PI3Kδ/γ inhibitor RP6530 might affect both HRS cells and TME, ultimately leading to an enhanced antitumor response. EXPERIMENTAL DESIGN: Hodgkin lymphoma cell lines (L-540, KM-H2, and L-428) and primary human macrophages were used to investigate the activity of RP6530 in vitro and in vivo in Hodgkin lymphoma cell line xenografts. RESULTS: In vitro, RP6530 besides killing and inhibiting the proliferation of Hodgkin lymphoma cells, downregulated lactic acid metabolism, switching the activation of macrophages from an immunosuppressive M2-like phenotype to a more inflammatory M1-like state. By RNA sequencing, we define tumor glycolysis as a specific PI3Kδ/γ-dependent pathway implicated in the metabolic reprogramming of cancer cells. We identify the metabolic regulator pyruvate kinase M2 as the main mediator of tumor-induced immunosuppressive phenotype of macrophages. Furthermore, we show in human tumor xenografts that RP6530 repolarizes TAMs into proinflammatory macrophages and inhibits tumor vasculature, leading to tumor regression. Interestingly, patients with Hodgkin lymphoma experiencing objective responses (complete response and partial response) in a phase I trial using RP6530 showed a significant inhibition of circulating myeloid-derived suppressor cells and an average mean reduction in serum thymus and activation-regulated chemokine levels of 40% (range, 4%-76%). CONCLUSIONS: Our results support PI3Kδ/γ inhibition as a novel therapeutic strategy that targets both malignant cells and the TME to treat patients with Hodgkin lymphoma.

Novel Biomarker Approaches in Classic Hodgkin Lymphoma.

Classic Hodgkin lymphoma (cHL) is one of the most common lymphomas in the Western world. Advances in the management of cHL have led to high cure rates exceeding 80%. Nevertheless, relapse or refractory disease in a subset of patients and treatment-related toxicity still represents unsolved clinical problems. The introduction of targeted treatments such as PD-1 blockade and the CD30 antibody drug conjugate, brentuximab vedotin, has broadened treatment options in cHL, emphasizing the critical need to identify biomarkers with the goal to provide rationales for treatment selection, increase effective drug utilization, and minimize toxicity. The unique biology of cHL featuring low abundant tumor cells and numerous nonmalignant immune cells in the tumor microenvironment can provide various types of promising biomarkers related to the tumor cells directly, tumor microenvironment cross-talk, and host immune response. Here, we comprehensively review novel biomarkers including circulating tumor DNA and gene expression-based prognostic models that might guide the ideal management of cHL in the future.

Guía de práctica médica linfoma de Hodgkin en personas de 15 años y más / Hodgkin Lymphoma Medical Practice Guide in People 15 Years and Over

El linfoma de Hodgkin (LH) recibió su nombre del patólogo británico Thomas Hodgkin, quien en el año 1832 describió varios casos de personas con síntomas de un cáncer que afecta los ganglios linfáticos, denominándose "enfermedad de Hodgkin" durante aproximadamente 170 años. A fines del siglo XX, se determina que esta enfermedad es consecuencia de una lesión en el ADN de un linfocito (un tipo de glóbulo blanco)(1), motivo por el cual es llamada "linfoma de Hodgkin" neoplasia hematológica que en la actualidad constituye uno de los tipos de cáncer más curables.

Análisis en áreas pequeñas del cáncer pediátrico en el municipio de Murcia / Analysis of small areas of pediatric cancer in the municipality of Murcia (Spain)

INTRODUCCIÓN: Ocasionalmente, los pediatras, sobre todo los de Atención Primaria, alertan de la presencia de pequeños agrupamientos de casos de cáncer pediátrico (CP) y con frecuencia sus expectativas se ven frustradas al aplicar los métodos estadísticos. El estudio de áreas pequeñas en epidemiología espacial ha permitido realizar algunos avances en la identificación de clústeres y de los factores de riesgo medioambientales implicados. El objetivo de este trabajo es describir la incidencia del CP y la distribución espacial a nivel de sección censal, así como presentar el primer mapa urbano municipal de CP de España. MATERIAL Y MÉTODOS: Estudio descriptivo de base poblacional, por sexo, grupos de edad, subperiodos y tipo tumoral de los casos de CP diagnosticados en menores de 15 años, entre 1998 y 2013 en el municipio de Murcia. Georreferenciación de casos en el momento del diagnóstico y análisis de clústeres espaciales y espacio-temporales a nivel de sección censal mediante los estadísticos FleXScan y SatScan. RESULTADOS: Un total de 155 casos fueron diagnosticados. La incidencia global (138 por millón de niños menores de 15 años) y por tipos tumorales está dentro de los márgenes de referencia del área europea. Identificación de un clúster espacio-temporal de linfomas de Hodgkin. CONCLUSIONES: El análisis de áreas pequeñas de los casos diagnosticados de CP es una herramienta útil para identificar clústeres de casos que permita plantear hipótesis sobre las causas que originan la enfermedad y desarrollar modelos urbanos de vigilancia ambiental del cáncer infantil

INTRODUCTION: Occasionally, primary care pediatricians notice the presence of small clusters of pediatric cancer (PC), but are often frustrated by the findings after statistical analysis. The study of small areas in spatial epidemiology has led to advances in identifying clusters and the environmental risk factors involved. The purpose of this study was to describe the PC incidence and the spatial distribution at the minimum level of disaggregation possible in Murcia, presenting the first urban municipality map of PC in Spain. MATERIALS AND METHODS: A population-based descriptive study was conducted on the PC cases diagnosed in children younger than 15 years, between 1998 and 2013 in the municipality of Murcia. Cases were classified by sex, age group, and tumor type. Coordinates of home addresses at the time of diagnosis were assigned to each case, and spatial and spatio-temporal analyses were carried out at the level of census tracts, using FleXScan and SatScan. RESULTS: A total of 155 cases of PC were diagnosed during this period. The overall incidence of PC (138/106 of children under the age of 15) and the incidence for individual tumor types were within the expected ranges for Europe. A spatio-temporal cluster of Hodgkin lymphoma was identified. CONCLUSIONS: Small area analysis of PC cases may be a useful tool for the identification of PC clusters, which would allow for the generation of hypotheses regarding disease etiology, as well as developing urban models for environmental surveillance of PC

DLI after haploidentical BMT with post-transplant CY.

Forty-two patients relapsing after an unmanipulated haploidentical BM transplant and post-transplant CY (PT-CY), were given 108 DLI, with median interval from transplant of 266 days (range, 67-1372). DLI were given at escalating doses, expressed as CD3+ cells/kg, without GVHD prophylaxis, and ranged from 1 × 10(3) to 1 × 10(7) cells/kg (median 5 × 10(5) cells/kg). The average number of DLI per patient was 2.6 (range, 1-6). The diagnosis was leukemias (n=32) grafted with a myeloablative regimen and Hodgkin's disease (n=10), grafted with a nonmyeloablative regimen. Leukemic patients with molecular relapse (n=20), received DLI alone (n=17) or in association with azacytidine (n=3); leukemic patients with hematologic relapse (n=12) received chemotherapy followed by DLI (n=11) or DLI alone (n=1); Hodgkin patients received DLI following 1-3 courses of chemotherapy. In these three groups the incidence of acute GVHD II-III was 15%, 17% and 10%; response rate was 45%, 33% and 70%; 2-year actuarial survival was 43%, 19% and 80% respectively. This study confirms that escalating doses of DLI can be given in the haploidentical setting with PT-CY, with a relatively low risk of acute GVHD. Response rates and survival are dependent on the underlying disease.

Keeping those telomeres short! an innovative intratumoral long-term drug delivery system.

BACKGROUND: Telomerase activation and an alternative lengthening of telomeres (ALT) mechanism are two telomere-lengthening cancer cell survival mechanisms elicited by both chemo- and/or radiotherapy. Telomere lengthening interferes with cell lethality and results in the immortalization of cancer cells. To counteract these mechanisms, we developed a drug delivery system (DDS) consisting of a polymeric implant that is inserted directly into tumors. The DDS releases, continuously and gradually, a cationic porphyrin (PdTMPyP4) for >30 days after a single application, and inhibits telomerase activation. METHODS: The PdTMPyP4 porphyrin is incorporated into a poly(co-glycolic lactic)acid (PLGA) polymer, solidified and cut into small rods. PdTMPyP4 release from the rods was measured spectrophotometrically over time. Uptake of Pd in the DNA of in L428 Hodgkins lymphoma cells was measured by ICP-MS, and telomerase activation by the TRAP assay. The rods were placed into the growth medium of cells whose growth rate was measured for 11 and 19 days. The cylinders were also inserted directly into KHJJ murine mammary tumors borne on the thighs of BALB/c mice and the tumor growth rate measured. RESULTS: In vitro, >10(9)Pd atoms were measured in the DNA of each L428 cell and telomerase activity was reduced by ~15% within 24 h. A one-time application of the rod in the cell medium induced a factor of >5 greater lethality compared to a blank rod or untreated controls. In vivo, a one-time insertion of the rod into tumors resulted in the retardation of the growth rate by factors of 3-5 compared to untreated controls. Systemic uptake after intratumoral insertion of the rod was negligible. CONCLUSION: The results suggest that the direct intratumoral insertion of a PdTMPyP4-containing polymeric rod would be of benefit as an adjuvant treatment for patients undergoing chemo- or radiotherapy. By preventing the lengthening of telomeres and therefore the unrestricted growth of cancer cells, our DDS will provide a significant therapeutic advantage to these treatments without affecting normal tissues.

Selective JAK2 inhibition specifically decreases Hodgkin lymphoma and mediastinal large B-cell lymphoma growth in vitro and in vivo.

PURPOSE: Classical Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma (MLBCL) share similar histologic, clinical, and genetic features. In recent studies, we found that disease-specific chromosome 9p24.1/JAK2 amplification increased JAK2 expression and activity in both cHL and MLBCL. This prompted us to assess the activity of a clinical grade JAK2 selective inhibitor, fedratinib (SAR302503/TG101348), in in vitro and in vivo model systems of cHL and MLBCL with defined JAK2 copy numbers. EXPERIMENTAL DESIGN: We used functional and immunohistochemical analyses to investigate the preclinical activity of fedratinib and associated biomarkers in cell lines and murine xenograft models of cHL and MLBCL with known 9p24.1/JAK2 copy number. RESULTS: Chemical JAK2 inhibition decreased the cellular proliferation of cHL and MLBCL cell lines and induced their apoptosis. There was an inverse correlation between 9p24.1/JAK2 copy number and the EC50 of fedratinib. Chemical JAK2 inhibition decreased phosphorylation of JAK2, STAT1, STAT3, and STAT6 and reduced the expression of additional downstream targets, including PD-L1, in a copy number-dependent manner. In murine xenograft models of cHL and MLBCL with 9p24.1/JAK2 amplification, chemical JAK2 inhibition significantly decreased JAK2/STAT signaling and tumor growth and prolonged survival. In in vitro and in vivo studies, pSTAT3 was an excellent biomarker of baseline JAK2 activity and the efficacy of chemical JAK2 inhibition. CONCLUSIONS: In in vitro and in vivo analyses, cHL and MLBCL with 9p24.1/JAK2 copy gain are sensitive to chemical JAK2 inhibition suggesting that clinical evaluation of JAK2 blockade is warranted.

Current survivorship recommendations for patients with Hodgkin lymphoma: focus on late effects.

Long-term survivors of Hodgkin lymphoma (HL) are at an increased risk for a range of late complications, with subsequent malignant neoplasm and cardiovascular disease representing the 2 leading causes of death in these patients. Raising awareness, close follow-up, and adoption of selected early-detection and risk-reduction strategies may help to reduce the adverse impact of these late effects on patients. This chapter reviews known long-term complications of HL therapy, risk factors, and the timing of their occurrence. Where available, data on the efficacy of screening for selected late effects of HL are presented. Current evidence-based and consensus-based recommendations on follow-up of long-term HL survivors are also reviewed. As HL therapy evolves over time, late effects and implications on follow-up of patients treated in the contemporary era should be considered and opportunities for future research should be explored.

Exposure to UV radiation and risk of Hodgkin lymphoma: a pooled analysis.

Ultraviolet radiation (UVR) exposure has been inversely associated with Hodgkin lymphoma (HL) risk, but only inconsistently, only in a few studies, and without attention to HL heterogeneity. We conducted a pooled analysis of HL risk focusing on type and timing of UVR exposure and on disease subtypes by age, histology, and tumor-cell Epstein-Barr virus (EBV) status. Four case-control studies contributed 1320 HL cases and 6381 controls. We estimated lifetime, adulthood, and childhood UVR exposure and history of sunburn and sunlamp use. We used 2-stage estimation with mixed-effects models and weighted pooled effect estimates by inverse marginal variances. We observed statistically significant inverse associations with HL risk for UVR exposures during childhood and adulthood, sunburn history, and sunlamp use, but we found no significant dose-response relationships. Risks were significant only for EBV-positive HL (pooled odds ratio, 0.56; 95% confidence interval, 0.35 to 0.91 for the highest overall UVR exposure category), with a significant linear trend for overall exposure (P = .03). Pooled relative risk estimates were not heterogeneous across studies. Increased UVR exposure may protect against HL, particularly EBV-positive HL. Plausible mechanisms involving UVR induction of regulatory T cells or the cellular DNA damage response suggest opportunities for new prevention targets.

Perspectives of a lifelong cancer survivor--improving survivorship care.

Many of the 14 million cancer survivors in the USA live with physical, emotional and day-to-day concerns related to their cancer long after their treatment ends. Addressing the needs of the growing cancer-survivor population will be a considerable task. In this article, Ruth Rechis--a 20-year survivor of Hodgkin lymphoma--describes her personal account of surviving cancer and her experience as a researcher and advocate in the field of survivorship. Results from a national USA survey on survivorship are shared, illustrating gaps in meeting the needs of long-term survivors. A list of 'essential elements' of survivorship care is highlighted to introduce all practitioners to the components necessary for the provision of care after treatment ends. Finally, Rechis provides recommendations for engaging survivors as active participants in their post-treatment, long-term survivorship care and to ensure appropriate care is universally available as part of patient-centred comprehensive care.

Early relapse and refractory disease remain risk factors in the anthracycline and autologous transplant era for patients with relapsed/refractory classical Hodgkin lymphoma: a single centre intention-to-treat analysis.

An intention-to-treat (ITT) analysis was performed in 103 unselected patients with relapsed/refractory classical Hodgkin lymphoma (CHL) comparing early relapse (<12 months) or failure of first-line therapy (ER/FTF) with late relapses (LR). Seventy one percentage proceeded to high-dose therapy/autologous stem cell rescue (HDT/ASCR) following salvage treatment. By ITT, 5-year overall survival (OS) was 50% for ER/FTF compared to 73% for LR patients (P = 0·012). However OS was equivalent for both groups if salvage treatment response was adequate to proceed to HDT/ASCR. ER/FTF patients remain a high-risk group largely due to a failure of salvage therapy: a point at which novel interventions could impact survival.

mTOR as a target of everolimus in refractory/relapsed Hodgkin lymphoma.

Despite impressive treatment advances, few options for refractory or relapsed Hodgkin Lymphoma (HL) are available and there is a need for new compounds development. A number of promising agents with multiple mechanisms of action are under investigation. Microenvironment and neoangiogenesis are acquiring a rising relevance in the pathophysiology and progression of HL. Everolimus (RAD001) is an oral antineoplastic agent derived from rapamycin, a macrocyclic lactone antibiotic, targeting the mammalian target of rapamycin (mTOR). Although the importance of mTOR signaling in the deregulated cell growth of human neoplastic cells has been recognized, this pathway is also emerging as a key regulator of the tumor response to hypoxia, as well as endothelial and stromal cells function, thereby regulating neoangiogenesis. Furthermore, mTOR plays an important role in anticancer drug resistance. The actions of everolimus within the mTOR pathway in HL result in decreased protein synthesis and cell cycle arrest, as well as in decreased angiogenesis. Everolimus has shown preliminary evidence of efficacy as a single-agent in heavily pretreated relapsed/refractory HL, with an overall fair safety profile. The purpose of this review is to discuss the employment of everolimus as an antiproliferative and antiangiogenic agent in HL and to report the critical role of the mTOR pathway and angiogenesis in this malignancy.

Patterns of social support among lymphoma patients considering stem cell transplantation.

There is lack of literature addressing factors that influence the process of care for patients with hematological malignancies. We evaluated the forms of social support available for patients with relapsed lymphoma considering stem cell transplantation and examined the influence of support on treatment delay. Data were collected from 119 patients with relapsed lymphoma using a questionnaire to capture sociodemographic information and emotional, informational, and instrumental forms of social support. Sixty-four percent of the patients were married, 56% had children over 18 years of age, 43% were employed, and 72% had private health insurance. Family members formed a major source of emotional support (83%), while 47% of patients considered personal prayers to be important. While 79% of patients received clinical support from nurses, few received formal group support or formal peer support (6.7% and 1.7% respectively). Support from extended family and peer groups reduced the likelihood of treatment delays. The potential benefits of peer group support should be reinforced for patients considering transplantation given how infrequent this form of social support is utilized and its positive impact on the process of care. Future studies should test the impact of social support on health outcomes especially among the underserved population.

Chemotherapy only for localized Hodgkin lymphoma.

Radiation therapy (RT) alone and more recently in combination with chemotherapy (combined modality therapy; CMT) has been the cornerstone of curative treatment for early-stage Hodgkin lymphoma (HL) for over 40 years. Because of increasing awareness of the late morbidity and mortality associated with RT, recent treatment regimens have attempted to limit its use. Chemotherapy only has been demonstrated to be a treatment option for most patients with localized HL. Current clinical trials have targeted subgroups of such patients who may be at an increased risk of recurrence for the addition of limited RT to chemotherapy.

Combined ifosfamide, etoposide and oxalipatin chemotherapy, a low-toxicity regimen for first-relapsed or refractory Hodgkin lymphoma after ABVD/EBVP: a prospective monocentre study on 34 patients.

Around 20% of Hodgkin lymphoma (HL) patients are refractory to first-line therapy with ABVD (adriamycin-bleomycin-vinblastine-dacarbazine) or relapse after complete remission. Salvage regimens frequently have delayed courses or require dose-reduction because of haemotoxicity. We evaluated the IVOx (ifosfamide-etoposide-oxaliplatin) salvage regimen in terms of response rate, toxicity and stem-cell mobilization. Thirty-four patients with relapsed/refractory HL after anthracycline-containing chemotherapy prospectively received IVOx, consisting of ifosfamide (1500 mg/m(2) days 1-3), etoposide (150 mg/m(2) days 1-3) and oxaliplatin (130 mg/m(2) day 1). Patients <65 years old received high-dose therapy followed by autologous stem-cell transplantation (HDT-ASCT). Response was assessed by computed and positron-emission tomographies. Overall and complete response rates were 76% and 32%, respectively, after 2 cycles. Three episodes of febrile neutropenia occurred, and three patients required dose-reductions. Twenty-six patients underwent HDT-ASCT. With median follow-up at 5 years, the 5-year overall and event-free survival rates were 74% and 63%, respectively. IVOx is a well-tolerated outpatient regimen for relapsed HL, that does not hamper stem-cell mobilization, achieves good response rates and compares favourably with previously published salvage regimens.