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Meropi Plousiou,1 Alessandro De Vita,2 Giacomo Miserocchi,2 Erika Bandini,1 Ivan Vannini,1 Mattia Melloni,1 Nestory Masalu,3 Francesco Fabbri,1 Patrizia Serra4 1Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; 2Osteoncology Unit, Bioscience Laboratory IRCCS Istituto Romagnolo Per lo Studio dei Tumori (IRST), “Dino Amadori”, 47014 Meldola, Italy; 3Unit of Biostatistics and Clinical Trials, Bioscience Laboratory IRCCS Istituto Romagnolo Per lo Studio dei Tumori (IRST), “Dino Amadori”, 47014 Meldola, Italy; 4Unit of Biostatistics and Clinical Trials, IRCCS Istituto Scientifico Romagnolo Per lo Studio dei Tumori (IRST), “Dino Amadori”, Meldola, ItalyCorrespondence: Meropi Plousiou, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy, Tel +39 0543739298, Fax +39 0543739221, Email meropi.plousiou@irst.emr.itIntroduction: Retinoblastoma (Rb) is the most common ocular paediatric malignancy and is caused by a mutation of the two alleles of the tumor suppressor gene, RB1. The tumor microenvironment (TME) represents a complex system whose function is not yet well defined and where microvesicles, such as exosomes, play a key role in intercellular communication. Micro-RNAs (mRNAs) have emerged as important modifiers of biological mechanisms involved in cancer and been able to regulate tumor progression.Methods: Co-culture of monocytes with retinoblastoma cell lines, showed a significant growth decrease. Given the interaction between Rb cells and monocytes, we investigated the role of the supernatant in the cross-talk between cell lines, by taking the product of the co-culture and then using it as a culture medium for Rb cells.Results: miR-142-3p showed to be particularly over-expressed both in the Rb cell line and in the medium used for their culture, comparing to control cell line and the normal supernatant, respectively. Therefore, we provided evidence that miR-142-3p is released by monocytes in the co-culture medium’s exosomes and that it is subsequently up-taken by Rb cells, causing the inhibition of proliferation of Rb cell line by affecting cell cycle progression.Conclusion: This study highlights the role of exosomic miR-142-3p in the TME of Rb and identifies new molecular targets, which are able to control tumor growth aiming the development of a forward-looking miR-based strategy.Keywords: tumor microenvironment, microvescicles, microRNAs, co-culture, monocytes, cross-talk

B Introduction: b Burkitt lymphoma (BL) is an aggressive B-cell lymphoma with hallmark somatic I IG i :: I MYC i chromosomal translocations. Additional analyses were performed using genomic, epigenomic and expression data from the BL and ICGC MMML-Seq genome sequencing projects to provide insight into the potential mechanisms by which the novel loci may influence BL risk in African children. GENOME-WIDE ASSOCIATION STUDY OF CHILDHOOD BURKITT LYMPHOMA IN EAST AFRICA IDENTIFIES A NOVEL GERMLINE SUSCEPTIBILITY LOCUS ON CHROMOSOME 21. [Extracted from the article]

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According to the World Health Organisation (WHO), deaths from non-communicable diseases (NCDs) will increase globally, with the largest increase being on the African continent. On our continent, projections have indicated that deaths from NCDs will exceed all combined communicable, maternal, perinatal and nutritional diseases as the most common causes of death by 2030. Hence, the importance of a functional and improved pathology system in the diagnosis of cancer cannot be debated. Recently, the African Organization for Research and Training in Cancer (AORTIC) organised its East African regional meeting in Mwanza, Tanzania on 25-26 June 2015, with the focus being ‘Pathology and oncology: Education and training for the future in cancer research'. The main themes of the workshop were around improving cancer care and the role of twinning in Eastern Africa, in particular the Mwanza cancer project, telepathology, e-health and biobanking. The outcomes of a 2 day strategic meeting were developing an efficient and effective plan to guide the improvement in pathology training and cancer research in Africa. [ABSTRACT FROM AUTHOR]

Abstract Background Non-Hodgkin’s Lymphomas (NHL) are common in African children, with endemic Burkitt’s lymphoma (BL) being the most common subtype. While the role of Epstein-Barr Virus (EBV) in endemic BL is known, no data are available about clinical presentations of NHL subtypes and their relationship to Human Immunodeficiency Virus (HIV) infection and Epstein Barr Virus (EBV) load in peripheral blood of children in north-western, Tanzania. Methods A matched case control study of NHL subtypes was performed in children under 15 years of age and their respective controls admitted to Bugando Medical Centre, Sengerema and Shirati district designated hospitals in north-western, Tanzania, between September 2010 and April 2011. Peripheral blood samples were collected on Whatman 903 filter papers and EBV DNA levels were estimated by multiplex real-time PCR. Clinical and laboratory data were collected using a structured data collection tool and analysed using chi-square, Fisher and Wilcoxon rank sum tests where appropriate. The association between NHL and detection of EBV in peripheral blood was assessed using conditional logistic regression model and presented as odds ratios (OR) and 95% confidence intervals (CI). Results A total of 35 NHL cases and 70 controls matched for age and sex were enrolled. Of NHLs, 32 had BL with equal distribution between jaw and abdominal tumour, 2 had large B cell lymphoma (DLBCL) and 1 had NHL-not otherwise specified (NHL-NOS). Central nervous system (CNS) presentation occurred only in 1 BL patient; 19 NHLs had stage I and II of disease. Only 1 NHL was found to be HIV-seropositive. Twenty-one of 35 (60%) NHL and 21 of 70 (30%) controls had detectable EBV in peripheral blood (OR = 4.77, 95% CI 1.71 – 13.33, p = 0.003). In addition, levels of EBV in blood were significantly higher in NHL cases than in controls (p = 0.024). Conclusions BL is the most common childhood NHL subtype in north-western Tanzania. NHLs are not associated with HIV infection, but are strongly associated with EBV load in peripheral blood. The findings suggest that high levels of EBV in blood might have diagnostic and prognostic relevance in African children.

Abstract Background Despite marked decreases in its incidence, particularly in developed countries, gastric cancer is still the second most common tumor worldwide. There is a paucity of information regarding gastric cancer in northwestern Tanzania. This study was undertaken to describe our experience, in our local setting, on the management of gastric cancer, outlining the clinicopathological and treatment outcome of these patients and suggesting ways to improve the treatment outcome. Methods This was a retrospective study of histologically confirmed cases of gastric cancer seen at Bugando Medical Centre between January 2007 and December 2011. Data were retrieved from patients’ files and analyzed using SPSS computer software version 17.0. Results A total of 232 gastric cancer patients were enrolled in the study, representing 4.5% of all malignancies. The male to female ratio was 2.9:1. The median age of patients was 52 years. The majority of the patients (92.1%) presented late with advanced gastric cancer (Stages III and IV). Lymph node and distant metastasis at the time of diagnosis was recorded in 31.9% and 29.3% of cases, respectively. The antrum was the most frequent anatomical site (56.5%) involved and gastric adenocarcinoma (95.1%) was the most common histopathological type. Out of 232 patients, 223 (96.1%) patients underwent surgical procedures for gastric cancer of which gastro-jejunostomy was the most frequent performed surgical procedure, accounting for 53.8% of cases. The use of chemotherapy and radiotherapy was documented in 56 (24.1%) and 12 (5.1%) patients, respectively. Postoperative complication and mortality rates were 37.1% and 18.1%, respectively. According to multivariate logistic regression analysis, preoperative co-morbidity, histological grade and stage of the tumor, presence of metastases at the time of diagnosis was the main predictors of death (P P Conclusions Gastric cancer in this region shows a trend towards relative young age at diagnosis and the majority of patients present late with an advanced stage. Lack of awareness of the disease, poor accessibility to health care facilities and lack of screening programs in this region may contribute to advanced disease at the time of diagnosis. There is a need for early detection, adequate treatment and proper follow-up to improve treatment outcome.

Abstract Background Evidence for the association between Human immunodeficiency virus infection and cervical cancer has been contrasting, with some studies reporting increased risk of cervical cancer among HIV positive women while others report no association. Similar evidence from Tanzania is scarce as HIV seroprevalence among cervical cancer patients has not been rigorously evaluated. The purpose of this study was to determine the association between HIV and tumor differentiation among patients with cervical cancer at Bugando Medical Centre and Teaching Hospital in Mwanza, North-Western Tanzania. Methods This was a descriptive analytical study involving suspected cervical cancer patients seen at the gynaecology outpatient clinic and in the gynaecological ward from November 2010 to March 2011. Results A total of 91 suspected cervical cancer patients were seen during the study period and 74 patients were histologically confirmed with cervical cancer. The mean age of those confirmed of cervical cancer was 50.5 ± 12.5 years. Most patients (39 of the total 74–52.7%) were in early disease stages (stages IA-IIA). HIV infection was diagnosed in 22 (29.7%) patients. On average, HIV positive women with early cervical cancer disease had significantly more CD4+ cells than those with advanced disease (385.8 ± 170.4 95% CI 354.8-516.7 and 266.2 ± 87.5, 95% CI 213.3-319.0 respectively p = 0.042). In a binary logistic regression model, factors associated with HIV seropositivity were ever use of hormonal contraception (OR 5.79 95% CI 1.99-16.83 p = 0.001), aged over 50 years (OR 0.09 95% CI 0.02-0.36 p = 0.001), previous history of STI (OR 3.43 95% CI 1.10-10.80 p = 0.035) and multiple sexual partners OR 5.56 95% CI 1.18-26.25 p = 0.030). Of these factors, only ever use of hormonal contraception was associated with tumor cell differentiation (OR 0.16 95% CI 0.06-0.49 p = 0.001). HIV seropositivity was weakly associated with tumor cell differentiation in an unadjusted analysis (OR 0.21 95% CI 0.04-1.02 p = 0.053), but strong evidence for the association was found after adjusting for ever use of hormonal contraception with approximately six times more likelihood of HIV infection among women with poorly differentiated tumor cells compared to those with moderately and well differentiated cells (OR 5.62 95% CI 1.76-17.94 p = 0.004). Conclusion Results from this study setting suggest that HIV is common among cervical cancer patients and that HIV seropositivity may be associated with poor tumour differentiation. Larger studies in this and similar settings with high HIV prevalence and high burden of cervical cancer are required to document this relationship.

Abstract Background Marjolin's ulcer is a rare but highly aggressive squamous cell cancer that is most often associated with chronic burn wounds. Although many individual case reports exist, no comprehensive evaluation of Marjolin's ulcer patients has been conducted in our setting. This study was conducted to describe the clinicopathological presentation and treatment outcome of this condition in our local setting and to identify predictors of outcome. Methods This was a retrospective study of histologically confirmed cases of Marjolin's ulcer seen at Bugando Medical Centre over a period of 10-years between January 2001 and December 2010. Data were retrieved from patients' files and analyzed using SPSS computer software version 15.0 Results A total of 56 patients were studied. Male to female ratio was 2.1:1. Burn scars (89.3%) were the most common causative lesions of Marjolin's ulcer. The mean latent period between original injury and diagnosis of Marjolin's ulcer was 11.34 ± 6.14 years. Only 12.0% of the reported cases were grafted at the time of injury (P < 0.00). Most patients (48.2%) presented between one and five years of onset of illness. The lower limb (42.9%) was the most frequent site for Marjolin's ulcers. The median tumor size at presentation was 8 cm and the vast majority of patients (85.7%) presented with large tumors of ≥ 5 cm in diameter. Lymph node metastasis at the time of diagnosis was recorded in 32.1% of cases and distant metastasis accounted for 26.9% of cases. Squamous cell carcinoma (91.1%) was the most common histopathological type. Wide local excision was the most common surgical procedure performed in 80.8% of cases. Post-operative complication rate was 32.1% of which surgical site infection was the most common complication in 38.9% of patients. Local recurrence was noted in 33.3% of cases who were treated surgically. The mean length of hospital stay for in-patients was 7.9 ± 2.3 days. Mortality rate was 7.1%. According to multivariate logistic regression analysis, stage and grade of the tumor and presence of local recurrence were the main predictors of death (P < 0.001). Conclusion Marjolin's ulcers are not rare in our environment and commonly occur in burn scars that were not skin grafted and were left to heal secondarily. A high index of suspicion is required in the management of chronic non-healing ulcers and all suspected lesions should be biopsed. Early recognition and aggressive treatment of Marjolin's ulcers and close follow-up are urgently needed to improve outcomes in our environment.

Cervical cancer is the most diagnosed cancer in Tanzania, a lower-middle income country (LMIC) that as a group bears nearly 90% of deaths from cervical cancer globally. Radiotherapy, including brachytherapy (BT), is the global-standard-of-care for locally advanced cervical cancer. Development in these settings is often limited by a lack of economic investment. To help inform these efforts, we aimed to characterize the costs associated with brachytherapy at Bugando Medical Centre (BMC), one of two public radiotherapy facilities for a country of 60 million and the only one in northern Tanzania. Time-drive activity-based costing (TDABC) is a methodology used to evaluate costs in healthcare delivery using a bottom-up approach. Process maps for each component of BT were developed through two onsite visits. Salary and equipment cost data were obtained from administrative, physician, and physics staff. Amounts recorded in Tanzanian shillings (TZS) were converted to USD. This was used to calculate the capacity cost rate (CCR) for each resource, which was multiplied by process times in each step of the BT workflow to calculate total costs of treatment. Three-fraction high dose rate (HDR)-BT using tandem-and-ring under anesthesia using one Cobalt-60 afterloader followed external beam radiotherapy for patients with locally advanced cervical cancer at BMC. There is a yearly contract for the HDR afterloader which accounted for source exchanges without additional costs. The process maps detailed steps from physician consultation, pre-op evaluation, BT procedure, C-arm imaging, 2D treatment planning, treatment delivery, applicator removal, and post-op recovery. The personnel CCR was $0.35/min for radiation oncologists, $0.12/min for anesthesia, $0.10/min for nurses, $0.23/min for medical physicists and $0.14/min for radiation therapists. The equipment CCR was $0.99/min for the HDR afterloader and $0.24/min for the mobile C-arm. The cost for a 3-fraction course of HDR-BT was $158.8. The costs of additional fractions of brachytherapy were modeled and calculated at $48.9 per additional fraction. Pre-op evaluation accounted for 11.9% of this cost, BT procedure 21.2%, treatment planning 8.4%, treatment delivery 53.4%, and post-op recover 5.1%. BT is a covered service under Tanzania's National Health Insurance Plan, however a minority of patients (13%) treated in the department were insured. To our knowledge, this is the first study on radiotherapy costs in Tanzania. Limited data exist in LMICs on costs and cost-effectiveness for radiotherapy. These results provide a detailed understanding of the costs associated with brachytherapy delivery in this low-resource setting. BT machine time remain the most expensive resource in the department. Overall, BT services provide significant returns on investment at $158.8 per 3-fraction course. Future studies are ongoing to examine the clinical and economic impact of radiotherapy in Tanzania. [ABSTRACT FROM AUTHOR]