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The LAURA trial (NCT03521154) will evaluate the efficacy and safety of osimertinib as maintenance therapy in patients with locally advanced, unresectable, epidermal growth factor receptor mutation-positive (EGFRm), stage III non-small-cell lung cancer (NSCLC) without disease progression during/following definitive platinum-based chemoradiation therapy (CRT). Eligible patients include adults aged ≥ 18 years (≥ 20 years in Japan) with locally advanced, unresectable, stage III NSCLC with local/central confirmation of an EGFR exon 19 deletion/L858R mutation. Patients must have received ≥ 2 cycles of concurrent/sequential platinum-based CRT, have no investigator-assessed progression, and have creatinine 1.5 × upper limit of normal and creatinine clearance ≥ 30 mL/min. In this phase III trial, patients will be randomized 2:1 to once-daily osimertinib 80 mg or placebo, until objective radiological disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, confirmed by blinded independent central review (BICR). The primary objective is to assess the efficacy of osimertinib per BICR-confirmed progression-free survival (PFS). Secondary objectives include central nervous system PFS, overall survival, PFS by mutation status and safety. Patients with BICR-confirmed disease progression (or investigator-confirmed progression if after primary PFS analysis) may be unblinded and receive open-label osimertinib; all will have post-progression follow-up. Serious adverse events and adverse events of special interest will be collected throughout the trial and survival follow-up. The first patient was enrolled in July 2018, with results expected in late 2022.

PURPOSE: Lymphoma is the commonest pediatric cancer in sub-Saharan Africa (SSA). Frequent treatment abandonment contributes to suboptimal outcomes. We examined risk factors and reasons for treatment abandonment for this population in Malawi. METHODS: We conducted a mixed methods study among children

Lymphoma is highly associated with HIV in sub-Saharan Africa (SSA), which contributes to worse outcomes relative to resource-rich settings, and frequent failure of first-line chemotherapy. However, there are no second-line treatment descriptions for adults with relapsed or refractory lymphoma (RRL) in SSA. We describe HIV+ and HIV- patients with RRL receiving salvage chemotherapy in Malawi. Patients were prospectively treated at a national teaching hospital in Lilongwe, with the modified EPIC regimen (etoposide, prednisolone, ifosfamide, cisplatin) between June 2013 and May 2016, after failing prior first-line chemotherapy. Among 21 patients (18 relapsed, 3 refractory), median age was 40 years (range 16–78), 12 (57%) were male. Thirteen patients (62%) were HIV+, of whom 12 (92%) were on antiretroviral therapy (ART) at initiation of salvage chemotherapy, with median CD4 cell count 139 cells/μL (range 12–529) and 11 (85%) with suppressed HIV RNA. Median number of EPIC cycles was 3 (range 1–6), and the commonest toxicity was grade 3/4 neutropenia in 19 patients (90%). Fifteen patients responded (3 complete, 12 partial, overall response rate 71%), but durations were brief. Median overall survival was 4.5 months [95% confidence interval (CI) 2.4–5.6]. However, three patients, all HIV+, experienced sustained remissions. Tolerability, response, and survival did not differ by HIV status. The appropriateness and cost-effectiveness of this approach in severely resource-limited environments is uncertain, and multifaceted efforts to improve first-line lymphoma treatment should be emphasized, to reduce frequency with which patients require salvage chemotherapy. NCT02835911 . Registered 19 January 2016.

Point-of-care tools are needed in sub-Saharan Africa (SSA) to improve pediatric Burkitt lymphoma (BL) diagnosis and treatment. We evaluated plasma Epstein-Barr virus (pEBV) DNA as a pediatric BL biomarker in Malawi. Prospectively enrolled children with BL were compared to classical Hodgkin lymphoma (cHL) and nonlymphoma diagnoses. Pediatric BL patients received standardized chemotherapy and supportive care. pEBV DNA was measured at baseline, mid-treatment, and treatment completion. Of 121 assessed children, pEBV DNA was detected in 76/88 (86%) with BL, 16/17 (94%) with cHL, and 2/16 (12%) with nonlymphoma, with proportions higher in BL versus nonlymphoma (p

Given scarce data from sub-Saharan Africa (SSA), we sought to describe CD4 count and HIV RNA trends over time among patients with HIV-positive lymphoproliferative disorders in Malawi. We prospectively enrolled HIV-positive individuals with pathologically confirmed lymphoproliferative disorders between 2013 and 2016. Chemotherapy was standardized with concurrent antiretroviral therapy (ART). We assessed CD4 count and HIV RNA at baseline and every 6 months for up to 2 years. Of 72 HIV-positive patients, 59 had non-Hodgkin lymphoma (NHL), 5 classical Hodgkin lymphoma (CHL), and 8 multicentric Castleman disease (MCD). Median age was 43 years (range 23–64). Fifty-five patients (76%) were on ART at enrollment for a median 47 months (range 1–387), with median CD4 count of 138 cells/μl (range 2–2,235) and median HIV RNA of 2.2 log10copies/ml (range 0.3–7.3). MCD patients had longer median ART durations, higher median CD4 counts, and lower median HIV RNA at baseline than NHL or CHL patients. CD4 count and HIV RNA steadily improved during follow-up, with different patterns in different histological groups. Twelve-month overall survival (OS) was 55% [95% confidence interval (CI) 42%–66%]. There were trends toward baseline CD4 count 2.0 log10copies/ml being associated with worse OS. However, CD4 count and HIV RNA improvements during follow-up were independent of possible effects on OS. Distribution of HIV-positive lymphoproliferative disorders may change with continued ART scale-up in SSA. Chemotherapy and concurrent ART can lead to good immunological and virological outcomes.

In their recent News & Views article (Sustainability and affordability of cancer drugs: a novel pricing model. Nat. Rev. Clin.Oncol. 15, 405–406 (2018))1, Uyl- De Groot and Lowenberg outline a new universal algorithm for setting the price of new drugs in oncology. Their ambitious proposal is intended to standardize a complicated and fragmented pricing process. The international drug market is dynamic and diverse2. Having a universal pricing mechanism could indeed be helpful in addressing the imbalances in drug pricing and improve access to medicines for many patients, including those with nononcological diseases. However, we would like to point out some thoughts on the proposed algorithm.

The binding of some novel bicalutamide analogues to human serum albumin (HSA) and rat serum albumin (RSA) was investigated by surface plasmon resonance (SPR) based optical biosensor technique. The serum protein binding of the bicalutamide analogues was determined and compared to that of the parent compound. Furthermore, HSA and RSA were used as target plasma proteins, in order to highlight possible differences among species when performing pharmacokinetic studies. HSA and RSA were covalently immobilized on carboxymethyl dextran matrixes, using an amine coupling procedure. The anchoring method was validated by determining the dissociation constant (KD) of a standard analyte to confirm that the binding properties of the proteins were maintained. The ranking of the bicalutamide analogues for their HSA and RSA bound fractions was used to compare the behaviour of the two albumins. Most of the bicalutamide analogues showed higher binding levels with respect to the lead compound, (R)-bicalutamide. Further, meaningful differences in the binding level to the two serum proteins were obtained. The dissociation constants (KD) of the interaction between the lead compound, (R)-bicalutamide, and the two proteins were calculated. As a result, the KD obtained with HSA was one order of magnitude higher than that obtained with RSA.The observed differences in the HSA and RSA bonding of the bicalutamide analogues increase the knowledge on the possible low reliability in extrapolating the distribution data obtained on animals to humans. This work demonstrates that SPR based optical biosensor technique is well suited for the medium-high throughput screening of compounds' ligand binding to serum albumins.

Background Extranodal NK/T-cell lymphoma (ENKTCL) reports from sub-Saharan Africa (SSA) are remarkably rare, despite early childhood acquisition and high prevalence of the causative infectious agent, Epstein-Barr virus (EBV), and frequent occurrence of other lymphoproliferative disorders causally associated with EBV. Case presentations At a national teaching hospital in Malawi, three patients of African descent were seen with ENKTCL between 2013 and 2014. Patients were aged between 29 and 60 years, two with craniofacial involvement and one with a primary abdominal tumor, and all were HIV-negative. All had systemic B symptoms, and two severely impaired performance status. On histologic review, morphology and immunophenotyping demonstrated classical ENKTCL features in all cases, including diffuse proliferations of intermediate-to-large atypical lymphocytes with high mitotic activity and extensive background necrosis, positivity for CD3 and CD56, and negativity for CD20. By in situ hybridization, all three tumors were positive for EBV-encoded RNA (EBER). Baseline plasma EBV DNA was also markedly elevated for all three patients. Due to radiotherapy and chemotherapy limitations, patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) with rapid disease progression. All three patients died from progressive lymphoma within 3 months of initial diagnosis. Conclusions Our experience with these three patients in Malawi can highlight that ENKTCL does indeed occur in SSA, increase familiarity with ENKTCL among clinicians and pathologists throughout the region, and emphasize the need for better diagnosis and treatment for this neglected population.

INTRODUCTION Internationally validated tools to measure patient-reported health-related quality of life (HRQoL) are available, but efforts to translate and culturally validate such tools in sub-Saharan Africa (SSA) are scarce, particularly among children. METHODS The Patient-Reported Outcomes Measurement Information System 25-item pediatric short form (PROMIS-25) assesses six HRQoL domains-mobility, anxiety, depression, fatigue, peer relationships, and pain interference-by asking four questions per domain. There is a single-item pain intensity item. The PROMIS-25 was translated into Chichewa and validated for use in Malawi using mixed qualitative and quantitative methods. The validity and reliability of the PROMIS-25 was assessed. RESULTS Fifty-four pediatric patients with lymphoma completed the PROMIS-25. Structural validity was supported by interitem correlations and principal component analysis. Reliability of each scale was satisfactory (range alpha = 0.71-0.93). Known group validity testing showed that anemic children had worse fatigue (P = 0.016) and children with poor performance status had worse mobility (P

In their Original Investigation published in a recent issue of JAMAInternal Medicine, Prasad and Mailankody examine the costs of bringing a single drug with an oncological indication to the market. They conclude that 10 selected companies had a median investment cost of $648 million for the development of their drug, whereas the median revenue in 4 years on average was $1658.4 million. This further reinforces the notion that there are large profits to be made with drug development, and that current pharmaceutical drug prices are unrelated to the actual costs for research and development.

The possibility of gene doping, defined as the transfer of nucleic acid sequences and/or the use of normal or genetically modified cells to enhance sport performance, is a real concern in sports medicine. The abuse of knowledge and techniques gained in the area of gene therapy is a form of doping, and is prohibited for competitive athletes. As yet there is no conclusive evidence that that gene doping has been practiced in sport. However, given that gene therapy techniques improve continuously, the likelihood of abuse will increase. A literature search was conducted to identify the most relevant proteins based on their current gene doping potential using articles from Pubmed, Scopus and Embase published between 2006 and 2011. The final list of selected proteins were erythropoietin, insulin-like growth factor, growth hormone, myostatin, vascular endothelial growth factor, fibroblast growth factor, endorphin and enkephalin, a actinin 3, peroxisome proliferator-activated receptor-delta (PPAR delta) and cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C). We discuss these proteins with respect to their potential benefits, existing gene therapy experience in humans, potential risks, and chances of detection in current and future anti-doping controls. We have identified PPARd and PEPCK-C as having high potential for abuse. But we expect that for efficiency reasons, there will be a preference for inserting gene target combinations rather than single gene doping products. This will also further complicate detection.

Pediatric lymphoma is common in sub-Saharan Africa, where survival estimates are often based on limited follow-up with incomplete retention, introducing potential for bias. We compared follow-up and overall survival (OS) between passive and active tracing within a prospective cohort of children with lymphoma in Malawi. Median follow-up times were 4.4 months (interquartile range [IQR] 2.0-9.4) and 10.8 months (IQR 6.2-20.6) in passive and active follow-up, respectively. Twelve-month overall survival (OS) was 69% (95% confidence interval [CI] 54-80) in passive and 44% (95% CI 34-54) in active follow-up. Passive follow-up significantly overestimated the OS and underestimated the mortality. Efforts to improve retention in regional studies are needed.

Introduction: The global distribution of sickle cell disease (SCD) overlaps with that of food scarcity and nutritional deficiencies. Chronic anemia secondary to SCD contributes to nutritional deficiencies, for example folic acid. Few studies have evaluated associations between malnutrition and SCD, nor effects of malnutrition on SCD outcomes. Moreover,hydroxyurea(HU), a disease modifying agent for SCD, has not been specifically evaluated in malnourished children although it is known to bind pharmacologically to human serum albumin. Methods: We conducted a cross-sectional nutritional assessment of children receiving chronic SCD care at a referral hospital in the capital city of Malawi, Lilongwe, between January and June 2016. Participants were measured for height, weight, and mid-upper arm circumference. Z-scores and percentiles for anthropomorphic indices were calculated using WHOAnthroSoftware. Nutritional measures of interest were BMI-for-age Z-score to assess wasting and height-for-age Z-score to assess stunting. We examined associations between nutritional status and clinical and laboratory data collected longitudinally at six-month intervals during routine care. Differences based on HU use were examined. Results: Fourteen of 99 (14.1%) participants had moderate-to-severe wasting and 36 of 101 (35.6%) moderate-to-severe stunting. The wasted group was significantly older than the non-wasted group but there was no significant difference in age between the stunted and non-stunted groups (Table 1). We observed significantly lower white blood cell (WBC) and lymphocyte counts in the wasted group when compared to the non-wasted group. The stunted group had significantly lower hemoglobin (Hb) than the non-stunted group. There was also a significantly higher prevalence of fevers in the stunted group than the non-stunted group. Forty-four of 151 (29.1%) participants were receiving HU for a median duration of 126 days (IQR 29 - 196 days). There were no significant differences in age or sex between the HU group and the non-HU group. We observed significantly lower Hb in the HU group when compared to the non-HU group, as expected as HU is typically prescribed for children with more severe SCD in Lilongwe. We also observed higher WBC, absolute neutrophil (ANC), and lymphocyte counts in the HU group. Again reflecting greater SCD severity, we observed a significantly more frequent history of fevers, upper respiratory tract infections, and splenomegaly in the HU group. There were no significant differences in the proportions of wasted participants by HU status [5/33 (15.2%) HUvs20/68 (29.4%) non-HU, p=0.84], and a trend toward more frequent stunting among HU users again likely reflecting growth effects of greater chronic SCD severity [16/33 (48.5%) HUvs9/66 (13.6%) non-HU, p=0.061]. Among HU users, peripheral blood counts were not significantly different in wastedvsnon-wasted children, nor stuntedvsnon-stunted children (Table 2). Conclusion: In a pediatric SCD cohort in Malawi we observed 14.1% of children with significant wasting and 35.6% with significant stunting, highlighting growth effects of chronic illness in this population even among children receiving regular SCD care. Among children prescribed HU, nutritional status did not seem to be associated with HU tolerability. Notably, HU was not associated with significantmyelosuppressionin our cohort including those children with wasting or stunting. More studies are needed to clarify interactions between nutritional status, SCD, and HU, but our data suggests wasting or stunting should not be contraindications to HU use when indicated for pediatric SCD in sub-Saharan Africa. Table 1 Table 1. Table 2 Table 2. Disclosures No relevant conflicts of interest to declare.