Risk factors and reasons for treatment abandonment among children with lymphoma in Malawi.

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 < 18 years old with newly diagnosed lymphoma, prospectively enrolled during 2013-2016. All children received standardized diagnosis and treatment, and were followed for up to 2 years. Treatment abandonment was defined as failure to attend prescribed chemotherapy within 4 weeks, or post-treatment visit within 3 months. Child, guardian, and household characteristics associated with treatment abandonment were assessed. Semi-structured interviews were conducted with primary caregivers of children experiencing treatment abandonment. RESULTS: Of 121 children with newly diagnosed lymphoma, 72 (60%) had complete information regarding child, guardian, and household characteristics. Of these, 56 (78%) had Burkitt's and 16 (22%) Hodgkin's lymphoma. Forty-nine (68%) were male, median age was 10.6 years (interquartile range [IQR] 7.9-13.0), and 26 (36%) experienced treatment abandonment. Lack of guardian education and travel time ≥ 4 h to clinic were independently associated with treatment abandonment, with adjusted hazard ratio (aHR) 3.8 [95% confidence interval (CI) 1.5-8.9, p = 0.005] and aHR 2.9 (95% CI 1.2-6.9, p = 0.019), respectively. Commonest reasons for treatment abandonment endorsed by 15 guardians were community influence, suboptimal clinic environment, logistical challenges, transport costs, treatment toxicities, loss of hope, alternative healers, and beliefs about cure. CONCLUSIONS: These findings highlight families at risk for treatment abandonment, underlying reasons, and opportunities to improve retention in care for pediatric cancer patients in SSA.

Short Communication: CD4 Count and HIV RNA Trends for HIV-Associated Lymphoproliferative Disorders in Malawi.

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 <100 cells/µl and HIV RNA >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.

Salvage chemotherapy for adults with relapsed or refractory lymphoma in Malawi.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION: NCT02835911. Registered 19 January 2016.

Nanosecond, high-intensity pulsed electric fields induce apoptosis in human cells.

Electroporation by using pulsed electric fields with long durations compared with the charging time of the plasma membrane can induce cell fusion or introduce xenomolecules into cells. Nanosecond pulse power technology generates pulses with high-intensity electric fields, but with such short durations that the charging time of the plasma membrane is not reached, but intracellular membranes are affected. To determine more specifically their effects on cell structure and function, human cells were exposed to high intensity (up to 300 kV/cm) nanosecond (10-300 ns) pulsed electric fields (nsPEF) and were analyzed at the cellular and molecular levels. As the pulse duration decreased, plasma membrane electroporation decreased and appearances of apoptosis markers were delayed. NsPEF induced apoptosis within tens of minutes, depending on the pulse duration. Annexin-V binding, caspase activation, decreased forward light scatter, and cytochrome c release into the cytoplasm were coincident. Apoptosis was caspase- and mitochondria-dependent but independent of plasma membrane electroporation and thermal changes. The results suggest that with decreasing pulse durations, nsPEF modulate cell signaling from the plasma membrane to intracellular structures and functions. NsPEF technology provides a unique, high-power, energy-independent tool to recruit plasma membrane and/or intracellular signaling mechanisms that can delete aberrant cells by apoptosis.

Prehospital triage of acute myocardial infarction: wireless transmission of electrocardiograms to the on-call cardiologist via a handheld computer.

BACKGROUND: Use of intravenous fibrinolytic agents and percutaneous coronary interventions produce the greatest benefit when they are implemented in the first 2 hours after symptom onset. Further delays in the time to treatment typically lead to reduced benefits and poorer outcomes. METHODS: Cabarrus County Emergency Medical Service personnel complete an acute myocardial infarction case report form and assess a 12-lead electrocardiogram (ECG) to determine if ST elevation of at least 1 mV in at least 2 contiguous leads is present and then to transmit the ECG wirelessly to the emergency department (ED). The ECG is then forwarded wirelessly from the ED to the on-call cardiologist who is carrying the IPAQ handheld computer. RESULTS: Five representative patients managed using this system during the initial year of its implementation are presented. CONCLUSION: The examples included in this article illustrate that the system and technology can work if applied in a coordinated fashion using multiple disciplines including emergency medical service, cardiologists, ED personnel, and the hospital cardiac care team, which includes the catheterization laboratory call team, acute coronary care nurses, and clerical support staff.

The effects of intense submicrosecond electrical pulses on cells.

A simple electrical model for living cells predicts an increasing probability for electric field interactions with intracellular substructures of both prokaryotic and eukaryotic cells when the electric pulse duration is reduced into the sub-microsecond range. The validity of this hypothesis was verified experimentally by applying electrical pulses (durations 100 micros-60 ns, electric field intensities 3-150 kV/cm) to Jurkat cells suspended in physiologic buffer containing propidium iodide. Effects on Jurkat cells were assessed by means of temporally resolved fluorescence and light microscopy. For the longest applied pulses, immediate uptake of propidium iodide occurred consistent with electroporation as the cause of increased surface membrane permeability. For nanosecond pulses, more delayed propidium iodide uptake occurred with significantly later uptake of propidium iodide occurring after 60 ns pulses compared to 300 ns pulses. Cellular swelling occurred rapidly following 300 ns pulses, but was minimal following 60 ns pulses. These data indicate that submicrosecond pulses achieve temporally distinct effects on living cells compared to microsecond pulses. The longer pulses result in rapid permeability changes in the surface membrane that are relatively homogeneous across the cell population, consistent with electroporation, while shorter pulses cause surface membrane permeability changes that are temporally delayed and heterogeneous in their magnitude.