A roadmap to establishing global oncology as a priority initiative within a National Cancer Institute-designated cancer center.

As the burden of cancers impacting low- and middle-income countries is projected to increase, formation of strategic partnerships between institutions in high-income countries and low- and middle-income country institutions may serve to accelerate cancer research, clinical care, and training. As the US National Cancer Institute and its Center for Global Health continue to encourage cancer centers to join its global mission, academic cancer centers in the United States have increased their global activities. In 2015, the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, responded to the call for international partnership in addressing the global cancer burden through the establishment of the Global Cancer Program as a priority initiative. In developing the Global Cancer Program, we galvanized institutional support to foster sustained, bidirectional, equitable, international partnerships in global cancer control. Our focus and intent in disseminating this commentary is to share experiences and lessons learned from the perspective of a US-based, National Cancer Institute-designated cancer center and to provide a roadmap for other high-income institutions seeking to strategically broaden their missions and address the complex challenges of global cancer control. Herein, we review the formative evaluation, governance, strategic planning, investments in career development, funding sources, program evaluation, and lessons learned. Reflecting on the evolution of our program during the first 5 years, we observed in our partners a powerful shift toward a locally driven priority setting, reduced dependency, and an increased commitment to research as a path to improve cancer outcomes in resource-constrained settings.

Human Papillomavirus-Associated Head and Neck Malignancies in Sub-Saharan Africa: A Systematic Review.

PURPOSE: The proportion of head and neck cancers (HNCs) with human papillomavirus (HPV) positivity in sub-Saharan Africa (SSA) is poorly characterized. Characterizing this has implications in staging, prognosis, resource allocation, and vaccination policies. This study aims to determine the proportion of HPV-associated HNC in SSA. MATERIALS AND METHODS: This systematic review included searches from PubMed, EMBASE, Web of Science, African Index Medicus, Google Scholar, and African Journals Online. All English publications reporting the proportion of HNC specimens from SSA patients who tested positive for HPV and/or p16 were included. Study quality was assessed using the National Institutes of Health Quality Assessment Tool for Case Series Studies. RESULTS: In this systematic review of 31 studies and 3,850 patients, the overall p16 positivity was 13.6% (41 of 1,037 patients tested) with the highest proportion among oropharyngeal cancers (20.3%, 78 of 384 patients) and the overall HPV polymerase chain reaction positivity was 15.3% (542 of 3,548 samples tested) with the highest proportion among nasopharyngeal cancers (16.5%, 23 of 139 patients). Among the 369 HPV strains detected, the most common genotypes were HPV 16 (226 patients, 59.2%) and HPV 18 (78, 20.4%). CONCLUSION: HPV was found to be associated with a significant proportion of HNC in SSA. The genotypes reported suggest that the nine-valent vaccine and gender-neutral vaccination policies should be considered. Given that these studies may not accurately capture prevalence nor causation of HPV in HNC subsites, additional research is needed to provide a more thorough epidemiologic understanding of HPV-associated HNC in SSA, including risk factors and clinical outcomes.

An international report on bacterial communities in esophageal squamous cell carcinoma.

The incidence of esophageal squamous cell carcinoma (ESCC) is disproportionately high in the eastern corridor of Africa and parts of Asia. Emerging research has identified a potential association between poor oral health and ESCC. One possible link between poor oral health and ESCC involves the alteration of the microbiome. We performed an integrated analysis of four independent sequencing efforts of ESCC tumors from patients from high- and low-incidence regions of the world. Using whole genome sequencing (WGS) and RNA sequencing (RNAseq) of ESCC tumors from 61 patients in Tanzania, we identified a community of bacteria, including members of the genera Fusobacterium, Selenomonas, Prevotella, Streptococcus, Porphyromonas, Veillonella and Campylobacter, present at high abundance in ESCC tumors. We then characterized the microbiome of 238 ESCC tumor specimens collected in two additional independent sequencing efforts consisting of patients from other high-ESCC incidence regions (Tanzania, Malawi, Kenya, Iran, China). This analysis revealed similar ESCC-associated bacterial communities in these cancers. Because these genera are traditionally considered members of the oral microbiota, we next explored whether there was a relationship between the synchronous saliva and tumor microbiomes of ESCC patients in Tanzania. Comparative analyses revealed that paired saliva and tumor microbiomes were significantly similar with a specific enrichment of Fusobacterium and Prevotella in the tumor microbiome. Together, these data indicate that cancer-associated oral bacteria are associated with ESCC tumors at the time of diagnosis and support a model in which oral bacteria are present in high abundance in both saliva and tumors of some ESCC patients.

Risk Factors Associated With Early-Onset Esophageal Cancer in Tanzania.

PURPOSE: Eastern Africa is one of several regions affected by high incidence rates of esophageal squamous cell carcinoma (ESCC). A unique epidemiologic feature of ESCC in Eastern Africa is the high incidence in young people, with one-third of cases diagnosed at age < 45 years. This study aimed to investigate risk factors for early-onset ESCC in Tanzania through a secondary analysis of a matched case-control study. MATERIALS AND METHODS: From 2013 to 2015, ESCC cases were recruited at Muhimbili National Hospital and Ocean Road Cancer Institute in Dar es Salaam, Tanzania. Hospital controls were identified from patients with nonmalignant conditions and matched 1:1 for sex and age (± 10 years). Questionnaires were used to assess sociodemographic characteristics and environmental, dietary, and lifestyle risk exposures. Multivariate logistic regression models were used to estimate age-specific odds ratios of ESCC for exposures among participants age 30-44 and ≥ 45 years. RESULTS: A total of 471 cases and 471 controls were enrolled. Among cases, 100 (21%) were < 45 years. Multiple exposures were identified as risk factors for early-onset ESCC, several of which were unique to this age group, including infrequent teeth cleaning, secondhand tobacco smoke exposure, and pest infestation of grain and/or nuts. Lower socioeconomic status, family history of ESCC, tobacco smoking, home-brewed alcohol consumption, home storage of grain and/or nuts, and use of firewood for cooking were associated in the older but not the younger age group. Hot beverage intake was associated with increased ESCC risk in both age groups. CONCLUSION: Our results suggest that ESCC risk factors in Tanzania vary between age groups. With the data currently available, environmental and behavioral risk factors appear to play an important role in the high incidence of ESCC among young people.

Treatment outcomes of esophageal cancer in Eastern Africa: protocol of a multi-center, prospective, observational, open cohort study.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a major cause of cancer morbidity and mortality in Eastern Africa. The majority of patients with ESCC in Eastern Africa present with advanced disease at the time of diagnosis. Several palliative interventions for ESCC are currently in use within the region, including chemotherapy, radiation therapy with and without chemotherapy, and esophageal stenting with self-expandable metallic stents; however, the comparative effectiveness of these interventions in a low resource setting has yet to be examined. METHODS: This prospective, observational, multi-center, open cohort study aims to describe the therapeutic landscape of ESCC in Eastern Africa and investigate the outcomes of different treatment strategies within the region. The 4.5-year study will recruit at a total of six sites in Kenya, Malawi and Tanzania (Ocean Road Cancer Institute and Muhimbili National Hospital in Dar es Salaam, Tanzania; Kilimanjaro Christian Medical Center in Moshi, Tanzania; Tenwek Hospital in Bomet, Kenya; Moi Teaching and Referral Hospital in Eldoret, Kenya; and Kamuzu Central Hospital in Lilongwe, Malawi). Treatment outcomes that will be evaluated include overall survival, quality of life (QOL) and safety. All patients (≥18 years old) who present to participating sites with a histopathologically-confirmed or presumptive clinical diagnosis of ESCC based on endoscopy or barium swallow will be recruited to participate. Key clinical and treatment-related data including standardized QOL metrics will be collected at study enrollment, 1 month following treatment, 3 months following treatment, and thereafter at 3-month intervals until death. Vital status and QOL data will be collected through mobile phone outreach. DISCUSSION: This study will be the first study to prospectively compare ESCC treatment strategies in Eastern Africa, and the first to investigate QOL benefits associated with different treatments in sub-Saharan Africa. Findings from this study will help define optimal management strategies for ESCC in Eastern Africa and other resource-limited settings and will serve as a benchmark for future research. TRIAL REGISTRATION: This study was retrospectively registered with the ClinicalTrials.gov database on December 15, 2021,  NCT05177393 .

Views from Multidisciplinary Oncology Clinicians on Strengthening Cancer Care Delivery Systems in Tanzania.

BACKGROUND: In response to the increasing burden of cancer in Tanzania, the Ministry of Health, Community Development, Gender, Elderly and Children launched National Cancer Treatment Guidelines (TNCTG) in February 2020. The guidelines aimed to improve and standardize oncology care in the country. At Ocean Road Cancer Institute (ORCI), we developed a theory-informed implementation strategy to promote guideline-concordant care. As part of the situation analysis for implementation strategy development, we conducted focus group discussions to evaluate clinical systems and contextual factors that influence guideline-based practice prior to the launch of the TNCTG. MATERIALS AND METHODS: In June 2019, three focus group discussions were conducted with a total of 21 oncology clinicians at ORCI, stratified by profession. A discussion guide was used to stimulate dialogue about facilitators and barriers to delivery of guideline-concordant care. Discussions were audio recorded, transcribed, translated, and analyzed using thematic framework analysis. RESULTS: Participants identified factors both within the inner context of ORCI clinical systems and outside of ORCI. Themes within the clinical systems included capacity and infrastructure, information technology, communication, efficiency, and quality of services provided. Contextual factors external to ORCI included interinstitutional coordination, oncology capacity in peripheral hospitals, public awareness and beliefs, and financial barriers. Participants provided pragmatic suggestions for strengthening cancer care delivery in Tanzania. CONCLUSION: Our results highlight several barriers and facilitators within and outside of the clinical systems at ORCI that may affect uptake of the TNCTG. Our findings were used to inform a broader guideline implementation strategy, in an effort to improve uptake of the TNCTGs at ORCI. IMPLICATIONS FOR PRACTICE: This study provides an assessment of cancer care delivery systems in a low resource setting from the unique perspectives of local multidisciplinary oncology clinicians. Situational analysis of contextual factors that are likely to influence guideline implementation outcomes is the first step of developing an implementation strategy for cancer treatment guidelines. Many of the barriers identified in this study represent actionable targets that will inform the next phases of our implementation strategy for guideline-concordant cancer care in Tanzania and comparable settings.

Improving Access to Self-Expanding Metal Stents for Patients With Esophageal Cancer in Eastern Africa: A Stepwise Implementation Strategy.

PURPOSE: The eastern corridor of Africa is affected by a high burden of esophageal cancer (EC), with > 90% of patients presenting with advanced disease. Self-expanding metal stents (SEMS) have been previously reported as safe and effective for palliation of malignant dysphagia in resource-limited settings; however, access is limited throughout Eastern Africa. METHODS: In response to demand for palliative interventions for patients with dysphagia because of EC, the African Esophageal Cancer Consortium (AfrECC) partnered with the Clinton Health Access Initiative to improve access to SEMS in Eastern Africa. We undertook a stepwise implementation approach to (1) identify barriers to SEMS access, (2) conduct a market analysis, (3) select an industry partner, (4) establish regulatory and procurement processes, (5) develop endoscopic training resources, (6) create a medical device registry, and (7) establish principles of accountability. RESULTS: Following an evaluation of market demand and potential SEMS manufacturers, Boston Scientific Corporation announced its commitment to launch an access program to provide esophageal SEMS to patients in Tanzania, Kenya, Malawi, and Zambia at a subsidized price. Parallel regulatory and procurement processes were established in each participating country. Endoscopy training courses were designed and conducted, using the Training-of-Trainers model. A device registry was created to centralize data for quality control and to monitor channels of SEMS distribution. Principles of accountability were developed to guide the sustainability of this endeavor. CONCLUSION: The AfrECC Stent Access Initiative is an example of a multisector partnership formed to provide an innovative solution to align regional needs with a supply chain for a high-priority medical device.

Optimal management of esophageal cancer in Africa: A systemic review of treatment strategies.

Esophageal cancer (EC) is a leading cause of cancer morbidity and mortality in Africa. Despite the high burden of disease, optimal management strategies for EC in resource-constrained settings have yet to be established. This systematic review evaluates the literature on treatments for EC throughout Africa and compares the efficacy and safety of varying treatment strategies in this context (PROSPERO CRD42017071546). PubMed, Embase and African Index Medicus were searched for studies published on treatment strategies for EC in Africa from 1980 to 2020. Searches were supplemented by examining bibliographies of included studies and relevant conference proceedings. Methodological quality/risk of bias was assessed using the Cochrane Risk-of-Bias tool and the Newcastle-Ottawa Scale. Forty-six studies were included. Case series constituted the majority of studies: 13 were case series reporting on outcomes of esophagectomies, 17 on palliative luminal or surgical interventions, four on radiotherapy and three on concurrent chemoradiation. Nine randomized controlled trials were identified, of which four prospectively compared different treatment modalities (one investigating radiotherapy vs chemoradiation, three evaluating rigid plastic stents vs other treatments). This review summarizes the research on EC treatments in Africa published over the last four decades and outlines critical gaps in knowledge related to management in this context. Areas in need of further research include (a) evaluation of the safety and efficacy of neoadjuvant therapy in patients with locally advanced disease; (b) strategies to improve long-term survival in patients treated with definitive chemoradiation; and (c) the comparative effectiveness of modern palliative interventions, focusing on quality of life and survival as outcome measures.

A Case-Control Study to Evaluate Environmental and Lifestyle Risk Factors for Esophageal Cancer in Tanzania.

BACKGROUND: East Africa is affected by a disproportionately high burden of esophageal squamous cell carcinoma (ESCC). METHODS: We conducted an incident case-control study in Dar es Salaam, Tanzania with 1:1 matching for gender and age. A questionnaire evaluated known and putative risk factors for ESCC. Cochran-Mantel-Haenszel and multivariable conditional logistic regression analyses were applied to evaluate associations with ESCC risk, with adjustment for geographic zone. RESULTS: Of 471 cases and 471 controls, the majority were male (69%); median ages were 59 and 55, respectively. In a multivariable logistic regression model, a low International Wealth Index (IWI) score [OR 2.57; 95% confidence interval (CI), 1.41-4.68], former smoking (OR 2.45; 95% CI, 1.46-4.13), second-hand smoke in the household (OR 1.67; 95% CI, 1.01-2.77), daily spicy chilies (OR 1.62; 1.04-2.52), and daily salted foods (OR 2.02; 95% CI, 1.06-3.85) were associated with increased risk of ESCC. Daily consumption of raw greens (OR 0.36; 95% CI, 0.16-0.80), fruit (OR 0.47; 95% CI, 0.27-0.82), and smoked fish (OR 0.31; 95% CI, 0.15-0.66) were protective. Permanent residence in the Central (OR 5.03; 95% CI, 2.16-11.73), Northern-Lake (OR 2.40; 95% CI, 1.46-3.94), or Southern Highlands zones (OR 3.18; 95% CI, 1.56-6.50) of Tanzania were associated with increased risk compared with residence in the Eastern zone. CONCLUSIONS: Low IWI score, smoke exposure(s), geographic zone, and dietary factors were associated with risk for ESCC in Tanzania. IMPACT: These findings will inform the development of future hypothesis-driven studies to examine risk factors for the high burden of ESCC in East Africa.See related commentary by McCormack et al., p. 248.

Development of a theory-driven implementation strategy for cancer management guidelines in sub-Saharan Africa.

BACKGROUND: Despite recent international efforts to develop resource-stratified clinical practice guidelines for cancer, there has been little research to evaluate the best strategies for dissemination and implementation in low- and middle-income countries (LMICs). Guideline publication alone is insufficient. Extensive research has shown that structured, multifaceted implementation strategies that target barriers to guideline use are most likely to improve adherence; however, most of this research has been conducted in high-income countries. There is a pressing need to develop and evaluate guideline implementation strategies for cancer management in LMICs in order to address stark disparities in cancer outcomes. METHODS: In preparation for the launch of Tanzania's first National Cancer Treatment Guidelines, we developed a theory-driven implementation strategy for guideline-based practice at Ocean Road Cancer Institute (ORCI). Here, we use the Intervention Mapping framework to provide a detailed stepwise description of our process. First, we conducted a needs assessment to identify barriers and facilitators to guideline-based practice at ORCI. Second, we defined both proximal and performance objectives for our implementation strategy. Third, we used the Capability, Opportunity, Motivation and Behavior/Behavior Change Wheel (COM-B/BCW) framework to categorize the barriers and facilitators, choose behavior change techniques most likely to overcome targeted barriers and leverage facilitators, and select a feasible mode of delivery for each technique. Fourth, we organized these modes of delivery into a phased implementation strategy. Fifth, we operationalized each component of the strategy. Sixth, we identified the indicators of the process, outcome, and impact of our intervention and developed an evaluation plan to measure them using a mixed methods approach. DISCUSSION: We developed a robust, multifaceted guideline implementation strategy derived from a prominent behavior change theory for use in Tanzania. The barriers and strategies we generated are consistent with those well established in the literature, enhancing the validity and generalizability of our process and results. Through our rigorous evaluation plan and systematic account of modifications and adaptations, we will characterize the transferability of "proven" guideline implementation strategies to LMICs. We hope that by describing our process in detail, others may endeavor to replicate it, meeting a widespread need for dedicated efforts to implement cancer guidelines in LMICs.

Factors influencing survival among Kenyan children diagnosed with endemic Burkitt lymphoma between 2003 and 2011: A historical cohort study.

Discovering how to improve survival and establishing clinical reference points for children diagnosed with endemic Burkitt lymphoma (eBL) in resource-constrained settings has recaptured international attention. Using multivariate analyses, we evaluated 428 children with eBL in Kenya for age, gender, tumor stage, nutritional status, hemoglobin, lactate dehydrogenase (LDH), Epstein-Barr virus (EBV) and Plasmodium falciparum prior to induction of chemotherapy (cyclophosphamide, vincristine, methotrexate and doxorubicin) to identify predictive and prognostic biomarkers of survival. During this 10 year prospective study period, 22% died in-hospital and 78% completed six-courses of chemotherapy. Of those, 16% relapsed or died later; 31% achieved event-free-survival; and 31% were lost to follow-up; the overall one-year survival was 45%. After adjusting for covariates, low hemoglobin (<8 g/dL) and high LDH (>400 mU/ml) were associated with increased risk of death (adjusted Hazard Ratio (aHR) = 1.57 [0.97-2.41]) and aHR = 1.84, [0.91-3.69], respectively). Anemic children with malaria were 3.55 times more likely to die [1.10-11.44] compared to patients without anemia or malarial infection. EBV load did not differ by tumor stage nor was it associated with survival. System-level factors can also contribute to poor outcomes. Children were more likely to die when inadvertently overdosed by more than 115% of the correct dose of cyclophosphamide (a HR = 1.43 [0.84-2.43]) or doxorubicin (a HR = 1.25, [0.66-2.35]), compared with those receiving accurate doses of the respective agent in this setting. This study codifies risk factors associated with poor outcomes for eBL patients in Africa and provides a benchmark by which to assess improvements in survival for new chemotherapeutic approaches.

Factors influencing time to diagnosis and initiation of treatment of endemic Burkitt Lymphoma among children in Uganda and western Kenya: a cross-sectional survey.

BACKGROUND: Survival rates for children diagnosed with Burkitt lymphoma (BL) in Africa are far below those achieved in developed countries. Late stage of presentation contributes to poor prognosis, therefore this study investigated factors leading to delays in BL diagnosis and treatment of children in Uganda and western Kenya. METHODS: Guardians of children diagnosed with BL were interviewed at the Jaramogi Oginga Odinga Teaching and Referral Hospital (JTRH) and Uganda Cancer Institute (UCI) from Jan-Dec 2010. Information on sociodemographics, knowledge, attitudes, illness perceptions, health-seeking behaviors and prior health encounters was collected using a standardized, pre-tested questionnaire. RESULTS: Eighty-two guardians were interviewed (20 JTRH, 62 UCI). Median "total delay" (1st symptoms to BL diagnosis) was 12.1 weeks [interquartile range (IQR) 4.9-19.9] in Kenya and 12.9 weeks (IQR 4.3-25.7) in Uganda. In Kenya, median "guardian delay" (1st symptoms to 1st health encounter) and "health system delay" (1st health encounter to BL diagnosis) were 9.0 weeks (IQR 3.6-15.7) and 2.0 weeks (IQR 1.6-5.8), respectively. Data on guardian and health system delay in Uganda were only available for those with < 4 prior health encounters (n = 26). Of these, median guardian delay was 4.3 weeks (range 0.7-149.9), health system delay 2.6 weeks (range 0.1-16.0), and total delay 10.7 weeks (range 1.7-154.3). Guardians in Uganda reported more health encounters than those in Kenya (median 5, range 3-16 vs. median 3, range 2-6). Among Kenyan guardians, source of income was the only independent predictor of delay, whereas in Uganda, guardian delay was influenced by guardians' beliefs on the curability of cancer, health system delay, by guardians' perceptions of cancer as a contagious disease, and total delay, by the number of children in the household and guardians' role as caretaker. Qualitative findings suggest financial costs, transportation, and other household responsibilities were major barriers to care. CONCLUSIONS: Delays from symptom onset to BL treatment were considerable given the rapid growth rate of this cancer, with guardian delay constituting the majority of total delay in both settings. Future interventions should aim to reduce structural barriers to care and increase awareness of BL in particular and cancer in general within the community, as well as among health professionals.

Long-term follow-up of a phase II trial of chemotherapy plus hormone therapy for biochemical relapse after definitive local therapy for prostate cancer.

OBJECTIVE: To evaluate long-term follow-up of a phase II trial of chemohormonal therapy in 62 men with prostate cancer biochemical relapse (BR). METHODS: Treatment was 4 cycles of docetaxel (70 mg/m(2)) every 3 weeks and estramustine 280 mg three times a day (days 1-5) followed by 15 months of goserelin acetate/bicalutamide. The primary endpoint was the proportion with prostate-specific antigen (PSA) <0.1 with recovered testosterone 5 years after completion of therapy. Secondary endpoints included time to progression (TTP), time to reinitiate androgen deprivation therapy (ADT), the proportion with castration-resistant prostate cancer (CRPC), and overall survival (OS). RESULTS: Median follow-up was 8.6 years (range 1.3-11.1 years). At 5 year follow-up, 7 patients (11%) had PSA <0.1 (5 undetectable); 8 (13%) had PSA >0.1 but without reinitiation of ADT (median PSA 0.37). Of the 15 (24%) men without reinitiation of ADT, and 14 have recovered testosterone to normal range. Median TTP for the complete cohort was 35.0 months (95% confidence interval [CI] 31.7-39.2). Baseline PSA <3.0 ng/dL, no prior ADT, and prostatectomy (vs radiation) were associated with longer TTP (P = .0001, P = .0055, and P = .0398, respectively). At the time of analysis, 42 men (68%) had restarted ADT, 23 men had CRPC (37%), and 11 (18%) had chemotherapy. Median time to reinitiation of ADT was 32.6 months (range 0-107.6 months). Median OS has not been reached; there were 15 deaths. CONCLUSION: Chemotherapy plus ADT for BR resulted in durable (>5 years) complete responses (<0.1 ng/mL) in 7 men (11%). Twenty-four percent of men have not re-initiated ADT 5 years from completion of protocol therapy.

Typhoid fever and paratyphoid fever: Systematic review to estimate global morbidity and mortality for 2010.

BACKGROUND: Typhoid and paratyphoid fever remain important causes of morbidity worldwide. Accurate disease burden estimates are needed to guide policy decisions and prevention and control strategies. METHODS: We conducted a systematic literature review of the PubMed and Scopus databases using pre-defined criteria to identify population-based studies with typhoid fever incidence data published between 1980 and 2009. We also abstracted data from annual reports of notifiable diseases in countries with advanced surveillance systems. Typhoid and paratyphoid fever input data were grouped into regions and regional incidence and mortality rates were estimated. Incidence data were extrapolated across regions for those lacking data. Age-specific incidence rates were derived for regions where age-specific data were available. Crude and adjusted estimates of the global typhoid fever burden were calculated. RESULTS: Twenty-five studies were identified, all of which contained incidence data on typhoid fever and 12 on paratyphoid fever. Five advanced surveillance systems contributed data on typhoid fever; 2 on paratyphoid fever. Regional typhoid fever incidence rates ranged from <0.1/100 000 cases/y in Central and Eastern Europe and Central Asia to 724.6/100 000 cases/y in Sub-Saharan Africa. Regional paratyphoid incidence rates ranged from 0.8/100 000 cases/y in North Africa/Middle East to 77.4/100 000 cases/y in Sub-Saharan Africa and South Asia. The estimated total number of typhoid fever episodes in 2010 was 13.5 million (interquartile range 9.1-17.8 million). The adjusted estimate accounting for the low sensitivity of blood cultures for isolation of the bacteria was 26.9 million (interquartile range 18.3-35.7 million) episodes. These findings are comparable to the most recent analysis of global typhoid fever morbidity, which reported crude and adjusted estimates of 10.8 million and 21.7 million typhoid fever episodes globally in 2000. CONCLUSION: Typhoid fever remains a significant health burden, especially in low- and middle-income countries. Despite the availability of more recent data on both enteric fevers, additional research is needed in many regions, particularly Africa, Latin America and other developing countries.

Phase II trial of RAD001 and bicalutamide for castration-resistant prostate cancer.

UNLABELLED: Study Type--Therapy (cohort) Level of Evidence 2a. What's known on the subject? and What does the study add? Despite expanding treatment options for castration-resistant prostate cancer (CRPC), therapies with long response duration remain intangible due to prostate cancer cells' natural ability to develop iterative resistance. Androgen receptor (AR) signaling has been shown to play a critical role in CRPC and its expression is regulated by the PI3K-Akt pathway. Thus inhibition of AR signalling and PI3K-Akt-mTOR (a downstream mediator of the PI3K-Akt pathway) pathway is a logical combination in CRPC and we report a phase II trial of RAD001 and bicalutamide. Our study is the first clinical trial report of an AR inhibitor of PI3K-Akt-mTOR. The AR pathway and the PI3K-Akt-mTOR pathway are two of the most relevant growth pathway for CRPC. Despite low efficacy results from our trial there will be significant interest in the field for these data (dose, schedule, response, toxicity, trial design) as newer generations of both AR inhibitors and PI3K-Akt-mTOR inhibitors are in development and likely will be tested in combination in CRPC. OBJECTIVES: • To determine best overall response and duration of response of RAD001, a selective inhibitor of mammalian target of rapamycin, in combination with bicalutamide in castration-resistant prostate cancer (CRPC). • To characterize the toxicity profile of RAD001 in combination with bicalutamide in patients with CRPC. PATIENTS AND METHODS: • A phase II study was conducted to explore the efficacy and tolerability of RAD001 (10 mg daily) in combination with bicalutamide (50 mg daily) in men with progressive CRPC. • The primary endpoint was a composite of prostate-specific antigen (PSA) level and measurable disease response by standard criteria. • This single-stage trial with a sample size of 38 eligible patients provided 90% power to differentiate a response rate of ≥ 40% from a response rate of ≤ 20%, as expected for bicalutamide alone (α= 0.10, power = 0.90). RESULTS: • In total, 36 men were enrolled, with a median (range) age of 68 (60-72) years and median (range) baseline PSA level of 22.2 (8.4-121.3) ng/mL, and 89% had metastatic disease. • There were 31 (86%) patients had previously used bicalutamide for a median duration of 7.4 months. • There were two patients with a confirmed PSA level decline ≥ 50%. • The median (interquartile range) time to progression was 8.7 (7.9-15.9) weeks. • The most common toxicity was grade 1/2 mucositis, which was observed in 20 (56%) patients. CONCLUSION: • The combination of RAD001 and bicalutamide in men with CRPC was well tolerated but had low activity and failed to achieve the primary endpoint of improved response compared to the results previously achieved for bicalutamide alone in this population.

Double-blind, randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated metastatic urothelial cancer.

PURPOSE: Vandetanib is an oral once-daily tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 and epidermal growth factor receptor. Vandetanib in combination with docetaxel was assessed in patients with advanced urothelial cancer (UC) who progressed on prior platinum-based chemotherapy. PATIENTS AND METHODS: The primary objective was to determine whether vandetanib 100 mg plus docetaxel 75 mg/m(2) intravenously every 21 days prolonged progression-free survival (PFS) versus placebo plus docetaxel. The study was designed to detect a 60% improvement in median PFS with 80% power and one-sided α at 5%. Patients receiving docetaxel plus placebo had the option to cross over to single-agent vandetanib at progression. Overall survival (OS), overall response rate (ORR), and safety were secondary objectives. RESULTS: In all, 142 patients were randomly assigned and received at least one dose of therapy. Median PFS was 2.56 months for the docetaxel plus vandetanib arm versus 1.58 months for the docetaxel plus placebo arm, and the hazard ratio for PFS was 1.02 (95% CI, 0.69 to 1.49; P = .9). ORR and OS were not different between both arms. Grade 3 or higher toxicities were more commonly seen in the docetaxel plus vandetanib arm and included rash/photosensitivity (11% v 0%) and diarrhea (7% v 0%). Among 37 patients who crossed over to single-agent vandetanib, ORR was 3% and OS was 5.2 months. CONCLUSION: In this platinum-pretreated population of advanced UC, the addition of vandetanib to docetaxel did not result in a significant improvement in PFS, ORR, or OS. The toxicity of vandetanib plus docetaxel was greater than that for vendetanib plus placebo. Single-agent vandetanib activity was minimal.

Assessment of liver disease (noninvasive methods).

PURPOSE OF REVIEW: The purpose of this review is to highlight new findings published in 2010-2011 related to noninvasive fibrosis assessment in HIV/hepatitis C virus (HCV) co-infected patients. Overall, in 2010-2011, 15 studies were published, of which two were excluded because they were published in languages other than English. RECENT FINDINGS: Eleven studies focused on serum marker panels. Studies sought to validate established panels in HIV/HCV co-infected patients often by comparing multiple serum marker panels in the same population; establish new marker panels using combinations of markers used in previously validated panels; and develop new marker panels using novel methodology. Overall, all panels performed within similar ranges of diagnostic accuracy as measured by the area under the receiver operating characteristic curve (AUROC) but the FibroMeter panel and its derivations achieved the highest performance. Four studies focused on transient elastography. Two studies confirmed its accuracy for identifying fibrosis and cirrhosis and two studies confirmed that misclassification rates are higher in the presence of elevated triglycerides and steatosis. SUMMARY: Overall, performance of transient elastography appeared superior to the majority of serum marker panels for the detection of significant fibrosis and cirrhosis in HIV/HCV co-infected patients. Challenges of widespread application of transient elastography remain high misclassification in some subgroups, lack of standardized cut-points and lack of widespread availability. Panels that were newly developed in 2010-2011 specifically for HIV/HCV appeared to perform better than existing panels such as APRI and FIB-4; however, additional external validation will be needed to confirm their accuracy.