Sexually Transmitted Infection Risks and Symptoms Heightened Among Female Sex Workers who Started Selling Sex Before the Age of 18 in Five Cities in Cameroon.

Many adolescents under 18 years old who sell sex are at elevated risk for sexually transmitted infection (STI) acquisition, which may persist into adulthood. There has been limited study of the burden of the risks and vulnerabilities among women who started selling sex as adolescents across Sub-Saharan Africa. In this study, a Adult female sex workers (FSW) recruited through respondent-driven sampling in five cities in Cameroon from December 2015 to October 2016 completed a questionnaire and human immunodeficiency virus (HIV) and syphilis testing. Multivariable logistic regression analysis controlling for age was used to identify factors associated with reporting selling sex before age 18. Selling sex before age 18 was reported by 11.5% (256/2,220) of FSW. Initiation of selling sex as an adolescent was positively associated with experiencing dysuria (adjusted odds ratio [aOR]:1.50, 95% confidence interval [CI]:1.08-2.10) or genital warts (aOR:1.78, 95% CI:1.08-2.94) and negatively associated with prior recent testing for HIV (aOR:0.71, 95% CI:0.53-0.96) or STIs (aOR:0.65, 95% CI:0.44-0.96). Consistent condom use with clients was negatively associated with early initiation of selling sex (aOR:0.58, 95% CI:0.42-0.80), while experience of recent sexual violence was positively associated with early initiation (aOR:1.74, 95% CI:1.15-2.63). There were no independent significant differences in HIV (24.5%) or syphilis (8.3%) prevalence. Given the limited use of HIV and STI testing services by women who sold sex as adolescents, the prevalence of forced sex, condomless sex, and STI symptoms were high. Programs serving FSW should more vigorously aim to serve adolescents and adults who began selling sex early.

Modeling the potential impact of pre-exposure prophylaxis for HIV among men who have sex with men in Cameroon.

BACKGROUND: Men who have sex with men (MSM) are consistently burdened by HIV at higher levels than other adults. While HIV prevention programs for MSM are growing in coverage and quality, HIV incidence remains high. In response, pre-exposure prophylaxis (PrEP) was introduced in 2019 to support HIV risk reduction among MSM in Cameroon. Understanding how PrEP initiation programs will change the HIV prevalence among MSM in Cameroon is important to developing effective programs. METHODS: This study uses a mathematical model to simulate population-level HIV transmission among MSM in the cities of Yaoundé and Douala, Cameroon. PrEP is incorporated into the model at rates that equal 25%, 50%, or 75% coverage after twenty years to assess the potential effects on HIV prevalence among MSM, requiring annual initiation rates of 2.5%, 6.8%, and 17.2% for Yaoundé and 2.2%, 5.6%, and 13.4% for Douala, respectively. The data utilized for this model are from a cross sectional study which recruited MSM through respondent-driven sampling of MSM in two major cities in Cameroon: Yaoundé and Douala. RESULTS: The model estimated an HIV prevalence of 43.2% among MSM, annual HIV diagnoses of 300 per 10,000 MSM and antiretroviral therapy (ART) coverage of 53.9% in Yaoundé. In Douala, estimated prevalence is 26.5% among MSM, 167 per 10,000 MSM annual diagnoses and ART coverage of 72.0%. Standalone PrEP interventions aimed at 50% coverage at the end of a 20-year program would reduce the prevalence from 43.2% to 35.4% in Yaoundé and from 26.5 to 20.1% in Douala. Combining PrEP with a 10% increase in HIV testing would decrease the number of MSM living with HIV and unaware of their status from 9.8 to 6.0% in Yaoundé and from 8.7 to 4.6% in Douala. CONCLUSIONS: PrEP would be beneficial in reducing prevalence even at varying initiation and coverage levels. Combination of PrEP and increased HIV testing further decreased the number of undiagnosed MSM. This study supports the utility of implementing PrEP as part of comprehensive HIV prevention programming among MSM in Cameroon.

A Phase I Study of Apolizumab, an Anti-HLA-DR ß-chain Monoclonal Antibody, in Patients With Solid Tumor Malignancies.

BACKGROUND: Human leukocyte antigen (HLA)-DR, a member of the major histocompatibility complex class II antigen family, is a target for antibody-based therapeutics. Apolizumab (Hu1D10, Remitogen), a humanized IgG1 monoclonal anti-HLA-DR ß-chain antibody targets the antigen, 1D10, expressed on a wide variety of hematologic and solid tumor malignancies. In this Phase 1 trial, the maximum tolerated dose and dose-limiting toxicity of weekly apolizumab in patients with advanced solid tumor malignancies were determined. PATIENTS AND METHODS: Eligible patients with refractory solid tumors were initially screened for ID10 Ag on their tumor. Patients whose tumors expressed 1D10 were administered apolizumab 0.5, 1.0, 1.5, or 3.0 mg/kg intravenously over 90 minutes weekly for 4 consecutive weeks, followed by a 4-week break, and assessment of response. Patients whose disease had not progressed were offered additional treatment. RESULTS: Tumors from 75 patients were screened for 1D10 Ag of which 17 patients were positive and underwent treatment. The first 3 dose levels were well-tolerated. Dose-limiting toxicities of grade 3 infusion-related hypersensitivity reactions and grade 3 headache and hypertension occurred in 2 patients, respectively, at apolizumab 3.0 mg/kg. Four patients, 1 each with breast carcinoma, melanoma, renal cell carcinoma, and sarcoma had stable disease for a median of 15 weeks (range: 12 to 19 wk). CONCLUSION: Apolizumab can be administered safely at a maximum tolerated dose of 1.5 mg/kg for 4 consecutive weeks. Adverse events and limited clinical data in both hematologic and solid tumor malignancies resulted in discontinuation of clinical development of apolizumab. HLA-DR remains an interesting immunotherapeutic target.

HIV Pre-exposure Prophylaxis Uptake and Continuation Among Key Populations in Cameroon: Lessons Learned From the CHAMP Program.

INTRODUCTION: Pre-exposure prophylaxis (PrEP) is proven to be a highly effective HIV prevention method for key populations. However, its scale-up in resource-limited settings remains suboptimal. This paper seeks to describe PrEP initiation and continuation among key populations in Cameroon. METHODOLOGY: From June 2019 through October 2020, we collected routine program data on PrEP uptake and continuation among female sex workers (FSWs) and men who have sex with men (MSM) in the Continuum of prevention, care and treatment of HIV/AIDS with Most-at-risk Populations (CHAMP) program in Cameroon. PrEP was offered to clients who tested negative for HIV and were assessed to potentially benefit from PrEP. Using survival analysis, we identified factors associated with PrEP discontinuation over time with significance set at 5%. RESULTS: Overall, 27,750 clients were sensitized for PrEP of whom 3,138 persons were eligible to start PrEP and 1,409 (45%; FSW: 691 and MSM: 718) initiated PrEP. The PrEP continuation rate was 37% at 3 months, 28% at 6 months and 19% at 12 months. PrEP discontinuation was significantly higher among FSW than MSM [adjusted hazard ratio (aHR) 1.5 (95% CI: 1.2 to 1.9)] in Yaounde [aHR 1.5 (95% CI: 1.2 to 1.9)] and Bafoussam/Bertoua [aHR 3.1 (2.2-4.5)] relative to Douala. Discontinuation was lower among those with moderate [aHR 0.3 (0.3-0.4)] or good adherence [aHR 0.4 (0.3-0.6)] compared with poor adherence (all P < 0.001). CONCLUSION: Differentiated approaches to deliver PrEP, create demand, and provide more intensive support for adherence and continuation may support scale-up of PrEP in Cameroon for equitable and prolonged impact on HIV prevention.

A Systematic Review of Gender-Based Violence Prevention and Response Interventions for HIV Key Populations: Female Sex Workers, Men Who Have Sex With Men, and People Who Inject Drugs.

Gender-based violence (GBV) is that perpetrated based on sex, gender identity, or perceived adherence to socially defined gender norms. This human rights violation is disproportionately experienced by HIV key populations including female sex workers (FSW), people who inject drugs (PWID), and men who have sex with men (MSM). Consequently, addressing GBV is a global priority in HIV response. There is limited consensus about optimal interventions and little known about effectiveness. Our systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was registered in International Prospective Register of Systematic Reviews. Peer-reviewed and non-peer-reviewed literature were searched for articles that described a GBV prevention or response intervention specifically for key populations including FSW, PWID, and MSM. Results were organized by level(s) of implementation and pillars of a comprehensive GBV response: prevention, survivor support, and accountability/justice. Of 4,287 articles following removal of duplicates, 32 unique interventions (21 FSW, seven PWID, and nine MSM, not mutually exclusive) met inclusion criteria, representing 13 countries. Multisectoral interventions blended empowerment, advocacy, and crisis response with reductions in violence. Individual-level interventions included violence screening and response services. Violence-related safety promotion and risk reduction counseling within HIV risk reduction programming reduced violence. Quantitative evaluations were limited. Violence prevention and response interventions for FSW, PWID, and MSM span individual, community, and multisectoral levels with evidence of promising practices at each level. The strongest evidence supported addressing violence in the context of sexually transmitted infection/HIV risk reduction. As interventions continue to emerge, the rigor of accompanying evaluations must simultaneously advance to enable clarity on the health and safety impact of GBV prevention and response programming.

Assessing the Potential Impact of Disruptions Due to COVID-19 on HIV Among Key and Lower-Risk Populations in the Largest Cities of Cameroon and Benin.

BACKGROUND: The COVID-19 pandemic indirectly impacts HIV epidemiology in Central/West Africa. We estimated the potential impact of COVID-19-related disruptions to HIV prevention/treatment services and sexual partnerships on HIV incidence and HIV-related deaths among key populations including female sex workers (FSW), their clients, men who have sex with men, and overall. SETTING: Yaoundé (Cameroon) and Cotonou (Benin). METHODS: We used mathematical models of HIV calibrated to city population-specific and risk population-specific demographic/behavioral/epidemic data. We estimated the relative change in 1-year HIV incidence and HIV-related deaths for various disruption scenarios of HIV prevention/treatment services and decreased casual/commercial partnerships, compared with a scenario without COVID-19. RESULTS: A 50% reduction in condom use in all partnerships over 6 months would increase 1-year HIV incidence by 39%, 42%, 31%, and 23% among men who have sex with men, FSW, clients, and overall in Yaoundé, respectively, and 69%, 49%, and 23% among FSW, clients, and overall, respectively, in Cotonou. Combining a 6-month interruption of ART initiation and 50% reduction in HIV prevention/treatment use would increase HIV incidence by 50% and HIV-related deaths by 20%. This increase in HIV infections would be halved by a simultaneous 50% reduction in casual and commercial partnerships. CONCLUSIONS: Reductions in condom use after COVID-19 would increase infections among key populations disproportionately, particularly FSW in Cotonou, who need uninterrupted condom provision. Disruptions in HIV prevention/treatment services have the biggest impacts on HIV infections and deaths overall, only partially mitigated by equal reductions in casual/commercial sexual partnerships. Maintaining ART provision must be prioritized to minimize short-term excess HIV-related deaths.

Unmet Need for Family Planning and Experience of Unintended Pregnancy Among Female Sex Workers in Urban Cameroon: Results From a National Cross-Sectional Study.

BACKGROUND: Female sex workers (FSWs) in Cameroon commonly have unmet need for contraception posing a high risk of unintended pregnancy. Unintended pregnancy leads to a range of outcomes, and due to legal restrictions, FSWs often seek unsafe abortions. Aside from the high burden of HIV, little is known about the broader sexual and reproductive health of FSWs in Cameroon. METHODS: From December 2015 to October 2016, we recruited FSWs aged ≥18 years through respondent-driven sampling across 5 Cameroonian cities. Cross-sectional data were collected through a behavioral questionnaire. Modified-robust Poisson regression was used to approximate adjusted prevalence ratios (aPR) for TOP and current use of effective nonbarrier contraception. RESULTS: Among 2,255 FSWs (median age 28 years), 57.6% reported history of unintended pregnancy and 40.0% reported prior TOP. In multivariable analysis, TOP history was associated with current nonbarrier contraceptive use (aPR=1.23, 95% confidence interval [CI]=1.07, 1.42); ever using emergency contraception (aPR=1.34, 95% CI=1.17, 1.55); >60 clients in the past month (aPR=1.29, 95% CI= 1.07, 1.54) compared to ≤30; inconsistent condom use with clients (aPR=1.17, 95% CI=1.00, 1.37); ever experiencing physical violence (aPR=1.24, 95% CI=1.09, 1.42); and older age. Most (76.5%) women used male condoms for contraception, but only 33.2% reported consistent condom use with all partners. Overall, 26.4% of women reported currently using a nonbarrier contraceptive method, and 6.2% reported using a long-acting method. Previous TOP (aPR=1.41, 95%CI=1.16, 1.72) and ever using emergency contraception (aPR=2.70, 95% CI=2.23, 3.26) were associated with higher nonbarrier contraceptive use. Recent receipt of HIV information (aPR=0.72, 95% CI=0.59, 0.89) and membership in an FSW community-based organization (aPR=0.73, 95% CI=0.57, 0.92) were associated with lower use nonbarrier contraceptive use. CONCLUSIONS: Experience of unintended pregnancies and TOP is common among FSWs in Cameroon. Given the low use of nonbarrier contraceptive methods and inconsistent condom use, FSWs are at risk of repeat unintended pregnancies. Improved integration of client-centered, voluntary family planning within community-led HIV services may better support the sexual and reproductive health and human rights of FSWs consistent with the United Nations Declaration of Human Rights.

Lifetime experiences of gender-based violence, depression and condom use among female sex workers in Cameroon.

BACKGROUND: In general populations, consistent data highlight the relationships among violence, HIV risk behavior and depression; however, these patterns are not well understood among female sex workers (FSWs). We examined the relationship between FSWs' experiences with sexual violence and consistent condom use as a key HIV risk behavior and explored mental health as a potential mediator. METHODS: In total, 2,165 FSWs were recruited via respondent-driven sampling in Cameroon in 2016. The women answered questions about violence, condom use and mental health. RESULTS: Inconsistent condom use with clients was reported by 23.5% of participants (508/2,165). Lifetime sexual violence was prevalent with 33.0% (713/2,163) of participants. Almost 50% (1,067/2,143) of respondents had some level of depression. Sexual violence was significantly associated with inconsistent condom use (adjusted risk ratio (aRR) 1.4, 95% confidence interval (CI) (1.2-1.6)). Of FSWs with no depression, 24.9% (267/1,071) reported sexual violence, versus 56.1% (32/57) of respondents with severe depression (p < .01). Severe depression significantly increased risk of condomless sex (aRR 1.8, 95% CI (1.3-2.6)); in mediation analysis, both sexual violence and severe depression remained significant predictors of condomless sex (aRR 1.4, 95% CI (1.2, 1.6) and aRR 1.7, 95% CI (1.2-2.4), respectively). Depression did not mediate the relationship between sexual violence and condom use. CONCLUSION: Sexual violence and depression are prevalent and independently associated with condom nonuse with clients among FSWs in Cameroon. Results highlight the need for interventions to address mental health as well as gender-based violence for FSWs.

Characterising unmet HIV prevention and treatment needs among young female sex workers and young men who have sex with men in Cameroon: a cross-sectional analysis.

BACKGROUND: In Cameroon, female sex workers (FSWs) and men who have sex with men (MSM) carry disproportionately high burdens of HIV. Despite specific vulnerabilities and health needs, young key populations remain understudied and underserved in Cameroon owing to legal, ethical, and social challenges. We aimed to assess and compare HIV-related behavioural and structural risks and coverage of HIV prevention and treatment services between young and older key populations to inform implementation strategies. METHODS: FSWs and MSM aged 18 years or older were recruited through respondent-driven-sampling for a biobehavioural survey carried out in five Cameroonian cities. Prevalence of HIV, risk, stigma, and health service engagement were compared between young (18-24 years) and older (≥25 years) key populations. Multivariable Poisson regression models, disaggregated by key population, were constructed to estimate prevalence ratios (PR) by age group for HIV service engagement. FINDINGS: Participants were recruited between Nov 30, 2015, and Oct 12, 2016. Among FSWs, 724 (32%) of 2255 were aged 18-24 years, and median age of first transactional or compensated sex was 22 years (IQR 19-28). Among MSM, 840 (63%) of 1323 were aged 18-24 years, and median age of first anal sex was 18 years (IQR 17-21). RDS-adjusted HIV prevalence was 8·5% (95% CI 4·7-15·2) among young FSWs and 12·9% (9·5-18·2) among young MSM. HIV viral suppression (<1000 copies per mL) was evident in 24 (43%) of 56 young and 292 (61%) of 479 older FSWs (p=0·0091) and 40 (34%) of 119 of young and 64 (42%) of 153 older MSM (p=0·17). Young FSWs were less likely than older FSWs to report recent peer education (PR 0·65, 95% CI 0·48-0·88), or membership of an FSW community-based organisation (PR 0·69, 0·55-0·86) and were more likely to report untreated sexually transmitted infection symptoms in the past year (PR 1·29, 1·03-1·61). Young MSM were less likely than older MSM to report an HIV test in the past year (PR 0·88, 0·78-0·98), recent peer education (PR 0·77, 0·62-0·95) and receipt of free condoms (PR 0·77, 0·67-0·89). By key population, condom use and recent experiences of stigma and violence were similar between age groups (p>0·05). INTERPRETATION: Young key populations have similar behavioural and structural risks to older populations but have lower coverage of HIV preventive and treatment services. Achieving an AIDS-free generation in Cameroon and elsewhere in the region necessitates overcoming social and legal challenges and delivering innovative, evidence-based, and human rights-affirming HIV prevention and treatment interventions for young key populations. FUNDING: PEPFAR, USAID.

Predictors of early childhood HIV testing among children of sex workers living with HIV in Cameroon.

BACKGROUND: Despite recent progress, there exist gaps in the prevention of vertical HIV transmission program access and uptake in Cameroon. Female sex workers (FSW), many of whom are mothers, are disproportionately affected by HIV and have specific barriers to HIV testing and treatment access. Testing for HIV-exposed infants is crucial in monitoring for incident infection and timely intervention. This study explores the level of early childhood testing and also associations between antenatal care (ANC) attendance and other factors and early childhood HIV testing among FSW in Cameroon. METHODS: FSW were recruited to participate in an integrated biobehavioral survey in Cameroon between December 2015 and October 2016. Women were included in these analyses if they were living with HIV and had at least one living child. Both univariate and multivariable logistic regression were used to look at predictors of a child being tested for HIV before age five. RESULTS: A total of 481/2255 FSW were eligible for these analyses as they were HIV seropositive and had at least one living child at the time of the study. Women included in these analyses had a median age of 35(IQR 30-41). Nearly 70% reported none of their children had been tested for HIV before age five (326/481), and 3.5%(17/481) reported one or more of their children had been diagnosed with HIV. ANC attendance (adjusted OR 2.12, 95% CI: [1.02, 4.55]), awareness of HIV status (aOR 3.70[2.30, 5.93]), pregnancy intentions (aOR 1.89[1.16, 3.08]), and higher education (aOR 2.17[1.01, 4.71]) were all independently associated with increased odds of women having a greater proportion of children tested for HIV before age five. Regional differences in early childhood testing were also observed. CONCLUSION: Vertical transmission of HIV remains a challenge in Cameroon, and HIV testing among children of FSW living with HIV was very low. ANC attendance and promotion of the mother's health were associated with increased child HIV testing. For women at high risk of HIV and for whom engagement in the health system is low, strategies to promote and ensure ANC attendance are essential for their health and the health of their children.

Characterizing Sociostructural Associations With New HIV Diagnoses Among Female Sex Workers in Cameroon.

BACKGROUND: Female sex workers (FSW) are disproportionately affected by HIV in Cameroon, with an estimated 23.6% HIV prevalence. Given the unavailability of HIV incidence data, to better understand associations with acquiring HIV we assessed the prevalence and associations with new HIV diagnoses among FSW in Cameroon. METHODS: In 2016, FSW were recruited through respondent-driven sampling from 5 cities for a biobehavioral survey. Participants self-reporting living with HIV or with an indeterminate test status were excluded from analysis. New diagnoses were defined as testing HIV-positive when participants self-reported HIV-negative or unknown status. A multivariable modified Poisson regression model was developed to assess determinants of new HIV diagnosis (referent group: HIV-negative) using key covariates; adjusted prevalence ratios (aPR) are reported if statistically significant (P < 0.05). RESULTS: Overall 2255 FSW were recruited. Excluding participants who self-reported living with HIV (n = 297) and indeterminate test results (n = 7), 260/1951 (13.3%) FSW were newly diagnosed with HIV. Variables significantly associated with new HIV diagnosis were: no secondary/higher education [aPR: 1.56, 95% confidence interval (CI): 1.12 to 2.15], 5+ dependents compared with none (aPR: 2.11, 95% CI: 1.01 to 4.40), 5+ years involved in sex work compared with <1 year (aPR: 2.84, 95% CI: 1.26 to 6.42), history of incarceration (aPR: 2.13, 95% CI: 1.13 to 3.99), and low social capital (aPR: 1.53, 95% CI: 1.12 to 2.10). Higher monthly income (>250,000 FCFA vs. <50,000 FCFA) was associated with lower prevalence of new HIV diagnosis (aPR: 0.22, 95% CI: 0.05 to 0.86). CONCLUSIONS: There are significant sociostructural factors that seem to potentiate risk of HIV infection and delay diagnosis among FSW in Cameroon. Initiatives to build social capital and integrate services such as pre-exposure prophylaxis and HIV self-testing into HIV programs may reduce new infections and decrease time to diagnosis and treatment.

Influence of ciprofloxacin-based additives on the hydrolysis of nanofiber polyurethane membranes.

A degradable polycarbonate urethane (PCNU) and an antimicrobial oligomer (AO) were used to generate anti-infective nanofiber scaffolds through blend electrospinning. The AO consists of two molecules of ciprofloxacin (CF) bound through hydrolysable linkages to triethylene glycol. The membranes were conceived for use as tissue engineering scaffolds for the regeneration of soft tissues for the periodontium, where there would be a need for a local dose of antibiotic to the periodontal space as the scaffold degrades in order to prevent biomaterial-associated infection. Scaffolds were made using AO at 7 and 15% w/w equivalent CF, and compared to scaffolds with 15% w/w CF (with HCl counterion). AO was hydrolyzed and released CF continuously over 28 days, while the 15% w/w CF HCl scaffolds showed a burst release within hours, with no subsequent release in the subsequent 28 day period. Released CF from both the AO and CF HCl scaffolds had a similar minimum inhibitory concentration to that of off-the-shelf CF. Interestingly, the introduction of drug in either form (AO or CF HCl) was found to increase the hydrolytic stability of the electrospun degradable PCNU scaffold matrix itself. The alteration of hydrolysis kinetics was attributed to changes in the hydrogen bonding character and microstructure within the scaffolds, introduced by the presence of CF. This study has revealed that in generating in situ drug release systems, the secondary effects of the added drug on the degradation properties of the polymeric carriers must be considered, particularly for systems that act dually as tissue engineering scaffolds. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1211-1222, 2018.

First-Line Aldoxorubicin vs Doxorubicin in Metastatic or Locally Advanced Unresectable Soft-Tissue Sarcoma: A Phase 2b Randomized Clinical Trial.

IMPORTANCE: Standard therapy for advanced soft-tissue sarcoma has not changed substantially in decades, and patient prognosis remains poor. Aldoxorubicin, a novel albumin-binding prodrug of doxorubicin, showed clinical activity against advanced soft-tissue sarcoma in phase 1 studies. OBJECTIVE: To evaluate efficacy and safety of aldoxorubicin vs doxorubicin in patients with advanced soft-tissue sarcoma. DESIGN, SETTING, AND PARTICIPANTS: International, multicenter, phase 2b, open-label, randomized study at general community practices, private practices, or institutional practices. Between August 2012 and December 2013, 140 patients with previously untreated locally advanced, unresectable, or metastatic soft-tissue sarcoma were screened. INTERVENTIONS: Randomization (2:1) to aldoxorubicin 350 mg/m2 (dose equivalent to doxorubicin 260 mg/m2) or doxorubicin 75 mg/m2, administered once every 3 weeks for up to 6 cycles. MAIN OUTCOMES AND MEASURES: Primary end point was progression-free survival. Secondary end points were 6-month progression-free survival, overall survival, tumor response rate, and safety. All efficacy end points were evaluated by independent and local review. RESULTS: A total of 126 patients were randomized, and 123 received aldoxorubicin (n = 83) or doxorubicin (n = 40). Median (range) patient age was 54.0 (21-77 years); 42 (34%) had leiomyosarcoma. By independent review, median progression-free survival was significantly improved (5.6 [95% CI, 3.0-8.1] vs 2.7 [95% CI, 1.6-4.3] months; P = .02) with aldoxorubicin compared with doxorubicin, as was the rate of 6-month progression-free survival (46% and 23%; P = .02). Median overall survival was 15.8 (95% CI, 13.0 to not available) months with aldoxorubicin and 14.3 (95% CI, 8.6-20.6) months with doxorubicin (P = .21). Overall tumor response rate (by Response Evaluation Criteria in Solid Tumors, version 1.1) by independent review was higher with aldoxorubicin than with doxorubicin (25% [20 patients, all partial response] vs 0%). Grade 3 or 4 neutropenia was more frequent with aldoxorubicin than with doxorubicin (24 [29%] vs 5 [12%]), but not grade 3 or 4 febrile neutropenia (12 [14%] vs 7 [18%]). No acute cardiotoxic effects were observed with either treatment, although left ventricular ejection fraction less than 50% occurred in 3 of 40 patients receiving doxorubicin. CONCLUSIONS AND RELEVANCE: Single-agent aldoxorubicin therapy showed superior efficacy over doxorubicin by prolonging progression-free survival and improving rates of 6-month progression-free survival and tumor response. Aldoxorubicin therapy exhibited manageable adverse effects, without unexpected events, and without evidence of acute cardiotoxicity. Further investigation of aldoxorubicin therapy in advanced soft-tissue sarcoma is warranted. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01514188.

A phase 1B/2 study of aldoxorubicin in patients with soft tissue sarcoma.

BACKGROUND: Aldoxorubicin, a prodrug of doxorubicin, covalently binds to serum albumin, allowing for the administration of much higher doses of doxorubicin in a previous clinical study. The current phase 1B/2 study evaluated the safety of aldoxorubicin, including preliminary efficacy and safety of its maximum tolerated dose (MTD). METHODS: Patients aged 18 to 70 years with recurrent/refractory malignant solid tumors received aldoxorubicin at a dose of 230 mg/m(2) , 350 mg/m(2) , or 450 mg/m(2) (170 mg/m(2) , 260 mg/m(2) , or 335 mg/m(2) doxorubicin equivalents, respectively) by intravenous infusion once every 21 days for up to 8 consecutive cycles. RESULTS: A total of 25 patients were enrolled, including 17 patients (68%) with advanced soft tissue sarcoma (STS). The MTD of aldoxorubicin was 350 mg/m(2) ; dose-limiting toxicities included grade 4 neutropenia and grade 3 febrile neutropenia (NCI CTCAE v4.0). Drug-related adverse events included myelosuppression, nausea, fatigue, alopecia, stomatitis, vomiting, and oropharyngeal pain. No clinically significant cardiac toxicities were reported. Seven patients (28%) had elevated serum troponin levels while taking part in the study, but these elevations were not clinically significant or associated with cardiac findings. A partial response was achieved in 20% of patients, and stable disease was reported in 40% of patients. The median progression-free survival was 4.80 months, and the median overall survival was 11.25 months. Among patients with STS who were treated at the MTD (13 patients), a partial response was achieved in 38% and stable disease in 46%; the median progression-free survival was 11.25 months and the median overall survival was 21.71 months. CONCLUSIONS: Aldoxorubicin at a dose of 350 mg/m(2) administered once every 21 days for up to 8 cycles was found to be acceptably safe and demonstrated preliminary efficacy in patients with advanced solid tumors, including STS. Further investigation of aldoxorubicin is ongoing.

Pharmacokinetic study of aldoxorubicin in patients with solid tumors.

Introduction Aldoxorubicin, a prodrug of doxorubicin, binds covalently to serum albumin in the bloodstream and accumulates in tumors. Aldoxorubicin can be administered at doses several-fold higher than doxorubicin can, without associated acute cardiotoxicity. Purpose This study fully evaluated the pharmacokinetic profile of aldoxorubicin (serum and urine). Methods Eighteen patients with advanced solid tumors received aldoxorubicin 230 or 350 mg/m(2) (equivalent in drug load to doxorubicin at doses of 170 or 260 mg/m(2), respectively) once every 21 days. Blood samples were taken in cycle 1 before aldoxorubicin infusion, and at 5, 15, 30, and 60 min, and at 2, 4, 8, 12, 16, 24, 48, and 72 h after infusion. Urine samples were taken in cycle 1 at 24, 48, and 72 h after infusion. Limited blood sampling was done in cycle 3, before aldoxorubicin infusion, and at 60 min and at 2, 4, and 8 h after infusion. Results The long mean half-life (20.1-21.1 h), narrow mean volume of distribution (3.96-4.08 L/m(2)), and slow mean clearance rate (0.136-0.152 L/h/m(2)) suggest that aldoxorubicin is stable in circulation and does not accumulate readily in body compartments outside of the bloodstream. Very little doxorubicin and its major metabolite doxorubicinol, which has been implicated in doxorubicin-associated cardiotoxicity, are excreted in urine. This might explain the lack of cardiotoxicity observed thus far with aldoxorubicin. Conclusions Our findings support dosing and administration schemas used in an ongoing phase 3 clinical study of aldoxorubicin in soft tissue sarcoma, and phase 2 clinical studies in small cell lung cancer, glioblastoma, and Kaposi's sarcoma.

Therapeutic efficacy of aldoxorubicin in an intracranial xenograft mouse model of human glioblastoma.

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with a median survival of 12 to 15 months after diagnosis. Acquired chemoresistance, high systemic toxicity, and low penetration of the blood brain barrier by many anticancer drugs contribute to the failure of anti-GBM therapies. To circumvent some of these obstacles, we tested a novel prodrug approach to evaluate anti-GBM efficacy by utilizing serum albumin-binding doxorubicin (Doxo), aldoxorubicin (Aldoxo), which is less toxic, is released from albumin in an acidic environment and accumulates in tumor tissues. A human GBM cell line that expresses a luciferase reporter (U87-luc) was stereotactically injected into the left striatum of the brain of immunodeficient mice. Following initial tumor growth for 12 days, mice were injected once a week in the tail-vein with Aldoxo [24 mg/kg or 18 mg/kg of doxorubicin equivalents-3/4 maximum tolerated dose (MTD)], Doxo [6 mg/kg (3/4 MTD)], or vehicle. Aldoxo-treated mice demonstrated significantly slower growth of the tumor when compared to vehicle-treated or Doxo-treated mice. Five out of eight Aldoxo-treated mice remained alive more than 60 days with a median survival of 62 days, while the median survival of vehicle- and Doxo-treated mice was only 26 days. Importantly, Aldoxo-treated mice exhibited high levels of Doxo within the tumor tissue, accompanied by low tumor cell proliferation (Ki67) and abundant intratumoral programmed cell death (cleaved caspase-3). Effective accumulation of Aldoxo in brain tumor tissues but not normal brain, its anti-tumor efficacy, and low toxicity, provide a strong rationale for evaluating this novel drug conjugate as a treatment for patients afflicted with GBM.

Basiliximab does not increase efficacy of corticosteroids in patients with steroid-refractory ulcerative colitis.

BACKGROUND & AIMS: Basiliximab is a chimeric monoclonal antibody that binds CD25 and thereby inhibits interleukin (IL)-2-mediated proliferation of lymphocytes. IL-2 might contribute to the resistance of T cells to corticosteroids. We investigated the efficacy and safety of basiliximab as a corticosteroid-sensitizing agent in patients with corticosteroid-refractory ulcerative colitis (UC). METHODS: We studied 149 patients with moderate to severe UC (Mayo score ≥6 and endoscopic subscore ≥2) despite treatment for at least 14 days with oral prednisone (40-50 mg/day). Subjects were randomly assigned to groups that were given 20 mg (n = 46) or 40 mg (n = 52) basiliximab or placebo (n = 51) at weeks 0, 2, and 4. All subjects received 30 mg/day prednisone through week 2; the dose was reduced by 5 mg each week to 20 mg/day, which was maintained until week 8. At week 8, we compared the rates of clinical remission (Mayo score ≤2, no subscore >1) for patients given basiliximab with the rate for patients given placebo. RESULTS: Twenty-eight percent of patients given placebo, 29% of those given the 40-mg dose of basiliximab, and 26% of those given the 20-mg dose of basiliximab achieved clinical remission (P = 1.00 vs placebo for each dose). Basiliximab was generally well tolerated. Six subjects who received basiliximab had serious adverse events (6.1%) compared with 2 who received placebo (3.9%; P = .72). In subjects given basiliximab, incomplete saturation of CD25 (<50%) on peripheral T cells was associated with the presence of anti-basiliximab antibodies (odds ratio, 21; 95% confidence interval, 2.4-184). CONCLUSIONS: Basiliximab does not increase the effect of corticosteroids in the induction of remission in outpatients with corticosteroid-resistant moderate to severe UC.

The odontology victim identification skill assessment system.

Mass fatality identification efforts involving forensic odontology can involve hundreds of dental volunteers. A literature review was conducted and forensic odontologists and dental educators consulted to identify lessons learned from past mass fatality identification efforts. As a result, the authors propose a skill assessment system, the Odontology Victim Identification Skill Assessment System (OVID-SAS), which details qualifications required to participate on the Antemortem, Postmortem, Ante/Postmortem Comparison, Field, and Shift Leader/Initial Response Teams. For each qualification, specific skills have been identified along with suggested educational pedagogy and skill assessment methods. Courses and assessments can be developed by dental schools, professional associations, or forensic organizations to teach and test for the skills required for dental volunteers to participate on each team. By implementing a system, such as OVID-SAS, forensic odontologists responsible for organizing and managing a forensic odontology mass fatality identification effort will be able to optimally utilize individuals presenting with proven skills.

In vivo pharmacodynamic effects of Hu1D10 (remitogen), a humanized antibody reactive against a polymorphic determinant of HLA-DR expressed on B cells.

The humanized monoclonal antibody Hu1D10 (Remitogen, Protein Design Labs, Fremont, CA) recognizes a polymorphic determinant of human leukocyte antigen-DR expressed on the majority of B-cell lymphomas and on normal B cells of most individuals. Hu1D10 mediates complement-mediated cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and apoptosis of 1D10 antigen (Ag)-positive B cells in vitro. The 1D10 Ag is expressed on a variety of tissues but is restricted primarily to lymphocytes, macrophages, and mesenchymal dendritic cells. The safety and pharmacology of Hu1D10 were investigated in rhesus macaques. Animals were prescreened for 1D10 Ag expression on circulating B cells. Sixteen animals received either placebo (4 Ag+ animals), 1 mg/kg Hu1D10 (4 Ag+ animals), or 10 mg/kg Hu1D10 (4 Ag+ animals and 4 Ag- animals) daily via intravenous (i.v.) bolus-injection for 5 consecutive days, and 4 Ag+ animals received 10 mg/kg Hu1D10 via 90 min i.v. infusion x 5 days. Bolus-injection of Hu1D10 resulted in type 1 hypersensitivity reactions in the majority of Ag+ animals and one death due to anaphylaxis. Slow infusion of Hu1D10 was associated with only mild hypersensitivity reactions after the first dose but not subsequent doses. In animals treated with 10 mg/kg Hu1D10 via bolus-injection, the median terminal elimination half-life of Hu1D10 was 2.6 and 8.4 days in Ag+ and Ag- animals, respectively. Administration of Hu1D10 to Ag+ animals resulted in rapid and profound depletion of circulating B cells for 7-10 days following the last dose. No B-cell depletion was observed in Ag- animals, despite slower elimination of Hu1D10. These studies demonstrate that Hu1D10 reacts with antigen-presenting cells in rhesus macaques. It can be safely administered as a slow i.v. infusion but causes severe toxicity when given as a bolus. This study provides the foundation for testing Hu1D10 for the treatment of B-cell malignancies in humans.