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M Sigrid Mac Donald-Ottevanger,1 Malti R Adhin,2 Jeetendra Kumar Jitan,3 Gustavo Bretas,4 Stephen GS Vreden1 1Foundation for Scientific Research Suriname (SWOS), 2Department of Biochemistry, Anton de Kom University of Suriname, 3Department of Public Health, Ministry of Health, Paramaribo, Suriname; 4Independent consultant, Rio de Janeiro, Brazil Background: Recurrent episodes of Plasmodium vivax are caused by dormant liver stages of the parasite, which are not eradicated by choloroquine. Therefore, effective treatment also includes the use of primaquine (PQ). However, this secondary preventive therapy is often not effective, mostly due to poor adherence to the relatively long treatment course, justifying a comparative study of the efficacy of different durations of PQ treatment. Materials and methods: We included patients presenting with an acute and documented P. vivax infection from January 2006 to February 2008. All patients received chloroquine 25 mg/kg over a 3-day period. Subsequently, patients in group 7D received PQ 30 mg/day for 7 days, and patients in group 14D received standard PQ 15 mg/day for 14 days. All doses were given under supervision and patients were followed up for at least 6 months. The Kaplan–Meier method was used to estimate cumulative probability of recurrence up to 12 months after treatment initiation stratified by treatment group. Cox regression was used to assess possible determinants for recurrent parasitemia. Results: Forty-seven of the 79 included patients (59.5%) were allocated to group 7D and 32 patients (40.5%) were allocated to group 14D. Recurrent parasitemia was detected in 31.9% of the cases in group 7D compared to 12.5% of the cases in group 14D (hazard ratio [HR] =3.36, 95% CI 1.11–10.16). Cumulative probability for recurrent parasitemia at 3, 6, and 12 months was 0.201 (95% CI 0.106–0.362), 0.312 (95% CI 0.190–0.485), and 0.424 (95% CI 0.274– 0.615) for group 7D and 0.100 (95% CI 0.033–0.279), 0.100 (95% CI 0.033–0.279), and 0.138 (95% CI 0.054–0.327) for group 14D, respectively. When adjusted for possible confounders, differences in recurrent parasitemia remained significant between the two regimens in Cox regression analysis. Conclusion: More than 30% of the patients receiving shorter treatment course had recurrent parasitemia, suggesting that the standard dose of 15 mg/day PQ for 14 days is more efficacious than 30 mg for 7 days in preventing P. vivax recurrent episodes. Furthermore, we suggest that P. vivax treatment in Suriname should be changed to PQ 30 mg/day for 14 days, as per Center for Disease Control and Prevention recommendation, in light of a recurrence rate of over 10%, even in group 14D. Keywords: malaria, vivax, recurrent episode, primaquine, treatment duration, efficacy

Mariana Ribeiro Monteiro,1,2 Natalia Cristina Cardoso Nunes,3 Aumilto Augusto da Silva Junior,4 Angelo Bezerra de Souza Fêde,5 Gustavo de Oliveira Bretas,6 Cristiano de Pádua Souza,7 Max Mano,8 Jesse Lopes da Silva6,9,10 1Instituto Americas, São Paulo, Brazil; 2Hospital Samaritano, São Paulo, Brazil; 3Instituto Americas, Rio de Janeiro, Brazil; 4Hospital Santa Catarina Paulista, São Paulo, Brazil; 5DASA Oncologia, São Paulo, Brazil; 6Grupo Oncoclínicas, Rio de Janeiro, Brazil; 7Hospital do Câncer de Barretos, São Paulo, Brazil; 8Grupo Oncoclínicas, São Paulo, Brazil; 9Divisão de Pesquisa Clínica e Desenvolvimento Tecnológico, Instituto Nacional do Câncer, Rio de Janeiro, Brazil; 10Hospital da Força Aérea do Galeão, Rio de Janeiro, BrazilCorrespondence: Mariana Ribeiro Monteiro, Email marianarmonteiro@hotmail.comAbstract: Antibody-drug conjugates (ADCs) have surfaced as a promising group of anticancer agents employing the precise targeting capacity of monoclonal antibodies to transport highly effective cytotoxic payloads. Compared to conventional chemotherapy, they aim to selectively eradicate cancer cells while minimizing off-target toxicity on healthy tissues. An increasing body of evidence has provided support for the efficacy of ADCs in treating breast cancer across various contexts and tumor subtypes, resulting in significant changes in clinical practice. Nevertheless, unlocking the full potential of these therapeutic agents demands innovative molecular designs to address complex clinical challenges, including drug resistance, tumor heterogeneity, and treatment-related adverse events. This thorough review provides an in-depth analysis of the clinical data on ADCs, offering crucial insights from pivotal clinical trials that assess the efficacy of ADCs in diverse breast cancer settings. This aids in providing a comprehensive understanding of the current state of ADCs in breast cancer therapy, while also providing valuable perspectives for the future.Keywords: breast cancer, cancer therapy, target therapy, antibody–drug conjugates, ADCs

Alberto JA Wainstein,1,2 Ana P Drummond-Lage,1 Milhem JM Kansaon,2 Gustavo O Bretas,2 Rodrigo F Almeida,3 Ana LF Gloria,3 Ana RP Figueiredo3 1Faculty of Medical Sciences of Minas Gerais, 2Oncad Surgical Oncology, 3Ophthalmology Department, Federal University of Minas Gerais, Belo Horizonte, Brazil Background: The purpose of this report is to examine the viability and safety of preoperative lymphoscintigraphy and radio guided sentinel lymph node (SLN) biopsy for conjunctival melanoma, and to identify the best technique to perform this procedure.Methods: Three patients diagnosed with malignant melanoma of the conjunctiva underwent lymphoscintigraphy and SLN biopsy using a dual technique comprising isosulfan blue dye and technetium Tc 99m sulfur colloid. Each patient was anesthetized and the conjunctival melanoma was excised. SLNs were localized by a gamma probe, identified according to radioactivity and sentinel blue printing, and dissected, along with drainage of the associated lymphatic basins. The SLNs were evaluated by a pathologist using hematoxylin-eosin staining following serial sectioning and immunohistochemistry using a triple melanoma cocktail (S-100, Melan-A, and HMB-45 antigens).Results: Two SLNs were stained in the jugular chain during preoperative lymphoscintigraphy in the first patient, two SLNs were identified in the preauricular and submandibular areas in the second patient, and two SLNs were identified in the submandibular and parotid areas in the third patient. All lymph nodes identified by lymphoscintigraphy were dissected and identified at surgery with 100% accuracy in all three patients. All SLNs were histologically and immunohistochemically negative. Patients had good cosmetic and functional results, and maintained their visual acuity and ocular motility.Conclusion: Patients with conjunctival melanoma can undergo preoperative lymphoscintigraphy and SLN biopsy safely using radioactive technetium and isosulfan blue dye. Keywords: ocular melanoma, sentinel lymph node biopsy, lymphoscintigraphy, conjunctival melanoma

Abstract Background Despite a significant reduction in the number of malaria cases in Guyana and Suriname, this disease remains a major problem in the interior of both countries, especially in areas with gold mining and logging operations, where malaria is endemic. National malaria control programmes in these countries provide treatment to patients with medicines that are procured and distributed through regulated processes in the public sector. However, availability to medicines in licensed facilities (private sector) and unlicensed facilities (informal sector) is common, posing the risk of access to and use of non-recommended treatments and/or poor quality products. Methods To assess the quality of circulating anti-malarial medicines, samples were purchased in the private and informal sectors of Guyana and Suriname in 2009. The sampling sites were selected based on epidemiological data and/or distance from health facilities. Samples were analysed for identity, content, dissolution or disintegration, impurities, and uniformity of dosage units or weight variation according to manufacturer, pharmacopeial, or other validated method. Results Quality issues were observed in 45 of 77 (58%) anti-malarial medicines sampled in Guyana of which 30 failed visual & physical inspection and 18 failed quality control tests. The proportion of monotherapy and ACT medicines failing quality control tests was 43% (13/30) and 11% (5/47) respectively. A higher proportion of medicines sampled from the private sector 34% (11/32) failed quality control tests versus 16% (7/45) in the informal sector. In Suriname, 58 medicines were sampled, of which 50 (86%) were Artecom®, the fixed-dose combination of piperaquine-dihydroartemisinin-trimethoprim co-blistered with a primaquine phosphate tablet. All Artecom samples were found to lack a label claim for primaquine, thus failing visual and physical inspection. Conclusions The findings of the studies in both countries point to significant problems with the quality of anti-malarial medicines available in private and informal sector facilities as well as the availability of therapy not compliant with national treatment guidelines. They also stress the need to strengthen regulatory control efforts on the availability of anti-malarial medicines in these sectors and in endemic areas.

Abstract Background Ensuring the quality of malaria medicines is crucial in working toward malaria control and eventual elimination. Unlike other validated tests that can assess all critical quality attributes, which is the standard for determining the quality of medicines, basic tests are significantly less expensive, faster, and require less skilled labour; yet, these tests provide reproducible data and information on several critical quality attributes, such as identity, purity, content, and disintegration. Visual and physical inspection also provides valuable information about the manufacturing and the labelling of medicines, and in many cases this inspection is sufficient to detect counterfeit medicines. The Promoting the Quality of Medicines (PQM) programme has provided technical assistance to Amazon Malaria Initiative (AMI) countries to implement the use of basic tests as a key screening mechanism to assess the quality of malaria medicines available to patients in decentralized regions. Methods Trained personnel from the National Malaria Control Programmes (NMCPs), often in collaboration with country’s Official Medicine Control Laboratory (OMCL), developed country- specific protocols that encompassed sampling methods, sample analysis, and data reporting. Sampling sites were selected based on malaria burden, accessibility, and geographical location. Convenience sampling was performed and countries were recommended to store the sampled medicines under conditions that did not compromise their quality. Basic analytical tests, such as disintegration and thin layer chromatography (TLC), were performed utilizing a portable mini-laboratory. Results Results were originally presented at regional meetings in a non-standardized format that lacked relevant medicines information. However, since 2008 information has been submitted utilizing a template specifically developed by PQM for that purpose. From 2005 to 2010, the quality of 1,663 malaria medicines from seven AMI countries was evaluated, mostly collected from the public sector, 1,445/1,663 (86.9%). Results indicate that 193/1,663 (11.6%) were found not to meet quality specifications. Most failures were reported during visual and physical inspection, 142/1663 (8.5%), and most of these were due to expired medicines, 118/142 (83.1%). Samples failing TLC accounted for 27/1,663 (1.6%) and those failing disintegration accounted for 24/1,663 (1.4%). Medicines quality failures decreased significantly during the last two years. Conclusions Basic tests revealed that the quality of medicines in the public sector improved over the years, since the implementation of this type of quality monitoring programme in 2005. However, the lack of consistent confirmatory tests in the quality control (QC) laboratory, utilizing methods that can also evaluate additional quality attributes, could still mask quality issues. In the future, AMI countries should improve coordination with their health authorities and their QC lab consistently, to provide a more complete picture of malaria medicines quality and support the implementation of corrective actions. Facilities in the private and informal sectors also should be included when these sectors constitute an important source of medicines used by malaria patients.

Abstract Anopheles darlingi is one of the most important malaria vectors in the Americas. In this era of new tools and strategies for malaria and vector control it is essential to have knowledge on the ecology and behavior of vectors in order to evaluate appropriateness and impact of control measures. This paper aims to provide information on the importance, ecology and behavior of An. darlingi. It reviews publications that addressed ecological and behavioral aspects that are important to understand the role and importance of An. darlingi in the transmission of malaria throughout its area of distribution. The results show that Anopheles darlingi is especially important for malaria transmission in the Amazon region. Although numerous studies exist, many aspects determining the vectorial capacity of An. darlingi, i.e. its relation to seasons and environmental conditions, its gonotrophic cycle and longevity, and its feeding behavior and biting preferences, are still unknown. The vector shows a high degree of variability in behavioral traits. This makes it difficult to predict the impact of ongoing changes in the environment on the mosquito populations. Recent studies indicate a good ability of An. darlingi to adapt to environments modified by human development. This allows the vector to establish populations in areas where it previously did not exist or had been controlled to date. The behavioral variability of the vector, its adaptability, and our limited knowledge of these impede the establishment of effective control strategies. Increasing our knowledge of An. darlingi is necessary.

Brazilian garimpeiros are a highly hard-to-reach and mobile population, with little access to basic hygiene and health services, and have been crossing the border to work irregularly in gold mines in French Guiana since the 1990s. This study aimed to characterize this population and identify their main health problems. A cross-sectional study was carried out in the municipality of Oiapoque-AP, with two surveys: before (2018) and after (2019) the implementation of Malakit. Individuals were recruited from resting places and given a questionnaire regarding demographic variables, history and knowledge of malaria, and health issues in the mines. Simultaneously, a clinical evaluation was performed. The garimpeiros were mainly men from Maranhão, Pará, and Amapá, with a low educational level and who had worked on average for 10 years in the mining sites. The study population mentioned numerous health problems: malaria, followed by leishmaniasis, flu, body aches, headaches, and digestive problems. Other diseases mentioned were skin diseases, bat bites, hepatitis, and HIV infection. This vulnerable population is constantly subjected to heavy routines and exposed to different diseases and infections that can spread across borders. Knowledge of this is essential for developing public health policies that can be integrated into specific epidemiological situations.

By presenting a comprehensive analysis of low-grade serous carcinomas (LGSCs), a subset of epithelial ovarian cancers, this review delves into their distinct molecular characteristics, clinicopathological features and systemic therapy options, emphasizing their differences from high-grade serous carcinomas (HGSCs). Notably, LGSCs exhibit prevalent RAS/RAF/MEK/MAPK pathway activation, KRAS and BRAF mutations, and infrequent p53 mutations. While chemotherapy is commonly employed, LGSCs display lower responsiveness compared to HGSCs. Hormone therapy, particularly endocrine maintenance therapy, is explored due to the higher estrogen receptor expression. Novel therapeutic approaches involving CDK4/6 inhibitors, MEK inhibitors, and antiangiogenic agents like bevacizumab are also investigated. Ongoing clinical trials are striving to enhance LGSC treatment strategies, offering valuable insights for future therapeutic advancements in this challenging ovarian cancer subtype., Competing Interests: GG, JS, GO, AS, LB, and AM were employed by company Oncoclínicas&Co – Medica Scientia Innovation Research (MEDSIR). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Giannecchini, da Silva, de Oliveira Bretas, dos Santos, Baltar and de Melo.)

Patients in Brazil continue to present with late-stage breast cancer. Notwithstanding these figures, policies and programs to overcome this long-lasting scenario have had limited results. We enlist the main barriers for advancing breast cancer diagnosis in Brazil, based on the available evidence, and we propose feasible strategies that may serve as a platform to address this major public health challenge., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2021 The Author(s).)

Background: Suriname has moved from being the country with the highest annual parasite index in the Americas to one on the threshold of elimination. The progress toward elimination in the stable populations of Suriname between 2000 and 2015 is reviewed., Methods: Data was obtained from the Medical Mission and the Ministry of Health Malaria Programme case-reporting systems, and analysed with a focus on disease burden and differentiation of the disease geographically, by malaria species, age, gender, ethnicity, incidence and gametocytaemia., Results: Between 2000 and 2015 there were 57,811 locally acquired cases of malaria in the stable populations of Suriname. A significant reduction in indigenous malaria cases was observed from 2006 to 2015. The number of imported malaria cases saw a relative increase compared to the number of autochthonous cases. In 2015 over 95% of the cases reported in stable communities are imported, mainly from neighbouring French Guiana, a department of France. The overall decline in malaria case incidence followed the mass-distribution of free long-lasting insecticide-impregnated mosquito nets and increased awareness building efforts, improved access to malaria services as a result of the introduction of Rapid Diagnostic Tests and the implementation of active case detection in high risk areas. In addition, improved management of Plasmodium falciparum infections was achieved with the introduction of artemisinin combination therapy., Conclusions: The existence of a network of policlinics in the interior ran by Medical Mission, for the indigenous population, allowed the rapid implementation of the strategy in stable communities. The success of malaria control in Suriname indicates that the availability at local level, of prompt and adequate prevention, diagnosis and treatment is a key requirement for the elimination of malaria.

Leptospira spp., which comprise 3 clusters (pathogenic, saprophytic, and intermediate) that vary in pathogenicity, infect >1 million persons worldwide each year. The disease burden of the intermediate leptospires is unclear. To increase knowledge of this cluster, we used new molecular approaches to characterize Leptospira spp. in 464 samples from febrile patients in rural, semiurban, and urban communities in Ecuador; in 20 samples from nonfebrile persons in the rural community; and in 206 samples from animals in the semiurban community. We observed a higher percentage of leptospiral DNA-positive samples from febrile persons in rural (64%) versus urban (21%) and semiurban (25%) communities; no leptospires were detected in nonfebrile persons. The percentage of intermediate cluster strains in humans (96%) was higher than that of pathogenic cluster strains (4%); strains in animal samples belonged to intermediate (49%) and pathogenic (51%) clusters. Intermediate cluster strains may be causing a substantial amount of fever in coastal Ecuador.

The aim of this translational study was to show the use of molecular surveillance for polymorphisms and copy number as a monitoring tool to track the emergence and dynamics of Plasmodium falciparum drug resistance. A molecular baseline for Suriname was established in 2005, with P. falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance (pfmdr1) markers and copy number in 40 samples. The baseline results revealed the existence of a uniformly distributed mutated genotype corresponding with the fully mefloquine-sensitive 7G8-like genotype (Y184F, S1034C, N1042D, and D1246Y) and a fixed pfmdr1 N86 haplotype. All samples harbored the pivotal pfcrtK76T mutation, showing that chloroquine reintroduction should not yet be contemplated in Suriname. After 5 years, 40 samples were assessed to trace temporal changes in the status of pfmdr1 polymorphisms and copy number and showed minor genetic alterations in the pfmdr1 gene and no significant changes in copy number, thus providing scientific support for prolongation of the current drug policy in Suriname.

A parasitological cross-sectional survey was undertaken from September 2000 through February 2001 to estimate the prevalence of malaria parasitemia in Eritrea. A total of 12,937 individuals from 176 villages were screened for both Plasmodium falciparum and Plasmodium vivax parasite species using the OptiMal Rapid Diagnostic Test. Malaria prevalence was generally low but highly focal and variable with the proportion of parasitemia at 2.2% (range: 0.4% to 6.5%). Despite no significant differences in age or sex-specific prevalence rates, 7% of households accounted for the positive cases and 90% of these were P. falciparum. Multivariate regression analyses revealed that mud walls were positively associated with malaria infection (OR [odds ratio] = 1.6 [95% CI: 1.2, 2.2], P < 0.008). For countries with low and seasonal malaria transmission, such information can help programs design improved strategic interventions.

Studies on the spatial distribution of anopheline mosquito larvae were conducted in 302 villages over two transmission seasons in Eritrea. Additional longitudinal studies were also conducted at eight villages over a 24-mo period to determine the seasonal variation in anopheline larval densities. Eight anopheline species were identified with Anopheles arabiensis predominating in most of the habitats. Other species collected included: An. cinereus, An. pretoriensis, An. d'thali, An. funestus, An. squamosus, An. adenensis, and An. demeilloni. An. arabiensis was found in five of the six aquatic habitats found positive for anopheline larvae during the survey. Anopheles larvae were sampled predominantly from stream edges and streambed pools, with samples from this habitat type representing 91.2% (n = 9481) of the total anopheline larval collection in the spatial distribution survey. Other important anopheline habitats included rain pools, ponds, dams, swamps, and drainage channels at communal water supply points. Anopheline larvae were abundant in habitats that were shallow, slow flowing and had clear water. The presence of vegetation, intensity of shade, and permanence of aquatic habitats were not significant determinants of larval distribution and abundance. Larval density was positively correlated with water temperature. Larval abundance increased during the wet season and decreased in the dry season but the timing of peak densities was variable among habitat types and zones. Anopheline larvae were collected all year round with the dry season larval production restricted mainly to artificial aquatic habitats such as drainage channels at communal water supply points. This study provides important information on seasonal patterns of anopheline larval production and larval habitat diversity on a countrywide scale that will be useful in guiding larval control operations in Eritrea.

This paper describes genetic subtypes of HIV-1 found in blood samples from 31 HIV-1-infected people who visited the Counseling and Testing AIDS Center of Instituto de Medicina Tropical in Manaus, Brazil. Manaus, the main city in Brazil's Amazon Basin, is also the closest urban connection for more than 100,000 Indians living in the rain forests of this region. Although to date there is no evidence of increased incidence of HIV-1 infection among the indigenous population, our understanding of both the prevalence and nature of the epidemic in the region as a whole is limited. From the 31 samples analyzed by C2V3 sequencing, we found almost equal proportions of HIV-1 strains belonging to subtype B (n = 16; 51.6%) and subtype F (n = 15; 48.4%), a finding that differs from results from previous studies conducted in urban areas of southeastern Brazil. We also observed the presence of the GWGR amino-acid sequence in the critical tetra-peptide crown of the env V3 loop in the HIV-1 subtype B samples analyzed. Among these samples, we also found 14 mosaic genomes (45.16%) in which different combinations of subtypes B, C, and F were identified between the p24 gag, pro, and env regions. Our data support the hypothesis that the Amazonian HIV-1 infections linked to the urban epidemic in southeastern Brazil. The genetic diversity and the prevalence of mosaic genomes among the isolates in our study confirm an integral role of recombination in the complex Brazilian epidemic.