Romiplostim use in pregnant women with immune thrombocytopenia.

Treatment for immune thrombocytopenia (ITP) in pregnancy is hampered by the lack of fetal safety evidence of maternally-administered medications. The Pregnancy Surveillance Program (PSP) collected patient information from 2017-2020 for pregnancy, birth outcomes, and adverse events (AEs) for 186 women exposed to romiplostim from 20 days before pregnancy to the end of pregnancy. Timing of exposure was available in 128 women. Seventy-one mothers (38%) had prepregnancy exposure to romiplostim; intrapartum exposure was known for the first (for many mothers when they discovered their pregnancy), second, and third trimesters for 74 (40%), 22 (12%), and 44 (24%) mothers, respectively, with 15 mothers exposed during >1 trimester. Among the 86 mothers with known pregnancy outcomes, 46 (53%) had at least one pregnancy-related serious AE (SAE); approximately 2/3 of SAEs were due to underlying ITP. Of 92 mothers with known birth outcomes, 60 (65%) had a normal pregnancy and 16 (17%) had complications, with both categories including term and preterm births; there were 12 (14%) spontaneous miscarriages/stillbirths, 3 (3%) ectopic pregnancies, and 1 (1%) molar pregnancy. Most abnormal births resulted from abnormal pregnancies. There were five neonatal/postnatal AEs of note: inguinal hernia, cytomegalovirus infection, trisomy 8 (third trimester single-dose romiplostim exposure), single umbilical artery without known anomalies, and development of autism at age 2 years. Seven of 12 infants with neonatal thrombocytopenia had resolution of thrombocytopenia before discharge; all 12 were discharged. Review of pregnancies in women exposed to romiplostim did not reveal any specific safety concerns for mothers, fetuses, or infants.

A prospective study to evaluate febrile neutropenia incidence in patients receiving pegfilgrastim on-body injector vs other choices.

PURPOSE: We evaluated the incidence of febrile neutropenia (FN) and related clinical outcomes among patients treated with myelosuppressive chemotherapy for nonmyeloid malignancies who received pegfilgrastim on-body injector (OBI) or other options (Other) for FN prophylaxis. METHODS: In this prospective observational study, adult patients with breast, prostate, or lung cancer, or non-Hodgkin lymphoma at risk for FN were stratified into subgroups based on FN prophylaxis used in the first chemotherapy cycle: pegfilgrastim OBI vs Other (pegfilgrastim or biosimilar pegfilgrastim prefilled syringe, daily filgrastim, or no granulocyte colony-stimulating factor [G-CSF]) for up to 4 planned chemotherapy cycles. RESULTS: This US study enrolled 2575 eligible patients (OBI, 1624; Other, 951). FN incidence was lower in the OBI group (6.4% [95% CI, 5.2-7.6%]) than in the Other group (9.4% [7.5-11.2%]), with a relative risk (RR) of 0.66 (0.47-0.91; p = .006). A decreased risk of dose delays among patients receiving pegfilgrastim OBI vs Other was observed (RR for ≥ 5 days: 0.64 [0.42-0.96], p = .023; RR for ≥ 7 days: 0.62 [0.40-0.91], p = .016). Adherence, defined as G-CSF support for all chemotherapy cycles, was 94.0% (92.9-95.2%) in the OBI group compared with 58.4% (55.2-61.5%) in the Other group. Compliance with pegfilgrastim, defined as administration the day after chemotherapy, was 88.3% in the OBI group and 48.8% in the prefilled syringe group. CONCLUSION: Patients receiving pegfilgrastim OBI had a lower incidence of FN compared with those receiving alternatives. The OBI was associated with improved adherence to and compliance with clinically recommended G-CSF prophylaxis.

A prospective cohort study to evaluate the incidence of febrile neutropenia in patients receiving pegfilgrastim on-body injector versus other options for prophylaxis of febrile neutropenia: breast cancer subgroup analysis.

BACKGROUND: Breast cancer chemotherapy often carries a high risk of febrile neutropenia (FN); guidelines recommend prophylaxis with granulocyte colony-stimulating factor (G-CSF), such as pegfilgrastim. Neulasta® Onpro® on-body injector (OBI) is a delivery device administering pegfilgrastim approximately 27 h after application. METHODS: This prospective study examined patients with breast cancer who received chemotherapy with a high risk of FN, receiving OBI ("OBI") or other options (other G-CSF or none; "other"). The primary endpoint was FN incidence; secondary endpoints included chemotherapy delivery, adherence (G-CSF in all cycles), compliance (G-CSF day after chemotherapy), and FN incidence in patients receiving curative or palliative treatment. RESULTS: A total of 1776 patients with breast cancer were enrolled (OBI, n = 1196; other, n = 580). Across all cycles, FN incidence was lower for OBI (4.4% [95% CI, 3.3-5.6%]) than other (7.4% [5.3-9.6%]). For curative treatment, the FN incidence across all cycles was lower for OBI (4.6% [3.4-5.8%]) than for other (7.1% [5.0-9.3%]). For palliative treatment (OBI, n = 33; other, n = 20), 3 patients (15%) in the other and none in the OBI group had FN. After adjusting for baseline covariates, FN incidence remained lower for OBI (4.6% [3.5-6.1%]) versus other (7.8% [5.7-10.5%]). Adherence was higher for OBI (93.8%) than for other G-CSF (69.8%), as was compliance (90.5 and 53.2%, respectively). Chemotherapy dose delays/reductions were similar for OBI (4.7%/32.3%, respectively) and other (4.7%/30.0%) groups. CONCLUSION: Pegfilgrastim OBI was associated with a lower FN incidence in patients with breast cancer compared to other options for FN prophylaxis. TRIAL REGISTRATION: www. CLINICALTRIALS: gov , NCT02178475, registered 30 June, 2014.

Prophylactic pegfilgrastim to prevent febrile neutropenia among patients receiving biweekly (Q2W) chemotherapy regimens: a systematic review of efficacy, effectiveness and safety.

BACKGROUND: Pegfilgrastim, a long-acting granulocyte colony-stimulating factor (G-CSF), is commonly used to prevent febrile neutropenia (FN), a potentially life-threatening complication, following myelosuppressive chemotherapy. The FDA label for pegfilgrastim specifies that it should not be administered 14 days before or within 24 h of administration of myelosuppressive chemotherapy, precluding the use of pegfilgrastim in biweekly (Q2W) regimens. The National Comprehensive Cancer Network and the European Organisation for Research and Treatment of Cancer guidelines support the use of prophylactic pegfilgrastim in patients receiving Q2W regimens. The objective of this study was to systematically review evidence from randomized clinical trials (RCTs) and observational studies that describe the effectiveness and safety of prophylactic pegfilgrastim in preventing FN among patients receiving Q2W regimens. METHODS: An Ovid MEDLINE, Embase, and Cochrane Library literature search was conducted to evaluate the evidence regarding efficacy, effectiveness, and safety of prophylactic pegfilgrastim versus no prophylactic pegfilgrastim or prophylaxis with other G-CSF in patients who were receiving Q2W chemotherapy regimens with high (> 20%) or intermediate (10-20%) risk of FN for a non-myeloid malignancy. Studies that addressed absolute or relative risk of FN, grade 1-4 neutropenia, all-cause or any hospitalization, dose delays or dose reductions, adverse events, or mortality were included. Studies where the comparator was a Q3W chemotherapy regimen with primary prophylactic pegfilgrastim were also included. RESULTS: The initial literature search identified 2258 publications. Thirteen publications met the eligibility criteria, including eight retrospective, one prospective, one phase 1 dose escalation study, and three RCTs. In nine of the 13 studies reporting incidence of FN, and in seven of the nine studies reporting incidence of neutropenia, administration of prophylactic pegfilgrastim in patients receiving Q2W regimens resulted in decreased or comparable rates of FN or neutropenia compared with patients receiving filgrastim, no G-CSF, lipefilgrastim or pegfilgrastim in Q3W regimens. In six of the nine studies reporting safety data, lower or comparable safety profiles were observed between pegfilgrastim and comparators. CONCLUSIONS: In a variety of non-myeloid malignancies, administration of prophylactic pegfilgrastim was efficacious in reducing the risk of FN in patients receiving high- or intermediate-risk Q2W regimens, with an acceptable safety profile. TRIAL REGISTRATION: PROSPERO registration no: CRD42019155572 .

Risk of chemotherapy-induced febrile neutropenia in patients with metastatic cancer not receiving granulocyte colony-stimulating factor prophylaxis in US clinical practice.

OBJECTIVES: To evaluate the use of granulocyte colony-stimulating factor (G-CSF) prophylaxis in US patients with selected metastatic cancers and chemotherapy-induced febrile neutropenia (FN) incidence and associated outcomes among the subgroup who did not receive prophylaxis. METHODS: This retrospective cohort study was conducted at four US health systems and included adults with metastatic cancer (breast, colorectal, lung, non-Hodgkin lymphoma [NHL]) who received myelosuppressive chemotherapy (2009-2017). Patients were stratified by FN risk level based on risk factors and chemotherapy (low/unclassified risk, intermediate risk without any risk factors, intermediate risk with ≥ 1 risk factor [IR + 1], high risk [HR]). G-CSF use was evaluated among all patients stratified by FN risk, and FN/FN-related outcomes were evaluated among patients who did not receive first-cycle G-CSF prophylaxis. RESULTS: Among 1457 metastatic cancer patients, 20.5% and 28.1% were classified as HR and IR + 1, respectively. First-cycle G-CSF prophylaxis use was 48.5% among HR patients and 13.9% among IR + 1 patients. In the subgroup not receiving first-cycle G-CSF prophylaxis, FN incidence in cycle 1 was 7.8% for HR patients and 4.8% for IR + 1 patients; during the course, corresponding values were 16.9% and 15.9%. Most (> 90%) FN episodes required hospitalization, and mortality risk ranged from 7.1 to 26.9% across subgroups. CONCLUSION: In this retrospective study, the majority of metastatic cancer chemotherapy patients for whom G-CSF prophylaxis is recommended did not receive it; FN incidence in this subgroup was notably high. Patients with elevated FN risk should be carefully identified and managed to ensure appropriate use of supportive care.

A phase 1, first-in-child, multicenter study to evaluate the safety and efficacy of the oncolytic herpes virus talimogene laherparepvec in pediatric patients with advanced solid tumors.

Background: The survival rates for pediatric patients with relapsed and refractory tumors are poor. Successful treatment strategies are currently lacking and there remains an unmet need for novel therapies for these patients. We report here the results of a phase 1 study of talimogene laherparepvec (T-VEC) and explore the safety of this oncolytic immunotherapy for the treatment of pediatric patients with advanced non-central nervous system tumors. Methods: T-VEC was delivered by intralesional injection at 106 plaque-forming units (PFU)/ml on the first day, followed by 108 PFU/ml on the first day of week 4 and every 2 weeks thereafter. The primary objective was to evaluate the safety and tolerability as assessed by the incidence of dose-limiting toxicities (DLTs). Secondary objectives included efficacy indicated by response and survival per modified immune-related response criteria simulating the Response Evaluation Criteria in Solid Tumors (irRC-RECIST). Results: Fifteen patients were enrolled into two cohorts based on age: cohort A1 (n = 13) 12 to ≤21 years old (soft-tissue sarcoma, n = 7; bone sarcoma, n = 3; neuroblastoma, n = 1; nasopharyngeal carcinoma, n = 1; and melanoma, n = 1) and cohort B1 (n = 2) 2 to <12 years old (melanoma, n = 2). Overall, patients received treatment for a median (range) of 5.1 (0.1, 39.4) weeks. No DLTs were observed during the evaluation period. All patients experienced at least one treatment-emergent adverse event (TEAE), and 53.3% of patients reported grade ≥3 TEAEs. Overall, 86.7% of patients reported treatment-related TEAEs. No complete or partial responses were observed, and three patients (20%) overall exhibited stable disease as the best response. Conclusions: T-VEC was tolerable as assessed by the observation of no DLTs. The safety data were consistent with the patients' underlying cancer and the known safety profile of T-VEC from studies in the adult population. No objective responses were observed. Trial Registration: ClinicalTrials.gov: NCT02756845. https://clinicaltrials.gov/ct2/show/NCT02756845.

Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes.

TNFRSF13B encodes transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a B cell- specific tumor necrosis factor (TNF) receptor superfamily member. Both biallelic and monoallelic TNFRSF13B mutations were identified in patients with common variable immunodeficiency disorders. The genetic complexity and variable clinical presentation of TACI deficiency prompted us to evaluate the genetic, immunologic, and clinical condition in 50 individuals with TNFRSF13B alterations, following screening of 564 unrelated patients with hypogammaglobulinemia. We identified 13 new sequence variants. The most frequent TNFRSF13B variants (C104R and A181E; n=39; 6.9%) were also present in a heterozygous state in 2% of 675 controls. All patients with biallelic mutations had hypogammaglobulinemia and nearly all showed impaired binding to a proliferation-inducing ligand (APRIL). However, the majority (n=41; 82%) of the pa-tients carried monoallelic changes in TNFRSF13B. Presence of a heterozygous mutation was associated with antibody deficiency (P< .001, relative risk 3.6). Heterozygosity for the most common mutation, C104R, was associated with disease (P< .001, relative risk 4.2). Furthermore, heterozygosity for C104R was associated with low numbers of IgD(-)CD27(+) B cells (P= .019), benign lymphoproliferation (P< .001), and autoimmune complications (P= .001). These associations indicate that C104R heterozygosity increases the risk for common variable immunodeficiency disorders and influences clinical presentation.

Clinical overview and practical considerations for optimizing romiplostim therapy in patients with immune thrombocytopenia.

The fundamental treatment goal for patients with immune thrombocytopenia (ITP) is reduced or ameliorated bleeding. Although various treatment options exist for the management of ITP, recent advances have led to the approval of three thrombopoietin receptor agonists (TPO-RAs; romiplostim, eltrombopag, and avatrombopag) in the United States and European Union. Current treatment guidelines for ITP indicate that medical therapy is preferred over surgical therapy and support the use of TPO-RAs as early as 3 months after disease onset. More recent data are available on the use of romiplostim in patients who have had ITP for <1 year, and romiplostim is now indicated for the treatment of adults who have not responded adequately to initial treatment, as well as children aged ≥1 year who have had ITP for ≥6 months. Here we review the role of romiplostim in the management of ITP, with a focus on efficacy and safety data, emerging data on early use (beginning within 3 months of disease onset) and treatment-free remission, and practical considerations for optimal management of ITP.

A Review of Romiplostim Mechanism of Action and Clinical Applicability.

Thrombocytopenia results from a variety of conditions, including radiation, chemotherapy, autoimmune disease, bone marrow disorders, pathologic conditions associated with surgical procedures, hematopoietic stem cell transplant (HSCT), and hematologic disorders associated with severe aplastic anemia. Immune thrombocytopenia (ITP) is caused by immune reactions that accelerate destruction and reduce production of platelets. Thrombopoietin (TPO) is a critical component of platelet production pathways, and TPO receptor agonists (TPO-RAs) are important for the management of ITP by increasing platelet production and reducing the need for other treatments. Romiplostim is a TPO-RA approved for use in patients with ITP in the United States, European Union, Australia, and several countries in Africa and Asia, as well as for use in patients with refractory aplastic anemia in Japan and Korea. Romiplostim binds to and activates the TPO receptor on megakaryocyte precursors, thus promoting cell proliferation and viability, resulting in increased platelet production. Through this mechanism, romiplostim reduces the need for other treatments and decreases bleeding events in patients with thrombocytopenia. In addition to its efficacy in ITP, studies have shown that romiplostim is effective in improving platelet counts in various settings, thereby highlighting the versatility of romiplostim. The efficacy of romiplostim in such disorders is currently under investigation. Here, we review the structure, mechanism, pharmacokinetics, and pharmacodynamics of romiplostim. We also summarize the clinical evidence supporting its use in ITP and other disorders that involve thrombocytopenia, including chemotherapy-induced thrombocytopenia, aplastic anemia, acute radiation syndrome, perisurgical thrombocytopenia, post-HSCT thrombocytopenia, and liver disease.

Clinical and treatment characteristics of patients treated with the first therapeutic oncology biosimilars bevacizumab-awwb and trastuzumab-anns in the US.

BACKGROUND: In July 2019, bevacizumab-awwb and trastuzumab-anns were marketed in the USA as the first therapeutic oncology biosimilars. We aimed to investigate the initial real-world use of bevacizumab-awwb and trastuzumab-anns for cancer management in US oncology practices. METHODS: A retrospective, observational analysis of data from US cancer patients (⩾18 years of age) was carried out to describe the use of bevacizumab-awwb and trastuzumab-anns during the first 12 months following their market entry, using structured data from the Flatiron Health electronic health record-derived database. RESULTS: A total of 2952 and 2997 patients with recorded use of bevacizumab-awwb and trastuzumab-anns, respectively, were included in the analysis. The first use of bevacizumab-awwb and trastuzumab-anns was in a patient with metastatic colorectal cancer (mCRC) within 10 days of market availability and in a patient with early stage breast cancer (eBC) within 4 days, respectively. The use of these biosimilars was observed across all approved cancer indications; 68% of bevacizumab-awwb users were those diagnosed with mCRC and 72% of trastuzumab-anns users were those diagnosed with eBC. Approximately half the patients were previously exposed to reference product (RP) prior to initiation of bevacizumab-awwb or trastuzumab-anns. Among pre-exposed patients, the majority received the biosimilars [bevacizumab-awwb (63-85%) or trastuzumab-anns (75-81%)] within 28 days of the last infusion of the RP. For both biosimilars, no major differences were observed in patient characteristics between RP-naïve and pre-exposed patients. CONCLUSION: Initial evidence from the first 12 months following market entry suggests rapid clinical adoption of bevacizumab-awwb and trastuzumab-anns across all approved tumor types. Usage of these two biosimilars was observed in both RP-naïve patients and patients who were previously treated with RP, with no distinctive differences in patient characteristics between the two groups.A video abstract is available for this article as part of the Kanjintionline supplemental material.

Assessment of romiplostim immunogenicity in pediatric patients in clinical trials and in a global postmarketing registry.

Development of first-generation thrombopoietins (TPOs) was halted due to antibodies that neutralized endogenous TPO, causing protracted thrombocytopenia in some patients. The second-generation TPO receptor agonist romiplostim, having no homology to TPO, was developed to circumvent potential immunogenicity. We examined the development of binding and neutralizing antibodies to romiplostim and TPO among pediatric patients with primary immune thrombocytopenia (ITP) in 5 clinical trials and a global postmarketing registry. In the trials, 25 of 280 (8.9%) patients developed anti-romiplostim binding antibodies. The first positive result was detected 67 weeks (median) after romiplostim treatment was initiated. The median romiplostim dose was 8 µg/kg, and the median platelet count was 87 × 109/L. Most patients who developed anti-romiplostim binding antibodies (18 of 25 [72%]) had ≥90% of platelet assessments showing a response. Anti-romiplostim neutralizing antibodies developed in 8 of 280 (2.9%) patients. The development of anti-romiplostim neutralizing antibodies was unrelated to the romiplostim dose, and most patients who developed the antibodies (7 of 8 [88%]) had platelet response. Nine of 279 (3.2%) patients developed anti-TPO binding antibodies, and 1 (0.4%) developed transient anti-TPO neutralizing antibodies. In 8 patients who developed anti-romiplostim neutralizing antibodies, no TPO cross-reactivity was observed. In the postmarketing registry, 3 of 19 (15.8%) patients developed anti-romiplostim binding antibodies; 1 (5.3%) patient developed anti-romiplostim neutralizing antibodies. These results suggest that immunogenicity to romiplostim occurs infrequently in pediatric patients with ITP and is generally not associated with loss of platelet response or other negative clinical sequelae.

IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease.

BACKGROUND: About 2% of childhood episodes of invasive pneumococcal disease (IPD) are recurrent, and most remain unexplained. OBJECTIVE: To report two cases of otherwise healthy, unrelated children with recurrent IPD as the only clinical infectious manifestation of an inherited disorder in nuclear factor-kappaB(NF-kappaB)-dependent immunity. RESULTS: One child carried two germline mutations in IRAK4, and had impaired cellular responses to interleukin (IL)1 receptor and toll-like receptor (TLR) stimulation. The other child carried a hemizygous mutation in NEMO, associated with a broader impairment of NF-kappaB activation, with an impaired cellular response to IL-1R, TLR and tumour necrosis factor receptor stimulation. The two patients shared a narrow clinical phenotype, associated with two related but different genotypes. CONCLUSIONS: Otherwise healthy children with recurrent IPD should be explored for underlying primary immunodeficiencies affecting the IRAK4-dependent and NEMO-dependent signalling pathways.

Final 5-Year Follow-Up Results Evaluating Neoadjuvant Talimogene Laherparepvec Plus Surgery in Advanced Melanoma: A Randomized Clinical Trial.

This randomized clinical trial presents the final 5-year follow-up results of neoadjuvant talimogene laherparepvec (T-VEC) plus surgery in patients with advanced melanoma.

Use of minimal residual disease assessment in the treatment of chronic lymphocytic leukemia.

Progress in chronic lymphocytic leukemia (CLL) therapies has extended greatly the length and depth of remission, with the goal of treatment advancing towards a cure for some patients. Accordingly, clinical endpoints must evolve to capture these outcomes, and to provide faster access to novel therapies. Minimal residual disease (MRD) is an important endpoint representing more accurately the depth of remission than complete response (CR), and is highly prognostic of progression-free survival (PFS) and overall survival (OS). MRD could be considered a key outcome of clinical trials and, as a surrogate for PFS, could identify the most cost-effective and durable treatment sequencing. MRD testing could also determine which patients would benefit from additional therapy and, accordingly, ascertain when therapy should be stopped earlier, to reduce toxicity and increase treatment-free intervals. Our article discusses possible uses of MRD in the modern era of CLL, including its definition, measurement, and value as a surrogate endpoint in clinical trials, and its potential roles in clinical practice.

Heritable defects of the human TLR signalling pathways.

Recently, three human primary immunodeficiencies associated with impaired TLR signalling were described. Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), either X-linked recessive or autosomal dominant, is caused by hypomorphic mutations in NEMO or hypermorphic mutation in IKBA, respectively, both involved in nuclear factor-kappaB (NF-kappaB) activation. These patients present with abnormal development of ectoderm-derived structures and suffer from a broad spectrum of infectious diseases. In vitro studies of the patients' cells showed an impaired, but not abolished, NF-kappaB activation in response to a large set of stimuli, including TLR agonists. More recently, patients with autosomal recessive amorphic mutations in IRAK4 have been reported, presenting no developmental defect and a more restricted spectrum of infectious diseases, mostly caused by pyogenic encapsulated bacteria, principally, but not exclusively Gram-positive. In vitro studies carried out with these patients' cells showed a specific impairment of the Toll-interleukin-1 receptor (TIR)-interleukin-1 receptor associated kinase (IRAK) signalling pathway. NF-kappaB- and mitogen activated protein kinase (MAPK) pathways are impaired in response to all TIR agonists tested. These data, therefore, suggest that TLRs play a critical role in host defence against pyogenic bacteria, but may be dispensable or redundant for immunity to most other infectious agents in humans.

O câncer de colo do útero no Brasil: uma retrospectiva sobre as políticas públicas voltadas à saúde da mulher / Cervical cancer in Brazil: a retrospective on public policies for women's health

O câncer de colo do útero é a terceira neoplasia mais incidente entre as brasileiras, com taxa de mortalidade acima de 5/100 mil mulheres, apesar de possuir bom prognóstico quando diagnosticado em fases precoces. No Brasil, políticas públicas voltadas para o câncer de colo do útero vêm sendo desenvolvidas desde a década de 1970 e incluíram diversos programas de rastreamento, que conseguiram aumentar o acesso ao teste de Papanicolau, com patamar de cobertura estável nos últimos anos, em torno dos 83%. Em 2014, a vacina anti-HPV foi incluída no Calendário Nacional de Vacinação. O mais recente Plano de Ações Estratégicas possui metas de aumento da cobertura de exame citopatológico e tratamento de todas as mulheres com lesões precursoras. Outras duas iniciativas foram criadas: o Programa de Qualificação de Ginecologistas para Assistência Secundária às Mulheres com Alterações Citológicas Relacionadas às Lesões Intraepiteliais e ao Câncer de Colo do Útero e a formalização da Rede Colaborativa para a Prevenção do Câncer de Colo do útero. Mesmo com o constante avanço dessas medidas, mais de 70% das brasileiras são diagnosticadas em fases avançadas da doença, o que impacta negativamente no prognóstico. A análise dos protocolos de tratamento voltados para a saúde coletiva mostra defasagem em relação ao cenário internacional e nacional preconizado por sociedades médicas, especialmente no tratamento de fases tardias da doença. Apesar dos avanços na difusão de medidas preventivas e alcance de ampla cobertura do rastreamento, o câncer de colo do útero continua a ser um problema de saúde importante no país.

Cervical cancer is the third most frequent neoplasm among Brazilian women, with a mortality rate of more than 5/100 thousand women, despite having a good prognosis when diagnosed in the early stages. In Brazil, public policies for cervical cancer have been developed since the 1970s and have included several screening programs that have been able to increase access to the Papanicolaou test, with a stable coverage level in recent years, around 83%. In 2014, the anti-HPV vaccine was included in the National Vaccination Calendar. The most recent Strategic Action Plan has targets to increase coverage of cytopathological examination and treatment of all women with precursor lesions. Two other initiatives were created: the Qualification Program of Gynecologists for Secondary Care for Women with Cytologic Alterations Related to Intraepithelial Lesions and Cervical Cancer, and the formalization of the Collaborative Network for the Prevention of Cervical Cancer. Even with constant progress of these measures, more than 70% of Brazilian women are diagnosed in advanced stages of the disease, which negatively impacts the prognosis. The analysis of treatment protocols aimed at public health shows lag in relation to international and national scenario recommended by medical societies, especially in the treatment of late stage disease. Despite the advances in the dissemination of preventive measures and the scope of extensive screening coverage, cervical cancer remains a major health problem in the country.

Autosomal-dominant primary immunodeficiencies.

The vast majority of known primary immunodeficiencies (PIDs) are autosomal or X-linked recessive Mendelian traits. Only four classical primary immunodeficiencies are thought to be autosomal-dominant, three of which still lack a well-defined genetic etiology: isolated congenital asplenia, isolated chronic mucocutaneous candidiasis, and hyper IgE syndrome. The large deletions on chromosome 22q11.2 associated with Di George syndrome suggest that this disease may be dominant but not Mendelian, possibly involving several genes. The clinical and genetic features of six novel autosomal-dominant primary immunodeficiencies have however been described in recent years. These primary immunodeficiencies are caused by germline mutations in seven genes: ELA2, encoding a neutrophil elastase, and GFI1, encoding a regulator of ELA2 (mutations associated with severe congenital neutropenia); CXCR4, encoding a chemokine receptor (warts, hypogammaglobulinemia, infections and myelokathexis syndrome); LCRR8, encoding a key protein for B-cell development (agammaglobulinemia); IFNGR1, encoding the ligand-binding chain of the interferon-gamma receptor; STAT1, encoding the signal transducer and activator of transcription 1 downstream from interferon-gammaR1 (Mendelian susceptibility to mycobacterial diseases); and IKBA, encoding IkappaBalpha, the inhibitor alpha of NF-kappaB (anhidrotic ectodermal dysplasia with immunodeficiency). These recent data suggest that many more autosomal-dominant PIDs are likely to be identified in the near future.

Inherited disorders of human Toll-like receptor signaling: immunological implications.

In vitro nine of 10 known human Toll-like receptors (TLRs) are engaged by well-defined chemical agonists that mimic microbial compounds, raising the possibility that human TLRs play a critical role in protective immunity in vivo. We thus review here the recently described human primary immunodeficiencies caused by germline mutations in genes encoding molecules involved in cell signaling downstream from TLRs. Subjects with anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) carry either X-linked recessive hypomorphic mutations in NEMO or autosomal dominant hypermorphic mutations in IKBA. Their cells show a broad defect in nuclear factor-kappaB (NF-kappaB) activation, with an impaired, but not abolished response to a large variety of stimuli including TLR agonists. EDA-ID patients show developmental anomalies of skin appendages and a broad spectrum of infectious diseases. Patients with autosomal recessive amorphic mutations in IRAK4 present a purely immunological syndrome and more restricted defects, with specific impairment of the Toll and interleukin-1 receptor (TIR)-interleukin-1 receptor-associated kinase (IRAK) signaling pathway. In these subjects, the NF-kappaB- and mitogen-activated protein kinase-mediated induction of inflammatory cytokines in response to TIR agonists is impaired. The patients present a narrow range of pyogenic bacterial infections that become increasingly rare with age. Altogether, these data suggest that human TLRs play a critical role in host defense. However, they do not provide compelling evidence, as even the infectious phenotype of patients with mutations in IRAK4 may result from impaired signaling via receptors other than TLRs. Paradoxically, these experiments of nature raise the possibility that the entire set of human TLRs is largely redundant in protective immunity in vivo.

Impacto do tratamento com imunoglobulina humana intravenosa no número de pneumonias em pacientes com deficiência de anticorpo / Efficacy of immunoglobulin therapy in reducing pneumonia

A imunodeficiência comum variável (ICV) e a agamaglobulinemia ligada ao X (ALX) são imunodeficiências primárias caracterizadas por deficiência de anticorpos e susceptibilidade aumentada a infecções, sendo a pneumonia a infecção mais frequente. Esses pacientes são tratados com infusões regulares de imunoglobulina intravenosa (IGIV). Objetivo: Avaliar a frequência de pneumonias e o impacto do tratamento com IGIV em 25 pacientes com ICV ou ALX. Métodos: Análise retrospectiva dos prontuários médicos de pacientes com diagnóstico confirmado de ICV ou ALX, em tratamento regular com IGIV. Resultados: Analisamos 25 pacientes (18 com ICV e 7 com ALX; 14 homens e 11 mulheres; média de idade atual de 18 anos). A média de idade ao início dos sintomas foi de 5,7 anos e a média de idade ao diagnóstico foi de 11,5 anos. Treze pacientes (52%) apresentaram pneumonia como primeira manifestação da imunodeficiência. A pneumonia foi a infecção mais frequente nesses pacientes antes do diagnóstico – 22 pacientes (88%) tiveram pelo menos um episódio de pneumonia antes do diagnóstico e, desses, 59% tiveram mais do que 5 episódios – antes do diagnóstico houve uma média de 6,2 episódios de pneumonia por paciente. Após início do tratamento com IGIV, 10 pacientes (40%) tiveram algum episódio de pneumonia, com uma média de 1,5 episódio por paciente. Nove pacientes (36%) apresentavam algum tipo de sequela pulmonar antes do diagnóstico da imunodeficiência. Conclusão: O tratamento com IGIV é eficaz na redução dos episódios de pneumonia nesses pacientes. O diagnóstico e tratamento precoces são de extrema importância.

Common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA) are primary immune disorders characterized by antibody deficiency and increased susceptibility to infections, especially pneumonia. Replacement therapy with intravenous immunoglobulin (IVIG) is the standard treatment. Objective: To assess the frequency of pneumonia in 25 patients with CVID or XLA and the effectiveness of intravenous immunoglobulin replacement therapy in these patients. Methods: a descriptive study, based on a retrospective analysis of medical records from 25 patients with diagnosis of CVID or XLA treated with IVIG. Results: A total of 25 patients were studied (18 with CVID and 7 with XLA; 14 male and 11 female; mean current age, 18 years). The mean age of onset of symptoms was 5.7 years and the mean age of diagnosis was 11.5 years. Pneumonia was the most common primary clinical presentation (13 patients – 52%). Twenty-two (88%) of the 25 patients had pneumonia at least once before diagnosis and 13 out of 22 of these patients had more than 5 episodes. Pre-diagnosis patients had an average of 6.2 episodes of pneumonia. After treatment with IVIG, ten patients (40%) had pneumonia – with an average of 1.5 episode of pneumonia per patient. Conclusion: IVIG treatment provides a remarkable reduction in pneumonia in these patients. Early diagnosis and treatment is mandatory for a positive prognosis.

Adenite pós vacina BCG em dois pacientes com deficiência parcial de receptor 1 do INFgama / Post BCG vaccination adenitis in two patients with partial INF gamma receptor 1 deficiency

Objetivo: Apresentar caso clínico de dois irmãos com reação a BCG e discutir possibilidades diagnósticas. Descrição: Dois irmãos com quadro de adenite após vacina BCG que necessitaram tratamento específico e evoluíram com drenagem espontânea do abscesso. Exames laboratoriais preliminares mostraram hemograma, Imunoglobulinas séricas, NBT e CD3, CD4 e CD8 sem alterações. Exames específicos do eixo IL12-23/INFγ foram realizados mostrando, in vitro, níveis baixos de IL12p40 produzida após estímulo com INFγ e níveis baixos de IL10 produzida após estímulo com INFα. Comentários: Trata-se de dois irmãos com Defeito Parcial INFGR1 suspeitado a partir da história clínica e agente infeccioso em questão. Após a suspeita clínica, exames específicos para se avaliar o eixo IL12-23/INFγ como dosagens de IL12 e INFγ após estímulos específicos, foram realizados, que poderão nos orientar dentro do grupo de doenças relacionados à Susceptibilidade Mendeliana a Infecções por Micobactéria (SMIM), onde estes defeitos estão classificados. Ainda assim, a suspeita clínica e laboratorial importante deve ser confirmada a nível genético para melhor orientação do paciente e sua família. A importância do diagnóstico correto proporciona melhor atendimento médico com orientação e aconselhamento genético para a família, já que estamos diante de doença de herança mendeliana.