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High-grade neuroendocrine cervical cancers (NETc) are exceedingly rare, highly aggressive tumors. We analyzed 64 NETc tumor samples by whole-exome sequencing (WES). Human papillomavirus DNA was detected in 65.6% (42/64) of the tumors. Recurrent mutations were identified in PIK3CA, KMT2D/MLL2, K-RAS, ARID1A, NOTCH2, and RPL10. The top mutated genes included RB1, ARID1A, PTEN, KMT2D/MLL2, and WDFY3, a gene not yet implicated in NETc. Somatic CNV analysis identified two copy number gains (3q27.1 and 19q13.12) and five copy number losses (1p36.21/5q31.3/6p22.2/9q21.11/11p15.5). Also, gene fusions affecting the ACLY-CRHR1 and PVT1-MYC genes were identified in one of the eight samples subjected to RNA sequencing. To resolve evolutionary history, multiregion WES in NETc admixed with adenocarcinoma cells was performed (i.e., mixed-NETc). Phylogenetic analysis of mixed-NETc demonstrated that adenocarcinoma and neuroendocrine elements derive from a common precursor with mutations typical of adenocarcinomas. Over one-third (22/64) of NETc demonstrated a mutator phenotype of C > T at CpG consistent with deficiencies in MBD4, a member of the base excision repair (BER) pathway. Mutations in the PI3K/AMPK pathways were identified in 49/64 samples. We used two patient-derived-xenografts (PDX) (i.e., NET19 and NET21) to evaluate the activity of pan-HER (afatinib), PIK3CA (copanlisib), and ATR (elimusertib) inhibitors, alone and in combination. PDXs harboring alterations in the ERBB2/PI3K/AKT/mTOR/ATR pathway were sensitive to afatinib, copanlisib, and elimusertib (P < 0.001 vs. controls). However, combinations of copanlisib/afatinib and copanlisib/elimusertib were significantly more effective in controlling NETc tumor growth. These findings define the genetic landscape of NETc and suggest that a large subset of these highly lethal malignancies might benefit from existing targeted therapies.
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Adenocarcinoma , Carcinoma Neuroendócrino , Tumores Neuroendócrinos , Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Afatinib , Filogenia , Fosfatidilinositol 3-Quinases/genética , Mutação , Classe I de Fosfatidilinositol 3-Quinases/genética , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Análise Mutacional de DNARESUMO
OBJECTIVES: Uterine carcinosarcomas (UCS) are rare, biologically aggressive tumors. Since UCS may harbor mutations in RAS/MAPK pathway genes we evaluated the preclinical in vitro and in vivo efficacy of the RAF/MEK clamp avutometinib in combination with the focal adhesion kinase (FAK) inhibitors defactinib or VS-4718 against multiple primary UCS cell lines and xenografts. METHODS: Whole-exome-sequencing (WES) was used to evaluate the genetic landscape of 5 primary UCS cell lines. The in vitro activity of avutometinib ± FAK inhibitor was evaluated using cell viability and cell cycle assays against primary UCS cell lines. Mechanistic studies were performed using western blot assays while in vivo experiments were completed in UCS tumor bearing mice treated with avutometinib ± FAK inhibitor by oral gavage. RESULTS: WES results demonstrated multiple UCS cell lines harbor genetic alterations including KRAS, PTK2, BRAF, MAP2K, and MAP2K1, potentially sensitizing to FAK and RAF/MEK inhibition. Four out of five of the UCS cell lines demonstrated in vitro sensitivity to FAK and/or RAF/MEK inhibition when used alone or in combination. By western blot assays, exposure of UCS cell lines to the combination of defactinib/avutometinib demonstrated decreased phosphorylated (p)-FAK as well as decreased p-ERK. In vivo, the combination of avutometinib/VS-4718 demonstrated superior tumor growth inhibition and longer survival compared to single agent treatment and controls starting at day 10 (p < 0.002) in UCS xenografts. CONCLUSION: The combination of avutometinib and defactinib demonstrates promising in vitro and in vivo anti-tumor activity against primary UCS cell lines and xenografts.
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Carcinossarcoma , Neoplasias Uterinas , Ensaios Antitumorais Modelo de Xenoenxerto , Feminino , Humanos , Animais , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/patologia , Neoplasias Uterinas/genética , Neoplasias Uterinas/metabolismo , Linhagem Celular Tumoral , Camundongos , Carcinossarcoma/tratamento farmacológico , Carcinossarcoma/patologia , Carcinossarcoma/genética , Carcinossarcoma/metabolismo , Quinase 1 de Adesão Focal/antagonistas & inibidores , Quinase 1 de Adesão Focal/metabolismo , Quinase 1 de Adesão Focal/genética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Indóis/farmacologia , Quinases raf/antagonistas & inibidores , Quinases raf/metabolismo , Quinases raf/genética , Sequenciamento do Exoma , Camundongos Nus , Benzamidas , Pirazinas , SulfonamidasRESUMO
OBJECTIVES: Low-grade-serous-ovarian-carcinoma (LGSOC) is characterized by a high recurrence rate and limited therapeutic options. About one-third of LGSOC contains mutations in MAPK pathway genes such as KRAS/NRAS/BRAF. Avutometinib is a dual RAF/MEK inhibitor while defactinib and VS-4718 are focal-adhesion-kinase-inhibitors (FAKi). We determined the preclinical efficacy of avutometinib±VS-4718 in LGSOC patient-derived-tumor-xenografts (PDX). METHODS: Whole-exome-sequencing (WES) was used to evaluate the genetic fingerprint of 3 patient-derived LGSOC (OVA(K)250, PERIT(M)17 and A(PE)148). OVA(K)250 tissue was successfully xenografted as PDX into female CB17/lcrHsd-Prkdc/SCID-mice. Animals were treated with either control, avutometinib, VS-4718, or avutometinib/ VS-4718 once daily five days on and two days off through oral gavage. Mechanistic studies were performed ex vivo using avutometinib±defactinib treated LGSOC tumor samples by western blot. RESULTS: WES results demonstrated wild-type KRAS in all 3 LGSOC. OVA(K)250 PDX showed gain-of-function mutations (GOF) in PTK2 and PTK2B genes, and loss-of-heterozygosity in ADRB2, potentially sensitizing to FAK and RAF/MEK inhibition. The combination of avutometinib/ VS-4718 demonstrated strong tumor-growth inhibition compared to controls starting at day 9 (p < 0.002) in OVA(K)250PDX. By 60 days, mice treated with avutometinib alone and avutometinib/VS-4718 were still alive; compared to median survival of 20 days in control-treated mice and of 35 days in VS-4718-treated mice (p < 0.0001). By western-blot assays exposure of OVA(K)250 to avutometinib, FAKi defactinib and their combination demonstrated decreased phosphorylated FAK (p-FAK) as well as decreased p-ERK. CONCLUSION: Avutometinib, and to a larger extent its combination with FAK inhibitor VS-4718, demonstrated promising in vivo activity against a KRAS wild-type LGSOC-PDX. These data support the ongoing registration-directed study (RAMP201/NCT04625270).
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Quinase 1 de Adesão Focal , Neoplasias Ovarianas , Ensaios Antitumorais Modelo de Xenoenxerto , Feminino , Humanos , Animais , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Camundongos , Quinase 1 de Adesão Focal/antagonistas & inibidores , Quinase 1 de Adesão Focal/genética , Quinase 1 de Adesão Focal/metabolismo , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/genética , Inibidores de Proteínas Quinases/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Sequenciamento do Exoma , Benzamidas , Difenilamina/análogos & derivados , Pirazinas , SulfonamidasRESUMO
INTRODUCTION: Epithelial ovarian cancer (EOC) is associated with the highest gynecologic cancer mortality. The development of novel, effective combinations of targeted therapeutics remains an unmet medical need. We evaluated the preclinical activity of datopotamab deruxtecan (Dato-Dxd), a novel TROP2 targeting antibody drug conjugate (ADC) in ovarian cancer cell lines and xenografts with variable TROP2 expression. METHODS: In vitro cell viability with Dato-DXd was assessed using flow-cytometry based assays against a panel of EOC primary cell lines with variable TROP2 expression. Fluorescent anti-phospho-histone H2A.X antibody was used to detect dsDNA breaks by flow-cytometry. The in vivo antitumor activity of Dato-DXd was tested in TROP2 overexpressing xenografts. RESULTS: TROP2 overexpressing (3+) and moderate (2+) expressing EOC cell lines demonstrated higher sensitivity to Dato-DXd when compared to TROP2 negative tumors. Dato-DXd exposed TROP2+ EOC demonstrated increased dsDNA breaks and Annexin-V positivity (a marker of apoptosis) when compared to tumor cells exposed to the non-binding conjugate (p = 0.001 and p = 0.016, respectively). Dato-DXd induced significant antibody-dependent cellular cytotoxicity (ADCC) in the presence of peripheral-blood-lymphocytes. While negligible activity was detected against EOC cell lines with low TROP2 expression, Dato-DXd demonstrated significant bystander killing against tumor cells with low/negligible TROP2 when such cells were admixed with TROP2 3+ tumor cells in vitro. Dato-DXd showed tumor growth suppression against EOC cell line derived xenograft models that overexpress TROP2 at 3+ levels, prolonging survival when compared to controls, with minimal toxicity. CONCLUSION: Dato-DXd shows promising preclinical activity against TROP2 overexpressing ovarian cancers. Future clinical trials in ovarian cancer patients are warranted.
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Antibody-drug conjugates (ADCs) are a new class of targeted anti-cancer therapies that combine a monoclonal tumor-surface-receptor-targeting antibody with a highly cytotoxic molecule payload bonded through specifically designed cleavable or non-cleavable chemical linkers. One such tumor surface receptor is human epidermal growth factor 2 (HER2), which is of interest for the treatment of many gynecologic tumors. ADCs enable the targeted delivery of a variety of cytotoxic therapies to tumor cells while minimizing delivery to healthy tissues. This review summarizes the existing literature about HER2-targeting ADC therapies approved for use in gynecologic malignancies, relevant preclinical studies, strategies to address ADC resistance, and ongoing clinical trials.
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Antineoplásicos , Neoplasias dos Genitais Femininos , Imunoconjugados , Feminino , Humanos , Imunoconjugados/uso terapêutico , Imunoconjugados/química , Neoplasias dos Genitais Femininos/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Anticorpos Monoclonais/química , Fator de Crescimento Epidérmico , Receptor ErbB-2/metabolismoRESUMO
OBJECTIVE: To assess survival among patients diagnosed with uterine carcinosarcoma (CS) who underwent sentinel lymph node (SLN) biopsy alone vs. systematic lymph node dissection (LND). METHODS: We identified newly diagnosed CS patients who underwent primary surgical management from January 1996-December 2019. The SLN cohort underwent SLN biopsy alone with bilateral SLNs identified. The systematic LND cohort did not undergo SLN biopsy. RESULTS: Ninety-nine patients underwent SLN biopsy, and 100 patients underwent systematic LND. There was no difference by age, stage, body mass index, myoinvasion (<50%, ≥50%), lymphovascular space invasion, or positive washings. Eighty-five SLN (85.9%) and 15 LND (15%) underwent minimally invasive surgery (P < 0.001). The median total node count was four (range, 1-13) for SLN and 19 (range, 2-50) for LND (P < 0.001). Nodal metastasis occurred in 23 (23.2%) SLN and in 22 (22%) LND (P = 0.4). Postoperative therapy was administered to 85 (85.9%) SLN and 71 (71%) LND (P = 0.02). Median follow-up was 33 months (range, 1-205) for SLN and 55.3 months (range, 1-269) for LND (P = 0.001). The three-year progression-free survival (PFS) was 62.9% (SE 5.2%) for SLN and 52.3% (SE 5.3%) for LND (P = 0.13). The three-year overall survival (OS) was 72.1% (SE 5.1%) for SLN and 71.6% (SE 4.6%) for LND (P = 0.68). An isolated nodal recurrence occurred in two (2%) SLN and four (4%) LND (P = 0.26). CONCLUSIONS: There is no difference in PFS or OS among CS patients who undergo SLN biopsy vs. systematic LND. SLN biopsy detects nodal metastasis without compromising oncologic outcomes.
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Carcinossarcoma , Biópsia de Linfonodo Sentinela , Carcinossarcoma/cirurgia , Humanos , Excisão de Linfonodo , Oncologia , Intervalo Livre de Progressão , Fator de Crescimento Transformador betaRESUMO
Despite the growing importance of carbapenem-resistant Klebsiella pneumoniae (CRKP), the clonal relationships between CRKP and antibiotic-susceptible isolates remain unclear. We compared the genetic diversity and clinical features of CRKP, third-generation and/or fourth-generation cephalosporin-resistant (Ceph-R) K. pneumoniae, and susceptible K. pneumoniae isolates causing bloodstream infections at a tertiary care hospital in New York City between January 2012 and July 2013. Drug susceptibilities were determined with the Vitek 2 system. Isolates underwent multilocus sequence typing and PCR sequencing of the wzi and blaKPC genes. Clinical and microbiological data were extracted from patient records and correlated with molecular data. Among 223 patients, we identified 272 isolates. Of these, 194 were susceptible, 30 Ceph-R, and 48 CRKP, belonging to 144 sequence types (STs). Susceptible (127 STs) and Ceph-R (20 STs) isolates were highly diverse. ST258 dominated CRKP strains (12 STs, with 63% ST258). There was minimal overlap in STs between resistance groups. The blaKPC-3 gene (30%) was restricted to ST258/wzi154, whereas blaKPC-2 (70%) was observed for several wzi allele types. CRKP infections occurred more frequently among solid organ transplant (31%) and dialysis (17%) patients. Mortality rates were high overall (28%) and highest among CRKP-infected patients (59%). In multivariable analyses, advanced age, comorbidities, and disease severity were significant predictors of 30-day mortality rates, whereas the K. pneumoniae susceptibility phenotype was not. Among CRKP infections, we observed a borderline significant association of increased mortality rates with ST258 and the wzi154 allele. Although the clonal spread of ST258 continues to contribute substantially to the dissemination of CRKP, non-ST258 strains appear to be evolving. Further investigations into the mechanisms promoting CRKP diversification and the effects of clonal backgrounds on outcomes are warranted.
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Farmacorresistência Bacteriana Múltipla , Variação Genética , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/classificação , Klebsiella pneumoniae/efeitos dos fármacos , Sepse/microbiologia , Feminino , Genes Bacterianos , Genótipo , Humanos , Infecções por Klebsiella/epidemiologia , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/isolamento & purificação , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Tipagem de Sequências Multilocus , Cidade de Nova Iorque/epidemiologia , Reação em Cadeia da Polimerase , Estudos Retrospectivos , Sepse/epidemiologia , Análise de Sequência de DNA , Centros de Atenção TerciáriaRESUMO
Background: Treatment of recurrent platinum-resistant high grade serous ovarian cancer (HGSOC) remains a challenge. Novel treatment options for recurrent disease are an unmet need. Case: A 69-year-old with recurrent, metastatic, platinum-resistant HGSOC overexpressing TROP2 experienced a significant response to the antibody-drug conjugate (ADC) sacituzumab govitecan after multiple failed lines of chemotherapy and targeted treatment. Following sacituzumab govitecan treatment she experienced a confirmed partial response as well as a return of CA-125 to baseline. Having now completed 8 cycles (ie, over 6 months of treatment), her disease continues to demonstrate a response to sacituzumab govitecan treatment. The ADC has been well tolerated at a dose of 10 mg/kg with no dose-limiting toxicity or need for dose reductions. Conclusion: Sacituzumab govitecan may represent a treatment option for platinum-resistant/recurrent HGSOC that have previously failed prior lines of chemotherapy. Clinical trials with sacituzumab govitecan in platinum-resistant ovarian cancer patients are currently ongoing (https://classic.clinicaltrials.gov/ct2/show/NCT06028932).
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BACKGROUND: High-grade endometrial cancers (EAC) are aggressive tumors with a high risk of progression after treatment. As EAC may harbor mutations in the RAS/MAPK pathways, we evaluated the preclinical in vitro and in vivo efficacy of avutometinib, a RAF/MEK clamp, in combination with the focal adhesion kinase (FAK) inhibitors defactinib or VS-4718, against multiple primary EAC cell lines and xenografts. METHODS: Whole-exome sequencing (WES) was used to evaluate the genetic landscape of five primary EAC cell lines. The in vitro activity of avutometinib and defactinib as single agents and in combination was evaluated using cell viability, cell cycle, and cytotoxicity assays. Mechanistic studies were performed using Western blot assays while in vivo experiments were completed in UTE10 engrafted mice treated with either vehicle, avutometinib, VS-4718, or their combination through oral gavage. RESULTS: WES results demonstrated multiple EAC cell lines to harbor genetic derangements in the RAS/MAPK pathway including KRAS/PTEN/PIK3CA/BRAF/ARID1A, potentially sensitizing to FAK and RAF/MEK inhibition. Five out of five of the EAC cell lines demonstrated in vitro sensitivity to FAK and/or RAF/MEK inhibition. By Western blot assays, exposure of EAC cell lines to defactinib, avutometinib, and their combination demonstrated decreased phosphorylated FAK (p-FAK) as well as decreased p-MEK and p-ERK. In vivo the combination of avutometinib/VS-4718 demonstrated superior tumor growth inhibition compared to single-agent treatment and controls starting at Day 9 (p < 0.02 and p < 0.04) in UTE10 xenografts. CONCLUSIONS: Avutometinib, defactinib, and to a larger extent their combinations, demonstrated promising in vitro and in vivo activity against EAC cell lines and xenografts. These preclinical data support the potential clinical evaluation of this combination in high-grade EAC patients.
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Neoplasias do Endométrio , Ensaios Antitumorais Modelo de Xenoenxerto , Feminino , Humanos , Animais , Camundongos , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/genética , Linhagem Celular Tumoral , Carcinoma Endometrioide/tratamento farmacológico , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/metabolismo , Sequenciamento do Exoma , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Gradação de Tumores , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinase 1 de Adesão Focal/metabolismo , Quinase 1 de Adesão Focal/antagonistas & inibidores , Oxazepinas , Sulfonamidas , Pirazinas , Benzamidas , ImidazóisRESUMO
High-grade serous ovarian cancer (HGSOC) and ovarian clear cell carcinoma (CC), are biologically aggressive tumors endowed with the ability to rapidly metastasize to the abdominal cavity and distant organs. About 10% of HGSOC and 30% of CC demonstrate HER2 IHC 3 + receptor over-expression. We evaluated the efficacy of trastuzumab deruxtecan (T-DXd; DS-8201a), a novel HER2-targeting antibody-drug conjugate (ADC) to an ADC isotype control (CTL ADC) against multiple HGSOC and CC tumor models. Eleven ovarian cancer cell lines including a matched primary and metastatic cell line established from the same patient, were evaluated for HER2 expression by immunohistochemistry and flow cytometry, and gene amplification by fluorescence in situ hybridization assays. In vitro experiments demonstrated T-DXd to be significantly more effective against HER2 3 + HGSOC and CC cell lines when compared to CTL ADC (p < 0.0001). T-DXd induced efficient bystander killing of HER2 non-expressing tumor cells when admixed with HER2 3 + cells. In vivo activity of T-DXd was studied in HER2 IHC 3 + HGSOC and CC mouse xenograft models. We found T-DXd to be significantly more effective than CTL ADC against HER2 3 + HGSOC (KR(CH)31) and CC (OVA10) xenografts with a significant difference in tumor growth starting at day 8 (p = 0.0003 for KR(CH)31, p < 0.0001 for OVA10). T-DXd also conferred a survival advantage in both xenograft models. T-DXd may represent an effective ADC against primary and metastatic HER2-overexpressing HGSOC and CC.
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PURPOSE: We report the results of a randomized phase II trial of imiquimod, a topical immune-response modulator versus imiquimod plus a 9-valent human papillomavirus (HPV) vaccine (9vHPV) versus clinical surveillance in cervical intraepithelial neoplasia (CIN2/3) patients. PATIENTS AND METHODS: We randomly allocated 133 patients with untreated CIN2/3 in equal proportions to a 4-month treatment with self-applied vaginal suppositories containing imiquimod (Arm B) or imiquimod plus a 9vHPV (Arm C) versus clinical surveillance (Arm A). The main outcome was efficacy, defined as histologic regression to CIN1 or less. Secondary outcomes were HPV clearance and tolerability. Exploratory objectives included the comparison of cervical CD4/CD8 T-cell infiltration at baseline, mid-study, and posttreatment by flow cytometry among study arms. RESULTS: Of the 114 evaluable patients 77% and 23% harbored CIN2 and CIN3, respectively. Regression to CIN1 or less was observed in 95% of patients in the imiquimod group (Arm B) compared with 79% in the control/surveillance (Arm A); P = 0.043 and 84% in the imiquimod+9vHPV group (Arm C; P = 0.384 vs. Arm A). Neither of the treatment-arm differences from Arm A reached the prespecified α = 0.025 significance level. No significant differences were noted in the secondary outcome of rate of HPV clearance. The number of tissue-resident memory CD4/CD8 T cells in cytobrush samples demonstrated a >5-fold increase in Arm B/imiquimod when compared with Arm A/surveillance (P < 0.01). In contrast, there was no significant difference in T-cell responses among participants in Arm C when compared with Arm A. Imiquimod treatment was well tolerated. CONCLUSIONS: Although imiquimod induced a higher regression to CIN1 or less and significant increases in CD4/CD8 T cells infiltrating the cervix, it did not meet its prespecified statistical outcome for efficacy. A higher regression rate than expected was observed in the surveillance arm of this prospective trial. Future clinical trials with imiquimod targeting CIN3 patients are warranted.
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Imiquimode , Infecções por Papillomavirus , Vacinas contra Papillomavirus , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Humanos , Imiquimode/administração & dosagem , Feminino , Vacinas contra Papillomavirus/administração & dosagem , Adulto , Displasia do Colo do Útero/imunologia , Displasia do Colo do Útero/tratamento farmacológico , Displasia do Colo do Útero/patologia , Displasia do Colo do Útero/virologia , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Pessoa de Meia-Idade , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Aminoquinolinas/administração & dosagem , Aminoquinolinas/efeitos adversos , Aminoquinolinas/uso terapêutico , Resultado do Tratamento , Linfócitos T CD8-Positivos/imunologia , Lesões Pré-Cancerosas/tratamento farmacológico , Lesões Pré-Cancerosas/patologia , Lesões Pré-Cancerosas/imunologia , Gradação de Tumores , Adulto JovemRESUMO
Uterine serous carcinoma (USC) and uterine carcinosarcoma (UCS) are two rare histologic variants of uterine carcinoma, with distinct molecular profiles and aggressive metastatic potential. As the effectivity of traditional platinum-based chemotherapy for USC and UCS is low, and there are high rates of resistance and recurrence, the development of novel targeted therapeutics is needed. Human epidermal growth factor receptor 2 (HER2) has proven to be an oncogene of increasing interest in these cancers, as HER2 protein overexpression and/or c-ERBB2 gene amplification ranges from ~30 to 35% in USC, and between ~15 and 20% in UCS. This review summarizes the existing clinical and preclinical evidence, as well as ongoing clinical trials of HER2-targeting therapeutics, and identifies potential areas of further development and inquiry.
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BACKGROUND: Given the unpredictable nature of preterm birth and the short-term impact of antenatal corticosteroids on neonatal outcomes, optimal timing of antenatal corticosteroid administration (2-7 days from expected birth) remains challenging. OBJECTIVE: We set out to evaluate the likelihood of delivery between 2 and 7 days after antenatal corticosteroid administration in the late preterm period and whether this differs based on the indication for corticosteroid administration. STUDY DESIGN: Retrospective cohort of all singletons that received antenatal corticosteroids in the late preterm period (34 0/7 to 36 6/7 weeks' gestation) and delivered within a large health system between November 2017 and March 2020. Women who received antenatal corticosteroids before the late preterm period, major fetal structural malformations, and cases with missing data were excluded. Cases were stratified on the basis of the indication for antenatal corticosteroid administration, that is, anticipated spontaneous late preterm birth or medically indicated late preterm birth. The primary outcome was delivery between 2 and 7 days after the administration of the first dose of antenatal corticosteroids. Secondary outcomes included time interval from antenatal corticosteroid administration to delivery and delivery during the first 2 days or later than 7 days after antenatal corticosteroid administration. Multivariable logistic regression was performed to evaluate factors associated with optimal timing while adjusting for potential confounders. RESULTS: Of the 1238 patients included in the study, 656 (53%) delivered within the first day after antenatal corticosteroid administration and thus received only the first of 2 doses. Regardless of the indication for late preterm antenatal corticosteroid administration, the likelihood of delivery between 2 and 7 days later was 13.3% (165 of 1238). Moreover, it was more common (23.4% vs 5.0%; P≤.001) (Table 2) and more likely (adjusted odds ratio, 5.88; 95% confidence interval, 4.00-9.09) in women at risk of medically indicated preterm birth than in those with anticipated spontaneous preterm birth. Furthermore, women with anticipated spontaneous preterm birth had a shorter time interval from antenatal corticosteroid administration to delivery (10.7 vs 49.71 hour; P≤.001). CONCLUSION: Regardless of the indication for late preterm antenatal corticosteroid administration, the likelihood of delivery between 2 and 7 days later was low. Nevertheless, our data suggested that delivery within the desired time interval of antenatal corticosteroid administration is more common in women at risk of medically indicated late preterm birth compared with those at risk of spontaneous late preterm birth.
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BACKGROUND: Although administration of antenatal corticosteroids has been shown to decrease neonatal respiratory morbidity when given to women at risk for late preterm birth, the time interval from antenatal corticosteroid administration to delivery that is associated with the greatest neonatal benefit remains unknown. OBJECTIVE: This study aimed to evaluate whether the time interval from administration of late preterm antenatal corticosteroids to delivery is associated with a change in the likelihood of transient tachypnea of the newborn, respiratory distress syndrome, and hypoglycemia. STUDY DESIGN: This was a retrospective cohort study of all singleton neonates who were exposed to 1 or 2 doses of antenatal corticosteroids in the late preterm period (34+0 to 36+6 weeks' gestation) within a large healthcare system between November 2017 and March 2020. Neonates exposed to antenatal corticosteroids before 34 weeks' gestation and those with major fetal structural malformations and chromosomal disorders were excluded. Cases were stratified into the following groups based on the time interval from the first dose of antenatal corticosteroid administration to delivery: <2 days, 2 to 7 days, and >7 days. The primary outcome of transient tachypnea of the newborn was compared among the 3 groups. Secondary outcomes included respiratory distress syndrome and hypoglycemia. A multivariable logistic regression was performed to evaluate the association between the time interval and neonatal outcomes while adjusting for potential confounders. For each outcome, delivery within 2 to 7 days from the first dose of betamethasone administration was defined as the reference group. Data were presented as adjusted odds ratios with 95% confidence intervals, and statistical significance was defined as P < .05. RESULTS: The study cohort comprised 1248 neonates. Of those, 649 (52%) were exposed to 1 dose of antenatal corticosteroids. There were statistically significant differences in the maternal characteristics such as nulliparity, pregnancies complicated by hypertensive disorders and fetal growth restriction, gestational age at antenatal corticosteroid administration, gestational age at delivery, and mode of delivery among the 3 groups. There was a significantly increased risk for transient tachypnea of the newborn (adjusted odds ratio, 4.81; 95% confidence interval, 1.72-12.92) and respiratory distress syndrome (adjusted odds ratio, 9.86; 95% confidence interval, 1.15-84.24) associated with delivery <2 days of antenatal corticosteroid administration. The risk for hypoglycemia was highest in the delivery <2 days group (adjusted odds ratio, 3.44; 95% confidence interval, 2.10-5.63) and decreased as the time interval from antenatal corticosteroid administration to delivery increased (adjusted odds ratio, 0.32; 95% confidence interval, 0.20-0.51 for delivery >7 days). CONCLUSION: Adverse neonatal outcomes such as transient tachypnea of the newborn, respiratory distress syndrome, and hypoglycemia are more common when late preterm birth occurs <2 days after antenatal corticosteroid administration when compared with birth 2 to 7 days after administration. In addition, delivery >7 days after antenatal corticosteroid administration is associated with a decreased risk for hypoglycemia. Understanding the impact of antenatal corticosteroid timing on neonatal outcomes is essential in caring for patients at risk for late preterm birth.
Assuntos
Nascimento Prematuro , Síndrome do Desconforto Respiratório do Recém-Nascido , Corticosteroides/efeitos adversos , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Gravidez , Nascimento Prematuro/epidemiologia , Síndrome do Desconforto Respiratório do Recém-Nascido/tratamento farmacológico , Estudos RetrospectivosRESUMO
BACKGROUND: Measles and congenital rubella syndrome remain significant causes of morbidity and mortality despite available vaccines. HIV-infected youth may be at increased risk of measles because of greater waning immunity after vaccination. At a population level, they constitute a potentially large pool of susceptibles to measles and rubella. More data among HIV-infected youth in sub-Saharan Africa are needed to guide vaccination policy and control strategies. METHODS: This cross-sectional study was nested within 2 ongoing studies of malaria and HIV in Zambia. Dried blood spot cards from youth (5-15 years) in these studies from 2009 to 2013 were tested for IgG antibodies to measles and rubella viruses. HIV-uninfected youth, HIV-infected treatment-naive youth and HIV-infected youth receiving antiretroviral therapy (ART) were compared. RESULTS: A total of 617 HIV-uninfected, 144 HIV-infected treatment-naive and 128 HIV-infected youth receiving ART were included in this study. The proportion seropositive for measles virus was significantly higher among HIV-uninfected youth (92.5%) compared with HIV-infected treatment-naive youth (74.1%) and HIV-infected youth receiving ART (71.9%). No differences by age were observed. The proportion seropositive for rubella virus was significantly higher among HIV-uninfected youth (54.7%) compared with HIV-infected treatment-naive youth (41.7%) and HIV-infected youth receiving ART (49.6%), with increases observed by age for all groups. CONCLUSIONS: Measles seroprevalence was lower among HIV-infected than uninfected youth, consistent with waning immunity after measles vaccination. HIV-infected youth would benefit from revaccination. Half of all youth in rural Zambia were susceptible to rubella and may need targeting for catch-up rubella campaigns when measles-rubella vaccine is introduced.