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OBJECTIVES: The primary objective was to evaluate the impact of a multimodal perioperative pain regimen on length of hospital stay for patients undergoing laparotomy with a gynecologic oncologist. METHODS: We compared 52 patients who underwent laparotomy with a gynecologic oncologist at a single institution between 2017 and 2018, after implementation of a multimodal perioperative pain regimen, to a historic cohort of 94 patients (2016-2017). The multimodal pain regimen included pre- and post-operative administration of oral acetaminophen, gabapentin, and celecoxib, in addition to standard narcotics and optional epidural analgesia. Demographic, surgical, and post-operative data were collected. RESULTS: On multivariable analysis, bowel resection, stage, surgery length, age, and cohort group were retained as significant independent predictors of length of stay. Patients undergoing laparotomy prior to the pain protocol had a length of stay 1.26 times longer than patients during the post-implementation period (p < 0.01). For complex surgical patients, this translated into a reduction in length of hospital stay of 1.73 days. There was a significant reduction in pain scale score on post-operative day zero from 5 to 3 (p = 0.02) and a non-significant overall reduction of post-operative morphine equivalents, with similar adverse outcomes. CONCLUSION: Implementation of a multimodal perioperative pain regimen in patients undergoing gynecologic oncology laparotomy was associated with a significant reduction of length of hospital stay and improved patient-perceived pain, even in the absence of a complete Enhanced Recovery After Surgery (ERAS) protocol.
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Laparotomia , Dor Pós-Operatória , Analgésicos Opioides , Feminino , Procedimentos Cirúrgicos em Ginecologia , Hospitais , Humanos , Tempo de Internação , Dor Pós-Operatória/tratamento farmacológico , Estudos RetrospectivosRESUMO
OBJECTIVE: In previous studies, neoadjuvant chemotherapy followed by interval debulking surgery was not inferior to primary cytoreductive surgery as initial treatment for advanced epithelial ovarian cancer. Our study aimed to compare surgical and survival outcomes between the two treatments in a large national database. METHODS: Data were extracted from the National Cancer Database from January 2004 to December 2015. Patients with FIGO (International Federation of Gynecologists and Obstetricians) stage III-IV epithelial ovarian cancer and known sequence of treatment were included: primary cytoreductive (surgery=26 717 and neoadjuvant chemotherapy=9885). Tubal and primary peritoneal cancer diagnostic codes were not included. Residual disease after treatment was defined based on recorded data: R0 defined as microscopic or no residual disease; R1 defined as macroscopic residual disease. Multivariate Cox proportional HR was used for survival analysis. Multivariate logistic regression analysis was utilized to compare mortality between groups. Outcomes were adjusted for significant covariates. Validation was performed using propensity score matching of significant covariates. RESULTS: A total of 36 602 patients were included in the analysis. Patients who underwent primary cytoreductive surgery had better survival than those treated with neoadjuvant chemotherapy followed by interval surgery, after adjusting for age, co-morbidities, stage, and residual disease (p<0.001). Primary cytoreductive surgery patients with R0 disease had best median survival (62.6 months, 95% CI 60.5-64.5). Neoadjuvant chemotherapy patients with R1 disease had worst median survival (29.5 months, 95% CI 28.4-31.9). There were small survival differences between primary cytoreductive surgery with R1 (38.9 months) and neoadjuvant chemotherapy with R0 (41.8 months) (HR 0.93, 95% CI 0.87 to 1.0), after adjusting for age, co-morbidities, grade, histology, and stage. Neoadjuvant chemotherapy had 3.5 times higher 30-day mortality after surgery than primary cytoreductive surgery (95% CI 2.46 to 5.64). The 90-day mortality was higher for neoadjuvant chemotherapy in multivariate analysis (HR 1.31, 95% CI 1.06 to 1.61) but similar to primary cytoreductive surgery after excluding high-risk patients. CONCLUSIONS: Most patients with advanced epithelial ovarian cancer may benefit from primary cytoreductive surgery. Patients treated with neoadjuvant chemotherapy should be those with co-morbidities unfit for surgery.
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Carcinoma Epitelial do Ovário/cirurgia , Procedimentos Cirúrgicos de Citorredução , Terapia Neoadjuvante , Neoplasias Ovarianas/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/mortalidade , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Estudos Retrospectivos , Análise de Sobrevida , Estados Unidos/epidemiologia , Adulto JovemRESUMO
Minimally invasive surgery has become a standard in the surgical treatment for many women with gynecologic cancers. Within the scope of minimally invasive surgery, several techniques exist. Here, we provide an overview of the challenging and controversial aspects of minimally invasive surgery in the field of gynecologic oncology, including single-site surgery, operating on morbidly obese patients, sentinel lymph node mapping, and recent trials and controversy of treating gynecologic cancer patients with a minimally invasive surgical approach.
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Neoplasias dos Genitais Femininos/cirurgia , Feminino , Procedimentos Cirúrgicos em Ginecologia , Humanos , Laparoscopia , Procedimentos Cirúrgicos Minimamente Invasivos , Procedimentos Cirúrgicos RobóticosRESUMO
Catecholamines and prostaglandins are secreted abundantly during the perioperative period in response to stress and surgery, and were shown by translational studies to promote tumor metastasis. Here, in a phase-II biomarker clinical trial in breast cancer patients (nâ¯=â¯38), we tested the combined perioperative use of the ß-blocker, propranolol, and the COX2-inhibitor, etodolac, scheduled for 11 consecutive perioperative days, starting 5â¯days before surgery. Blood samples were taken before treatment (T1), on the mornings before and after surgery (T2&T3), and after treatment cessation (T4). Drugs were well tolerated. Results based on a-priori hypotheses indicated that already before surgery (T2), serum levels of pro-inflammatory IL-6, CRP, and IFNγ, and anti-inflammatory, cortisol and IL-10, increased. At T2 and/or T3, drug treatment reduced serum levels of the above pro-inflammatory cytokines and of TRAIL, as well as activity of multiple inflammation-related transcription factors (including NFκB, STAT3, ISRE), but not serum levels of cortisol, IL-10, IL-18, IL-8, VEGF and TNFα. In the excised tumor, treatment reduced the expression of the proliferation marker Ki-67, and positively affected its transcription factors SP1 and AhR. Exploratory analyses of transcriptome modulation in PBMCs revealed treatment-induced improvement at T2/T3 in several transcription factors that in primary tumors indicate poor prognosis (CUX1, THRa, EVI1, RORa, PBX1, and T3R), angiogenesis (YY1), EMT (GATA1 and deltaEF1/ZEB1), proliferation (GATA2), and glucocorticoids response (GRE), while increasing the activity of the oncogenes c-MYB and N-MYC. Overall, the drug treatment may benefit breast cancer patients through reducing systemic inflammation and pro-metastatic/pro-growth biomarkers in the excised tumor and PBMCs.
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Antagonistas Adrenérgicos beta/administração & dosagem , Neoplasias da Mama/sangue , Neoplasias da Mama/terapia , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Citocinas/sangue , Etodolac/administração & dosagem , Propranolol/administração & dosagem , Adulto , Idoso , Biomarcadores/sangue , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/metabolismo , Feminino , Humanos , Antígeno Ki-67/efeitos dos fármacos , Antígeno Ki-67/genética , Células Matadoras Naturais/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Pessoa de Meia-Idade , Período Perioperatório/métodos , Receptores Adrenérgicos beta/metabolismo , Transdução de Sinais , Transcriptoma/efeitos dos fármacosRESUMO
OBJECTIVES: Small cell cervical cancer is a rare malignancy with limited treatment options for recurrent disease. We sought to determine if tumor specimens of small cell cervical cancer harbor common somatic mutations and if any of these are actionable. METHODS: Using a registry of patients with neuroendocrine cervical cancer, we identified 44 patients with pure or mixed small cell cervical cancer who had undergone mutational analysis. Mutations had been detected using next generation sequencing of mutational hotspots in 50 cancer-related genes. RESULTS: Thirty-five mutations were identified in 24 patients (55%). Fifteen of these 24 patients (63%) had 1 mutation, 7 patients (29%) had 2 mutations, and 2 patients (8%) had 3 mutations. In all 44 patients, the most commonly seen mutations were mutations in PIK3CA (8 patients; 18%), KRAS (6 patients; 14%), and TP53 (5 patients; 11%). No other mutation was found in >7% of specimens. Of the 24 patients who had a mutation, 21 (88%) had at least 1 alteration for which there currently exists a class of biological agents targeting that mutation. In the entire cohort of 44 patients, 48% had at least 1 actionable mutation. CONCLUSION: Although no single mutation was found in the majority of patients with small cell cervical cancer, almost half had at least 1 actionable mutation. As treatment options for patients with recurrent small cell cervical cancer are currently very limited, molecular testing for targetable mutations, which may suggest potential therapeutic strategies, may be useful for clinicians and patients.
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Carcinoma Neuroendócrino/genética , Carcinoma de Células Pequenas/genética , Mutação , Neoplasias do Colo do Útero/genética , Adulto , Classe I de Fosfatidilinositol 3-Quinases , Análise Mutacional de DNA , Feminino , Genes p53 , Humanos , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Estudos Retrospectivos , Proteína Supressora de Tumor p53/genética , Adulto JovemRESUMO
â¢Rectovaginal septum mass in BRCA1 positive patient after risk reducing BSO years prior.â¢Papillary serous carcinoma presenting as a rectovaginal septum mass.â¢PAOLA-1 trial discussion for rectovaginal septum mass in BRCA1 positive patient.
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Angiosarcoma is an aggressive malignancy of endothelial cells that carries a high mortality rate. Cytotoxic chemotherapy can elicit clinical responses, but the duration of response is limited. Sequencing reveals multiple mutations in angiogenesis pathways in angiosarcomas, particularly in vascular endothelial growth factor (VEGFR) and mitogen-activated protein kinase (MAPK) signaling. We aimed to determine the biological relevance of these pathways in angiosarcoma. Tissue microarray consisting of clinical formalin-fixed paraffin embedded tissue archival samples were stained for phospho- extracellular signal-regulated kinase (p-ERK) with immunohistochemistry. Angiosarcoma cell lines were treated with the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, pan-VEGFR inhibitor cediranib, or combined trametinib and cediranib and viability was assessed. Reverse phase protein array (RPPA) was performed to assess multiple oncogenic protein pathways. SVR angiosarcoma cells were grown in vivo and gene expression effects of treatment were assessed with whole exome RNA sequencing. MAPK signaling was found active in over half of clinical angiosarcoma samples. Inhibition of MAPK signaling with the MEK inhibitor trametinib decreased the viability of angiosarcoma cells. Combined inhibition of the VEGF and MAPK pathways with cediranib and trametinib had an additive effect in in vitro models, and a combinatorial effect in an in vivo model. Combined treatment led to smaller tumors than treatment with either agent alone. RNA-seq demonstrated distinct expression signatures between the trametinib treated tumors and those treated with both trametinib and cediranib. These results indicate a clinical study of combined VEGFR and MEK inhibition in angiosarcoma is warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hemangiossarcoma/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Hemangiossarcoma/metabolismo , Hemangiossarcoma/patologia , Humanos , Camundongos , Camundongos Nus , Prognóstico , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Quinazolinas/administração & dosagem , Transcriptoma , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The immune system has many important regulatory roles in cancer development and progression. Given the emergence of effective immune therapies against many cancers, reliable predictors of response are needed. One method of determining response is by evaluating immune cell populations from treated and untreated tumor samples. The amount of material obtained from tumor biopsies can be limited; therefore, gene-based or protein-based analyses may be attractive because they require minimal tissue. Cell-specific signatures are being analyzed with use of the latest technologies, including NanoString's nCounter technology, intracellular staining flow cytometry, cytometry by time-of-flight, RNA-Seq, and barcoding antibody-based protein arrays. These signatures provide information about the contributions of specific types of immune cells to bulk tumor samples. To date, both tumor tissue and immune cells have been analyzed for molecular expression profiles that can assess genes and proteins that are specific to immune cells, yielding results of varying specificity. Here, we discuss the importance of profiling tumor tissue and immune cells to identify immune-cell-associated genes and proteins and specific gene profiles of immune cells. We also discuss the use of these signatures in cancer treatment and the challenges faced in molecular expression profiling of immune cell populations.
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Anti-angiogenesis therapy has shown clinical benefit in patients with high-grade serous ovarian cancer (HGSC), but adaptive resistance rapidly emerges. Thus, approaches to overcome such resistance are needed. We developed the setting of adaptive resistance to anti-VEGF therapy, and performed a series of in vivo experiments in both immune competent and nude mouse models. Given the pro-angiogenic properties of tumor-associated macrophages (TAMs) and the dominant role of CSF1R in macrophage function, we added CSF1R inhibitors following emergence of adaptive resistance to anti-VEGF antibody. Mice treated with a CSF1R inhibitor (AC708) after anti-VEGF antibody resistance had little to no measurable tumor burden upon completion of the experiment while those that did not receive a CSF1R inhibitor still had abundant tumor. To mimic clinically used regimens, mice were also treated with anti-VEGF antibody and paclitaxel until resistance emerged, and then a CSF1R inhibitor was added. The addition of a CSF1R inhibitor restored response to anti-angiogenesis therapy, resulting in 83% lower tumor burden compared to treatment with anti-VEGF antibody and paclitaxel alone. Collectively, our data demonstrate that the addition of a CSF1R inhibitor to anti-VEGF therapy and taxane chemotherapy results in robust anti-tumor effects.
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Even though hyperthermia is a promising treatment for cancer, the relationship between specific temperatures and clinical benefits and predictors of sensitivity of cancer to hyperthermia is poorly understood. Ovarian and uterine tumors have diverse hyperthermia sensitivities. Integrative analyses of the specific gene signatures and the differences in response to hyperthermia between hyperthermia-sensitive and -resistant cancer cells identified CTGF as a key regulator of sensitivity. CTGF silencing sensitized resistant cells to hyperthermia. CTGF small interfering RNA (siRNA) treatment also sensitized resistant cancers to localized hyperthermia induced by copper sulfide nanoparticles and near-infrared laser in orthotopic ovarian cancer models. CTGF silencing aggravated energy stress induced by hyperthermia and enhanced apoptosis of hyperthermia-resistant cancers.
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Fator de Crescimento do Tecido Conjuntivo/metabolismo , Hipertermia Induzida , Neoplasias Ovarianas/metabolismo , Neoplasias Uterinas/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Genes Neoplásicos , Humanos , Camundongos , Modelos Biológicos , Neoplasias Ovarianas/genética , Proteômica , Neoplasias Uterinas/genéticaRESUMO
BACKGROUND: The current management strategy for women with low-grade squamous intraepithelial lesions (LSILs) is inefficient and expensive because of the inability to identify patients at high risk for disease progression. The current study was designed to determine the genotypic patterns of human papillomavirus (HPV) associated with the persistence and progression of cervical lesions in women with an initial interpretation of LSIL. METHODS: One hundred sixty-seven women with LSIL on Papanicolaou tests collected between December 1, 2009 and March 30, 2011 were studied. HPV DNA was extracted from residual SurePath specimens, genotypes were determined with a DNA microarray containing 40 HPV genotype probes, and microarray data were confirmed by sequencing. Follow-up Papanicolaou tests and/or biopsies were performed within a 20- to 46-month period after the initial diagnosis. RESULTS: Ninety-seven of the 167 cases with follow-up results were included in the study. Compared with the women with a regressed cervical lesion, those with a persistent cervical lesion (PCL) were significantly more commonly infected with high-risk human papillomavirus (HR-HPV) genotypes (P < .01) and particularly with non-16/18 HR-HPV genotypes (P < .05). The PCL group also had a significantly higher average number of HR-HPV genotypes and non-16/18 HPV genotypes per specimen (P < .01). Infection with HPV-16/18 genotypes was not significantly associated with the persistence or progression of cervical lesions. CONCLUSIONS: Infection with non-16/18 HR-HPV genotypes but not with HPV-16/18 genotypes was a strong predictor of the persistence and progression of cervical disease upon follow-up. Genotyping solely for HPV-16/18 would miss the majority of patients with LSIL who progress to high-grade squamous intraepithelial lesions. Pooled HR-HPV tests provide a better predictive value than HPV-16/18 genotyping alone in guiding the clinical management of patients with LSIL.
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Carcinoma de Células Escamosas/patologia , DNA Viral/genética , Infecções por Papillomavirus/patologia , Displasia do Colo do Útero/patologia , Adulto , Fatores Etários , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/genética , China/epidemiologia , Doença Crônica , Estudos de Coortes , Progressão da Doença , Feminino , Genótipo , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Teste de Papanicolaou , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/genética , Valor Preditivo dos Testes , Prevalência , Estudos Retrospectivos , Medição de Risco , Esfregaço Vaginal , Adulto Jovem , Displasia do Colo do Útero/genética , Displasia do Colo do Útero/fisiopatologiaRESUMO
â¢Molecular testing may play a role in the determination of targeted therapy treatment options.â¢Targeted therapy provides treatment options for recurrent cervical cancer.â¢MEK inhibitor is a treatment option for recurrent cervical cancer in a patient with KRAS mutation.