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1.
Int J Gynecol Cancer ; 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38514101

RESUMO

BACKGROUND: Ovarian cancer with extensive metastatic disease involving pelvic structures often requires rectosigmoid resection for complete gross resection; however, it is associated with increased surgical morbidity. There are limited data, and none in ovarian cancer, on near-infrared assessment of perfusion in rectosigmoid resections with anastomosis. PRIMARY OBJECTIVE: To compare the rate of pelvic complications (pelvic abscesses, anastomotic leaks, and infections) within 30 days of surgery with and without near-infrared assessment of perfusion at time of rectosigmoid resection and re-anastomosis in patients undergoing cytoreductive surgery for ovarian cancer. STUDY HYPOTHESIS: We hypothesize the use of near-infrared technology (intravenous indocyanine green and endoscopic near-infrared fluorescence imaging), compared with standard intra-operative assessment, to evaluate anastomotic perfusion at time of rectosigmoid resection and re-anastomosis will result in lower rates of post-operative pelvic complications. TRIAL DESIGN: This is a planned multicenter randomized controlled trial. Patients who undergo rectosigmoid resection as part of their ovarian cytoreductive surgery will be randomized 1:1 to standard assessment of anastomosis with the surgeon's usual technique (control arm) or assessment with near-infrared angiography using indocyanine green and endoscopic fluorescence imaging (experimental arm). Randomization will occur after rectosigmoid resection has been completed and the surgeon declares their plan to create a diverting ostomy. Randomization will be stratified by plan for diverting ostomy. MAJOR INCLUSION/EXCLUSION CRITERIA: Main inclusion criteria include patients with primary or recurrent ovarian, fallopian tube, or primary peritoneal cancer who are scheduled for cytoreductive surgery with suspected need for low-anterior rectosigmoid resection. PRIMARY ENDPOINT: Rate of 30-day post-operative pelvic complications. SAMPLE SIZE: 310 (155 per arm) ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Q2 2027 and Q4 2027, respectively. TRIAL REGISTRATION: NCT04878094.

2.
Bioinformatics ; 40(4)2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38485690

RESUMO

MOTIVATION: The acquisition of somatic mutations in hematopoietic stem and progenitor stem cells with resultant clonal expansion, termed clonal hematopoiesis (CH), is associated with increased risk of hematologic malignancies and other adverse outcomes. CH is generally present at low allelic fractions, but clonal expansion and acquisition of additional mutations leads to hematologic cancers in a small proportion of individuals. With high depth and high sensitivity sequencing, CH can be detected in most adults and its clonal trajectory mapped over time. However, accurate CH variant calling is challenging due to the difficulty in distinguishing low frequency CH mutations from sequencing artifacts. The lack of well-validated bioinformatic pipelines for CH calling may contribute to lack of reproducibility in studies of CH. RESULTS: Here, we developed ArCH, an Artifact filtering Clonal Hematopoiesis variant calling pipeline for detecting single nucleotide variants and short insertions/deletions by combining the output of four variant calling tools and filtering based on variant characteristics and sequencing error rate estimation. ArCH is an end-to-end cloud-based pipeline optimized to accept a variety of inputs with customizable parameters adaptable to multiple sequencing technologies, research questions, and datasets. Using deep targeted sequencing data generated from six acute myeloid leukemia patient tumor: normal dilutions, 31 blood samples with orthogonal validation, and 26 blood samples with technical replicates, we show that ArCH improves the sensitivity and positive predictive value of CH variant detection at low allele frequencies compared to standard application of commonly used variant calling approaches. AVAILABILITY AND IMPLEMENTATION: The code for this workflow is available at: https://github.com/kbolton-lab/ArCH.


Assuntos
Hematopoiese Clonal , Neoplasias Hematológicas , Adulto , Humanos , Sequenciamento de Nucleotídeos em Larga Escala , Software , Reprodutibilidade dos Testes , Mutação , Hematopoese/genética
3.
Gynecol Oncol ; 171: 23-30, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36804618

RESUMO

OBJECTIVE: To assess postoperative complications after secondary cytoreductive surgery (SCS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC), we conducted an exploratory analysis of patients with platinum-sensitive recurrent ovarian cancer enrolled in a randomized phase II trial. METHODS: Complications occurring within 30 days of surgery were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0; only hemoglobin and platelet levels were assessed. Patients were grouped by CTCAE grade ≥ 3 and < 3 complications. RESULTS: Among 83 eligible patients, 33 (40%) had grade ≥ 3 complications and 50 (60%) had grade < 3 complications; anemia and abdominal infections were the most common. There were no perioperative mortalities. Time to initiation of postoperative chemotherapy for patients with grade ≥ 3 and grade < 3 events was 34 days (range, 18-60) and 31 days (range, 21-43), respectively (P = .017). Median progression-free survival (PFS) did not significantly differ between patients with grade ≥ 3 and grade < 3 complications (11.2 months [95% CI: 9.3-14.4] vs 14.9 months [95% CI: 11.3-16.5], respectively; P = .186), nor did median overall survival (OS) (46.9 months [95% CI: 34-NE] vs 68.2 months [95% CI: 52.1-NE], respectively; P = .053). CONCLUSION: Postoperative complications following SCS with or without HIPEC were associated with slight delays in chemotherapy initiation but did not significantly impact oncologic outcomes.


Assuntos
Hipertermia Induzida , Neoplasias Ovarianas , Humanos , Feminino , Quimioterapia Intraperitoneal Hipertérmica/efeitos adversos , Procedimentos Cirúrgicos de Citorredução/efeitos adversos , Terapia Combinada , Hipertermia Induzida/efeitos adversos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Carcinoma Epitelial do Ovário/cirurgia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Morbidade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
4.
Curr Opin Obstet Gynecol ; 35(1): 21-26, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36595646

RESUMO

PURPOSE OF REVIEW: Our objective is to provide a history, rationale, and review of the use of hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of ovarian cancer. RECENT FINDINGS: In the last decade, there has been an increase in the literature regarding HIPEC in the treatment of ovarian cancer. The rationale for HIPEC extends from earlier trials demonstrating improved survival using intraperitoneal chemotherapy. HIPEC provides a one-time opportunity for intraperitoneal chemotherapy at the time of cytoreduction and with the addition of hyperthermia. Cisplatin HIPEC has been demonstrated to have a survival benefit when used in the interval cytoreductive setting. In terms of safety, nephroprotection remains a key concern when administering HIPEC. Sodium thiosulfate provides nephroprotection and should be considered when performing HIPEC. Various institutions have created multidisciplinary protocols for administering HIPEC, which include operating room staff, nursing, anesthesia, pharmacy, and surgical teams. SUMMARY: HIPEC has a role in the treatment paradigm of ovarian cancer. Currently, HIPEC is approved in the interval cytoreductive surgery setting. Further trials are needed to understand the appropriate timing, chemotherapeutic agents, and protocolization of HIPEC.


Assuntos
Hipertermia Induzida , Neoplasias Ovarianas , Humanos , Feminino , Quimioterapia Intraperitoneal Hipertérmica , Hipertermia Induzida/métodos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Terapia Combinada , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
5.
Gynecol Oncol ; 168: 100-106, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36423444

RESUMO

OBJECTIVE: To determine the relationship between bowel preparation and surgical-site infection (SSI) incidence following colorectal resection during gynecologic oncology surgery. METHODS: This post-hoc analysis used data from a randomized controlled trial of patients enrolled from 03/01/2016-08/20/2019 with presumed gynecologic malignancy investigating negative-pressure wound therapy among those requiring laparotomy. Patients were treated preoperatively without bowel preparation, oral antibiotic bowel preparation (OABP), or OABP plus mechanical bowel preparation (MBP) per surgeon preference. Univariate and multivariable analyses with stepwise model selection for SSI were performed for confirmed gynecologic malignancies requiring colorectal resection. RESULTS: Of 161 cases, 15 (9%) had no preparation, 39 (24%) OABP only, and 107 (66%) OABP+MBP. The overall SSI rate was 19% (n = 31)-53% (n = 8/15) in the no preparation, 21% (n = 8/39) in the OABP alone, and 14% (n = 15/107) in the OABP+MBP groups (P = 0.003). The difference between OABP and OABP+MBP was non-significant (P = 0.44). The median length of stay was 9 (range, 6-12), 6 (range, 5-8), and 7 days (range, 6-10), respectively (P = 0.045). The overall complication rate (34%; n = 54) did not significantly vary by preparation type (P = 0.23). On univariate logistic regression analysis, OABP (OR, 0.23; 95% CI: 0.06-0.80) and OABP+MBP (OR, 0.14; 95% CI: 0.04-0.45) were associated with decreased SSI risk compared to no preparation (P = 0.004). On multivariate analysis, both methods of preparation retained a significant impact on SSI rates (P = 0.004). CONCLUSION: Bowel preparation is associated with reduced SSI incidence and is beneficial for patients undergoing gynecologic oncology surgery with anticipated colorectal resection. Further investigation is needed to determine whether OABP alone is sufficient.


Assuntos
Neoplasias Colorretais , Neoplasias dos Genitais Femininos , Humanos , Feminino , Neoplasias dos Genitais Femininos/tratamento farmacológico , Antibioticoprofilaxia , Cuidados Pré-Operatórios/métodos , Catárticos/uso terapêutico , Estudos Retrospectivos , Infecção da Ferida Cirúrgica/epidemiologia , Infecção da Ferida Cirúrgica/etiologia , Antibacterianos , Procedimentos Cirúrgicos Eletivos/métodos , Administração Oral , Neoplasias Colorretais/tratamento farmacológico
6.
Clin Cancer Res ; 28(19): 4302-4311, 2022 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-35849120

RESUMO

PURPOSE: Microsatellite instability-high (MSI-H) endometrial carcinomas are underpinned by distinct mechanisms of DNA mismatch repair deficiency (MMR-D). We sought to characterize the clinical and genetic features of MSI-H endometrial cancers harboring germline or somatic mutations in MMR genes or MLH1 promoter hypermethylation (MLH1ph). EXPERIMENTAL DESIGN: Of > 1,100 patients with endometrial cancer that underwent clinical tumor-normal sequencing, 184 had MSI-H endometrial cancers due to somatic MMR mutations or MLH1ph, or harbored pathogenic germline MMR mutations. Clinicopathologic features, mutational landscape, and tumor-infiltrating lymphocyte (TIL) scores were compared among MMR-D groups using nonparametric tests. Log-rank tests were used for categorical associations; Kaplan-Meier method and Wald test based on Cox proportional hazards models were employed for continuous variables and survival analyses. RESULTS: Compared with patients with germline (n = 25) and somatic (n = 39) mutations, patients with MLH1ph endometrial cancers (n = 120) were older (P < 0.001), more obese (P = 0.001) and had more advanced disease at diagnosis (P = 0.025). MLH1ph endometrial cancers were enriched for JAK1 somatic mutations as opposed to germline MMR-D endometrial cancers which showed enrichment for pathogenic ERBB2 mutations. MLH1ph endometrial cancers exhibited lower tumor mutational burden and TIL scores compared with endometrial cancers harboring germline or somatic MMR mutations (P < 0.01). MLH1ph endometrial cancer patients had shorter progression-free survival (PFS) on univariate analysis, but in multivariable models, stage at diagnosis remained the only predictor of survival. For stage I/II endometrial cancer, two-year PFS was inferior for patients with MLH1ph endometrial cancers compared with germline and somatic MMR groups (70% vs. 100%, respectively). CONCLUSIONS: MLH1ph endometrial cancers likely constitute a distinct clinicopathologic entity compared with germline and somatic MMR-D ECs with potential treatment implications.


Assuntos
Neoplasias do Endométrio , Instabilidade de Microssatélites , Neoplasias Encefálicas , Neoplasias Colorretais , DNA , Reparo de Erro de Pareamento de DNA/genética , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Mutação em Linhagem Germinativa , Humanos , Proteína 1 Homóloga a MutL/genética , Síndromes Neoplásicas Hereditárias
7.
Clin Cancer Res ; 28(22): 4947-4956, 2022 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-35816189

RESUMO

PURPOSE: To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes. EXPERIMENTAL DESIGN: We profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival. RESULTS: We detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including ARID1A (in 49% of tumors), PIK3CA (49%), TERT (20%), and TP53 (16%). Clustering of cancer driver mutations and RNA expression converged upon two distinct subclasses of CCOC. The first was dominated by ARID1A-mutated tumors with enriched expression of canonical CCOC genes and markers of platinum resistance; the second was largely comprised of tumors with TP53 mutations and enriched for the expression of genes involved in extracellular matrix organization and mesenchymal differentiation. Compared with the ARID1A-mutated group, women with TP53-mutated tumors were more likely to have advanced-stage disease, no antecedent history of endometriosis, and poorer survival, driven by their advanced stage at presentation. In women with ARID1A-mutated tumors, there was a trend toward a lower rate of response to first-line platinum-based therapy. CONCLUSIONS: Our study suggests that CCOC consists of two distinct molecular subclasses with distinct clinical presentation and outcomes, with potential relevance to both traditional and experimental therapy responsiveness. See related commentary by Lheureux, p. 4838.


Assuntos
Adenocarcinoma de Células Claras , Endometriose , Neoplasias Ovarianas , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Adenocarcinoma de Células Claras/tratamento farmacológico , Adenocarcinoma de Células Claras/genética , Mutação , Endometriose/genética , Endometriose/patologia
8.
Cancer ; 128(18): 3297-3309, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-35793549

RESUMO

BACKGROUND: A complex relationship between adipose tissue and malignancy, involving an inflammatory response, has been reported. The goal of this work was to assess the prevalence of white adipose tissue (WAT) inflammation in patients with endometrial cancer (EC), and the association with circulating inflammation markers. Furthermore, the aim was to characterize the pathways activated in and the cell type composition of adipose tissue in patients with EC. METHODS: Adipose tissue and blood samples were prospectively collected from 101 patients with EC at initial surgery. WAT inflammation was determined based on adipocytes surrounded by macrophages forming crown-like structures. Circulating levels of metabolic syndrome-associated and inflammatory markers were quantified. RNA-sequencing was performed on adipose samples (n = 55); differential gene expression, pathway, and cellular decomposition analyses were performed using state-of-the-art bioinformatics methods. RESULTS: WAT inflammation was identified in 46 (45.5%) of 101 EC patients. Dyslipidemia, hypertension, and diabetes mellitus were significantly associated with WAT inflammation (p < .05). WAT inflammation was associated with greater body mass index (p < .001) and higher circulating levels of leptin, high-sensitivity C-reactive protein, and interleukin-6, as well as lower levels of adiponectin and sex hormone-binding globulin (p < .05). Transcriptomic analysis demonstrated increased levels of proinflammatory and pro-neoplastic-related gene expression in inflamed omental adipose tissue. CONCLUSIONS: WAT inflammation is associated with metabolic syndrome, obesity, and inflammatory markers, as well as increased expression of proinflammatory and proneoplastic genes.


Assuntos
Neoplasias do Endométrio , Síndrome Metabólica , Tecido Adiposo Branco , Biomarcadores , Feminino , Humanos , Inflamação , Obesidade , Microambiente Tumoral
10.
Gynecol Oncol ; 165(2): 239-247, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35292180

RESUMO

OBJECTIVE: To determine the effect of hyperthermic intraperitoneal chemotherapy (HIPEC) with carboplatin on the transcriptomic profiles of normal and ovarian cancer (OC) tissues. METHODS: Normal and tumor samples from four OCs were prospectively collected pre- and immediately post-HIPEC treatment and subjected to RNA-sequencing. Differential gene expression, gene ontology enrichment and pathway analyses were performed. Heat shock protein and immune-response protein expression was assessed using protein arrays and western blotting. RESULTS: RNA-sequencing revealed 4231 and 322 genes significantly differentially expressed between pre- and post-treatment normal and OC tissues, respectively (both adjusted p-value <0.05). Gene enrichment analyses demonstrated that the most significantly upregulated genes in normal tissues played a role in immune as well as heat shock response (both adjusted p < 0.001). In contrast, HIPEC induced an increased expression of primarily heat shock response and protein folding-related genes in tumor tissues (both adjusted p < 0.001). HIPEC-induced heat shock protein (HSP) expression changes, including in HSP90, HSP40, HSP60, and HSP70, were also observed at the protein level in both normal and tumor tissues. CONCLUSIONS: HIPEC with carboplatin resulted in an upregulation of heat shock-related genes in both normal and tumor tissue, with an additional immune response gene induction in normal and protein folding in tumor tissue. The findings of our exploratory study provide evidence to suggest that HIPEC administration may suffice to induce gene expression changes in residual tumor cells and raises a biological basis for the consideration of combinatorial treatments with HSP inhibitors.


Assuntos
Hipertermia Induzida , Neoplasias Ovarianas , Carboplatina/farmacologia , Carboplatina/uso terapêutico , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução , Feminino , Proteínas de Choque Térmico/metabolismo , Humanos , Hipertermia Induzida/métodos , Quimioterapia Intraperitoneal Hipertérmica , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , RNA/uso terapêutico , Transcriptoma
12.
Gynecol Oncol Rep ; 37: 100834, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34368413

RESUMO

The ability to achieve complete or optimal cytoreduction in advanced or recurrent ovarian and uterine cancer is a well-established prognostic factor. Colonic resections are commonly required to achieve minimal or no residual disease. When multiple colonic resections are required there is a corresponding difficulty in obtaining sufficient colonic mobility to create tension-free anastomoses for restoration of gastrointestinal continuity; specifically, when a left hemicolectomy or a transverse colectomy is required in addition to a rectosigmoid resection, it may be difficult to achieve a tension-free colorectal anastomosis. We describe the use of retroileal routing of the colon to address this scenario in the context of gynecologic cancer debulking surgery. We report four cases in which the surgeon encountered limited colonic mobility after performing either a left hemicolectomy or a transverse colonic resection in addition to a rectosigmoid resection. In using a retroileal path to perform the colorectal anastomosis, we were able to achieve well-perfused and tension-free anastomoses. Complete gross resection was achieved in all four cases, with acceptable rates of perioperative complications.

13.
Gynecol Oncol ; 162(2): 268-276, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34090704

RESUMO

OBJECTIVE: To examine the role of non-exenterative secondary cytoreductive surgery (SCS) compared with non-surgical treatments and identify predictors of improved survival for patients with recurrent endometrial cancer (EC). METHODS: All patients undergoing primary surgical management for EC 1/1/2009-12/31/2017 who subsequently developed recurrence were retrospectively identified. Survival was determined from date of diagnosis of first recurrence to last follow-up and estimated using Kaplan-Meier method. Differences in survival were analyzed using Log-rank and Wald tests, based on Cox Proportional Hazards model. RESULTS: Among 376 patients with recurrent EC, median time to recurrence was 14.3 months (range, 0.2-102.2), post-recurrence median survival 29 months, median follow-up 29.2 months (range, 0-116). Sixty-one patients (16.2%) received SCS, 257 (68.4%) medical management (MM) (chemotherapy and/or radiation therapy), 32 (8.5%) hormonal therapy, 26 (6.9%) no further therapy. Patients selected for SCS were younger, had more endometrioid histology, more stage I disease at initial diagnosis, no residual disease after primary surgery, longer interval to first recurrence or progression, and the longest OS (57.6 months) (95% CI, 33.3-not reached). On multivariate analysis SCS was an independent predictor of improved survival. Among the 61 SCS patients, age < 70 at time of initial diagnosis, and endometrioid histology, were associated with improved post-relapse survival univariately (p = 0.008, 0.03, respectively). CONCLUSIONS: While MM was the most common treatment for first recurrence of EC, patients selected for surgery demonstrated the greatest survival benefit even after controlling for tumor size, site, histology, stage, time to recurrence. Careful patient selection and favorable tumor factors likely play a major role in improved outcomes. Surgical management should be considered whenever feasible in medically eligible patients, with additional consideration given to our suggested criteria.


Assuntos
Quimiorradioterapia Adjuvante/estatística & dados numéricos , Procedimentos Cirúrgicos de Citorredução/estatística & dados numéricos , Neoplasias do Endométrio/terapia , Recidiva Local de Neoplasia/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Tomada de Decisão Clínica/métodos , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/mortalidade , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/mortalidade , Estadiamento de Neoplasias , Neoplasia Residual , Seleção de Pacientes , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Taxa de Sobrevida
14.
J Clin Oncol ; 39(23): 2594-2604, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34019431

RESUMO

PURPOSE: The purpose of this phase II study was to evaluate hyperthermic intraperitoneal chemotherapy (HIPEC) with carboplatin for recurrent ovarian cancer during secondary cytoreductive surgery. MATERIALS AND METHODS: Patients were intraoperatively randomly assigned to carboplatin HIPEC (800 mg/m2 for 90 minutes) or no HIPEC, followed by five or six cycles of postoperative IV carboplatin-based chemotherapy, respectively. Based on a binomial single-stage pick-the-winner design, an arm was considered winner if ≥ 17 of 49 patients were without disease progression at 24 months post-surgery. Secondary objectives included postoperative toxicity and HIPEC pharmacokinetics. RESULTS: Of 98 patients, 49 (50%) received HIPEC. Complete gross resection was achieved in 82% of the HIPEC patients and 94% of the standard-arm patients. Bowel resection was performed in 37% of patients in the HIPEC arm compared with 65% in the standard (P = .008). There was no perioperative mortality and no difference in use of ostomies, length of stay, or postoperative toxicity. At 24 months, eight patients (16.3%; 1-sided 90% CI, 9.7 to 100) were without progression or death in the HIPEC arm and 12 (24.5%; 1-sided 90% CI, 16.5 to 100) in the standard arm. With a medium follow-up of 39.5 months, 82 patients progressed and 37 died. The median progression-free survival in the HIPEC and standard arms were 12.3 and 15.7 months, respectively (hazard ratio, 1.54; 95% CI, 1 to 2.37; P = .05). There was no significant difference in median overall survival (52.5 v 59.7 months, respectively; hazard ratio, 1.39; 95% CI, 0.73 to 2.67; P = .31). These analyses were exploratory. CONCLUSION: HIPEC with carboplatin was well tolerated but did not result in superior clinical outcomes. This study does not support the use of HIPEC with carboplatin during secondary cytoreductive surgery for platinum-sensitive recurrent ovarian cancer.


Assuntos
Carboplatina/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/cirurgia , Procedimentos Cirúrgicos de Citorredução/métodos , Quimioterapia Intraperitoneal Hipertérmica/métodos , Adulto , Idoso , Carboplatina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Intervalo Livre de Progressão
15.
Mol Oncol ; 15(4): 1024-1039, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33021035

RESUMO

Metaplastic breast carcinoma (MBC) and uterine carcinosarcoma (UCS) are rare aggressive cancers, characterized by an admixture of adenocarcinoma and areas displaying mesenchymal/sarcomatoid differentiation. We sought to define whether MBCs and UCSs harbor similar patterns of genetic alterations, and whether the different histologic components of MBCs and UCSs are clonally related. Whole-exome sequencing (WES) data from MBCs (n = 35) and UCSs (n = 57, The Cancer Genome Atlas) were reanalyzed to define somatic genetic alterations, altered signaling pathways, mutational signatures, and genomic features of homologous recombination DNA repair deficiency (HRD). In addition, the carcinomatous and sarcomatous components of an additional cohort of MBCs (n = 11) and UCSs (n = 6) were microdissected separately and subjected to WES, and their clonal relatedness was assessed. MBCs and UCSs harbored recurrent genetic alterations affecting TP53, PIK3CA, and PTEN, similar patterns of gene copy number alterations, and an enrichment in alterations affecting the epithelial-to-mesenchymal transition (EMT)-related Wnt and Notch signaling pathways. Differences were observed, however, including a significantly higher prevalence of FAT3 and FAT1 somatic mutations in MBCs compared to UCSs, and conversely, UCSs significantly more frequently harbored somatic mutations affecting FBXW7 and PPP2R1A as well as HER2 amplification than MBCs. Genomic features of HRD and biallelic alterations affecting bona fide HRD-related genes were found to be more prevalent in MBCs than in UCSs. The distinct histologic components of MBCs and UCSs were clonally related in all cases, with the sarcoma component likely stemming from a minor subclone of the carcinoma component in the samples with interpretable chronology of clonal evolution. Despite the similar histologic features and pathways affected by genetic alterations, UCSs differ from MBCs on the basis of FBXW7 and PPP2R1A mutations, HER2 amplification, and lack of HRD, supporting the notion that these entities are more than mere phenocopies of the same tumor type in different anatomical sites.


Assuntos
Neoplasias da Mama/genética , Carcinossarcoma/genética , Neoplasias Uterinas/genética , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Transição Epitelial-Mesenquimal , Proteína 7 com Repetições F-Box-WD/genética , Feminino , Humanos , Mutação , Proteína Fosfatase 2/genética , Receptor ErbB-2/genética , Sequenciamento do Exoma
16.
Mod Pathol ; 34(5): 994-1007, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33328602

RESUMO

Sporadic synchronous endometrial (ECs) and ovarian cancers (OCs), although clinically considered to be independent primaries, have been shown to be clonally related and likely constitute metastases from each other. We sought to define whether synchronous ECs/OCs in patients with DNA mismatch repair (MMR)-deficiency syndromes would be clonally related. We subjected synchronous ECs/OCs from four patients (LS3-LS6) with clinically confirmed Lynch syndrome (LS) and one patient with constitutional mismatch repair-deficiency syndrome (CMMRD) to massively parallel sequencing targeting 468 cancer-related genes. Somatic mutations, copy number alterations (CNAs), clonal relatedness and clonal decomposition analyses were performed using previously described bioinformatics methods. All synchronous ECs/OCs analyzed were considered independent primaries based on clinicopathologic criteria. Sequencing analysis revealed that the ECs/OCs of three cases (LS2-CMMRD, L3, L4) harbored similar repertoires of somatic mutations and CNAs and were clonally related. In these three cases, a subset of subclonal mutations in the EC became clonal in the OC, suggesting that the EC was likely the substrate from which the OC developed. LS5's EC/OC had distinct mutational profiles but shared specific CNAs. In contrast, LS6's EC/OC harbored distinct somatic mutations and lacked CNAs, consistent with each tumor constituting an independent primary lesion. In LS5 and LS6, PTEN mutations and PTEN loss of protein expression were found to be restricted to the EC. Finally, re-analysis of sequencing data of sporadic synchronous ECs/OCs supported the observations made in the current study that the directionality of progression is likely from the endometrium to the ovary. In conclusion, contrary to sporadic synchronous ECs/OCs, which are almost invariably clonally related, ECs/OCs simultaneously involving the uterus and ovary in LS patients may represent distinct primary tumors. A subset of MMR-deficiency syndrome-related synchronous ECs/OCs, however, may originate from a single primary tumor at variance with their clinical diagnosis, with the endometrium being the likeliest site of origin.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA/genética , Neoplasias do Endométrio/genética , Mutação , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Ovarianas/genética , Adulto , Neoplasias Encefálicas/patologia , Neoplasias Colorretais/patologia , Progressão da Doença , Neoplasias do Endométrio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/patologia , Neoplasias Ovarianas/patologia , Síndrome
17.
Gynecol Oncol ; 158(2): 397-401, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32460995

RESUMO

OBJECTIVES: Reducing anastomotic leak rates after rectosigmoid resection and anastomosis is a priority in patients undergoing gynecologic oncology surgery. Therefore, we investigated the implications of performing near-infrared angiography (NIR) via proctoscopy to assess anastomotic perfusion at the time of rectosigmoid resection and anastomosis. METHODS: We identified all patients who underwent rectosigmoid resection and anastomosis for a gynecologic malignancy between January 1, 2013 and December 31, 2018. NIR proctoscopy was assessed via the PINPOINT Endoscopic Imaging System (Stryker). RESULTS: A total of 410 patients were identified, among whom NIR was utilized in 133 (32.4%). There were no statistically significant differences in age, race, BMI, type of malignancy, surgery, histology, FIGO stage, hypertension, diabetes, or preoperative chemotherapy between NIR and non-NIR groups. All cases of rectosigmoid resection underwent stapled anastomosis. The anastomotic leak rate was 2/133 (1.5%) in the NIR cohort compared with 13/277 (4.7%) in the non-NIR cohort (p = 0.16). Diverting ostomy was performed in 9/133 (6.8%) NIR and 53/277 (19.9%) non-NIR patients (p < 0.001). Postoperative abscesses occurred in 8/133 (6.0%) NIR and 44/277 (15.9%) non-NIR patients (p = 0.004). The NIR cohort had significantly fewer post-operative interventional procedures (12/133, 9.0% NIR vs. 55/277, 19.9% non-NIR, p = 0.006) and significantly fewer 30-day readmissions (14/133, 10.5% NIR vs. 61/277, 22% non-NIR, p = 0.004). CONCLUSIONS: NIR proctoscopy is a safe tool for assessing anastomotic rectal perfusion after rectosigmoid resection and anastomosis, with a low anastomotic leak rate of 1.5%. Its potential usefulness should be evaluated in randomized trials in patients undergoing gynecologic cancer surgery.


Assuntos
Angiofluoresceinografia/métodos , Neoplasias dos Genitais Femininos/cirurgia , Proctoscopia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anastomose Cirúrgica/métodos , Fístula Anastomótica/prevenção & controle , Estudos de Coortes , Colo Sigmoide/cirurgia , Procedimentos Cirúrgicos de Citorredução/métodos , Feminino , Procedimentos Cirúrgicos em Ginecologia/métodos , Humanos , Pessoa de Meia-Idade , Reto/cirurgia , Estudos Retrospectivos , Adulto Jovem
19.
Int J Gynecol Cancer ; 30(3): 387-393, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31953349

RESUMO

Many tracers have been introduced into current medical practice with the purpose of improving lymphatic mapping techniques, anatomic visualization, and organ/tissue perfusion assessment. Among them, three tracers have dominated the field: indocyanine green, technetium-99m radiocolloid (Tc99m), and blue dye. Tc99m and blue dye are used individually or in combination; however, given particular challenges with these tracers, such as the need for a preoperative procedure by nuclear medicine and cost, other options have been sought. Indocyanine green has proven to be a promising alternative for certain procedures, as it is easy to use and has quick uptake. Its use in the management of gynecologic cancers was first described for sentinel lymph node mapping in cervical cancer, and later for endometrial and vulvar cancers. This review provides an in-depth look at these mapping substances, their uses, and the potential for new discoveries.


Assuntos
Neoplasias dos Genitais Femininos/patologia , Biópsia de Linfonodo Sentinela/métodos , Feminino , Neoplasias dos Genitais Femininos/cirurgia , Humanos , Linfonodos/patologia , Linfonodos/cirurgia , Metástase Linfática , Estadiamento de Neoplasias , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Linfonodo Sentinela/patologia , Linfonodo Sentinela/cirurgia
20.
Annu Int Conf IEEE Eng Med Biol Soc ; 2019: 32221-3225, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31947503

RESUMO

Monitoring human biomechanical movement is necessary for the analysis and development of kinesthetic exercise techniques in physical rehabilitation, professional sports, and performance arts. Optical fiber technology offers an attractive solution to motion capture sensing in terms of size, robustness, signal fidelity, and efficiency. We report on the development of PDMS-based fiber optic strain sensors for biomechanical sensing in real-time via the evaluation of skeletal joint angles. The fibers were fabricated using an elastomer and gel combination in a 3:2 ratio. The elasticity and optical loss of this novel fiber material was experimentally characterized for two fiber diameters of 3 mm and 5 mm. The experimental stress-strain behavior was fitted to a 3D hyperelastic Mooney-Rivlin model to obtain C01 and C10 material constants of 0.022 MPa and 0.0308 MPa respectively. Transmission monotonically decreased in response to a stress applied in both the longitudinal (elongation) and lateral (bending) directions. The sensors were demonstrated in a motion sensing implementation by monitoring the joint angle at the elbow in real-time. Measurements indicated a consistent performance of both fiber diameters over the range of motion of the elbow corresponding to flexion and extension. The optical loss increased by 0.1784 dB and 0.1147 dB for each degree of flexion with standard deviation error in measurement of 3.525° and 4.672° for the 3 mm and 5 mm fiber diameters, respectively. The results demonstrate the potential of this system for real-time, wearable biomechanical sensing, motion capture systems, and as a feedback mechanism in prosthetics and robotics.


Assuntos
Articulação do Cotovelo/fisiologia , Tecnologia de Fibra Óptica , Amplitude de Movimento Articular , Dispositivos Eletrônicos Vestíveis , Fenômenos Biomecânicos , Humanos , Movimento
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