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1.
Ann Surg Oncol ; 2024 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-39271567

RESUMEN

BACKGROUND: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a novel, minimally invasive, safe, and repeatable method to treat carcinomatosis. Evidence regarding the clinical benefit (quality of life and survival) of PIPAC compared with that of conventional standard therapy (ST) is lacking. METHODS: This is the secondary analysis of the phase 1 US-PIPAC trial for refractory colorectal and appendiceal carcinomatosis. A PIPAC cohort was compared with a retrospective cohort of consecutive patients receiving ST. The primary outcome was number of good days (number of days alive and out of the hospital). The secondary outcomes were overall survival (OS), progression-free survival (PFS), health-related quality of life (HRQoL), and objective functional recovery (daily step count). RESULTS: The study included 32 patients (PIPAC, 12; ST, 20) with similar baseline characteristics. Compared with the ST cohort, the PIPAC cohort had lower median inpatient hospital stays (> 24 h) within 6 months (0 vs 1; p = 0.015) and 1 year (1 vs 2; p = 0.052) and higher median good days at 6 months (181 vs 131 days; p = 0.042) and 1 year (323 vs 131 days; p = 0.032). There was no worsening of HRQoL after repeated PIPACs. Step counts diminished immediately after PIPAC but returned to baseline within 2-4 weeks. Kaplan-Meier analysis demonstrated a favorable association between receipt of PIPAC and OS (median, 11.3 vs 5.1 months; p = 0.036). CONCLUSION: Compared with ST, PIPAC was associated with higher number of good days, reduced hospitalization burden, and longer OS without a negative impact on HRQoL with repeated PIPACs. These findings are foundational for evaluation of PIPAC in a randomized clinical trial.

2.
Ann Surg Oncol ; 30(12): 7814-7824, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37501051

RESUMEN

BACKGROUND: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a laparoscopic locoregional treatment for peritoneal metastases (PM) from colorectal cancer (CRC) or appendiceal cancer (AC) in patients who cannot undergo cytoreductive surgery (CRS). While PIPAC has been studied in Europe and Asia, it has not been investigated in the USA. PATIENTS AND METHODS: We evaluated PIPAC with 90 mg/m2 oxaliplatin alone (cycle 1) and preceded by systemic chemotherapy with fluorouracil (5-FU) and leucovorin (LV) (cycle 2-3) as a multicenter prospective phase I clinical trial (NCT04329494). The primary endpoint was treatment-related adverse events (AEs). Secondary endpoints included survival and laparoscopic, histologic, and radiographic response. RESULTS: 12 patients were included: 8 with CRC and 4 with AC. Median prior chemotherapy cycles was 2 (interquartile range (IQR) 2-3). All patients were refractory to systemic oxaliplatin-based chemotherapy. Median peritoneal carcinomatosis index (PCI) was 28 (IQR 19-32). Six (50%) of twelve patients completed three PIPAC cycles. No surgical complications or dose-limiting toxicities were observed. Two patients developed grade 3 treatment-related toxicities (one abdominal pain and one anemia). Median overall survival (OS) was 12.0 months, and median progression-free survival (PFS) was 2.9 months. OS was correlated with stable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria but not with laparoscopic response by PCI or histologic response by peritoneal regression grading system (PRGS). CONCLUSIONS: This phase I trial in the USA demonstrated safety, feasibility, and early efficacy signal of PIPAC with oxaliplatin and chemotherapy in patients with PM from AC or CRC who are refractory to standard lines of systemic chemotherapy.


Asunto(s)
Neoplasias del Apéndice , Neoplasias Colorrectales , Neoplasias Peritoneales , Humanos , Oxaliplatino , Neoplasias del Apéndice/tratamiento farmacológico , Neoplasias Peritoneales/secundario , Estudios Prospectivos , Aerosoles , Fluorouracilo/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología
3.
Ann Surg Oncol ; 30(13): 8144-8155, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37710139

RESUMEN

PURPOSE: Hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin confers a survival benefit in epithelial ovarian cancer (EOC) but is associated with renal toxicity. Sodium thiosulfate (ST) is used for nephroprotection for HIPEC with cisplatin, but standard HIPEC practices vary. METHODS: A prospective, nonrandomized, clinical trial evaluated safety outcomes of HIPEC with cisplatin 75 mg/m2 during cytoreductive surgery (CRS) in patients with EOC (n = 34) and endometrial cancer (n = 6). Twenty-one patients received no ST (nST), and 19 received ST. Adverse events (AEs) were reported according to CTCAE v.5.0. Serum creatinine (Cr) was collected preoperatively and postoperatively (Days 5-8). Progression-free survival (PFS) was followed. Normal peritoneum was biopsied before and after HIPEC for whole transcriptomic sequencing to identify RNAseq signatures correlating with AEs. RESULTS: Forty patients had HIPEC at the time of interval or secondary CRS. Renal toxicities in the nST group were 33% any grade AE and 9% grade 3 AEs. The ST group demonstrated no renal AEs. Median postoperative Cr in the nST group was 1.1 mg/dL and 0.5 mg/dL in the ST group (p = 0.0001). Median change in Cr from preoperative to postoperative levels were + 53% (nST) compared with - 9.6% (ST) (p = 0.003). PFS did not differ between the ST and nST groups in primary or recurrent EOC patients. Renal AEs were associated with downregulation of metabolic pathways and upregulation of immune pathways. CONCLUSIONS: ST significantly reduces acute renal toxicity associated with HIPEC with cisplatin in ovarian cancer patients. As nephrotoxicity is high in HIPEC with cisplatin, nephroprotective agents should be considered.


Asunto(s)
Antineoplásicos , Hipertermia Inducida , Neoplasias Ováricas , Humanos , Femenino , Cisplatino/uso terapéutico , Quimioterapia Intraperitoneal Hipertérmica , Antineoplásicos/uso terapéutico , Estudios Prospectivos , Hipertermia Inducida/efectos adversos , Recurrencia Local de Neoplasia , Neoplasias Ováricas/patología , Carcinoma Epitelial de Ovario , Procedimientos Quirúrgicos de Citorreducción/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada
4.
Int Urogynecol J ; 34(1): 177-183, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-35501570

RESUMEN

INTRODUCTION AND HYPOTHESIS: At our institution, every patient seen by the gynecologic oncology service is screened for pelvic floor dysfunction. This study was aimed at determining if a combined surgical approach by gynecologic oncology and urogynecology services at our institution was feasible and safe for this patient population. METHODS: We performed a retrospective review of patients undergoing combined surgery by gynecologic oncology and urogynecology services at our institution from 2013 to 2021. Perioperative variables, postoperative adverse events, and long-term outcomes were assessed, and descriptive statistics were performed. RESULTS: From 20 December 2013 to 29 January 2021, a total of 102 patients underwent concurrent surgical repair of pelvic organ prolapse and/or stress urinary incontinence. Seventy-three patients (71.6%) had normal/benign pathologic conditions, and 29 (28.4%) had premalignant/malignant pathologic conditions. Ten patients (9.8%) had a postoperative complication, including reoperation for exposed midurethral sling (4.9%), urinary retention requiring midurethral sling release (2.9%), reoperation for hemoperitoneum (1.0%), and anemia requiring blood transfusion (1.0%). Nine complications occurred in patients with benign/normal pathologic conditions (12.3%), and one complication occurred in patients with pre-malignant/malignant pathologic conditions (3.4%). CONCLUSIONS: In our single-institution experience, concurrent gynecologic oncology and pelvic floor reconstructive surgery were safe and feasible in combination with no reported major morbidity events.


Asunto(s)
Neoplasias de los Genitales Femeninos , Prolapso de Órgano Pélvico , Cabestrillo Suburetral , Incontinencia Urinaria de Esfuerzo , Humanos , Femenino , Neoplasias de los Genitales Femeninos/cirugía , Estudios de Factibilidad , Estudios Retrospectivos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Incontinencia Urinaria de Esfuerzo/cirugía , Incontinencia Urinaria de Esfuerzo/etiología , Prolapso de Órgano Pélvico/cirugía , Prolapso de Órgano Pélvico/etiología , Procedimientos Quirúrgicos Ginecológicos/efectos adversos
5.
Ann Surg Oncol ; 29(1): 175-185, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34387765

RESUMEN

BACKGROUND: Peritoneal metastases (PM) from ovarian, gastric, appendiceal, or colorectal origin can be treated via cytoreductive surgery with or without the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) for selected patients. Unfortunately, not all patients are candidates for aggressive surgical debulking. For these patients, pressurized intraperitoneal aerosolized chemotherapy (PIPAC) has emerged as an alternative method for intraperitoneal (IP) chemotherapy administration. This report presents the design and implementation of the first phase 1 trial to evaluate the safety and efficacy of PIPAC in the United States. METHODS: This is an ongoing prospective phase 1 clinical trial of PIPAC for patients who have histologically confirmed ovarian, uterine, gastric, appendiceal, or colorectal cancer with PM and have progressed to at least one evidence-based chemotherapeutic regimen. The trial has two clinical arms. The patients in arm 1 have gynecologic and gastric malignancies treated with IP cisplatin and doxorubicin, and the arm 2 patients have colorectal and appendiceal malignancies treated with intravenous fluorouracil and leucovorin followed by IP oxaliplatin. All the patients are monitored for dose-limiting toxicities and adverse events. RESULTS: Practical and technical considerations for the phase 1 PIPAC trial are presented. These considerations include patient selection, operating room setup, and technical details for successful aerosolized chemotherapy delivery. The phase 1 study results will be reported separately at completion of the trial. CONCLUSIONS: The PIPAC treatment is a feasible, minimally invasive approach that permits IP delivery of chemotherapy. Once completed, the ongoing phase 1 trial will help to provide safety and initial efficacy data.


Asunto(s)
Neoplasias Peritoneales , Femenino , Humanos , Neoplasias Peritoneales/tratamiento farmacológico , Estudios Prospectivos
6.
Int Urogynecol J ; 32(4): 1037-1038, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-32737535

RESUMEN

This report presents our experience in performing prolapse repair after anterior exenteration. The patient had a history of invasive bladder cancer and underwent a robotically assisted laparoscopic anterior exenteration with extended bilateral pelvic lymph node dissection and creation of an Indiana pouch continent diversion. Her pelvic organ prolapse progressed over time despite multiple pessary fittings. She eventually decided to proceed with pelvic reconstructive surgery 6 years after her cancer surgery. She underwent a successful vaginal native tissue reconstruction with uterosacral ligament suspension, posterior repair and reconstruction of the anterior compartment. The patient has been followed for 16 months without recurrent prolapse. Vaginal native tissue pelvic reconstruction is feasible in a patient with a history of pelvic exenteration.


Asunto(s)
Prolapso de Órgano Pélvico , Femenino , Humanos , Histerectomía Vaginal , Ligamentos , Prolapso de Órgano Pélvico/cirugía , Pesarios , Vagina/cirugía
10.
Ann Surg Oncol ; 25(3): 688-693, 2018 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-29260417

RESUMEN

BACKGROUND: Cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) are complex surgeries with multiple comorbidities. The Clavien-Dindo classification (CDC) is the most commonly used method to report surgical morbidity, but limits it to the highest-grade complication. The Comprehensive Complication Index (CCI) is a score ranging from 0 to 100, calculated using all 30-day complications and their treatment after abdominal surgery. The aim of this study is to assess the CCI's validity in the HIPEC patient population. METHODS: A review of our institutional cytoreduction database from 2009 to 2015 was undertaken. Patient demographics, pathology, Peritoneal Carcinomatosis Index (PCI), complications and their treatments, and length of stay (LOS) were reviewed. The CCI was calculated for each patient. Linear regression was used to assess whether the CCI and CDC were predictors of LOS. RESULTS: Of 157 patients reviewed, 110 (70.1%) underwent HIPEC. The majority were female (77, 66.9%), and the mean age was 53.7 years. Mean PCI was 13.2 [interquartile range (IQR) 7-18]. Median CDC was grade 2 (IQR 0-2), and only 9.8% had CDC of grade 4 or higher. Mean CCI was 21.4, while the median was 20.9 (IQR 0-30.8). Mean LOS was 16.2 days, while the median was 11 days (IQR 8-15 days). The CCI strongly correlated with LOS with coefficient of 0.46 [95% confidence interval (CI) 0.38-0.54, p = 0.000]. CONCLUSIONS: The CCI is an adequate tool to capture all complications and their overall burden in patients having undergone HIPEC. This study shows that the CCI can predict LOS and could be used to quantify and compare the burden of multiple complications.


Asunto(s)
Quimioterapia del Cáncer por Perfusión Regional/efectos adversos , Procedimientos Quirúrgicos de Citorreducción/efectos adversos , Hipertermia Inducida/efectos adversos , Neoplasias Peritoneales/patología , Neoplasias Peritoneales/terapia , Complicaciones Posoperatorias/etiología , Índice de Severidad de la Enfermedad , Anciano , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Morbilidad , Pronóstico
12.
J Natl Compr Canc Netw ; 16(2): 211-218, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29439180

RESUMEN

Hematopoietic cell transplantation (HCT) results in long-term survival (≥10 years) in 85% of patients who survive transplant-related complications within the first 2 years posttransplant. Transplant survivors, however, are at an increased risk of chronic health conditions compared with the general population, including the emergence of secondary malignant neoplasms. In particular, female transplant survivors may face a greater risk of lower genital tract (cervical, vulvar, or vaginal) neoplasms due to chronic immune dysregulation in the peritransplant and posttransplant environment. Persistent immune suppression may facilitate the carcinogenesis of human papillomavirus (HPV), the causative agent of nearly all cervical cancers and most vulvar and vaginal cancers. Nevertheless, the risk of these cancers has not been sufficiently quantified in female transplant survivors. Small clinical studies have shown that the rate of cervical cytological abnormalities increases after allogeneic HCT, but large population-based studies have not consistently demonstrated an increased risk of secondary cervical cancer after transplant compared with the general population; the risk of developing secondary vulvar or vaginal cancer after transplant remains unclear. A better understanding of the natural history of HPV-associated lower genital tract neoplasms and their transplant-related risk factors would help delineate optimal long-term follow-up protocols in this population. In this systematic review, we summarize the current literature on this topic and discuss the implications for cervical cancer screening and vaccination in female transplant recipients.


Asunto(s)
Neoplasias de los Genitales Femeninos/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Neoplasias Primarias Secundarias/etiología , Toma de Decisiones Clínicas , Detección Precoz del Cáncer , Femenino , Neoplasias de los Genitales Femeninos/diagnóstico , Neoplasias de los Genitales Femeninos/epidemiología , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Incidencia , Tamizaje Masivo , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Secundarias/epidemiología , Guías de Práctica Clínica como Asunto , Medición de Riesgo , Factores de Riesgo , Vacunación/efectos adversos
13.
J Surg Oncol ; 118(1): 121-126, 2018 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-29878375

RESUMEN

BACKGROUND AND OBJECTIVES: Cytoreductive surgery with complete macroscopic resection in patients with ovarian cancer is associated with improved survival. Institutional reports of combined upper and lower abdominal cytoreductive surgery for more advanced disease have described multidisciplinary approaches. We sought to investigate outcomes in patients undergoing cytoreductive surgery in patients with upper and lower abdominal disease at our institution. METHODS: Patients who underwent cytoreductive surgery for ovarian malignancies from 2008 to 2015 were retrospectively identified from an institutional database. Upper abdominal cytoreduction was defined anatomically as debulking of disease proximal to the ligament of Treitz. Perioperative outcomes were analyzed. RESULTS: A total of 258 operations were performed, the majority for serous ovarian carcinoma (70%). The gynecologic oncologist was the primary surgeon and often assisted by either a surgical oncology fellow and/or attending. In operations with combined upper and lower abdominal cytoreduction, patients were more likely to have an American society of anesthesiologists physical status classification system (ASA) of 3, peritoneal implants, and liver/spleen metastases. Preoperative chemotherapy and optimal cytoreduction were similar between groups. Perioperative morbidity and mortality were not significantly different between groups. CONCLUSIONS: A collaborative surgical approach to combined upper and lower abdominal cytoreductive surgery in patients with ovarian cancer should be performed, if needed, to achieve an optimal cytoreduction.


Asunto(s)
Procedimientos Quirúrgicos de Citorreducción/métodos , Procedimientos Quirúrgicos Ginecológicos/métodos , Neoplasias Ováricas/cirugía , Abdomen/cirugía , Anciano , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Estudios Retrospectivos
14.
Int Urogynecol J ; 29(11): 1709-1711, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30121701

RESUMEN

INTRODUCTION AND HYPOTHESIS: We present our experience in performing concurrent prolpase repair at the time of gynecologic cancer surgery. METHODS: The uterosacral ligaments are tagged before performing hysterectomy and pelvic dissection. The uterosacral ligament suspensory sutures are then placed laparoscopically after completion of pelvic cancer surgery. The remainder of the prolapse surgery is performed through a transvaginal approach. RESULTS: Many of our patients who undergo concurrent prolapse repair and gynecolgical cancer surgery receive chemotherapy and pelivc radiation. Concuurent prolapse repair improves their prolaspe symptoms. CONCLUSION: Concurrent prolapse repair should be performed at the same time as gynecologic cancer surgery.


Asunto(s)
Neoplasias de los Genitales Femeninos/cirugía , Procedimientos Quirúrgicos Ginecológicos/métodos , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Prolapso de Órgano Pélvico/cirugía , Procedimientos de Cirugía Plástica/métodos , Anciano , Terapia Combinada , Femenino , Neoplasias de los Genitales Femeninos/complicaciones , Humanos , Persona de Mediana Edad , Diafragma Pélvico/cirugía , Prolapso de Órgano Pélvico/complicaciones , Resultado del Tratamiento
15.
Mol Carcinog ; 56(2): 436-446, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27253180

RESUMEN

Although many anti-VEGF agents are available for cancer treatment, side effects of these agents limit their application for cancer treatment and prevention. Here we studied the potential use of a diet-based agent as an inhibitor for VEGF production. Using a VEGF reporter assay, our data showed that an extract from cinnamon (CE) was a potent inhibitor of VEGF production in human cancer cells and suggested inhibition might be mediated through the suppression of HIF-1α gene expression and protein synthesis. Furthermore, CE treatment was found to inhibit expression and phosphorylation of STAT3 and AKT, which are key factors in the regulation of HIF-1α expression, and significantly reduce angiogenesis potential of cancer cells by migration assay. Consistent with these results, we observed significant suppression of VEGF expression, blood vessel formation, and tumor growth in a human ovarian tumor model in mice treated with CE. Cinnamaldehyde, a major component in cinnamon, was identified as one active component in CE that inhibits VEGF expression. Taken together, our findings provide a novel mechanism underlying anti-angiogenic and anti-tumor actions of CE and support the potential use of CE in cancer prevention and treatment. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Cinnamomum zeylanicum/química , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Neoplasias Ováricas/tratamiento farmacológico , Ovario/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/genética , Animales , Antineoplásicos Fitogénicos/química , Femenino , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/análisis , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ratones SCID , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Neoplasias Ováricas/irrigación sanguínea , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Ovario/irrigación sanguínea , Ovario/metabolismo , Ovario/patología , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/análisis , Factor A de Crecimiento Endotelial Vascular/metabolismo
16.
Ann Surg Oncol ; 24(9): 2707-2711, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28560593

RESUMEN

BACKGROUND: Base excess is important in assessing metabolic status. Postoperative management in patients undergoing cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal malignancies can be a challenge, and we therefore sought to investigate perioperative predictors of overall morbidity in CRS/HIPEC patients at our institution. METHODS: Patients who underwent CRS/HIPEC from 2012 to 2016 were identified retrospectively from a prospectively collected institutional database. Patient demographics and perioperative variables were obtained and the comprehensive complication index (CCI) was calculated for each patient in order to assess perioperative morbidity. Stepwise linear regression analyses were performed, with CCI as the outcome variable. RESULTS: A total of 72 CRS/HIPEC patients had recorded base excesses in the first 48 h postoperatively. Mean immediate postoperative base excess was -6.0 mmol/L (interquartile range [IQR] -8 to -4.1), mean delta base excess at 48 h was +4.3 mmol/L (IQR +2.1 to +6.2), and mean CCI was 25.2 (IQR 8.7-36.7). On multivariate analysis, delta base excess was the only significant predictor of CCI, demonstrating a protective effect (p = 0.001). In patients who experienced less than the mean delta base excess of +4.3 mmol/L, lower delta base excess was an independent predictor of complications (p < 0.001). CONCLUSIONS: Delta base excess is an independent predictor of morbidity in patients undergoing CRS/HIPEC. A delta base excess of greater than +4.3 mmol/L at 48 h may be an appropriate goal for resuscitation of CRS/HIPEC patients in the immediate postoperative period. Standardized protocols to correct the base deficit in CRS/HIPEC patients during the early postoperative period can potentially help mitigate perioperative morbidity.


Asunto(s)
Desequilibrio Ácido-Base/sangre , Procedimientos Quirúrgicos de Citorreducción/efectos adversos , Hipertermia Inducida/efectos adversos , Neoplasias Peritoneales/terapia , Complicaciones Posoperatorias/etiología , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/administración & dosificación , Femenino , Humanos , Ileus/etiología , Masculino , Persona de Mediana Edad , Mitomicina/administración & dosificación , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Neoplasias Peritoneales/secundario , Estudios Retrospectivos , Factores de Riesgo
17.
BMC Cancer ; 17(1): 184, 2017 03 10.
Artículo en Inglés | MEDLINE | ID: mdl-28283022

RESUMEN

BACKGROUND: Most cancer deaths result from tumor cells that have metastasized beyond their tissue of origin, or have developed drug resistance. Across many cancer types, patients with advanced stage disease would benefit from a novel therapy preventing or reversing these changes. To this end, we have investigated the unique WR domain of the transcription factor TWIST1, which has been shown to play a role in driving metastasis and drug resistance. METHODS: In this study, we identified evolutionarily well-conserved residues within the TWIST1 WR domain and used alanine substitution to determine their role in WR domain-mediated protein binding. Co-immunoprecipitation was used to assay binding affinity between TWIST1 and the NFκB subunit p65 (RELA). Biological activity of this complex was assayed using a dual luciferase assay system in which firefly luciferase was driven by the interleukin-8 (IL-8) promoter, which is upregulated by the TWIST1-RELA complex. Finally, in order to inhibit the TWIST1-RELA interaction, we created a fusion protein comprising GFP and the WR domain. Cell fractionation and proteasome inhibition experiments were utilized to elucidate the mechanism of action of the GFP-WR fusion. RESULTS: We found that the central residues of the WR domain (W190, R191, E193) were important for TWIST1 binding to RELA, and for increased activation of the IL-8 promoter. We also found that the C-terminal 245 residues of RELA are important for TWIST1 binding and IL-8 promoter activation. Finally, we found the GFP-WR fusion protein antagonized TWIST1-RELA binding and downstream signaling. Co-expression of GFP-WR with TWIST1 and RELA led to proteasomal degradation of TWIST1, which could be inhibited by MG132 treatment. CONCLUSIONS: These data provide evidence that mutation or inhibition of the WR domain reduces TWIST1 activity, and may represent a potential therapeutic modality.


Asunto(s)
Interleucina-8/genética , Mutación , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Factor de Transcripción ReIA/química , Factor de Transcripción ReIA/metabolismo , Proteína 1 Relacionada con Twist/química , Proteína 1 Relacionada con Twist/metabolismo , Sitios de Unión , Células HEK293 , Humanos , Proteínas Nucleares/genética , Regiones Promotoras Genéticas , Unión Proteica , Dominios Proteicos , Activación Transcripcional , Proteína 1 Relacionada con Twist/genética
18.
J Natl Compr Canc Netw ; 15(1): 121-128, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-28040722

RESUMEN

Vulvar cancer is a rare malignancy with high curability in early-stage disease, yet poor outcomes for advanced-stage and recurrent disease. Surgical management is at the cornerstone of treatment for most vulvar cancers, and includes conservative and radical resection of the primary vulvar tumor and excision of local lymph nodes, which are major prognostic factors and drive adjuvant treatment. This review summarizes the surgical management of primary squamous cell carcinoma of the vulva, specifically initial treatment guidelines by stage, based on the 2017 NCCN Clinical Practice Guidelines in Oncology for Vulvar Cancer.


Asunto(s)
Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/cirugía , Escisión del Ganglio Linfático , Recurrencia Local de Neoplasia/cirugía , Neoplasias de la Vulva/patología , Neoplasias de la Vulva/cirugía , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/radioterapia , Femenino , Humanos , Conducto Inguinal , Estadificación de Neoplasias , Exenteración Pélvica , Guías de Práctica Clínica como Asunto , Radioterapia Adyuvante , Factores de Riesgo , Biopsia del Ganglio Linfático Centinela , Vulva/cirugía , Neoplasias de la Vulva/diagnóstico , Neoplasias de la Vulva/radioterapia
19.
J Minim Invasive Gynecol ; 24(4): 531-532, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-27794476

RESUMEN

STUDY OBJECTIVE: To demonstrate the feasibility of multiquadrant staging of a uterine carcinosarcoma using the latest-generation robotic platform. DESIGN: Step-by-step explanation of the technique using videos and pictures (educative video). SETTING: Although laparoscopic and robotic-assisted laparoscopic staging of high-risk uterine cancer is well incorporated into many gynecologic oncology practices, extensive para-aortic lymphadenectomies above the inferior mesenteric artery are less commonly performed. Additionally, infracolic omentectomies are frequently performed in lieu of infragastric omentectomies. PATIENT: A 67-year-old woman with a newly diagnosed uterine carcinosarcoma. INTERVENTION: Multiquadrant comprehensive staging of uterine carcinosarcoma using the latest-generation robotic platform. MEASUREMENTS AND MAIN RESULTS: We demonstrate in this video a facile approach for robotic surgeons to perform an extensive para-aortic lymphadenectomy up to the renal vessels, as well an infragastric omentectomy, using the latest-generation multiquadrant robotic platform. This platform allows for facile rotation from an upper abdominal view to perform the para-aortic lymphadenectomy and omentectomy, to a pelvic view to complete the pelvic lymphadenectomies, hysterectomy and bilateral salpingo-oophorectomy. We demonstrate this technique in a 67-year-old woman with a newly diagnosed uterine carcinosarcoma who underwent a robotic-assisted laparoscopic total hysterectomy, bilateral salpingo-oophorectomy, bilateral pelvic and para-aortic lymphadenectomy, and infragastric omentectomy via the Xi Da Vinci Robot (Intuitive Surgical, Sunnyvale, CA). Total operative time was 280 minutes (50 minutes for the omentectomy, 86 minutes for the para-aortic lymphadenectomy). Estimated blood loss was 50 mL. Final pathology revealed a stage IA uterine carcinosarcoma; a total of 27 para-aortic lymph nodes and 20 pelvic lymph nodes were removed, and the size of the excised omentum was 68 × 10 × 1.2 cm. CONCLUSION: The technique of using alternating dual perspectives (upper abdominal or pelvic views) through a multiquadrant robotic platform enables the robotic surgeon to perform extensive para-aortic lymphadenectomies and omentectomies without resorting to laparoscopic surgery to complete these procedures.


Asunto(s)
Carcinosarcoma/patología , Escisión del Ganglio Linfático/métodos , Estadificación de Neoplasias/métodos , Procedimientos Quirúrgicos Robotizados/métodos , Neoplasias Uterinas/patología , Anciano , Femenino , Procedimientos Quirúrgicos Ginecológicos/métodos , Humanos , Ganglios Linfáticos/patología , Tempo Operativo
20.
Nanomedicine ; 13(3): 965-976, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-27890656

RESUMEN

Epithelial ovarian cancer (EOC) is the most deadly gynecologic malignancy on account of its late stage at diagnosis and frequency of drug resistant recurrences. Novel therapies to overcome these barriers are urgently needed. TWIST is a developmental transcription factor reactivated in cancers and linked to angiogenesis, metastasis, cancer stem cell phenotype, and drug resistance, making it a promising therapeutic target. In this work, we demonstrate the efficacy of TWIST siRNA (siTWIST) and two nanoparticle delivery platforms to reverse chemoresistance in EOC models. Polyamidoamine dendrimers and mesoporous silica nanoparticles (MSNs) carried siTWIST into target cells and led to sustained TWIST knockdown in vitro. Mice treated with cisplatin plus MSN-siTWIST exhibited lower tumor burden than mice treated with cisplatin alone, with most of the effect coming from reduction in disseminated tumors. This platform has potential application for overcoming the clinical challenges of metastasis and chemoresistance in EOC and other TWIST overexpressing cancers.


Asunto(s)
Nanopartículas/química , Neoplasias Glandulares y Epiteliales/terapia , Neoplasias Ováricas/terapia , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/uso terapéutico , Tratamiento con ARN de Interferencia/métodos , Dióxido de Silicio/química , Proteína 1 Relacionada con Twist/genética , Animales , Carcinoma Epitelial de Ovario , Línea Celular Tumoral , Dendrímeros/química , Femenino , Humanos , Ratones , Ratones Endogámicos NOD , Nanopartículas/ultraestructura , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Ovario/metabolismo , Ovario/patología , Porosidad , ARN Interferente Pequeño/genética
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