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BACKGROUND: Endometrial serous carcinoma (ESC) and tubo-ovarian high-grade serous carcinoma (HGSC) are characterized by late-stage presentation and high mortality. Current guidelines for prevention recommend risk-reducing salpingo-oophorectomy (RRSO) in patients with hereditary mutations in cancer susceptibility genes. However, HGSC displays extensive genetic heterogeneity with alterations in 168 genes identified in TCGA study, but current germline testing panels are often limited to the handful of recurrently mutated genes, leaving families with rare hereditary gene mutations potentially at-risk. OBJECTIVE: To determine if there are rare germline mutations that may aid in early identification of more patients at-risk for ESC and/or HGSC by evaluating patients with concurrent ESC, HGSC or precursor lesions, and endometrial atypical hyperplasia (CAH) or low-grade endometrial endometrioid adenocarcinoma (LGEEA). METHODS: We performed targeted next-generation sequencing using TSO 500, a 523 gene panel, on formalin-fixed paraffin-embedded tumor and matched benign non-tumor tissue blocks from 5 patients with concurrent ESC, HGSC or precursor lesions, and CAH or LGEEA. RESULTS: We identified germline pathogenic, likely pathogenic or uncertain significance variants in cancer susceptibility genes in 4 of 5 patients - affected genes included GLI1, PIK3R1, FOXP1, FANCD2, INPP4B and H3F3C. Notably, none of these genes were included in the commercially available germline testing panels initially used to evaluate the patients at the time of their diagnoses. CONCLUSION: Comprehensive germline testing of patients with concurrent LGEEA or CAH and ESC, HGSC or precursor lesions may aid in early identification of relatives at-risk for cancer who may be candidates for RRSO with hysterectomy.
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Carcinoma Endometrioide , Neoplasias Endometriales , Mutación de Línea Germinal , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias Ováricas , Humanos , Femenino , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patología , Persona de Mediana Edad , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patología , Anciano , Neoplasias de las Trompas Uterinas/genética , Neoplasias de las Trompas Uterinas/patología , Predisposición Genética a la Enfermedad , AdultoRESUMEN
Pregnancy-associated breast cancer (PABC) is diagnosed during or shortly after pregnancy. Although rare, PABC is a serious occurrence often of the triple negative (TNBC) subtype. Here we show progesterone, prolactin, and RANKL upregulate BRCA1-IRIS (IRIS) in separate and overlapping subpopulations of human mammary epithelial cell lines, which exacerbates the proliferation, survival, and the TNBC-like phenotype in them. Conversely, vitamin D3 reduces IRIS expression in TNBC cell lines, which attenuates growth, survival, and the TNBC-like phenotype in them. In the mouse, Brca1-Iris (Iris, mouse IRIS homolog) is expressed at low-level in nulliparous mice, increases ~10-fold in pregnant/lactating mice, to completely disappear in involuting mice, and reappears at low-level in regressed glands. Mice underwent 3 constitutive pregnancies followed by a forced involution (after 5 days of lactation) contained ~10-fold higher Iris in their mammary glands compared to those underwent physiological involution (after 21 days of lactation). While protein extracts from lactating glands promote proliferation in IRISlow and IRIS overexpressing (IRISOE) cells, extracts from involuting glands promote apoptosis in IRISlow, and aneuploidy in IRISOE cells. In a cohort of breast cancer patients, lack of breastfeeding was associated with formation of chemotherapy resistant, metastatic IRISOE breast cancers. We propose that terminal differentiation triggered by long-term breastfeeding reduces IRIS expression in mammary cells allowing their elimination by the inflammatory microenvironment during physiological involution. No/short-term breastfeeding retains in the mammary gland IRISOE cells that thrive in the inflammatory microenvironment during forced involution to become precursors for aggressive breast cancers shortly after pregnancy.
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PURPOSE: To test effects of positron emission tomography (PET)-based bone marrow-sparing (BMS) image-guided intensity modulated radiation therapy (IG-IMRT) on efficacy and toxicity for patients with locoregionally advanced cervical cancer. METHODS AND MATERIALS: In an international phase II/III trial, patients with stage IB-IVA cervical carcinoma were treated with either PET-based BMS-IG-IMRT (PET-BMS-IMRT group) or standard image-guided IMRT (IMRT group), with concurrent cisplatin (40 mg/m2 weekly), followed by brachytherapy. The phase II component nonrandomly assigned patients to PET-BMS-IMRT or standard IMRT. The phase III trial randomized patients to PET-BMS-IMRT versus IMRT, with a primary endpoint of progression-free survival (PFS) but was closed early for futility. Phase III patients were analyzed separately and in combination with phase II patients, comparing acute hematologic toxicity, cisplatin delivery, PFS, overall survival (OS), and patterns of failure. In a post-hoc exploratory analysis, we investigated the association between pretreatment absolute lymphocyte count (ALC) and OS. RESULTS: In total, 101 patients were enrolled on the phase II/III trial, including 29 enrolled in phase III (PET-BMS-IMRT group: 16; IMRT group: 13) before early closure. Median follow-up was 33 months for phase III patients and 39 months for all patients. PFS and OS at 5 years for all patients were 73.6% (95% confidence interval [CI], 64.9%-84.3%) and 84% (95% CI, 76%-92.9%]), respectively. There were no differences in number of cisplatin cycles, OS, PFS, or patterns of failure between groups for the combined cohort. The incidence of acute grade ≥ 3 neutropenia was significantly lower in the PET-BMS-IMRT group compared with IMRT for randomized patients (19% vs 54%, χ2P = .048) and in the combined cohort (13% vs 35%, χ2P = .01). Patients with pretreatment ALC ≤ 1.5 k/µL had nonsignificantly worse OS on multivariable analysis (HR 2.85; 95% CI, 0.94-8.62; adjusted P = .216), compared with patients with ALC > 1.5 k/µL. There was no difference in posttreatment ALC by treatment group. CONCLUSIONS: PET-BMS-IMRT significantly reduced acute grade ≥3 neutropenia, but not treatment-related lymphopenia, compared with standard IMRT. We found no evidence that PET-BMS-IMRT affected chemotherapy delivery or long-term outcomes, and weak evidence of an association between pretreatment ALC and OS.
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Radioterapia de Intensidad Modulada , Neoplasias del Cuello Uterino , Médula Ósea/efectos de la radiación , Cisplatino/uso terapéutico , Femenino , Humanos , Tomografía de Emisión de Positrones , Radioterapia Guiada por Imagen , Radioterapia de Intensidad Modulada/efectos adversos , Radioterapia de Intensidad Modulada/métodos , Resultado del Tratamiento , Neoplasias del Cuello Uterino/diagnóstico por imagen , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/radioterapiaRESUMEN
Radiomics has been applied to predict recurrence in several disease sites, but current approaches are typically restricted to analyzing tumor features, neglecting nontumor information in the rest of the body. The purpose of this work was to develop and validate a model incorporating nontumor radiomics, including whole-body features, to predict treatment outcomes in patients with previously untreated locoregionally advanced cervical cancer. Methods: We analyzed 127 cervical cancer patients treated definitively with chemoradiotherapy and intracavitary brachytherapy. All patients underwent pretreatment whole-body 18F-FDG PET/CT. To quantify effects due to the tumor itself, the gross tumor volume (GTV) was directly contoured on the PET/CT image. Meanwhile, to quantify effects arising from the rest of the body, the planning target volume (PTV) was deformably registered from each planning CT to the PET/CT scan, and a semiautomated approach combining seed-growing and manual contour review generated whole-body muscle, bone, and fat segmentations on each PET/CT image. A total of 965 radiomic features were extracted for GTV, PTV, muscle, bone, and fat. Ninety-five patients were used to train a Cox model of disease recurrence including both radiomic and clinical features (age, stage, tumor grade, histology, and baseline complete blood cell counts), using bagging and split-sample-validation for feature reduction and model selection. To further avoid overfitting, the resulting models were tested for generalization on the remaining 32 patients, by calculating a risk score based on Cox regression and evaluating the c-index (c-index > 0.5 indicates predictive power). Results: Optimal performance was seen in a Cox model including 1 clinical biomarker (whether or not a tumor was stage III-IVA), 2 GTV radiomic biomarkers (PET gray-level size-zone matrix small area low gray level emphasis and zone entropy), 1 PTV radiomic biomarker (major axis length), and 1 whole-body radiomic biomarker (CT bone root mean square). In particular, stratification into high- and low-risk groups, based on the linear risk score from this Cox model, resulted in a hazard ratio of 0.019 (95% CI, 0.004, 0.082), an improvement over stratification based on clinical stage alone, which had a hazard ratio of 0.36 (95% CI, 0.16, 0.83). Conclusion: Incorporating nontumor radiomic biomarkers can improve the performance of prognostic models compared with using only clinical and tumor radiomic biomarkers. Future work should look to further test these models in larger, multiinstitutional cohorts.
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Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias del Cuello Uterino , Femenino , Fluorodesoxiglucosa F18 , Humanos , Recurrencia Local de Neoplasia , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Pronóstico , Estudios Retrospectivos , Insuficiencia del Tratamiento , Neoplasias del Cuello Uterino/diagnóstico por imagen , Neoplasias del Cuello Uterino/terapiaRESUMEN
OBJECTIVE: To describe the practice patterns and outcomes of patients with stage 3B endometrial cancer. METHODS: We queried the National Cancer Database for all surgically staged, stage 3 patients between 2012 and 2016. Patients who received any pre-operative therapy were excluded. Demographics, tumor factors, and adjuvant therapy for the stage 3 substages were compared. Logistic regression was used to identify factors associated with adjuvant therapy. Kaplan Meier curves were generated and compared using the log-rank test. Multivariable Cox Proportional Hazards Model was used to adjust for prognostic factors. Findings with p < 0.05 were considered significant. RESULTS: Of 7363 patients with stage 3 disease, 478 (6%) had stage 3B; 1732 (23%) had stage 3A, 3457 (48%) had stage 3C1, and 1696 (23%) had stage 3C2 disease. Post-surgical treatment consisted of: combined chemotherapy (CT) and radiation (RT) (49%), CT alone (28%), RT alone (9%), 14% received no postoperative therapy. Among all stage 3 substages, patients with stage 3B disease were the least likely to receive any CT, and the most likely to receive RT alone. After adjusting for known prognostic factors, patients with stage 3A (Hazard ratio (HR) of death = 0.64) and 3C1 (HR of death = 0.79) disease had significantly worse overall survival compared to stage 3B; survival was not demonstrably different from patients with stage 3C2 disease. Patients with stage 3B disease who received CT + RT had the best overall survival. CONCLUSION: Survival of patients with stage 3B disease is similar to that of patients with para-aortic node metastases and is inferior to all others with stage 3 endometrial cancer. Less frequent CT and a higher rate of post-operative RT alone, describes a distinct practice from that seen in other stage 3 patients.
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Neoplasias Endometriales/mortalidad , Oncología Médica/estadística & datos numéricos , Pautas de la Práctica en Medicina/estadística & datos numéricos , Quimioradioterapia Adyuvante/estadística & datos numéricos , Quimioterapia Adyuvante/estadística & datos numéricos , Bases de Datos Factuales/estadística & datos numéricos , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/terapia , Femenino , Humanos , Histerectomía/métodos , Histerectomía/estadística & datos numéricos , Escisión del Ganglio Linfático/estadística & datos numéricos , Estadificación de Neoplasias , Estudios Prospectivos , Radioterapia Adyuvante/estadística & datos numéricos , Estudios Retrospectivos , Salpingooforectomía , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
OBJECTIVE: To investigate the representation of women as principal investigators (PI) in phase 3, gynecologic oncology clinical trials. METHODS: ClinicalTrials.gov was queried for all phase 3 clinical trials with start dates between January 1, 2010 and December 31, 2020 using the search terms: "ovarian cancer", "endometrial cancer", and "cervical cancer". Trial characteristics were abstracted from the website. Gender of the PI was assessed by name, image on institutional website or by querying the trial coordinator. Trials were considered to have women's representation if women were the sole PI or among multiple co-PIs. Chi-square tests and relative risks were used to compare proportions across groups. Linear regression was used to assess trends over time. RESULTS: 200 unique clinical trials were included in this analysis, of which women were represented as PI in 76 (38%). Women were more likely to be a PI of trials funded by multiple sites than a single entity (RR = 1.80, 95% confidence interval (CI) 1.25, 2.61, p = 0.01), registered outside of Asia than those in Asia (RR = 1.78, 95% CI 1.11, 2.88, p = 0.02), and trials with multiple co-PIs than with one PI (RR = 1.78 (95% CI 1.18, 2.67), p = 0.01). Overall, women's representation as a PI increased by 3% annually (by year of registration, R2 = 0.61, p = 0.01). This increase was most evident in trials registered in multiple continents and Europe (both 4% annually). CONCLUSIONS: Women's representation as PIs in clinical trials has increased in the last decade. Trials funded by multiple sources outside of Asia have the highest proportion of PIs who are women. These trends may represent ongoing leadership and mentorship opportunities for women gynecologic oncologists.
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Ensayos Clínicos como Asunto/organización & administración , Neoplasias de los Genitales Femeninos/terapia , Liderazgo , Oncología Médica/tendencias , Médicos Mujeres/tendencias , Asia , Ensayos Clínicos como Asunto/estadística & datos numéricos , Europa (Continente) , Femenino , Geografía , Humanos , Oncología Médica/organización & administración , Oncología Médica/estadística & datos numéricos , Médicos Mujeres/estadística & datos numéricosRESUMEN
OBJECTIVES: To describe the transition from a mentee to mentor role in a cohort of academic gynecologic oncologists by studying the evolution of authorship placement in peer reviewed publications by current gynecologic oncology (GO) fellowship directors. METHODS: Current GO fellowship directors were identified from the ACGME website. A Pubmed search identified all publications by all listed fellowship directors. Number of publications, and order of authorship were counted by years since medical school graduation. Milestones representing likely career transition points were developed and tracked. Descriptive statistics were used to characterize the individuals and associated institutions. Time to event curves were compared using the Kaplan Meier method. RESULTS: The study cohort comprised 58 GO fellowship program directors. The median time since medical school graduation was 22â¯years. Eight unique milestones reflecting the relative frequencies of authorship placement were studied. The median time to accomplishing these milestones ranged from 6 to 18â¯years. The timing of milestone attainment suggests a stepwise progression of events and was associated with both individual and institutional factors. CONCLUSIONS: In this cohort of 58 fellowship directors, a roadmap to mentorship was identified, that includes several measurable milestones, and representative times to attain each. Further analyses identified a set of factors associated with the rate of progression. We hope these findings can inform the evolution of mentorship in gynecologic oncology. It is possible that initiatives focused on mentorship training might include milestone tracking to facilitate development.
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Ginecología/educación , Oncología Médica/educación , Mentores , Academias e Institutos , Autoria , Estudios de Cohortes , Educación de Postgrado en Medicina , Becas , Femenino , Neoplasias de los Genitales Femeninos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: To describe our single-institution oncologic outcomes of patients who received neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: We compared clinicopathologic information and outcomes for all patients with advanced stage, high-grade serous ovarian cancer who received NACT and IDS with (Nâ¯=â¯20) or without (Nâ¯=â¯48) HIPEC at our institution from 2010 to 2019 RESULTS: Mean age (62â¯years with HIPEC and 60â¯years without HIPEC) and proportion of stage 4 disease (40% for both) did not differ between cohorts. HIPEC patients had higher rates of complete cytoreduction (95% vs 50%), longer mean duration of surgery (530 vs. 216â¯min), more grade 3 or 4 postoperative complications (65% vs. 4%), and longer mean length of hospital stay (8 vs. 5â¯days). HIPEC patients had significantly higher risk for platinum-refractory progression or platinum-resistance recurrence (50% vs 23%; RRâ¯=â¯2.18; 95% CI 1.11, 4.30, pâ¯=â¯0.024). Median progression free survival (11.5 vs. 12â¯months) and all-cause mortality (19.1 vs. 30.5â¯months) in the HIPEC and non-HIPEC cohorts, respectively, did not differ CONCLUSIONS: HIPEC was associated with increased risk for platinum refractory or resistant disease. Higher surgical complexity may contribute to higher complication rates without improving oncologic outcomes in our patients. Further investigations and long-term follow-up are needed to assess the utility of HIPEC in primary treatment of advanced stage ovarian cancer.
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Cisplatino/farmacología , Cistadenocarcinoma Seroso/terapia , Quimioterapia Intraperitoneal Hipertérmica/métodos , Neoplasias Ováricas/terapia , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Cisplatino/administración & dosificación , Estudios de Cohortes , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/cirugía , Procedimientos Quirúrgicos de Citorreducción/métodos , Resistencia a Antineoplásicos , Neoplasias de las Trompas Uterinas/tratamiento farmacológico , Neoplasias de las Trompas Uterinas/cirugía , Neoplasias de las Trompas Uterinas/terapia , Femenino , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/cirugía , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/cirugía , Neoplasias Peritoneales/terapia , Estudios Retrospectivos , Adulto JovenRESUMEN
OBJECTIVES: To determine the prevalence, risk factors for, and clinical implications of unintentional weight loss on oncologic outcomes in locally advanced cervical cancer (LACC) treated with concurrent chemotherapy and contemporary radiation techniques. METHODS: This a single-institution, retrospective cohort study of patients with LACC who received definitive chemoradiation (CRT) from 2010 to 2015. Clinicopathologic factors were abstracted by chart review and characterized using descriptive statistics. Factors associated with severe weight loss (≥10% from baseline) were determined by Chi-square test. Time-to-event analysis was performed using the Kaplan Meier method and regression was performed using the Cox Proportional hazards model. RESULTS: One hundred and eight patients comprised the cohort. The majority of patients were White, obese, and had squamous histology. Almost 80% of patients experienced at least some weight loss, with 14% of patients experiencing severe weight loss. Patients with FIGO 2009 stage 3 or 4 disease had a 3.4-fold increased risk of severe weight loss compared to those with earlier stage disease. Patients who had severe weight loss had a higher risk for death (HRâ¯=â¯2.37, 95% confidence interval [CI] 1.77, 7.37, pâ¯=â¯0.036) and a trend toward high risk for recurrence (HRâ¯=â¯1.43, 95% CI 0.46, 3.32, pâ¯=â¯0.107) compared to patients without severe weight loss. CONCLUSION: Unintentional weight loss is a common symptom of patients with LACC receiving CRT that affects oncologic outcomes, yet it remains under-recognized. Increased awareness of weight loss and malnutrition may encourage interventions to improve this potentially modifiable risk factor for worse prognosis and quality of life.
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Quimioradioterapia/métodos , Desnutrición/complicaciones , Calidad de Vida/psicología , Neoplasias del Cuello Uterino/complicaciones , Pérdida de Peso/fisiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/radioterapia , Adulto JovenRESUMEN
OBJECTIVES: 1.) To compare frequency of HIPEC use in ovarian cancer treatment before and after publication of the phase III study by van Driel et al. in January 2018. 2.) To compare associated rates of hospital-based outcomes, including length of stay, intensive care unit (ICU) admission, complications, and costs in ovarian cancer surgery with or without HIPEC. METHODS: We queried Vizient's administrative claims database of 550 US hospitals for ovarian cancer surgeries from January 2016-January 2020 using ICD-10 diagnosis and procedure codes. Sodium thiosulfate administration was used to identify HIPEC cases according to the published protocol. Student t-tests and relative risk (RR) were used to compare continuous variables and contingency tables, respectively. RESULTS: 152 ovarian cancer patients had HIPEC at 39 hospitals, and 20,014 ovarian cancer patients had surgery without HIPEC at 256 hospitals. Following the trial publication, 97% of HIPEC cases occurred. During the index admission, HIPEC patients had longer median length of stay (8.4 vs. 5.7 days, p < 0.001) and higher percentage of ICU admissions (63.1% vs. 11.0%, p < 0.001) and complication rates (RR = 1.87, p = 0.002). Index admission direct costs ($21,825 vs. $12,038, p < 0.001) and direct cost index (observed/expected costs) (1.87 vs. 1.11, p < 0.001) were also greater in the HIPEC patients. No inpatient deaths or 30-day readmissions were identified after HIPEC. CONCLUSIONS: Use of HIPEC for ovarian cancer increased in the US after publication of a phase III clinical trial in a high-impact journal, though the absolute number of cases remains modest. Incorporation of HIPEC was associated with increased cost, hospital length of stay, ICU admission, and hospital-acquired complication rates. Further studies are needed in order to evaluate long-term outcomes, including morbidity and survival.
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Carcinoma Epitelial de Ovario/terapia , Procedimientos Quirúrgicos de Citorreducción/efectos adversos , Quimioterapia Intraperitoneal Hipertérmica/tendencias , Neoplasias Ováricas/terapia , Complicaciones Posoperatorias/epidemiología , Anciano , Anciano de 80 o más Años , Carcinoma Epitelial de Ovario/economía , Carcinoma Epitelial de Ovario/mortalidad , Ensayos Clínicos Fase III como Asunto , Femenino , Costos de Hospital/estadística & datos numéricos , Costos de Hospital/tendencias , Humanos , Quimioterapia Intraperitoneal Hipertérmica/efectos adversos , Quimioterapia Intraperitoneal Hipertérmica/economía , Quimioterapia Intraperitoneal Hipertérmica/estadística & datos numéricos , Unidades de Cuidados Intensivos/economía , Unidades de Cuidados Intensivos/estadística & datos numéricos , Unidades de Cuidados Intensivos/tendencias , Tiempo de Internación/economía , Tiempo de Internación/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Neoplasias Ováricas/economía , Neoplasias Ováricas/mortalidad , Ovario/efectos de los fármacos , Ovario/cirugía , Admisión del Paciente/economía , Admisión del Paciente/estadística & datos numéricos , Admisión del Paciente/tendencias , Complicaciones Posoperatorias/economía , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Estados Unidos/epidemiologíaRESUMEN
PURPOSE: The use of concurrent doublet chemotherapy with radiation for locoregionally advanced cervical cancer (LACC) is limited by gastrointestinal and hematologic toxicity. By reducing radiation dose to bowel and bone marrow, image guided intensity modulated radiation therapy (IG-IMRT) may improve chemotherapy tolerance. The goal of this study was to determine whether IG-IMRT could lead to improved tolerance to concurrent cisplatin and gemcitabine for LACC. METHODS AND MATERIALS: We conducted an open-label, nonrandomized, prospective phase 1 dose escalation trial at a tertiary academic cancer center (ClinicalTrials.gov identifier: NCT01554410). We enrolled patients with stage IB-IVA cervical cancer, with either an intact cervix or posthysterectomy with residual/recurrent pelvic or paraortic nodal involvement, undergoing radical pelvic or extended field chemoradiation therapy. Treatment consisted of chemoradiation with IG-IMRT (45-47.6 Gy, 25-28 fractions to the pelvis ± paraortic nodes with simultaneous nodal boost to 53.2-59.4 Gy, 28 fractions) plus 5 cycles of concurrent weekly cisplatin 40 mg/m2 with escalating doses of gemcitabine (50, 75, 100, or 125 mg/m2). Cohorts were separated preregistration according to whether the patient received pelvic or extended field IG-IMRT and whether gemcitabine followed (CG) or preceded (GC) cisplatin delivery. Dose-limiting toxicity (DLT) events were monitored up to 30 days after chemoradiation therapy. The primary endpoint was maximum tolerated dose (MTD) resulting in DLT probability ≤20%. RESULTS: Between February 2011 and June 2019, 35 patients were registered. Overall, 7 patients (20.0%) experienced DLTs. For the pelvic field cohort, the estimated MTD was 100 mg/m2 with GC sequencing, which is higher than the previously reported MTD for this regimen. The extended field cohort was closed after 2 of 3 patients experienced a DLT at the first dose level. CONCLUSIONS: IG-IMRT can permit higher doses of concurrent gemcitabine with cisplatin and pelvic radiation for LACC. However, acute toxicity remains a factor with this regimen, depending on radiation volume and chemotherapy sequencing.
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Cisplatino/uso terapéutico , Desoxicitidina/análogos & derivados , Radioterapia Guiada por Imagen , Radioterapia de Intensidad Modulada , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/radioterapia , Adulto , Anciano , Cisplatino/efectos adversos , Terapia Combinada/efectos adversos , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Femenino , Humanos , Persona de Mediana Edad , Radioterapia Guiada por Imagen/efectos adversos , Radioterapia de Intensidad Modulada/efectos adversos , Resultado del Tratamiento , Neoplasias del Cuello Uterino/diagnóstico por imagen , Neoplasias del Cuello Uterino/patología , Adulto Joven , GemcitabinaRESUMEN
OBJECTIVE: Characterize change in rates of minimally invasive (MIS) radical hysterectomy after presentation of the LACC trial. METHODS: Longitudinal analysis of data from Vizient® database for surgically treated patients with invasive cervical cancer from April 2017-March 2019. Covariates studied included patient demographic and obesity categories, dates of LACC trial presentation and publication, and hospital characteristics. RESULTS: 2102 cervical cancer patients had surgery at 201 hospitals. Most were age 31-50 (51.2%), White (64.8%), and had public (49.2%) health insurance. Annual rates of MIS fell from 51.9% to 27.1% after the LACC trial presentation (RR 0.52, 95% CI 0.47, 0.58; p < 0.0001). Adjusting for within hospital correlation, the odds of MIS dropped by 13% per month (OR = 0.872 per month, 95% CI 0.852, 0.891; p < 0.001), without further change in rates of MIS after the peer-review publication (OR = 1.033 per month, 95% CI 0.897, 1.189; p = 0.65). Rates of MIS declined across all demographics (RR = 0.32-0.65; p < 0.01), except in morbidly obese women (RR = 0.90; p = 0.60). Applying mixed effects model, rates of MIS fell by 3% per month in morbidly obese women versus 18% per month if body mass index<40 kg/m2. NCCN member hospitals and hospitals with gynecologic oncology fellowship training programs significantly reduced rates of MIS radical hysterectomy faster, but not earlier, than other hospitals. CONCLUSIONS: Rates of MIS radical hysterectomy fell dramatically and pervasively after the LACC trial presentation, despite ongoing substantive controversy. Practice pattern changes were not significant in morbidly obese women.
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Histerectomía/educación , Histerectomía/estadística & datos numéricos , Difusión de la Información , Procedimientos Quirúrgicos Mínimamente Invasivos/educación , Procedimientos Quirúrgicos Mínimamente Invasivos/estadística & datos numéricos , Pautas de la Práctica en Medicina/estadística & datos numéricos , Neoplasias del Cuello Uterino/cirugía , Adulto , Femenino , Humanos , Estudios Longitudinales , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Obesidad Mórbida/epidemiología , Ensayos Clínicos Controlados Aleatorios como Asunto , Estados Unidos/epidemiología , Neoplasias del Cuello Uterino/epidemiologíaRESUMEN
OBJECTIVE: To determine incidence of ovarian clear cell cancer (OCCC) by race ethnicity and how that relationship is affected by birthplace among Asian Pacific Islanders (API). METHODS: The 18 registries of the U.S. Surveillance, Epidemiology, and End Results (SEER) dataset were queried to identify all women registered with epithelial ovarian cancer from 1973 to 2013. Relative risks of OCCC to non-OCCC based on ethnicity and birthplace were compared. RESULTS: We identified 72, 501 women with epithelial ovarian cancer in the dataset; of these, 5078 (7.0%) had OCCC and 4859 (6.7%) were API. The age-adjusted incidence rate/100,000 women of OCCC was significantly higher in API women (0.6, 0.5-0.6 95% CI) compared to any other ethnicity. A significantly higher proportion of API women had OCCC (14.5%) compared to their White (6.6%, RR 2.2, p < 0.0001) and Black counterparts (4.3%, RR 3.4, p < 0.0001). The majority of API women were foreign-born (70.8%). The relative risk of clear cell compared to non-clear cell epithelial ovarian cancer was not demonstrably different among foreign born API women with ovarian cancer (RR 1.1, 95% CI 0.9 to 1.3, p = 0.6). CONCLUSIONS: We have demonstrated that, in the US, there is an elevated risk of OCCC associated with API ethnicity. Place of birth does not appear to significantly modify the association, suggesting that the increased risk of OCCC in API women may not be affected by acculturation or environmental exposure. Future research exploring the complex relationships between ethnicity and risk of malignancy will be important as we make progress in understanding disease process and treatment.
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Adenocarcinoma de Células Claras/epidemiología , Nativos de Hawái y Otras Islas del Pacífico/estadística & datos numéricos , Neoplasias Ováricas/epidemiología , Adenocarcinoma de Células Claras/etnología , Anciano , Carcinoma Epitelial de Ovario/epidemiología , Carcinoma Epitelial de Ovario/etnología , Estudios de Cohortes , Femenino , Humanos , Persona de Mediana Edad , Nativos de Hawái y Otras Islas del Pacífico/etnología , Neoplasias Ováricas/etnología , Estudios Retrospectivos , Riesgo , Programa de VERF , Estados Unidos/epidemiologíaRESUMEN
CONTEXT: - Serous carcinoma of the gynecologic tract often involves the external bladder wall and can occasionally mimic primary urothelial carcinoma of the bladder. OBJECTIVE: - To define the spectrum of morphologic and immunohistochemical features that characterize serous carcinoma involving the bladder wall and its distinction from urothelial carcinoma. DESIGN: - We reviewed all cases of serous carcinoma secondarily involving the bladder wall from the University of California San Diego and Polytechnic Institute for histopathologic and immunohistochemical features. RESULTS: - We identified 20 cases of Müllerian high-grade serous carcinoma involving the bladder wall. Five cases were clinical mimics of urothelial carcinoma, including 2 cases that presented as a large, transmural, primary bladder mass without precedent gynecologic history in women younger than 60 years, and 3 cases presumed to be new bladder carcinoma occurring distant to a serous carcinoma diagnosis. A subset of cases were morphologic mimics of urothelial carcinoma, which showed nested growth patterns (2 of 20; 10%), squamouslike foci (2 of 20; 10%), spindled/sarcomatoid growth (2 of 20; 10%), basaloid morphology (3 of 20; 15%), and syncytial growth patterns (1 of 20; 5%). Immunohistochemical stains in 17 cases showed immunoreactivity for CK7 (17 of 17; 100%), WT1 (17 of 17; 100%), uroplakin (UP) II (1 of 17; 6%), p63 (2 of 17; 12%), GATA3 (2 of 17; 12%), and PAX8 (17 of 17; 100%). CONCLUSIONS: - A subset of serous carcinomas involving the bladder wall can mimic urothelial carcinoma. Awareness of this mimicker and use of an immunohistochemical panel that includes CK7, WT1, UPII, PAX8, p63, and GATA3 can be helpful in confirming the diagnosis.
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Biomarcadores de Tumor/análisis , Carcinoma de Células Transicionales/diagnóstico , Cistadenocarcinoma Seroso/diagnóstico , Diagnóstico Diferencial , Neoplasias de los Genitales Femeninos/diagnóstico , Neoplasias de la Vejiga Urinaria/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Transicionales/patología , Cistadenocarcinoma Seroso/patología , Femenino , Neoplasias de los Genitales Femeninos/patología , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia/diagnóstico , Metástasis de la Neoplasia/patología , Neoplasias de la Vejiga Urinaria/patología , Urotelio/patologíaRESUMEN
PURPOSE: To quantify longitudinal changes in active bone marrow (ABM) distributions within unirradiated (extrapelvic) and irradiated (pelvic) bone marrow (BM) in cervical cancer patients treated with concurrent chemoradiation therapy (CRT). METHODS AND MATERIALS: We sampled 39 cervical cancer patients treated with CRT, of whom 25 were treated with concurrent cisplatin (40 mg/m2) and 14 were treated with cisplatin (40 mg/m2) plus gemcitabine (50-125 mg/m2) (C/G). Patients underwent 18F-fluorodeoxyglucose positron emission tomographic/computed tomographic imaging at baseline and 1.5 to 6.0 months after treatment. ABM was defined as the subvolume of bone with standardized uptake value (SUV) above the mean SUV of the total bone. The primary aim was to measure the compensatory response, defined as the change in the log of the ratio of extrapelvic versus pelvic ABM percentage from baseline to after treatment. We also quantified the change in the proportion of ABM and mean SUV in pelvic and extrapelvic BM using a 2-sided paired t test. RESULTS: We observed a significant increase in the overall extrapelvic compensatory response after CRT (0.381; 95% confidence interval [CI]: 0.312, 0.449) and separately in patients treated with cisplatin (0.429; 95% CI: 0.340, 0.517) and C/G (0.294; 95% CI: 0.186, 0.402). We observed a trend toward higher compensatory response in patients treated with cisplatin compared with C/G (P=.057). Pelvic ABM percentage was reduced after CRT both in patients receiving cisplatin (P<.001) and in those receiving C/G (P<.001), whereas extrapelvic ABM percentage was increased in patients receiving cisplatin (P<.001) and C/G (P<.001). The mean SUV in pelvic structures was lower after CRT with both cisplatin (P<.001) and C/G (P<.001). The mean SUV appeared lower in extrapelvic structures after CRT in patients treated with C/G (P=.076) but not with cisplatin (P=.942). We also observed that older age and more intense chemotherapy regimens were correlated with a decreased compensatory response on multivariable analysis. In patients treated with C/G, mean pelvic bone marrow dose was found to be negatively correlated with the compensatory response. CONCLUSION: Patients have differing subacute compensatory responses after CRT, owing to variable recovery in unirradiated marrow. Intensive chemotherapy regimens appear to decrease the extrapelvic compensatory response, which may lead to increased hematologic toxicity.
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Enfermedades de la Médula Ósea/diagnóstico por imagen , Enfermedades de la Médula Ósea/etiología , Quimioradioterapia/efectos adversos , Traumatismos por Radiación/diagnóstico por imagen , Traumatismos por Radiación/etiología , Neoplasias del Cuello Uterino/terapia , Médula Ósea/diagnóstico por imagen , Médula Ósea/efectos de los fármacos , Médula Ósea/efectos de la radiación , Femenino , Humanos , Estudios Longitudinales , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Resultado del Tratamiento , Neoplasias del Cuello Uterino/complicaciones , Neoplasias del Cuello Uterino/diagnóstico por imagenRESUMEN
Identification of specific oncogenic gene changes has enabled the modern generation of targeted cancer therapeutics. In high-grade serous ovarian cancer (OV), the bulk of genetic changes is not somatic point mutations, but rather somatic copy-number alterations (SCNAs). The impact of SCNAs on tumour biology remains poorly understood. Here we build haploinsufficiency network analyses to identify which SCNA patterns are most disruptive in OV. Of all KEGG pathways (N=187), autophagy is the most significantly disrupted by coincident gene deletions. Compared with 20 other cancer types, OV is most severely disrupted in autophagy and in compensatory proteostasis pathways. Network analysis prioritizes MAP1LC3B (LC3) and BECN1 as most impactful. Knockdown of LC3 and BECN1 expression confers sensitivity to cells undergoing autophagic stress independent of platinum resistance status. The results support the use of pathway network tools to evaluate how the copy-number landscape of a tumour may guide therapy.
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Alelos , Haploinsuficiencia/genética , Mutación/genética , Neoplasias Ováricas/genética , Autofagia/genética , Línea Celular Tumoral , Proliferación Celular/genética , Variaciones en el Número de Copia de ADN/genética , Sistemas de Liberación de Medicamentos , Femenino , Genes Relacionados con las Neoplasias , Humanos , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Proteostasis/genéticaRESUMEN
OBJECTIVE: To examine the association between living in a county with gynecologic oncologist provision, the performance of fertility sparing surgery, and survival among young women with early epithelial ovarian cancer. METHODS: The present retrospective cohort study was based on the SEER 18 dataset of the US National Cancer Institute. Women younger than 45 years with early stage epithelial ovarian cancer diagnosed between 2000 and 2012 were included. Logistic regression and Cox proportional hazards methods were used to analyze all-cause survival. Adjustment was made for relevant clinical and demographic variables. RESULTS: In total, 1499 women were included. Women living in a county with gynecologic oncologist provision were less likely to undergo hysterectomy (adjusted odds ratio, 0.69; 95% confidence interval, 0.52-0.93) at the time of primary surgery. Women who underwent hysterectomy had a similar risk of mortality as women with uterine preservation (adjusted hazard ratio [HR], 0.73; 95% CI, 0.41-1.30). Living in a county with gynecologic oncologist provision was associated with reduced risk of mortality (adjusted HR, 0.53; 95% CI, 0.31-0.92). CONCLUSION: Living in a county with gynecologic oncologist provision was independently associated with the use of fertility sparing surgery among young women with early epithelial ovarian cancer.
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Preservación de la Fertilidad , Neoplasias Ováricas/cirugía , Adulto , Estudios de Cohortes , Femenino , Procedimientos Quirúrgicos Ginecológicos , Humanos , Modelos Logísticos , Persona de Mediana Edad , Neoplasias Ováricas/mortalidad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Programa de VERF , Análisis de Supervivencia , Estados Unidos/epidemiología , Servicios de Salud para Mujeres/estadística & datos numéricos , Adulto JovenRESUMEN
PURPOSE: To test the hypothesis that intensity modulated radiation therapy (IMRT) reduces acute hematologic and gastrointestinal (GI) toxicity for patients with locoregionally advanced cervical cancer. METHODS AND MATERIALS: We enrolled patients with stage IB-IVA cervical carcinoma in a single-arm phase II trial involving 8 centers internationally. All patients received weekly cisplatin concurrently with once-daily IMRT, followed by intracavitary brachytherapy, as indicated. The primary endpoint was the occurrence of either acute grade ≥3 neutropenia or clinically significant GI toxicity within 30 days of completing chemoradiation therapy. A preplanned subgroup analysis tested the hypothesis that positron emission tomography-based image-guided IMRT (IG-IMRT) would lower the risk of acute neutropenia. We also longitudinally assessed patients' changes in quality of life. RESULTS: From October 2011 to April 2015, 83 patients met the eligibility criteria and initiated protocol therapy. The median follow-up was 26.0 months. The incidence of any primary event was 26.5% (95% confidence interval [CI] 18.2%-36.9%), significantly lower than the 40% incidence hypothesized a priori from historical data (P=.012). The incidence of grade ≥3 neutropenia and clinically significant GI toxicity was 19.3% (95% CI 12.2%-29.0%) and 12.0% (95% CI 6.7%-20.8%), respectively. Compared with patients treated without IG-IMRT (n=48), those treated with IG-IMRT (n=35) had a significantly lower incidence of grade ≥3 neutropenia (8.6% vs 27.1%; 2-sided χ2P=.035) and nonsignificantly lower incidence of grade ≥3 leukopenia (25.7% vs 41.7%; P=.13) and any grade ≥3 hematologic toxicity (31.4% vs 43.8%; P=.25). CONCLUSIONS: IMRT reduces acute hematologic and GI toxicity compared with standard treatment, with promising therapeutic outcomes. Positron emission tomography IG-IMRT reduces the incidence of acute neutropenia.
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Médula Ósea , Quimioradioterapia/métodos , Cisplatino/uso terapéutico , Neutropenia/prevención & control , Tratamientos Conservadores del Órgano/métodos , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Radioterapia Guiada por Imagen/métodos , Radioterapia de Intensidad Modulada/métodos , Neoplasias del Cuello Uterino/terapia , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/patología , Adenocarcinoma/terapia , Antineoplásicos/uso terapéutico , Braquiterapia/métodos , Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Estudios de Factibilidad , Femenino , Tracto Gastrointestinal/efectos de la radiación , Humanos , Incidencia , Persona de Mediana Edad , Neutropenia/epidemiología , Dosificación Radioterapéutica , Neoplasias del Cuello Uterino/diagnóstico por imagen , Neoplasias del Cuello Uterino/patologíaRESUMEN
Clostridium difficile infection (CDI) is a major cause of nosocomial diarrhea with the potential for significant morbidity and mortality. Colonization in a susceptible individual, with risk factors such as prior antibiotic use, advanced age, or medical comorbidities, may result in symptomatic infection. Although patients with a gynecologic malignancy may be at a higher risk of developing CDI due to an increased likelihood of having one or more risk factors, data do not consistently support the idea that chemotherapy or cancer itself are independently associated with CDI. For diagnosis of CDI, we recommended using a multi-step approach, with a highly sensitive initial rapid test such as the enzyme immunoassay (EIA) for glutamate dehydrogenase (GDH) or nucleic acid amplification testing (NAAT), followed by confirmatory testing with of the above two tests or EIA toxin A/B, which has high specificity. Treatment varies based on the severity of disease. We recommend vancomycin as first-line therapy for an initial episode of mild/moderate or severe CDI, with consideration of fidaxomicin for patients at particularly high risk for recurrence. Rectal vancomycin may play an adjunctive role for some severe cases, while surgical intervention is indicated for fulminant CDI if no improvement six or more days after initiating medical therapy. For non-severe recurrent disease, the initial treatment regimen should be repeated, while subsequent episodes are more appropriately treated with a tapered and pulsed dose of vancomycin, fidaxomicin, or fecal microbiota transplantation.