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BACKGROUND: Malignant ovarian germ cell tumors usually occur in young women. The standard of care is fertility sparing surgery and comprehensive surgical staging followed by adjuvant chemotherapy with BEP (bleomycin, etoposide, cisplatin) if needed. The aim of this study was to analyze the reproductive outcomes after conservative treatment in patients diagnosed, treated and followed up in MITO (Multicenter Italian Trials in Ovarian Cancer) centers. METHODS: A questionnaire concerning gynecological symptoms, reproductive outcomes and fertility treatment was administered to 164 MOGCTs survivors. Data regarding patients deceased were collected from MITO-9 database. There were 114 patients diagnosed at reproductive age between 1983 and 2019 included. RESULTS: 109 patients answered the questionnaire and 5 patients decesased were included (median age 24.9 years). 78.1% were stage I,4.4% stage II, 14.9% stage III and 2.6% stage IV. 57.9% received chemotherapy, the mean number of cycles was 4.1. Median time to menstrual recovery after BEP was of 5.6 months range, only 1 case of premature ovarian failure was reported. Among the 114 patients 38 (33.3%) attempted to become pregnant, 29/38 (76.3%) got pregnant with a total of 44 conceptions. 40.9% received chemotherapy and 22.9% did not (p 0.048). Pregnancy desire was the only predictive factor associated with live births among women who attempted pregnancy after treatment. CONCLUSIONS: As MOGCTs affect women of child-bearing age, fertility preservation represents a major treatment issue. Our results are consistent with the available evidence, confirming that adjuvant chemotherapy for MOGCT does not impact the reproductive function and fertility.
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Neoplasias Embrionárias de Células Germinativas , Neoplasias Ovarianas , Gravidez , Feminino , Humanos , Adulto Jovem , Adulto , Tratamento Conservador , Estadiamento de Neoplasias , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Reprodução , Cisplatino , Neoplasias Embrionárias de Células Germinativas/patologia , Quimioterapia Adjuvante , Estudos RetrospectivosRESUMO
OBJECTIVE: PARP (poly adenosine diphosphate [ADP]-ribose polymerase) inhibitors are approved as maintenance therapy in platinum sensitive ovarian cancer (OC), in first line and in the recurrent setting, regardless of BRCA mutational status. Real-world data after the introduction of these agents are needed to evaluate whether the benefit observed in phase III randomized clinical trials can be translated into clinical practice. The aim of our study was to provide real-life data on efficacy and safety of niraparib administered as maintenance in platinum sensitive relapsed OC patients (PSROC). METHODS: This retrospective/prospective observational study included relapsed OC patients that received niraparib as maintenance, at the time of platinum sensitive recurrence within the Italian expanded-access program. Clinical data at the time of diagnosis and at the time of recurrence were collected and analyzed. Median progression free survival (PFS) and overall survival (OS) were calculated as the time from start of niraparib treatment to subsequent radiologically confirmed relapse and death or last contact, respectively. RESULTS: Among 304 eligible patients, 260 (85%) had BRCA wild-type tumor and 36. (11.9%) were BRCA mutated. Median PFS was 9.1 months (95% CI: 6.9-11.2) and 10.3 months (95% CI: 7.0-13.5) in the BRCAwt and BRCAmut cohorts, respectively. Furthermore, median OS was 41.7 months (95% CI: 31.6-41.9) and 34.6 months (95% CI: N.E.) in the BRCAwt and BRCAmut cohorts, respectively. CONCLUSION: Data from this large real-life dataset suggested that maintenance with niraparib in the real-life setting of platinum sensitive OC recurrence is effective and well tolerated.
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Indazóis , Recidiva Local de Neoplasia , Neoplasias Ovarianas , Piperidinas , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Feminino , Piperidinas/uso terapêutico , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Indazóis/uso terapêutico , Indazóis/administração & dosagem , Indazóis/efeitos adversos , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Idoso , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos Retrospectivos , Adulto , Estudos Prospectivos , Idoso de 80 Anos ou mais , Quimioterapia de Manutenção/métodos , Intervalo Livre de ProgressãoRESUMO
PURPOSE: We present a large real-world multicentric dataset of ovarian, uterine and cervical oligometastatic lesions treated with SBRT exploring efficacy and clinical outcomes. In addition, an exploratory machine learning analysis was performed. METHODS: A pooled analysis of gynecological oligometastases in terms of efficacy and clinical outcomes as well an exploratory machine learning model to predict the CR to SBRT were carried out. The CR rate following radiotherapy (RT) was the study main endpoint. The secondary endpoints included the 2-year actuarial LC, DMFS, PFS, and OS. RESULTS: 501 patients from 21 radiation oncology institutions with 846 gynecological metastases were analyzed, mainly ovarian (53.1%) and uterine metastases(32.1%).Multiple fraction radiotherapy was used in 762 metastases(90.1%).The most frequent schedule was 24 Gy in 3 fractions(13.4%). CR was observed in 538(63.7%) lesions. The Machine learning analysis showed a poor ability to find covariates strong enough to predict CR in the whole series. Analyzing them separately, in uterine cancer, if RT dose≥78.3Gy, the CR probability was 75.4%; if volume was <13.7 cc, the CR probability became 85.1%. In ovarian cancer, if the lesion was a lymph node, the CR probability was 71.4%; if volume was <17 cc, the CR probability rose to 78.4%. No covariate predicted the CR for cervical lesions. The overall 2-year actuarial LC was 79.2%, however it was 91.5% for CR and 52.5% for not CR lesions(p < 0.001). The overall 2-year DMFS, PFS and OS rate were 27.3%, 24.8% and 71.0%, with significant differences between CR and not CR. CONCLUSIONS: CR was substantially associated to patient outcomes in our series of gynecological cancer oligometastatic lesions. The ability to predict a CR through artificial intelligence could also drive treatment choices in the context of personalized oncology.
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Inteligência Artificial , Radiocirurgia , Humanos , Feminino , Pessoa de Meia-Idade , Radiocirurgia/métodos , Idoso , Adulto , Idoso de 80 Anos ou mais , Neoplasias Uterinas/patologia , Neoplasias Uterinas/radioterapia , Neoplasias Uterinas/cirurgia , Aprendizado de Máquina , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/radioterapia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/radioterapia , Neoplasias dos Genitais Femininos/patologia , Neoplasias dos Genitais Femininos/radioterapia , Adulto Jovem , Resultado do Tratamento , Estudos RetrospectivosRESUMO
BACKGROUND: Differential diagnosis between benign uterine smooth muscle tumors and malignant counterpart is challenging. We evaluated the accuracy of a clinical and ultrasound based algorithm in predicting mesenchimal uterine malignancies (MUMs), including smooth muscle tumors of uncertain malignant potential (STUMPs). METHODS: We report the twelve-months follow-up of an observational, prospective, single-centre study that included women with at least one myometrial lesion ≥3 cm on ultrasound examination. These patients were classified according to a three-class diagnostic algorithm, using symptoms and ultrasound features. "White" patients underwent annual telephone follow-up for 2 years, "Green" patients underwent a clinical and ultrasound follow-up at 6, 12 and 24 months and "Orange" patients underwent surgery. We further developed a risk class system to stratify the malignancy risk. FINDINGS: 2,268 women were included andtarget lesion was classified as benign in 2,158 (95.1%), as other malignancies in 58 (2.6%) an as mesenchymal uterine malignancies in 52 (2.3%) patients. At multivariable analysis, age (OR 1.05 (95% CI 1.03-1.07), tumor diameter >8 cm (OR 5.92 (95% CI 2.87-12.24), irregular margins (OR 2.34 (95% CI 1.09-4.98), color score=4 (OR 2.73 (95% CI 1.28-5.82), were identified as independent risk factors for malignancies, whereas acoustic shadow resulted in an independent protective factor (OR 0.39 (95% CI 0.19-0.82). The model, which included age as a continuous variable and lesion diameter as a dichotomized variable (cut-off 81 mm), provided the best AUC (0.87 (95% CI 0.82-0.91)). A risk class system was developed, and patients were classified as low-risk (predictive model value <0.39%: 0/606 malignancies, risk 0%), intermediate risk (predictive model value 0.40%-2.2%: 9/1,093 malignancies, risk 0.8%), high risk (predictive model value ≥2.3%: 43/566 malignancies, risk 7.6%). CONCLUSION: The preoperative three-class diagnostic algorithm and risk class system can stratify women according to risk of malignancy. Our findings, if confirmed in a multicentre study, will permit differentiation between benign and MUMs allowing a personalized clinical approach. FUNDING: Nothing to declare.
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OBJECTIVE: To evaluate disease characteristics and survival according to BRCA status, administration of poly-(ADP-ribose) polymerase inhibitors (PARPi), and surgery in patients with ovarian cancer and brain metastases. METHODS: This is a monocentric retrospective cohort of patients with ovarian cancer and brain metastases treated between 2000 and 2021. Data were collected by a retrospective review of medical records and analyzed according to: (1) BRCA mutation; (2) PARPi before and after brain metastases; (3) surgery for brain metastases. RESULTS: Eighty-five patients with ovarian cancer and brain metastasis and known BRCA status (31 BRCA mutated (BRCAm), 54 BRCA wild-type (BRCAwt)) were analyzed. Twenty-two patients had received PARPi before brain metastases diagnosis (11 BRCAm, 11 BRCAwt) and 12 after (8 BRCAm, 4 BRCAwt). Brain metastases occurred >1 year later in patients who had received previous PARPi. Survival was longer in the BRCAm group (median post-brain metastasis survival: BRCAm 23 months vs BRCAwt 8 months, p=0.0015). No differences were found based on BRCA status analyzing the population who did not receive PARPi after brain metastasis (median post-brain metastasis survival: BRCAm 8 months vs BRCAwt 8 months, p=0.31). In the BRCAm group, survival was worse in patients who had received previous PARPi (median post-brain metastasis survival: PARPi before, 7 months vs no-PARPi before, 24 months, p=0.003). If PARPi was administered after brain metastases, survival of the overall population improved (median post-brain metastasis survival: PARPi after, 46 months vs no-PARPi after, 8 months, p=0.00038).In cases of surgery for brain metastases, the prognosis seemed better (median post-brain metastasis survival: surgery 13 months vs no-surgery 8 months, p=0.036). Three variables were significantly associated with prolonged survival at multivariate analysis: BRCA mutation, multimodal treatment, and ≤1 previous chemotherapy line. CONCLUSIONS: BRCA mutations might impact brain metastasis occurrence and lead to better outcomes. In a multimodal treatment, surgery seems to affect survival even in cases of extracranial disease. PARPi use should be considered as it seems to prolong survival if administered after brain metastasis.
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Neoplasias Encefálicas , Carcinoma Epitelial do Ovário , Neoplasias Ovarianas , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Feminino , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/cirurgia , Neoplasias Encefálicas/mortalidade , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Estudos Retrospectivos , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/genética , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/cirurgia , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/secundário , Carcinoma Epitelial do Ovário/patologia , Idoso , Adulto , Proteína BRCA2/genética , Proteína BRCA1/genéticaRESUMO
OBJECTIVE: Vaginal carcinoma is a rare malignancy accounting for 1-2% of all gynecological cancers. Surgery has a limited role, while definitive radiotherapy-chemotherapy followed by interventional radiotherapy is considered a valid alternative. The aim of the TRIDENT (TRImodal DEfinitive invasive vagiNal carcinoma Treatment) pilot study was to report the results of a modern standardized trimodal protocol treatment consisting of image guided definitive radiotherapy-chemotherapy followed by image guided interventional radiotherapy in terms of safety and efficacy. METHODS: Between January 2019 and December 2021, we analyzed 21 consecutive patients with primary vaginal cancer who had received radiotherapy-chemotherapy followed by interventional radiotherapy. The primary study endpoint was local control, and secondary endpoints were metastasis free survival, overall survival, and rate and severity of acute and late toxicities. RESULTS: 14 patients had FIGO (International Federation of Gynecology and Obstetrics) stage II, five patients had stage III, and two had stage IVB disease. Median total external beam radiotherapy dose for the tumor was 45 Gy. Median total dose on positive nodes was 60 Gy. Median total dose for interventional radiotherapy was 28 Gy over four high dose rate fractions to achieve between 85 and 95 Gy equivalent dose, in 2 Gy fractions (EQD2)α/ß10, to the high risk clinical target volume, and 60 Gy EQD2α/ß10 to the intermediate risk clinical target volume. All patients received weekly platinum based chemotherapy. Median follow-up was 20 months (range 10-56 months). Two year actuarial local control, metastasis free survival, and overall survival rate were 79.4%, 90.5%, and 79.4%, respectively. In terms of acute toxicity, there were no grade 4 events and only one acute grade (G) 3 toxicity (skin). Only vaginal stenosis (G3) was documented 12 months after therapy due to late toxicity. CONCLUSIONS: In this study, definitive radiotherapy-chemotherapy followed by interventional radiotherapy was a safe and effective treatment modality for primary vaginal cancer.
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Neoplasias Vaginais , Humanos , Feminino , Neoplasias Vaginais/patologia , Neoplasias Vaginais/terapia , Neoplasias Vaginais/radioterapia , Pessoa de Meia-Idade , Idoso , Projetos Piloto , Adulto , Radioterapia Guiada por Imagem/métodos , Quimiorradioterapia , Prognóstico , Idoso de 80 Anos ou mais , Estadiamento de Neoplasias , Estudos RetrospectivosRESUMO
INTRODUCTION: Sentinel lymph node (SLN) biopsy is part of surgical treatment of apparent early-stage cervical cancer. SLN is routinely analyzed by ultrastaging and immunohistochemistry. The aim of this study was to assess the survival of patients undergoing SLN analyzed by one-step nucleic acid amplification (OSNA) compared with ultrastaging. METHODS: Single-center, retrospective, cohort study. Patients undergoing primary surgery and SLN mapping ( ±pelvic lymphadenectomy) for apparent early-stage cervical cancer between May 2017 and January 2021 were included. SLN was analyzed exclusively with OSNA or with ultrastaging. Patients with bilateral SLN mapping failure, with SLN analyzed alternatively/serially with OSNA and ultrastaging, and undergoing neo-adjuvant therapy were excluded. Baseline clinic-pathological differences between the two groups were balanced with propensity-match analysis. RESULTS: One-hundred and fifty-seven patients were included, 50 (31.8%) in the OSNA group and 107 (68.2%) in the ultrastaging group. Median follow up time was 41 months (95%CI:37.9-42.2). 5-year DFS in patients undergoing OSNA versus ultrastaging was 87.0% versus 91.0% (p = 0.809) and 5-year overall survival was 97.9% versus 98.6% (p = 0.631), respectively. No difference in the incidence of lymph node recurrence between the two groups was noted (OSNA 20.0% versus ultrastaging 18.2%, p = 0.931). In the group of negative SLN, no 5-year DFS difference was noted between the two groups (p = 0.692). No 5-year DFS and OS difference was noted after propensity-match analysis (87.6% versus 87.0%, p = 0.726 and 97.4% versus 97.9%, p = 0.998, respectively). CONCLUSION: The use of OSNA as method to exclusively process SLN in cervical cancer was not associated with worse DFS compared to ultrastaging. Incidence of lymph node recurrence in the two groups was not different.
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Linfadenopatia , Ácidos Nucleicos , Linfonodo Sentinela , Neoplasias do Colo do Útero , Feminino , Humanos , Linfonodo Sentinela/patologia , Metástase Linfática/patologia , Estudos de Coortes , Estudos Retrospectivos , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/cirurgia , Neoplasias do Colo do Útero/patologia , Biópsia de Linfonodo Sentinela/métodos , Linfonodos/patologia , Excisão de Linfonodo , Linfadenopatia/patologia , Técnicas de Amplificação de Ácido Nucleico/métodosRESUMO
OBJECTIVE: We aimed to assess disease-free survival (DFS), overall survival (OS) and treatment-related toxicity of two therapeutic strategies for treating bulky lymph nodes on imaging in patients with locally advanced cervical cancer (LACC): radiotherapy boost versus surgical debulking followed by radiotherapy. METHODS: We performed a systematic review of studies published up to October 2023. We selected studies including patients with LACC treated by external beam radiotherapy (EBRT) boost or lymph node debulking followed by EBRT (with or without boost). RESULTS: We included two comparative (included in the meta-analysis) and nine non-comparative studies. The estimated 3-year recurrence rate was 28.2% (95%CI:18.3-38.0) in the EBRT group and 39.9% (95%CI:22.1-57.6) in the surgical debulking plus EBRT group. The estimated 3-year DFS was 71.8% and 60.1%, respectively (p = 0.19). The estimated 3-year death rate was 22.2% (95%CI:11.2-33.2) in the EBRT boost group and 31.9% (95%CI:23.3-40.5) in the surgical debulking plus EBRT group. The estimated 3-year OS was 77.8% and 68.1%, respectively (p = 0.04). No difference in lymph node recurrence between the two comparative studies (p = 0.36). The meta-analysis of the two comparative studies showed no DFS difference (p = 0.13) but better OS in the radiotherapy boost group (p = 0.006). The incidence of grade≥3 toxicities (ranging 0-50%) was not different between the two approaches in the two comparative studies (p = 0.31). CONCLUSION: No DFS and toxicity difference when comparing EBRT boost with surgical debulking of enlarged lymph nodes and EBRT in patients with cervical cancer was evident. Radiotherapy boost had better OS. Further investigation is required to better understand the prognostic role of surgical lymph node debulking in light of radiotherapy developments.
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Metástase Linfática , Neoplasias do Colo do Útero , Humanos , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/radioterapia , Feminino , Procedimentos Cirúrgicos de Citorredução , Taxa de Sobrevida , Intervalo Livre de Doença , Linfonodos/patologia , Recidiva Local de Neoplasia/patologiaRESUMO
BACKGROUND: cemiplimab is an immunoglobulin G4 monoclonal antibody targeting the programmed cell death-1 receptor. A nominal use program is available in Italy in advanced cervical cancer (CC) patients treated with platinum based chemotherapy based on the results of EMPOWER-Cervical 1/GOG-3016/ENGOTcx9 trial. This real-world, retrospective cohort, multicenter study aimed at describing clinical outcomes of patients with advanced CC treated with cemiplimab in Italy. METHODS: The primary objective of the study was to assess the feasibility and the replicability of the initial results in a real world setting of cemiplimab nominal use. The primary endpoint of our analysis was progression free survival (PFS). Secondary endpoints included overall response rate (ORR), overall survival (OS) and safety data. RESULTS: From March 2022 to December 2023, 135 patients were treated in 12 Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) Centers. Forty-two percent of patients had one or more comorbidities, hypertension being the most common (23.4%). Median PFS was 4.0 months (range 3.0-6.0) and median OS was 12.0 months (12.0- NR) with no differences according to PD-L1 status. Complete response (CR) or no evidence of disease (NED) were observed in 8.6%; partial response (PR) in 21.1%, stable disease (SD) in 14.8% and progression was recorded in 44.5% of patients. Most common drug related adverse events (AEs) were anemia (39.1%) and fatigue (27.8%). Immune related AEs occurred in 18.0%. CONCLUSIONS: This study confirms the feasibility and the replicability of the cemiplimab nominal use in advanced CC, in a real-world practice in Italy.
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Anticorpos Monoclonais Humanizados , Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/tratamento farmacológico , Pessoa de Meia-Idade , Itália , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Idoso , Adulto , Estudos Retrospectivos , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Idoso de 80 Anos ou mais , Intervalo Livre de ProgressãoRESUMO
This study investigated whether radiomic features extracted from pretreatment [18F]FDG PET could improve the prediction of both histopathologic tumor response and survival in patients with locally advanced cervical cancer (LACC) treated with neoadjuvant chemoradiotherapy followed by surgery compared with conventional PET parameters and histopathologic features. Methods: The medical records of all consecutive patients with LACC referred between July 2010 and July 2016 were reviewed. [18F]FDG PET/CT was performed before neoadjuvant chemoradiotherapy. Radiomic features were extracted from the primary tumor volumes delineated semiautomatically on the PET images and reduced by factor analysis. A receiver-operating-characteristic analysis was performed, and conventional and radiomic features were dichotomized with Liu's method according to pathologic response (pR) and cancer-specific death. According to the study protocol, only areas under the curve of more than 0.70 were selected for further analysis, including logistic regression analysis for response prediction and Cox regression analysis for survival prediction. Results: A total of 195 patients fulfilled the inclusion criteria. At pathologic evaluation after surgery, 131 patients (67.2%) had no or microscopic (≤3 mm) residual tumor (pR0 or pR1, respectively); 64 patients (32.8%) had macroscopic residual tumor (>3 mm, pR2). With a median follow-up of 76.0 mo (95% CI, 70.7-78.7 mo), 31.3% of patients had recurrence or progression and 20.0% died of the disease. Among conventional PET parameters, SUVmean significantly differed between pathologic responders and nonresponders. Among radiomic features, 1 shape and 3 textural features significantly differed between pathologic responders and nonresponders. Three radiomic features significantly differed between presence and absence of recurrence or progression and between presence and absence of cancer-specific death. Areas under the curve were less than 0.70 for all parameters; thus, univariate and multivariate regression analyses were not performed. Conclusion: In a large series of patients with LACC treated with neoadjuvant chemoradiotherapy followed by surgery, PET radiomic features could not predict histopathologic tumor response and survival. It is crucial to further explore the biologic mechanism underlying imaging-derived parameters and plan a large, prospective, multicenter study with standardized protocols for all phases of the process of radiomic analysis to validate radiomics before its use in clinical routine.
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Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/terapia , Neoplasias do Colo do Útero/patologia , Pessoa de Meia-Idade , Prognóstico , Adulto , Resultado do Tratamento , Idoso , Quimiorradioterapia , Estudos Retrospectivos , Processamento de Imagem Assistida por Computador , Terapia Neoadjuvante , RadiômicaRESUMO
BACKGROUND AND PURPOSE: We aimed to develop and validate different machine-learning (ML) prediction models for the complete response of oligometastatic gynecological cancer after SBRT. MATERIAL AND METHODS: One hundred fifty-seven patients with 272 lesions from 14 different institutions and treated with SBRT with radical intent were included. Thirteen datasets including 222 lesions were combined for model training and internal validation purposes, with an 80:20 ratio. The external testing dataset was selected as the fourteenth Institution with 50 lesions. Lesions that achieved complete response (CR) were defined as responders. Prognostic clinical and dosimetric variables were selected using the LASSO algorithm. Six supervised ML models, including logistic regression (LR), classification and regression tree analysis (CART) and support vector machine (SVM) using four different kernels, were trained and tested to predict the complete response of uterine lesions after SBRT. The performance of models was assessed by receiver operating characteristic curves (ROC), area under the curve (AUC) and calibration curves. An explainable approach based on SHapley Additive exPlanations (SHAP) method was deployed to generate individual explanations of the model's decisions. RESULTS: 63.6% of lesions had a complete response and were used as ground truth for the supervised models. LASSO strongly associated complete response with three variables, namely the lesion volume (PTV), the type of lesions (lymph-nodal versus parenchymal), and the biological effective dose (BED10), that were used as input for ML modeling. In the training set, the AUCs for complete response were 0.751 (95% CI: 0.716-0.786), 0.766 (95% CI: 0.729-0.802) and 0.800 (95% CI: 0.742-0.857) for the LR, CART and SVM with a radial basis function kernel, respectively. These models achieve AUC values of 0.727 (95% CI: 0.669-0.795), 0.734 (95% CI: 0.649-0.815) and 0.771 (95% CI: 0.717-0.824) in the external testing set, demonstrating excellent generalizability. CONCLUSION: ML models enable a reliable prediction of the treatment response of oligometastatic lesions receiving SBRT. This approach may assist radiation oncologists to tailor more individualized treatment plans for oligometastatic patients.
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Neoplasias , Radiocirurgia , Humanos , Aprendizado de Máquina , Algoritmos , Área Sob a Curva , Resposta Patológica CompletaRESUMO
Immediate hypersensitivity reactions (iHSRs) to taxanes are observed in 6% and 4% of gynecologic and breast cancer patients, respectively. Drug desensitization is the only option, as no comparable alternative therapy is available. Surfactants in the taxane formulation have been implicated in the immunopathogenesis of iHSRs, although sporadic skin test (ST) positivity and iHSRs to nab-paclitaxel have suggested the involvement of the taxane moiety and/or IgE-mediated pathomechanisms. In vitro diagnostic tests might offer insights into mechanisms underlying iHSRs to taxanes. The aim of the present study was to address this unmet need by developing a novel basophil activation test (BAT). The study included patients (n = 31) undergoing paclitaxel/carboplatin therapy. Seventeen patients presented with iHSRs to paclitaxel (iHSR-Taxpos), and eleven were tolerant (iHSR-Taxneg). Fourteen patients presented with iHSRs to carboplatin (iHSR-Plpos), and fourteen were tolerant (iHSR-Plneg). The BAT median stimulation index (SI) values were 1.563 (range, 0.02-4.11; n = 11) and -0.28 (range -4.88-0.07, n = 11) in iHSR-Taxpos and iHSR-Taxneg, respectively. The BAT median SI values were 4.45 (range, 0.1-26.7; n = 14) and 0 (range, -0.51-1.65; n = 12) in iHSR-Plpos and iHSR-Plneg, respectively. SI levels were not associated with iHSR severity grading. Comparing BAT results in iHSR-Taxpos and iHSR-Taxneg showed the area under the receiver operator characteristic (ROC) curve to be 0.9752 (p = 0.0002). The cutoff calculated by the maximized likelihood ratio identified 90.91% of iHSR-Taxpos patients and 90.91% of iHSR-Taxneg patients. Comparing BAT results for iHSR-Plpos and iHSR-Plneg showed the area under the ROC curve to be 0.9286 (p = 0.0002). The cutoff calculated by the maximized likelihood ratio identified 78.57% of iHSR-Plpos patients and 91.67% of iHSR-Plneg patients. Most iHSR-Taxpos patients for which ST was available (10/11) scored ST-negative and BAT-positive, whereas most iHSR-Plpos patients for which ST was available (14/14) scored both BAT- and ST-positive. This suggested the intervention of non-IgE-mediated mechanisms in iHSR-Taxpos patients. Consistent with this view, an in silico molecular docking analysis predicted the high affinity of paclitaxel to the degranulation-competent MRGPRX2 receptor. This hypothesis warrants further in vitro investigations. In conclusion, the present study provides preliminary proof-of-concept evidence that this novel BAT has potential utility in understanding mechanisms underlying iHSRs to taxanes.