RESUMO
No prospective data have been described to inform guidelines on antibiotic prophylaxis for partial vulvectomies. Thus, we conducted a single-center, pilot, double-blind randomized controlled trial to assess the effectiveness of prophylactic antibiotics to prevent wound complications after partial vulvectomies. Patients were randomly assigned 1:1 to preoperative antibiotics or no preoperative antibiotics. The primary outcome of 30-day postoperative wound complications occurred in 31 (62 %) of all patients, with no differences between groups. The most common wound complications were superficial separation (54.2 % antibiotic prophylaxis vs. 65.3 % no prophylaxis, p = 0.37) and surgical site infection (0 % antibiotic prophylaxis vs 7.7 % no prophylaxis, p = 0.49). However, this study was limited by differences in patient characteristics between the groups. This study provides data to perform power calculations for a trial examining the effect of preoperative antibiotics on surgical site infection.
RESUMO
The Gynecologic Cancer InterGroup (GCIG) Endometrial Cancer Consensus Conference on Clinical Research (ECCC) was held in Incheon, South Korea, Nov 2-3, 2023. The aims were to develop consensus statements for future trials in endometrial cancer to achieve harmonisation on design elements, select important questions, and identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and finalisation of 18 statements within four topic groups, addressing adjuvant treatment in high-risk disease; treatment for metastatic and recurrent disease; trial designs for rare endometrial cancer subgroups and special circumstances; and specific methodology and adaptation for trials in low-resource settings. In addition, eight areas of unmet need were identified. This was the first GCIG Consensus Conference to include patient advocates and an expert on inclusion, diversity, equity, and access to take part in all aspects of the process and output. Four early-career investigators were also selected for participation, ensuring that they represented different GCIG member groups and regions. Unanimous consensus was obtained for 16 of the 18 statements, with 97% concordance for the remaining two. Using the described methodology from previous Ovarian Cancer Consensus Conferences, this conference did not require even one minority statement. The high acceptance rate following active involvement in the preparation, discussion, and refinement of the statements by all representatives confirmed the consensus progress within a global academic setting, and the expectation that the ECCC will lead to greater harmonisation, actualisation, inclusion, and resolution of unmet needs in clinical research for individuals living with and beyond endometrial cancer worldwide.
Assuntos
Consenso , Neoplasias do Endométrio , Feminino , Humanos , Pesquisa Biomédica/normas , Ensaios Clínicos como Assunto/normas , Neoplasias do Endométrio/terapia , Neoplasias do Endométrio/patologia , República da CoreiaRESUMO
Three novel nickel-phosphate structures are reported, Ni2(PO4)(OH) (I), Ni7(PO4)3(HPO4)(OH)3 (II), and NaNiPO4 (III). Each new system was prepared via a high-temperature hydrothermal synthesis at 600-650 °C. All three compounds are built of quasi-one-dimensional (quasi-1-D) Ni2+ containing chains with varying phosphate bridging modes and were characterized by single crystal X-ray diffraction and magnetic susceptibility. All three compounds display very different magnetic behavior. Anisotropic magnetic data is reported for Ni2(PO4)(OH) (I) exhibiting slow antiferromagnetic ordering in the high-temperature regime with substructures that begin to form below 32 K at different field strengths. These characteristics affirm I as being one of the few Haldane-like material candidates. The Ni7(PO4)3(HPO4)(OH)3 (II) material is a member of the unusual ellenbergerite structural family and displays complex inter- and intrachain magnetic interactions while NaNiPO4 (III) shows antiferromagnetic ordering near 18 K. This magnetic behavior is correlated with their structures.
RESUMO
What is this summary about? Dostarlimab, also known by the brand name JEMPERLI, is a medicine that uses a patient's own immune system to treat endometrial cancer. Dostarlimab is a type of medicine called an immunotherapy. Immunotherapies help the immune system find and attack cancer cells. Dostarlimab stops cancer cells from being able to hide from the immune system, which allows the patient to have a boosted immune response against their cancer.The RUBY study is a phase 3 clinical study of primary advanced (cancer that has spread outside the uterus) or recurrent (cancer that has come back) endometrial cancer. A phase 3 clinical study looks at how well a new treatment works compared to the standard, or usual, treatment in a large patient population. The RUBY study is testing how well dostarlimab given with chemotherapy, followed by dostarlimab alone, works at delaying primary advanced or recurrent endometrial cancer from getting worse and preventing patients from dying, compared to chemotherapy given alone (the current standard treatment for primary advanced or recurrent endometrial cancer).What were the results? When dostarlimab was given with chemotherapy, this combination was found to delay primary advanced or recurrent endometrial cancer from getting worse and to prevent patients from dying, compared with chemotherapy given alone (without dostarlimab). Patients in the study who received dostarlimab with chemotherapy had a 36% lower risk of dying or having their cancer get worse.What do the results mean? The results from this study contributed to the approval of dostarlimab with chemotherapy as a new treatment option for patients with mismatch repair deficient/microsatellite instability-high primary advanced or recurrent endometrial cancer. As of the publication of this plain language summary of publication (PLSP), this combination of dostarlimab with chemotherapy has been approved in the United States of America, the United Kingdom, the European Union and Hong Kong.Clinical Trial Registration: NCT03981796 (RUBY).
RESUMO
OBJECTIVES: Tissue banking procedures have evolved to keep pace with precision medicine, technology, emerging understanding of racial disparities, and regulatory requirements. However, there is little published guidance regarding strategies to create and maintain a successful biorepository. Our objective is to describe the infrastructure and protocols used by our Gynecologic Oncology Tissue Bank. METHODS: Our Tissue Bank was founded in 1992. In August 2022, internal funding was used to modernize the Tissue Bank. We hired three full-time employees, implemented universal screening of patients treated by gynecologic oncology faculty, updated consenting protocols, and standardized communication with providers. Tumor tissue, blood derivatives, ascites, and pleural fluid were collected from eligible, consenting patients and processed. Patient-derived cell lines and organoids were generated. For quality control purposes, one formalin-fixed, paraffin-embedded (FFPE) sample per tissue site was analyzed by a board-certified pathologist. All samples were labeled and tracked in an OpenSpecimen collection protocol and clinically annotated in a secure database. RESULTS: From August 2022 to October 2023, 227 patients (83% white, 15% Black, 1% Asian) were enrolled and 4249 specimens were collected. Adherent cell lines were generated from 15 patients with ovarian cancer and cell suspensions for organoid generation were collected from 46 patients with ovarian cancer. A recharge center was established to self-sustain the Tissue Bank. Samples have been shared with academic and commercial collaborators. CONCLUSIONS: Our Tissue Bank has enrolled a large number of diverse patients, collected numerous specimen types, and collaborated widely. The procedures described here provide guidance for other institutions establishing similar resources.
RESUMO
PURPOSE: Pelvic recurrence is a frequent pattern of relapse for women with endometrial cancer. A randomized trial compared progression-free survival (PFS) after treatment with radiation therapy alone as compared with concurrent chemotherapy. MATERIALS AND METHODS: Between February 2008 and August 2020, 165 patients were randomly assigned 1:1 to receive either radiation treatment alone or a combination of chemotherapy and radiation treatment. The primary objective of this study was to determine whether chemoradiation therapy was more effective than radiation therapy alone at improving PFS. RESULTS: The majority of patients had low-grade (1 or 2) endometrioid histology (82%) and recurrences confined to the vagina (86%). External beam with either the three-dimensional or intensity modulated radiation treatment technique was followed by a boost delivered with brachytherapy or external beam. Patients randomly assigned to receive chemotherapy were treated with once weekly cisplatin (40 mg/m2). Rates of acute toxicity were higher in patients treated with chemoradiation as compared with radiation treatment alone. Median PFS was longer for patients treated with radiation therapy alone as compared with chemotherapy and radiation (median PFS was not reached for RT v 73 months for chemoradiation, hazard ratio of 1.25 (95% CI, 0.75 to 2.07). At 3 years, 73% of patients treated definitively with radiation and 62% of patients treated with chemoradiation were alive and free of disease progression. CONCLUSION: Excellent outcomes can be achieved for women with localized recurrences of endometrial cancer when treated with radiation therapy. The addition of chemotherapy does not improve PFS for patients treated with definitive radiation therapy for recurrent endometrial cancer and increases acute toxicity. Patients with low-grade and vaginal recurrences who constituted the majority of those enrolled are best treated with radiation therapy alone.
Assuntos
Quimiorradioterapia , Cisplatino , Neoplasias do Endométrio , Recidiva Local de Neoplasia , Humanos , Feminino , Neoplasias do Endométrio/radioterapia , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/terapia , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/radioterapia , Idoso , Estudos Prospectivos , Quimiorradioterapia/métodos , Intervalo Livre de Progressão , Adulto , Braquiterapia/métodos , Braquiterapia/efeitos adversos , Antineoplásicos/uso terapêuticoRESUMO
OBJECTIVE: Investigate racial disparities in outcomes and molecular features in Black and White patients with endometrioid endometrial carcinoma (EEC). METHODS: Black and White patients diagnosed with EEC who underwent hysterectomy ± adjuvant treatment in SEER, National Cancer Database (NCDB), the Genomics Evidence Neoplasia Information Exchange (GENIE) project (v.13.0), and eight NCI-sponsored randomized phase III clinical trials (RCTs) were studied. Hazard ratio (HR) and 95% confidence interval (CI) were estimated for cancer-related death (CRD), non-cancer death (NCD), and all-cause death. RESULTS: Black (n = 4397) vs. White (n = 47,959) patients in SEER had a HR (95% CI) of 2.04 (1.87-2.23) for CRD and 1.22 (1.09-1.36) for NCD. In NCDB, the HR (95% CI) for death in Black (n = 13,468) vs. White (n = 155,706) patients was 1.52 (1.46-1.58) dropping to 1.29 (1.23-1.36) after propensity-score matching for age, comorbidity, income, insurance, grade, stage, LVSI, and treatment. In GENIE, Black (n = 109) vs. White (n = 1780) patients had fewer PTEN, PIK3R1, FBXW7, NF1, mTOR, CCND1, and PI3K-pathway-related gene mutations. In contrast, TP53 and DNA-repair-related gene mutation frequency as well as tumor mutational burden-high status were similar in Black and White patients. In RCTs, Black (n = 187) vs. White (n = 2877) patients were more likely to have advanced or recurrent disease, higher grade, worse performance status and progressive disease. Risk of death in Black vs. White patients in RCTs was 2.19 (1.77-2.71) persisting to 1.32 (1.09-1.61) after matching for grade, stage, and treatment arm while balancing age and performance status. CONCLUSIONS: Differences exist in clinical presentation, outcomes, and molecular features in Black vs. White patients with EEC in real-world registries and RCTs. Targeted-drug development, strategies to modify social determinants, and diverse inclusion in RCTs are approaches to reduce disparities.
Assuntos
Negro ou Afro-Americano , Carcinoma Endometrioide , Progressão da Doença , Neoplasias do Endométrio , População Branca , Humanos , Feminino , População Branca/estatística & dados numéricos , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/terapia , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/etnologia , Carcinoma Endometrioide/mortalidade , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/terapia , Neoplasias do Endométrio/etnologia , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/patologia , Pessoa de Meia-Idade , Negro ou Afro-Americano/estatística & dados numéricos , Idoso , Ensaios Clínicos Controlados Aleatórios como Assunto , Estados Unidos/epidemiologia , Programa de SEER , Sistema de Registros , Ensaios Clínicos Fase III como Assunto , AdultoRESUMO
OBJECTIVE: Recurrence remains a significant clinical problem for patients with cervical cancer, and early detection may improve outcomes. Serum squamous cell carcinoma antigen (SCCA) is a biomarker of prognosis and response to chemoradiotherapy. We hypothesized that elevated serum SCCA during surveillance is sensitive and specific for recurrence. METHODS: Pre-treatment and follow-up serum SCCA from patients treated with definitive-intent radiotherapy were measured via enzyme-linked immunosorbent assay in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory and analyzed retrospectively. Follow-up SCCA was defined as the value closest to recurrence, or as last available for patients without recurrence. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of follow-up SCCA for recurrence was determined for the whole cohort (Cohort 1), for patients with elevated (Cohort 2), and normal pre-treatment SCCA (Cohort 3). Patterns of failure were also evaluated. RESULTS: Of 227 patients in Cohort 1, 23% experienced recurrence, and 17% died of cervical cancer. Mean follow-up SCCA was 0.9 (±2.5) for patients with no recurrence and 6.0 (±18.7) for patients with recurrence (p=0.02). Sensitivity, specificity, PPV, and NPV of follow-up SCCA for recurrence in Cohort 1 were 38.5%, 97.1%, 80%, and 84.2%, and for patients in Cohort 2 were 54.5%, 95%, 78.3%, and 86.5%, respectively. Four of 86 patients in Cohort 3 had an elevated follow-up SCCA, two of these at the time of recurrence. Elevated pre-treatment SCCA and follow-up SCCA were associated with isolated pelvic recurrence. CONCLUSIONS: Surveillance serum SCCA has high specificity and NPV for recurrence, and may be of limited utility in patients with normal pre-treatment SCCA.
Assuntos
Antígenos de Neoplasias , Biomarcadores Tumorais , Quimiorradioterapia , Recidiva Local de Neoplasia , Serpinas , Neoplasias do Colo do Útero , Humanos , Feminino , Serpinas/sangue , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/terapia , Neoplasias do Colo do Útero/patologia , Antígenos de Neoplasias/sangue , Recidiva Local de Neoplasia/sangue , Pessoa de Meia-Idade , Estudos Retrospectivos , Biomarcadores Tumorais/sangue , Adulto , Idoso , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/patologia , Seguimentos , Prognóstico , Sensibilidade e Especificidade , Idoso de 80 Anos ou maisRESUMO
Endometrial cancer continues to be the only gynecologic malignancy with a rising incidence and mortality, with both regional and global implications. Combination carboplatin and paclitaxel has been the recognized chemotherapy backbone for the treatment of advanced-stage or recurrent disease, with modest clinical outcomes. Over the last year, significant advances were achieved in improving oncologic outcomes by capitalizing on the molecular characterization of this heterogenous disease. These advances include incorporation of immunotherapy, identification of effective hormonal approaches, the evolution of antibody drug conjugates, and utilization of alternate targeted therapies. PLAIN LANGUAGE SUMMARY: The molecular characterization of endometrial cancer has been critical in informing novel treatment strategies. Over the past year, significant gains have been made via the incorporation of immunotherapy, hormonal combinations as well as antibody drug conjugates.
Assuntos
Imunoterapia , Neoplasias Uterinas , Humanos , Feminino , Imunoterapia/métodos , Neoplasias Uterinas/terapia , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Endométrio/terapia , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/patologia , Terapia de Alvo Molecular/métodos , Imunoconjugados/uso terapêutico , Paclitaxel/uso terapêutico , Paclitaxel/administração & dosagem , Carboplatina/uso terapêutico , Carboplatina/administração & dosagemRESUMO
Cancer selective apoptosis remains a therapeutic challenge and off-target toxicity has limited enthusiasm for this target clinically. Sigma-2 ligands (S2) have been shown to enhance the cancer selectivity of small molecule drug candidates by improving internalization. Here, we report the synthesis of a novel drug conjugate, which was created by linking a clinically underperforming SMAC mimetic (second mitochondria-derived activator of caspases; LCL161), an inhibitor (antagonist) of inhibitor of apoptosis proteins (IAPinh) with the sigma-2 ligand SW43, resulting in the new chemical entity S2/IAPinh. Drug potency was assessed via cell viability assays across several pancreatic and ovarian cancer cell lines in comparison with the individual components (S2 and IAPinh) as well as their equimolar mixtures (S2 + IAPinh) both in vitro and in preclinical models of pancreatic and ovarian cancer. Mechanistic studies of S2/IAPinh-mediated cell death were investigated in vitro and in vivo using syngeneic and xenograft mouse models of murine pancreatic and human ovarian cancer, respectively. S2/IAPinh demonstrated markedly improved pharmacological activity in cancer cell lines and primary organoid cultures when compared to the controls. In vivo testing demonstrated a marked reduction in tumor growth rates and increased survival rates when compared to the respective control groups. The predicted mechanism of action of S2/IAPinh was confirmed through assessment of apoptosis pathways and demonstrated strong target degradation (cellular inhibitor of apoptosis proteins-1 [cIAP-1]) and activation of caspases 3 and 8. Taken together, S2/IAPinh demonstrated efficacy in models of pancreatic and ovarian cancer, two challenging malignancies in need of novel treatment concepts. Our data support an in-depth investigation into utilizing S2/IAPinh for the treatment of cancer.
Assuntos
Antineoplásicos , Neoplasias Ovarianas , Humanos , Animais , Camundongos , Feminino , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Apoptose , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Proteínas Inibidoras de Apoptose/metabolismo , Caspases/metabolismo , Linhagem Celular TumoralRESUMO
OBJECTIVE: This study investigated the risk of an aggressive endometrial cancer (EC) diagnosis by race, ethnicity, and country of origin to further elucidate histologic disparities in non-Hispanic Black (NHB), Hispanic, Asian/Pacific Islander (API), American Indian/Alaskan Native (AIAN) vs. non-Hispanic White (NHW) patients, particularly in Hispanic or API subgroups. METHODS: Patient diagnosed between 2004 and 2020 with low grade (LG)-endometrioid endometrial cancer (ECC) or an aggressive EC including grade 3 EEC, serous carcinoma, clear cell carcinoma, mixed epithelial carcinoma, or carcinosarcoma in the National Cancer Database were studied. The odds ratio (OR) and 95% confidence interval (CI) for diagnosis of an aggressive EC histology was estimated using logistic modeling. RESULTS: There were 343,868 NHW, 48,897 NHB, 30,013 Hispanic, 15,015 API and 1646 AIAN patients. The OR (95% CI) for an aggressive EC diagnosis was 3.07 (3.01-3.13) for NHB, 1.08 (1.06-1.11) for Hispanic, 1.17 (1.13-1.21) for API and 1.07 (0.96-1.19) for AIAN, relative to NHW patients. Subset analyses by country of origin illustrated the diversity in the OR for an aggressive EC diagnosis among Hispanic (1.18 for Mexican to 1.87 for Dominican), Asian (1.14 Asian Indian-Pakistani to 1.48 Korean) and Pacific Islander (1.00 for Hawaiian to 1.33 for Samoan) descendants. Hispanic, API and AIAN patients were diagnosed 5-years younger that NHW patients, and the risk for an aggressive EC histology were all significantly higher than NHW patients after correcting for age. Insurance status was another independent risk factor for aggressive histology. CONCLUSIONS: Risk of an aggressive EC diagnosis varied by race, ethnicity, and country of origin. NHB patients had the highest risk, followed by Dominican, South/Central American, Cuban, Korean, Thai, Vietnamese, and Filipino descendants.
Assuntos
Neoplasias do Endométrio , Humanos , Feminino , Neoplasias do Endométrio/etnologia , Neoplasias do Endométrio/patologia , Pessoa de Meia-Idade , Idoso , Estados Unidos/epidemiologia , Adulto , População Branca/estatística & dados numéricos , Hispânico ou Latino/estatística & dados numéricos , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma de Células Claras/etnologia , Adenocarcinoma de Células Claras/epidemiologia , Carcinossarcoma/patologia , Carcinossarcoma/etnologia , Havaiano Nativo ou Outro Ilhéu do Pacífico/estatística & dados numéricos , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/etnologia , Idoso de 80 Anos ou mais , Etnicidade/estatística & dados numéricos , Disparidades nos Níveis de Saúde , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/etnologia , Negro ou Afro-Americano/estatística & dados numéricosRESUMO
BACKGROUND: In the event that nonoperative treatment for sports hernia fails, surgical repair may be warranted. Bilateral repair can occur in up to 45% of surgically treated patients. PURPOSE: To investigate the clinical outcomes of athletes who underwent unilateral sports hernia repair and determine the proportion of patients who required contralateral sports hernia repair. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: We identified patients at our institution who underwent primary unilateral sports hernia repair (rectus abdominis-adductor longus aponeurotic plate repair and adductor lengthening) with a single surgeon between 2015 and 2020. We assessed patient-reported outcomes using the Hip Outcome Score-Sport (HOS-Sport), the Numeric Pain Rating Scale, and an internally developed return-to-play questionnaire. We further collected data regarding subsequent sports hernia procedures on the ipsilateral or contralateral side. We calculated summary statistics for outcomes and examined the association between preinjury patient characteristics and the HOS-Sport score at follow-up or successful return to preinjury sport using linear and logistic regression, respectively. RESULTS: A total of 104 of 128 (81.3%) eligible patients (mean age at surgery, 23.0 ± 6.2 years; 94.2% male; 51.9% American football athletes) completed follow-up at a mean time of 4.4 ± 1.5 years. Overall, 79.8% of athletes (n = 83) were able to return to their preinjury sport/activity, but 90.2% (83/92) who attempted to return were able to do so. When examining reasons for not returning to preinjury sport, only 9 patients reported not returning to preinjury sport because of limitations or persistent symptoms from their original injury. Only 4 patients underwent subsequent sports hernia procedures (3 contralateral, 1 ipsilateral revision) after their index unilateral sports hernia repair. At follow-up, the mean HOS-Sport score was high (94.0 ± 10.8), and the mean Numeric Pain Rating Scale score was low (0.31 ± 1.26). There were no preinjury patient characteristics associated with either the HOS-Sport score at follow-up or the successful return to preinjury sport. CONCLUSION: Patients with unilateral sports hernia symptoms can undergo repair and return to sport at the preinjury level with little concern for injuries to the contralateral groin. In our cohort, patient-reported hip function and pain outcomes at follow-up were excellent.
Assuntos
Futebol Americano , Herniorrafia , Humanos , Masculino , Adolescente , Adulto Jovem , Adulto , Feminino , Atletas , Hérnia , DorRESUMO
BACKGROUND: This phase 1b study (ClinicalTrials.gov identifier NCT03695380) evaluated regimens combining PARP and MEK inhibition, with or without PD-L1 inhibition, for BRCA wild-type, platinum-sensitive, recurrent ovarian cancer (PSROC). METHODS: Patients with PSROC who had received one or two prior treatment lines were treated with 28-day cycles of cobimetinib 60 mg daily (days 1-21) plus niraparib 200 mg daily (days 1-28) with or without atezolizumab 840 mg (days 1 and 15). Stage 1 assessed safety before expansion to stage 2, which randomized patients who had BRCA wild-type PSROC to receive either doublet or triplet therapy, stratified by genome-wide loss of heterozygosity status (<16% vs. ≥16%; FoundationOne CDx assay) and platinum-free interval (≥6 to <12 vs. ≥12 months). Coprimary end points were safety and the investigator-determined objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Potential associations between genetic parameters and efficacy were explored, and biomarker profiles of super-responders (complete response or those with progression-free survival [PFS] >15 months) and progressors (disease progression as the best response) were characterized. RESULTS: The ORR in patients who had BRCA wild-type PSROC was 35% (95% confidence interval, 20%-53%) with the doublet regimen (n = 37) and 27% (95% confidence interval, 14%-44%) with the triplet regimen (n = 37), and the median PFS was 6.0 and 7.4 months, respectively. Post-hoc analyses indicated more favorable ORR and PFS in the homologous recombination-deficiency-signature (HRDsig)-positive subgroup than in the HRDsig-negative subgroup. Tolerability was consistent with the known profiles of individual agents. NF1 and MKNK1 mutations were associated with sustained benefit from the doublet and triplet regimens, respectively. CONCLUSIONS: Chemotherapy-free doublet and triplet therapy demonstrated encouraging activity, including among patients who had BRCA wild-type, HRDsig-positive or HRDsig-negative PSROC harboring NF1 or MKNK1 mutations.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno B7-H1 , Recidiva Local de Neoplasia , Neoplasias Ovarianas , Ftalazinas , Piperidinas , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Feminino , Pessoa de Meia-Idade , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/mortalidade , Idoso , Adulto , Piperidinas/uso terapêutico , Piperidinas/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Ftalazinas/uso terapêutico , Ftalazinas/administração & dosagem , Indazóis/uso terapêutico , Indazóis/administração & dosagem , Proteína BRCA1/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/administração & dosagem , Idoso de 80 Anos ou mais , Platina/uso terapêutico , Platina/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Proteína BRCA2/genética , Intervalo Livre de Progressão , AzetidinasAssuntos
Reparo de Erro de Pareamento de DNA , Neoplasias do Endométrio , Feminino , Humanos , Reparo de Erro de Pareamento de DNA/genética , Instabilidade de Microssatélites , Neoplasias do Endométrio/genética , Biomarcadores Tumorais , Células Clonais/metabolismo , Proteína 1 Homóloga a MutL/genéticaRESUMO
We report a case of a 72-year-old man presenting with a 2-month history of a persistent, painful rash of the chest, axilla, and back. He had a history of recently resolved varicella zoster virus reactivation in the same distribution of the current rash and metastatic malignant melanoma treated with nivolumab and ipilimumab. The histopathology was consistent with granulomatous dermatitis (GD), and a diagnosis of postherpetic isotopic response manifesting as GD was made. Given the paucity of reported cases of postherpetic GD in the setting of treatment with immune checkpoint inhibitors (ICIs), we discuss the clinicopathologic features of this case and potential mechanisms by which ICIs may contribute to the development of granulomatous disease.
Assuntos
Doenças Autoimunes , Dermatite , Exantema , Melanoma , Masculino , Humanos , Idoso , Inibidores de Checkpoint Imunológico/efeitos adversos , Dermatite/etiologia , Dermatite/patologia , Melanoma/patologia , Nivolumabe/efeitos adversos , Ipilimumab/uso terapêutico , Doenças Autoimunes/complicaçõesRESUMO
PURPOSE: This paper reports the efficacy of the poly (ADP-ribose) polymerase inhibitor olaparib alone and in combination with the antiangiogenesis agent cediranib compared with cediranib alone in patients with advanced endometrial cancer. METHODS: This was open-label, randomized, phase 2 trial (NCT03660826). Eligible patients had recurrent endometrial cancer, received at least one (<3) prior lines of chemotherapy, and were Eastern Cooperative Oncology Group performance status 0 to 2. Patients were randomly assigned (1:1:1), stratified by histology (serous vs. other) to receive cediranib alone (reference arm), olaparib, or olaparib and cediranib for 28-day cycles until progression or unacceptable toxicity. The primary end point was progression-free survival in the intention-to-treat population. Homologous repair deficiency was explored using the BROCA-GO sequencing panel. RESULTS: A total of 120 patients were enrolled and all were included in the intention-to-treat analysis. Median age was 66 (range, 41-86) years and 47 (39.2%) had serous histology. Median progression-free survival for cediranib was 3.8 months compared with 2.0 months for olaparib (hazard ratio, 1.45 [95% CI, 0.91-2.3] p = .935) and 5.5 months for olaparib/cediranib (hazard ratio, 0.7 [95% CI, 0.43-1.14] p = .064). Four patients receiving the combination had a durable response lasting more than 20 months. The most common grade 3/4 toxicities were hypertension in the cediranib (36%) and olaparib/cediranib (33%) arms, fatigue (20.5% olaparib/cediranib), and diarrhea (17.9% cediranib). The BROCA-GO panel results were not associated with response. CONCLUSION: The combination of cediranib and olaparib demonstrated modest clinical efficacy; however, the primary end point of the study was not met. The combination was safe without unexpected toxicity.
Assuntos
Antineoplásicos , Neoplasias do Endométrio , Indóis , Neoplasias Ovarianas , Piperazinas , Quinazolinas , Humanos , Feminino , Idoso , Neoplasias Ovarianas/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Antineoplásicos/uso terapêutico , Ftalazinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Neoplasias do Endométrio/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Stress urinary incontinence (SUI) is a condition that most commonly affects aging women. Synthetic mid-urethral slings (MUS) have become the most common surgical treatment for SUI; however, complications such as mesh erosion and dyspareunia have been reported. This case report describes an 84-year-old female who presented with a tumor-like mass giant cell reaction surrounding the MUS and the management of this mass.
RESUMO
OBJECTIVES: To identify differential survival outcomes and immune checkpoint inhibitor (ICI) response in MLH1 hypermethylated versus MLH1 mutated ("Lynch-like") endometrial tumors and determine whether their molecular profiles can elucidate the differential outcomes. METHODS: 1673 mismatch repair deficient endometrial tumors were analyzed by next-generation sequencing and whole transcriptome sequencing (Caris Life Sciences, Phoenix, AZ). PD-L1, ER, and PR were tested by immunohistochemistry and immune cell infiltrates were calculated using MCP-counter. Significance was determined using Chi-square and Mann-Whitney U tests and adjusted for multiple comparisons. Overall survival (OS) was depicted using Kaplan-Meier survival curves. RESULTS: The endometrial cancer cohort comprised 89.2% patients with MLH1 hypermethylated tumors and 10.8% with MLH1 mutated tumors, with median ages of 67 and 60 years, respectively (p < 0.01). Patients with MLH1 hypermethylated tumors had significantly worse OS and trended toward worse OS following ICI treatment than patients with MLH1 mutated tumors. The immune microenvironment of MLH1 hypermethylated relative to MLH1 mutated was characterized by decreased PD-L1 positivity, immune checkpoint gene expression, immune cell infiltration, T cell inflamed scores, and interferon gamma (IFNγ) scores. MLH1 hypermethylation was also associated with decreased mutation rates in TP53 and DNA damage repair genes, but increased rates of JAK1, FGFR2, CCND1, and PTEN mutations, as well as increased ER and PR positivity. CONCLUSIONS: Endometrial cancer patients with MLH1 hypermethylation display significantly decreased survival and discrepant immunotherapy responses compared to patients with MLH1 mutated tumors, which was associated with differential mutational profiles, a more immune cold phenotype, and increased ER/PR expression in MLH1 hypermethylated tumors. Providers may consider early transition from single agent ICI to a multi-agent regimen or hormonal therapy for patients with MLH1 hypermethylated tumors.
RESUMO
OBJECTIVES: Clear cell carcinoma is a high-risk subtype of endometrial cancer. Some patients have a mixture of clear cell carcinoma with other histologic types (endometrioid or serous) or cannot be neatly assigned to one of these types. Protocol GOG-8032 within GOG-210 was designed to determine whether these tumors differ from pure clear cell carcinoma in stage at diagnosis, initial pattern of spread, or patient survival. METHODS: The term "mixed" was applied to tumors with multiple identifiable components, and "indeterminate" was applied to tumors with features intermediate between different histologic types. Three hundred eleven women with pure, mixed, or indeterminate clear cell carcinoma were identified in a larger cohort of patients undergoing hysterectomy for endometrial cancer in GOG-210. Histologic slides were centrally reviewed by expert pathologists. Baseline and follow-up data were analyzed. RESULTS: One hundred thirty-six patients had pure clear cell carcinoma and 175 had a mixed or indeterminate clear cell pattern. Baseline clinicopathologic characteristics were similar except for a small difference in age at presentation. Univariate survival analysis confirmed the significance of typical endometrial cancer prognostic factors. Patients in the mixed categories had disease-free and overall survival similar to pure clear cell carcinoma, but the indeterminate clear cell/endometrioid group had longer survival. CONCLUSION: In clear cell endometrial cancer, the presence of a definite admixed endometrioid or serous component did not correlate with a significant difference in prognosis. Patients whose tumors had indeterminate clear cell features had better prognosis. Some of these tumors may be endometrioid tumors mimicking clear cell carcinoma.