RESUMO
The interferon stimulated gene 15 (ISG15), a ubiquitin like protein and its conjugates have been implicated in various human malignancies. However, its role in ovarian cancer progression and metastasis is largely unknown. In high grade serous ovarian cancer (HGSOC), ascites is the major contributor to peritoneal metastasis. In this study, we identified significantly elevated ISG15 protein expression in HGSOC patient ascites, ascites derived primary ovarian cancer cells (POCCs), POCC small extracellular vesicles (sEVs) as well as metastatic tissue. Our results demonstrates that ISG15 increases exocytosis in ascites-derived POCCs by decreasing the endosome-lysosomal fusion, indicating a key role in sEV secretion. Further, knockdown (KD) of ISG15 resulted in a significant decrease in vesicles secretion from HGSOC cells and in vivo mouse models, leading to reduced HGSOC cell migration and invasion. Furthermore, our pre-clinical mouse model studies revealed the influence of vesicular ISG15 on disease progression and metastasis. In addition, knockdown of ISG15 or using the ISG15 inhibitor, DAP5, in combination therapy with carboplatin showed to improve the platinum sensitivity in-vitro and reduce tumour burden in-vivo. We also found that ISG15 expression within sEV represents a promising prognostic marker for HGSOC patients. Our findings suggest that ISG15 is a potential therapeutic target for inhibiting progression and metastasis in HGSOC and that vesicular ISG15 expression could be a promising biomarker in the clinical management of ovarian cancer. Significance: High-grade serous ovarian cancer (HGSOC) has high morbidity and mortality rates, but its progression and metastasis are still poorly understood, and there is an urgent need for early detection and targeted therapies. Our study presents novel findings that implicate ISG15-mediated vesicular proteins in the advancement and spread of HGSOC. These results offer pre-clinical evidence of potential new molecular targets, prognostic markers and therapeutic strategies for HGSOC that could ultimately enhance patient survival.
RESUMO
Inflammatory alopecia is an increasingly reported side effect of targeted cancer therapies. Here we report one case of inflammatory alopecia secondary to mitogen-activated protein kinase kinase (MEK) inhibitor agent Trametinib in a woman with ovarian cancer. Biopsies of the scalp were consistent with early scarring alopecia compatible with drug-induced alopecia. Significant improvement in hair loss occurred after treatment with intralesional Kenalog (ILK) injections and oral isotretinoin. Though acute alopecia has been described in patients using MEK inhibitors, this is the first reported case of inflammatory alopecia. J Drugs Dermatol. 2024;23(4):7802. doi:10.36849/JDD.7802e  .
Assuntos
Alopecia , Neoplasias Ovarianas , Humanos , Feminino , Alopecia/induzido quimicamente , Alopecia/diagnóstico , Alopecia/tratamento farmacológico , Triancinolona Acetonida , Inibidores de Proteínas Quinases/efeitos adversos , Neoplasias Ovarianas/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno/efeitos adversos , Proteínas Quinases Ativadas por MitógenoRESUMO
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/policies/article-withdrawal). This article has been retracted at the request of the Authors. The authors have independently identified an error in the formula that was utilized to calculate the Quality Adjusted Life Years which invalidates the data and the conclusion of the paper. The authors have contacted the journal requesting to retract the article. Apologies are offered to the readers of the journal for any confusion or inconvenience that may have resulted from the publication of this article.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Análise Custo-Benefício , Neoplasias do Endométrio , Recidiva Local de Neoplasia , Humanos , Feminino , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/economia , Recidiva Local de Neoplasia/economia , Recidiva Local de Neoplasia/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pessoa de Meia-Idade , Idoso , Anticorpos Monoclonais Humanizados/economia , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anos de Vida Ajustados por Qualidade de VidaRESUMO
⪠⪠âª.
Assuntos
Neoplasias dos Genitais Femininos , Feminino , Humanos , Neoplasias dos Genitais Femininos/cirurgia , Qualidade da Assistência à SaúdeRESUMO
â¢Leadership training is under-emphasized in traditional medical education.â¢An effective leadership curriculum must be dynamic and requires genuine investment from participants.â¢Through didactic education, self-reflection, and real-world perspective we can actively mold future leaders in gynecologic oncology.
Assuntos
Bolsas de Estudo , Ginecologia , Humanos , Feminino , Liderança , Ginecologia/educação , Educação de Pós-Graduação em Medicina , CurrículoRESUMO
PURPOSE: We examined associations between patient and treatment characteristics with longitudinally collected patient-reported outcome (PRO) measures to provide a data-informed description of the experiences of women undergoing treatment for endometrial cancer. METHODS: We administered National Institutes of Health Patient Reported Outcomes Measurement Information System (PROMIS) questionnaires at the preoperative visit and at 6 and 12 months after surgery. Anxiety, depression, fatigue, sleep disturbance, pain, physical function, and ability to participate in social roles were assessed. Analysis of variance (ANOVA) and linear mixed models were used to examine associations between patient characteristics and PRO measures at baseline and through time. RESULTS: Of 187 women enrolled, 174 (93%) and 103 (69%) completed the 6- and 12-month questionnaires, respectively. Anxiety was substantially elevated at baseline (half of one population-level standard deviation) and returned to general population mean levels at 6 and 12 months. Younger age, Medicaid/None/Self-pay insurance, prevalent diabetes, and current smoking were associated with higher symptom burden on multiple PRO measures across the three time points. Women with aggressive histology, higher disease stage, or those with adjuvant treatment had worse fatigue at 6 months, which normalized by 12 months. CONCLUSIONS: We observed a high symptom burden at endometrial cancer diagnosis, with most PRO measures returning to general population means by 1 year. Information on risk factor-PRO associations can be used during the clinical visit to inform supportive service referral. IMPLICATIONS FOR CANCER SURVIVORS: These findings can inform clinicians' discussions with endometrial cancer survivors regarding expected symptom trajectory following diagnosis and treatment.
RESUMO
OBJECTIVES: The use of a platinum doublet for the treatment of platinum-sensitive epithelial ovarian cancer (EOC) recurrence is well established. The impact of the nonplatinum chemotherapy used as part of a platinum doublet on PARP inhibitor (PARPi) and platinum sensitivity it not known. We aimed to describe oncologic outcomes in cases of recurrent EOC receiving PARPi as maintenance therapy based on preceding platinum doublet. METHODS: Retrospective study of patients with platinum-sensitive recurrent ovarian, fallopian tube or primary peritoneal cancer treated with platinum doublet followed by maintenance PARPi from 1/1/2015 and 1/1/2022. Comparisons were made between patients receiving carboplatin + pegylated liposomal doxorubicin (CD) versus other platinum doublets (OPDs). Descriptive statistics, Kaplan-Meier and univariate survival analyses were performed. RESULTS: 100 patients received PARPi maintenance following a platinum doublet chemotherapy regimen for platinum-sensitive recurrence. 25/100 (25%) received CD and 75/100 (75%) received OPDs. Comparing CD and OPDs, median progression-free survival was 8 versus 7 months (p = 0.26), median time to platinum resistance was 15 versus 13 months (p = 0.54), median OS was 64 versus 90 months (p = 0.28), and median OS from starting PARPi was 25 versus 26 months (p = 0.90), respectively. CONCLUSIONS: Using pegylated liposomal doxorubicin as part of a platinum doublet preceding maintenance PARPi for platinum-sensitive recurrence does not seem to hasten PARPi resistance or platinum resistance compared to OPDs. Although there was a non-significant trend towards increased OS among patients who received a platinum doublet other than CD prior to PARPi, the OS from PARPi start was similar between groups. Given the retrospective nature of this study and small study population, further research is needed to evaluate if the choice of platinum doublet preceding PARPi maintenance impacts PARPi resistance, platinum resistance and survival.
Assuntos
Doxorrubicina/análogos & derivados , Neoplasias Ovarianas , Humanos , Feminino , Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Estudos Retrospectivos , Platina/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , PolietilenoglicóisRESUMO
BACKGROUND: Mismatch-repair (MMR)/microsatellite instability (MSI) status has therapeutic implications in endometrial cancer (EC). The authors evaluated the concordance of testing and factors contributing to MMR expression heterogeneity. METHODS: Six hundred sixty-six ECs were characterized using immunohistochemistry (IHC), MSI testing, and mut-L homolog 1 (MLH1) methylation. Select samples underwent whole-transcriptome analysis and next-generation sequencing. MMR expression of metastatic/recurrent sites was evaluated. RESULTS: MSI testing identified 27.3% of cases as MSI-high (n = 182), MMR IHC identified 25.1% cases as MMR-deficient (n = 167), and 3.8% of cases (n = 25) demonstrated discordant results. A review of IHC staining explained discordant results in 18 cases, revealing subclonal loss of MLH1/Pms 1 homolog 2 (PMS2) (n = 10) and heterogeneous MMR IHC (mut-S homolog 6 [MSH6], n = 7; MLH1/PMS2, n = 1). MSH6-associated Lynch syndrome was diagnosed in three of six cases with heterogeneous expression. Subclonal or heterogeneous cases had a 38.9% recurrence rate (compared with 16.7% in complete MMR-deficient cases and 9% in MMR-proficient cases) and had abnormal MMR IHC results in all metastatic recurrent sites (n = 7). Tumors with subclonal MLH1/PMS2 demonstrated 74 differentially expressed genes (determined using digital spatial transcriptomics) when stratified by MLH1 expression, including many associated with epithelial-mesenchymal transition. CONCLUSIONS: Subclonal/heterogeneous MMR IHC cases showed epigenetic loss in 66.7%, germline mutations in 16.7%, and somatic mutations in 16.7%. MMR IHC reported as intact/deficient missed 21% of cases of Lynch syndrome. EC with subclonal/heterogeneous MMR expression demonstrated a high recurrence rate, and metastatic/recurrent sites were MMR-deficient. Transcriptional analysis indicated an increased risk for migration/metastasis, suggesting that clonal MMR deficiency may be a driver for tumor aggressiveness. Reporting MMR IHC only as intact/deficient, without reporting subclonal and heterogeneous staining, misses opportunities for biomarker-directed therapy. PLAIN LANGUAGE SUMMARY: Endometrial cancer is the most common gynecologic cancer, and 20%-40% of tumors have a defect in DNA proofreading known as mismatch-repair (MMR) deficiency. These results can be used to guide therapy. Tests for this defect can yield differing results, revealing heterogeneous (mixed) proofreading capabilities. Tumors with discordant testing results and mixed MMR findings can have germline or somatic defects in MMR genes. Cells with deficient DNA proofreading in tumors with mixed MMR findings have DNA expression profiles linked to more aggressive characteristics and cancer spread. These MMR-deficient cells may drive tumor behavior and the risk of spreading cancer.
Assuntos
Neoplasias Encefálicas , Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Neoplasias do Endométrio , Síndromes Neoplásicas Hereditárias , Humanos , Feminino , Neoplasias Colorretais Hereditárias sem Polipose/genética , Instabilidade de Microssatélites , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Neoplasias do Endométrio/patologia , Reparo de Erro de Pareamento de DNA/genética , DNA , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismoRESUMO
Just as vocalization proceeds in a continuous stream in speech, so too do movements of the hands, face, and body in sign languages. Here, we use motion-capture technology to distinguish lexical signs in sign language from other common types of expression in the signing stream. One type of expression is constructed action, the enactment of (aspects of) referents and events by (parts of) the body. Another is classifier constructions, the manual representation of analogue and gradient motions and locations simultaneously with specified referent morphemes. The term signing is commonly used for all of these, but we show that not all visual signals in sign languages are of the same type. In this study of Israeli Sign Language, we use motion capture to show that the motion of lexical signs differs significantly along several kinematic parameters from that of the two other modes of expression: constructed action and the classifier forms. In so doing, we show how motion-capture technology can help to define the universal linguistic category "word," and to distinguish it from the expressive gestural elements that are commonly found across sign languages.
Assuntos
Captura de Movimento , Língua de Sinais , Humanos , Linguística , Gestos , FalaRESUMO
PURPOSE: To determine if pelvic/ovarian and omental lesions of ovarian cancer can be reliably segmented on computed tomography (CT) using fully automated deep learning-based methods. METHODS: A deep learning model for the two most common disease sites of high-grade serous ovarian cancer lesions (pelvis/ovaries and omentum) was developed and compared against the well-established "no-new-Net" framework and unrevised trainee radiologist segmentations. A total of 451 CT scans collected from four different institutions were used for training (n = 276), evaluation (n = 104) and testing (n = 71) of the methods. The performance was evaluated using the Dice similarity coefficient (DSC) and compared using a Wilcoxon test. RESULTS: Our model outperformed no-new-Net for the pelvic/ovarian lesions in cross-validation, on the evaluation and test set by a significant margin (p values being 4 × 10-7, 3 × 10-4, 4 × 10-2, respectively), and for the omental lesions on the evaluation set (p = 1 × 10-3). Our model did not perform significantly differently in segmenting pelvic/ovarian lesions (p = 0.371) compared to a trainee radiologist. On an independent test set, the model achieved a DSC performance of 71 ± 20 (mean ± standard deviation) for pelvic/ovarian and 61 ± 24 for omental lesions. CONCLUSION: Automated ovarian cancer segmentation on CT scans using deep neural networks is feasible and achieves performance close to a trainee-level radiologist for pelvic/ovarian lesions. RELEVANCE STATEMENT: Automated segmentation of ovarian cancer may be used by clinicians for CT-based volumetric assessments and researchers for building complex analysis pipelines. KEY POINTS: ⢠The first automated approach for pelvic/ovarian and omental ovarian cancer lesion segmentation on CT images has been presented. ⢠Automated segmentation of ovarian cancer lesions can be comparable with manual segmentation of trainee radiologists. ⢠Careful hyperparameter tuning can provide models significantly outperforming strong state-of-the-art baselines.
Assuntos
Aprendizado Profundo , Cistos Ovarianos , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/diagnóstico por imagem , Redes Neurais de Computação , Tomografia Computadorizada por Raios XRESUMO
The growth and metastasis of solid tumours is known to be facilitated by the tumour microenvironment (TME), which is composed of a highly diverse collection of cell types that interact and communicate with one another extensively. Many of these interactions involve the immune cell population within the TME, referred to as the tumour immune microenvironment (TIME). These non-cell autonomous interactions exert substantial influence over cell behaviour and contribute to the reprogramming of immune and stromal cells into numerous pro-tumourigenic phenotypes. The study of some of these interactions, such as the PD-1/PD-L1 axis that induces CD8+ T cell exhaustion, has led to the development of breakthrough therapeutic advances. Yet many common analyses of the TME either do not retain the spatial data necessary to assess cell-cell interactions, or interrogate few (<10) markers, limiting the capacity for cell phenotyping. Recently developed digital pathology technologies, together with sophisticated bioimage analysis programs, now enable the high-resolution, highly-multiplexed analysis of diverse immune and stromal cell markers within the TME of clinical specimens. In this article, we review the tumour-promoting non-cell autonomous interactions in the TME and their impact on tumour behaviour. We additionally survey commonly used image analysis programs and highly-multiplexed spatial imaging technologies, and we discuss their relative advantages and limitations. The spatial organization of the TME varies enormously between patients, and so leveraging these technologies in future studies to further characterize how non-cell autonomous interactions impact tumour behaviour may inform the personalization of cancer treatment.â.
Assuntos
Neoplasias , Microambiente Tumoral , Humanos , Diagnóstico por Imagem , Linfócitos T CD8-Positivos , Processamento de Imagem Assistida por ComputadorRESUMO
OBJECTIVE: Endometrial cancer stage is a strong prognostic factor; however, the current stage classification does not incorporate transtubal spread as determined by intraluminal tumor cells (ILTCs). We examined relationships between ILTCs and survival outcomes according to histological subtype and stage and examined whether identification of ILTCs improves prognostic accuracy of endometrial cancer staging. METHODS: We conducted a retrospective cohort study of women diagnosed with endometrial cancer at five academic hospitals between 2007 and 2012. Pathologists determined ILTC presence (no vs. yes) and location (free in lumen vs. attached to epithelial surface) based on pathology review of hematoxylin and eosin-stained sections of fallopian tubes. Associations between ILTCs with time to recurrence (TTR) and overall survival (OS) were examined with Cox proportional hazards models adjusted for other prognostic factors. Model discrimination metrics were used to assess the addition of ILTCs to stage for prediction of 5-year TTR and OS. RESULTS: In the overall study population (N = 1303), ILTCs were not independently associated with TTR (HR = 0.95, 95% CI = 0.69-1.32) or OS (HR = 0.97, 95% CI = 0.72-1.31). Among 805 women with stage I disease, ILTCs were independently associated with worse TTR (HR = 2.31, 95% CI = 1.06-5.05) and OS (HR = 2.16, 95% CI = 1.14-4.11). Upstaging early-stage cases with ILTCs present did not increase model discrimination. CONCLUSION: While our data do not suggest that endometrial cancer staging guidelines should be revised to include ILTCs, associations between ILTCs and reduced survival observed among stage I cases suggest this tumor feature holds clinical relevance for subgroups of endometrial cancer patients.
Assuntos
Neoplasias do Endométrio , Humanos , Feminino , Prognóstico , Estudos Retrospectivos , Estadiamento de Neoplasias , Neoplasias do Endométrio/patologia , Tubas Uterinas/patologiaRESUMO
OBJECTIVE: We sought to assess the impact of antibiotic (ABX) and proton-pump inhibitor (PPI) use on progression-free (PFS) and overall survival (OS) in patients treated with adjuvant platinum-based chemotherapy (PC) for endometrial cancer (EC). METHODS: A retrospective, single-institution cohort study of EC patients treated with ≥four cycles of adjuvant PC following surgical staging from 2014 to 2020. Demographics and clinicopathologic features, including ABX and PPI use, were compared using χ2 and Fisher's exact tests. Univariate and multivariable analyses were performed, and survival outcomes were compared using the log-rank test. RESULTS: Of 325 patients, 95 (29%) received ABX, and 80 (24.6%) received PPI. ABX were associated with decreased 3-year PFS (49.9% vs. 66%; p = 0.0237) but not 3-year OS (68.9% vs. 79.9%; p = 0.0649). ABX targeting gram-positive bacteria were associated with decreased 3-year PFS (21.2% vs. 66.0% vs. 55.4%; p = 0.0038) and 3-year OS (36.5% vs. 79.9% vs. 75.6%; p = 0.0014) compared to no ABX and other ABX, respectively. PPI use was associated with decreased 3-year PFS (46.9% vs. 66.0%; p = 0.0001) and 3-year OS (60.7% vs. 81.9%; p = 0.0041) compared to no PPI. On multivariable regression analysis controlling for confounders including stage, histology, grade, radiation, and co-morbidities, PPI use was independently associated with worse PFS (HR 1.96, 95% CI 1.25-3.08; p = 0.0041) and OS (HR 2.06, 95% CI 1.01-4.18, p = 0.04). CONCLUSION: In this retrospective cohort study, we demonstrate that PPI use is independently associated with worse PFS and OS in patients with EC treated with PC. ABX use was associated with worse PFS on univariate analysis only. There is an unmet need to understand how PPI, ABX, and, potentially, the microbiome impact the effectiveness of chemotherapy in EC patients.
Assuntos
Neoplasias do Endométrio , Inibidores da Bomba de Prótons , Feminino , Humanos , Estudos Retrospectivos , Inibidores da Bomba de Prótons/uso terapêutico , Estudos de Coortes , Platina/uso terapêutico , Antibacterianos/uso terapêutico , Estadiamento de Neoplasias , Quimioterapia Adjuvante , Neoplasias do Endométrio/patologiaRESUMO
OBJECTIVE: To determine the prevalence of Type 2 diabetes mellitus (T2DM) diagnoses during the peri-operative and survivorship periods in patients following surgical management of endometrial cancer (EC). METHODS: An IRB-approved, retrospective single-institution cohort study was performed in patients who underwent surgical management of EC from 2014 to 2020. The perioperative period was defined as the 30 days before and after surgery. T2DM diagnoses occurring during survivorship were recorded. T2DM diagnoses were defined by a HgbA1c ≥6.5% or a random blood glucose ≥200 mg/dL. Sequelae of peri-operative T2DM and predictors of future T2DM were examined utilizing univariate analysis. RESULTS: Of 519 patients meeting inclusion criteria, 37 (7.1%) were diagnosed with T2DM in the perioperative period. Patients diagnosed with T2DM in the perioperative period had significantly higher BMI (p = 0.006) compared to no T2DM, but there were no significant differences in age (p = 0.20), ethnicity/race (p > 0.05) or ECOG score (p = 0.19). The rates of intraoperative complications between groups did not significantly differ, except for vascular complications (p = 0.005), and the incidence of any postoperative complication was higher in the perioperative T2DM group (p = 0.01). With a median follow-up of 29 months [range 11.6-49.0 months], an additional 18.3% (n = 88) of the cohort met diagnostic criteria for T2DM. BMI (p < 0.001), perioperative glucose (p < 0.001), and HgbA1c (p = 0.002) demonstrate risk for a T2DM diagnosis during survivorship. CONCLUSION(S): In this retrospective cohort of EC patients, 25.4% were diagnosed with T2DM, with the majority diagnosed in the survivorship period. Surgical management and subsequent surveillance of EC presents an opportunity to diagnose at-risk patients with T2DM.
RESUMO
Objective: To determine the safety and feasibility of same-day discharge (SDD) following minimally invasive hysterectomy (MIH) for elderly patients and to evaluate associations between age, frailty, and postoperative outcomes. Methods: Retrospective review was conducted of patients aged ≥ 70 who underwent MIH within a single gynecologic oncology institution from 2018 to 2020. Demographics, peri-operative factors, postoperative complications, and 30-day readmission rates were collected. Frailty was determined by an 11-point modified frailty index ≥ 2. Outcomes were compared between SDD and observation groups using Fisher's exact and Wilcoxon rank-sum tests. Results: Of 169 patients included in the analysis, 8.9% (n = 15) underwent SDD, and 91.1% (n = 154) were admitted for OBS following MIH. Demographics, peri-operative factors, and frailty rates (33% SDD vs 43.5% observation; p = 0.59) were similar between groups. 86.7% (n = 13) of SDD cases were completed before 12PM, and none were completed after 6PM. No SDD patients had early post-operative complications or hospital readmissions. Early postoperative complications were diagnosed in 9 (5.8%) patients admitted for OBS, and the 30-day hospital readmission rate for patients who underwent OBS was 8.4% (n = 13). While elderly patients who met objective frailty criteria (n = 72) did not have a higher likelihood of early post-operative complications (44.4% vs 55.6%; p = 0.909), they did have a higher likelihood of ED visit within 30 days of discharge (15.3 vs 3.1%; p = 0.009), and a trend was noted toward a higher rate of 30-day hospital readmission (12.5% vs 4.1%; p = 0.080). Conclusions: Elderly patients undergoing SDD following MIH did not have increased morbidity or mortality. Elderly patients who meet objective criteria for frailty, however, represent a more vulnerable population.
RESUMO
Background: Although optimal sequencing of systemic therapy in cancer care is critical to achieving maximal clinical benefit, there is a lack of analysis of treatment sequencing in advanced non-small cell lung cancer (aNSCLC) in real-world settings. Methods: A retrospective cohort study of 13,340 lung cancer patients within the Mount Sinai Health System (MSHS) was performed. Systemic therapy data of aNSCLC in 2,106 patients was the starting point in our analysis to investigate how treatment sequencing has evolved, the impact of sequencing patterns on clinical outcomes, and the effectiveness of 2nd line chemotherapy after patients progressed on immune checkpoint inhibitor (ICI)-based therapy as the 1st line of therapy (LOT). Results: There is a significant shift to more ICI-based therapy and multiple lines of targeted therapy after 2015. We compared clinical outcomes of two patient populations with different treatment sequencing patterns, with the 1st group receiving chemotherapy as the 1st LOT followed by ICI-based treatment, and the 2nd group treated in the opposite order receiving a 1st line ICI-containing regimen followed by a 2nd line chemotherapy. No statistically significant difference in overall survival (OS) was observed between the two groups [group 2 vs. group 1, adjusted hazard ratio (aHR) =1.36, P=0.39]. We assessed the efficacy of the 2nd line chemotherapy in three patient populations given either 1st line ICI single agent, 1st line ICI-chemotherapy combination, or 1st line chemotherapy alone, there was no statistically significant difference in time-to-next treatment (TTNT) and in OS among the three patient groups. Conclusions: Analysis of real-world data has shown two treatment sequencing patterns in aNSCLC, ICI followed by chemotherapy or chemotherapy followed by ICI, achieved similar clinical benefit. The chemotherapies routinely used following platinum doublet 1st LOT, is effective as the 2nd line option after ICI-chemotherapy combination in the 1st line setting.
RESUMO
INTRODUCTION: Ovarian cancer (OC) is the deadliest gynecologic malignancy, with an overall 5-year survival rate of less than 30%. The existing paradigm for OC detection involves a serum marker, CA125, and ultrasound examination, neither of which is sufficiently specific for OC. This study addresses this deficiency through the use of a targeted ultrasound microbubble directed against tissue factor (TF). METHODS: TF expression was examined in both OC cell lines and patient-derived tumor samples via western blotting and IHC. In vivo microbubble ultrasound imaging was analyzed using high grade serous ovarian carcinoma orthotopic mouse models. RESULTS: While TF expression has previously been described on angiogenic, tumor-associated vascular endothelial cells (VECs) of several tumor types, this is first study to show TF expression on both murine and patient-derived ovarian tumor-associated VECs. Biotinylated anti-TF antibody was conjugated to streptavidin-coated microbubbles and in vitro binding assays were performed to assess the binding efficacy of these agents. TF-targeted microbubbles successfully bound to TF-expressing OC cells, as well as an in vitro model of angiogenic endothelium. In vivo, these microbubbles bound to the tumor-associated VECs of a clinically relevant orthotopic OC mouse model. CONCLUSION: Development of a TF-targeted microbubble capable of successfully detecting ovarian tumor neovasculature could have significant implications towards increasing the number of early-stage OC diagnoses. This preclinical study shows potential for translation to clinical use, which could ultimately help increase the number of early OC detections and decrease the mortality associated with this disease.