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1.
Front Oncol ; 14: 1272432, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38939336

RESUMEN

Introduction: Field cancerization is suggested to arise from imbalanced differentiation in individual basal progenitor cells leading to clonal expansion of mutant cells that eventually replace the epithelium, although without evidence. Methods: We performed deep sequencing analyses to characterize the genomic and transcriptomic landscapes of field change in two patients with synchronous aerodigestive tract tumors. Results: Our data support the emergence of numerous genetic alterations in cancer-associated genes but refutes the hypothesis that founder mutation(s) underpin this phenomenon. Mutational signature analysis identified defective homologous recombination as a common underlying mutational process unique to synchronous tumors. Discussion: Our analyses suggest a common etiologic factor defined by mutational signatures and/or transcriptomic convergence, which could provide a therapeutic opportunity.

2.
PLoS One ; 19(4): e0300594, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38574044

RESUMEN

BACKGROUND: Peritoneal sarcomatosis (PS) is a difficult entity to treat with limited options and guarded prognosis. We aimed to determine if the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) could offer superior local recurrence-free survival in patients with retroperitoneal sarcoma at high risk of developing PS as opposed to extended resection alone. METHODS: This is a single arm, phase II intervention study where all patients with recurrent localized retroperitoneal sarcoma considered at high risk of developing PS were considered for enrolment (ClinicalTrials.gov identifier: NCT03792867). Upon enrolment, patients underwent vigorous preoperative testing to ensure fitness for the procedure. During surgery, patients underwent extended resection and HIPEC with doxorubicin. Patients were followed-up every 2 weeks (± 10 days) for the first month and subsequently every three months (± 1 month) up to a year post-surgery, and were assessed for potential chemotherapy toxicity and post-treatment complications. After a year from resection and HIPEC, patients were followed-up either during routine clinic review or contacted via telephone every year (± 1 month) for 3 years. RESULTS: Six patients were recruited but one patient dropped out due to adverse and unexpected intraoperative events. The remaining patients completed the procedure uneventfully. Post-HIPEC, all patients recurred with a disease-free interval ranging from six to 24 months. Three patients died due to complications from recurrent disease whereas the remaining three patients are alive as of their last visit. The overall survival at time at reporting ranged between 22 to 56 months. CONCLUSION: The procedure is feasible with no major morbidity to patients. However, we are unable to recommend for it to be implemented as a routine procedure at this current stage due to lack of improved survival outcomes. Further multi-institutional studies may be conducted to yield better results.


Asunto(s)
Hipertermia Inducida , Neoplasias Peritoneales , Neoplasias Retroperitoneales , Sarcoma , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada , Procedimientos Quirúrgicos de Citorreducción , Hipertermia Inducida/métodos , Quimioterapia Intraperitoneal Hipertérmica , Neoplasias Peritoneales/cirugía , Proyectos Piloto , Neoplasias Retroperitoneales/cirugía , Sarcoma/tratamiento farmacológico , Sarcoma/cirugía
3.
Artículo en Inglés | MEDLINE | ID: mdl-38670261

RESUMEN

BACKGROUND: Egg allergy is common and caused by sensitization to ovomucoid and/or ovalbumin. Many egg-allergic patients are able to tolerate eggs baked into other foods, such as muffins. Although heating egg extensively reduces allergens, the effect of other food ingredients on allergenicity of eggs, or the "matrix effect," is less well studied. OBJECTIVE: We aimed to define how food matrices impact the matrix effect in egg allergenicity. METHODS: Enzyme-linked immunosorbent assay was used to quantify ovalbumin and ovomucoid in extracts from various baked egg products: plain baked egg without a matrix, and muffins baked using either wheat flour, rice flour, or a wheat flour/banana puree mix. Allergen-specific immunoglobulin E (IgE)-blocking enzyme-linked immunosorbent assays were performed using the egg product extracts on egg-allergic patient sera to determine whether the amount of extracted egg protein in each extract correlated with how well the extracts could bind patients' egg IgE. RESULTS: Baking eggs in any muffin matrix led to an increase in the amount of extractable ovalbumin and a decrease in the amount of extractable ovomucoid compared with plain baked egg. Compared with wheat muffins, rice muffins had more extractable ovalbumin and wheat/banana muffins had more extractable ovalbumin and ovomucoid. The egg allergens in the extracts were able to block egg-allergic patients' egg IgE. CONCLUSIONS: Food matrices affect egg allergen availability. Patients and families should be advised that substitutions in baked egg muffin recipes can affect the amount of egg allergens in foods and potentially affect the risk of food allergic reaction.

4.
Ann Surg Open ; 4(4): e339, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38144489

RESUMEN

Objective: To examine the association between the performance of mapping biopsies and surgical outcomes postexcision of extramammary Paget's disease (EMPD). Background: Primary EMPD is a rare entity associated with poorly defined surgical margins and difficult-to-access sites of lesions. Surgical resection with clear margins remains the preferred management method. The use of mapping biopsies might be beneficial, particularly in lowering disease recurrence. Methods: Available literature was reviewed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology before a fixed-effect meta-analysis was performed to identify the presence of a correlation between performing mapping biopsies and positive margins on permanent sections as well as disease-free survival. Additional study results not included in the quantitative assessment were qualitatively assessed and reported. Results: A total of 12 studies were shortlisted for final analysis. 294 patients who underwent mapping biopsies and 48 patients who did not undergo mapping biopsies were included in the assessment. Forest plot analysis revealed a pooled rate ratio of 0.50 (95% CI, 0.32-0.77) in the prevalence of positive margins in patients with mapping biopsies performed as compared to patients without. The pooled rate ratio of the prevalence of disease-free survival in patients with mapping biopsies performed as compared to patients without was 1.38 (95% CI, 1.03-1.84). Qualitative assessment of the remaining selected studies revealed equivocal results. Conclusions: Mapping biopsies are able to improve EMPD surgical excision outcomes but given the rarity of the disease and heterogeneity of mapping biopsy procedures, further confirmation with randomized controlled trials or a larger patient pool is necessary.

5.
JBMR Plus ; 7(8): e10777, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37614298

RESUMEN

Preptin is derived from the cleavage of the E-peptide of pro-insulin-like growth factor (IGF)-II and is an insulin secretagogue. Observational studies have linked elevated circulating preptin to metabolic dysfunction in humans; however, a causal role for preptin in metabolic dysfunction has not been established. Additionally, preptin can promote osteoblast proliferation and differentiation, suggesting a link with skeletal health. We previously described a global preptin knockout (KO) model. In this study, we sought to uncover the impact of preptin KO in mice on the response to a moderately high-fat diet (HFD) and low-fat diet (LFD). HFD groups had higher weight and fat mass gain, lower trabecular and cortical bone volume and fracture load, and higher liver triglycerides. In males, preptin deficiency led to lower blood glucose than wild-type (WT) mice under LFD conditions. This was accompanied by differences in bone microarchitecture, including lower trabecular bone volume fraction, trabecular number, and lower cortical thickness. These differences were absent in female mice, although KO females had a HFD-driven increase in fat mass and liver triglycerides that was absent in WT mice. Female WT mice had increased glucose-stimulated insulin secretion under HFD conditions that was absent in female KO mice. Overall, preptin may have a detrimental impact on metabolism and a positive impact on bone health in male mice and may protect against liver fat storage in females while enabling islet compensation under HFD conditions. When we consider that serum preptin levels are elevated in humans of both sexes in pathological states in which insulin levels are elevated, the impact of preptin on comorbidity risk needs to be better understood. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

7.
Front Oncol ; 12: 891710, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36033535

RESUMEN

Retroperitoneal liposarcomas (RPLPSs) are a rare tumor group for which current guidelines recommend aggressive en bloc resection to attain microscopically negative (R0) margins. To ensure R0 margins, resection of adherent or adjacent organs is often required. However, it is still unclear if R0 margins confer any additional benefit to patients over a grossly negative but microscopically positive (R1) margin. We performed a systematic search of PubMed and Embase databases for studies including patients receiving R0 or R1 resection for RPLPS. Nine retrospective cohort studies, one prospective cohort study, and 49 case reports/case series were included. A total of 552 patients with RPLPS were evaluated: 346 underwent R0 resection and 206 underwent R1 resection. In the R0 group, 5-year overall survival (OS) ranged from 58.3% to 85.7%; local recurrence (LR) ranged from 45.5% to 52.3%. In the R1 group, 5-year OS ranged from 35% to 55.3%; LR ranged from 66.7% to 91.7%. Among cohort studies, OS, disease-free survival (DFS), LR rate, and LR-free survival (LRFS) were significantly associated with R0 resections. Assessment of case series and reports suggested that the R0 margin led to a slightly higher morbidity than that of R1. In conclusion, this review found the R0 margin to be associated with reductions in LR rates and improved OS when compared with the R1 margins, though accompanied by slight increases in morbidity. The roles of tumor histotype and perioperative chemotherapy or radiotherapy were not well-elucidated in this review.

8.
Pleura Peritoneum ; 7(2): 39-49, 2022 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-35812010

RESUMEN

Background: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) has recently emerged as a palliative alternative for patients with unresectable peritoneal metastasis (PM). Quality of life (QoL) has increasingly been used as an endpoint to evaluate treatment outcomes. This review aims to identify evidence on how PIPAC would impact the QoL of PM patients. Content: A systematic review was performed on articles identified from Medline, EMBASE, PsycInfo, and Web of Sciences. A meta-analysis was conducted on further selected studies. ACROBAT-NRSI was attempted to assess the risk of bias (RoB). Summary: Nine studies using the EORTC QLQ-C30 questionnaire to assess QoL after repeated PIPAC cycles were identified. Majority was found to be moderately biased and a great extent of heterogeneity was observed. Four studies on PM from either gastric cancer (GC) or epithelial ovarian cancer (EOC) were included for meta-analysis. In 31 GC patients and 104 EOC patients, QoL remained stable in 13/14 and 11/14 EORTC QLQ-C30 scales. PIPAC was inferior to cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) in global QoL and functioning but superior in symptom reduction. Outlook: PIPAC is a well-tolerated option for most GC and EOC patients with irresectable PM. Future trials are warranted to confirm the findings.

9.
STAR Protoc ; 3(3): 101548, 2022 09 16.
Artículo en Inglés | MEDLINE | ID: mdl-35842864

RESUMEN

Clinically relevant animal models are crucial for effective development of therapeutics for peritoneal carcinomatosis (PC). This protocol describes the generation of patient-derived ascites-dependent xenograft (PDADX) models from the cellular component of ascites. The use of routine intraperitoneal injection of the fluid component of ascites is analogous to the biological events occurring intra-abdominally in patients with PC. By serving as a proxy, PDADX models represent a valuable tool for preclinical testing of new therapeutics for PC. For complete details on the use and execution of this protocol, please refer to Hendrikson et al. (2022).


Asunto(s)
Neoplasias Peritoneales , Animales , Ascitis/tratamiento farmacológico , Modelos Animales de Enfermedad , Xenoinjertos , Humanos , Inyecciones Intraperitoneales , Ratones , Neoplasias Peritoneales/tratamiento farmacológico
10.
Cell Rep Med ; 3(2): 100526, 2022 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-35243423

RESUMEN

Peritoneal carcinomatosis (PC) present a ubiquitous clinical conundrum in all intra-abdominal malignancies. Via functional and transcriptomic experiments of ascites-treated PC cells, we identify STAT3 as a key signaling pathway. Integrative analysis of publicly available databases and correlation with clinical cohorts (n = 7,359) reveal putative clinically significant activating ligands of STAT3 signaling. We further validate a 3-biomarker prognostic panel in ascites independent of clinical covariates in a prospective study (n = 149). Via single-cell sequencing experiments, we uncover that PAI-1, a key component of the prognostic biomarker panel, is largely secreted by fibroblasts and mesothelial cells. Molecular stratification of ascites using PAI-1 levels and STAT3 activation in ascites-treated cells highlight a therapeutic opportunity based on a phenomenon of paracrine addiction. These results are recapitulated in patient-derived ascites-dependent xenografts. Here, we demonstrate therapeutic proof of concept of direct ligand inhibition of a prognostic target within an enclosed biological space.


Asunto(s)
Neoplasias Peritoneales , Animales , Ascitis , Modelos Animales de Enfermedad , Humanos , Ligandos , Ratones , Inhibidor 1 de Activador Plasminogénico/genética , Estudios Prospectivos
11.
Eur J Surg Oncol ; 48(3): 640-648, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-34716035

RESUMEN

Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) play an important role in the treatment of various peritoneal surface malignancies, but its efficacy in peritoneal sarcomatosis (PS) remains unknown. Hence, we performed a systematic review and meta-analysis to investigate outcomes of CRS-HIPEC in PS, in accordance with PRISMA guidelines. 16 studies with a total of 320 patients were included in the meta-analysis. Pooled mean length of hospital stay after CRS-HIPEC was 16.0 days (95% CI: 12.2-19.8) and rate of serious complications was 17.4% (95% CI: 9.8-26.3). The median DFS was 12.0 months (95% CI: 8.0-16.0) and the 5-year DFS was 21.8% (95% CI: 13.2-31.7). Overall pooled median OS was 29.3 months (95% CI: 23.8-34.8), with a 5-year OS of 35.3% (95% CI: 26.3-44.8). Subgroup analysis showed that patients with CC-0 cytoreduction had a higher median OS of 34.6 months (95% CI: 23.2-45.9). Median OS for patients with a primary tumour histology of leiomyosarcoma and liposarcoma was 33.5 months (95% CI: 15.9-51.1) and 39.1 months (95% CI: 20.8-57.5) respectively. The site of recurrence was locoregional in 57.3% (95% CI: 38.9-74.8), distant in 17.3% (95% CI: 3.9-35.6), and both in 17.4% (95% CI: 5.8-32.2). In conclusion, our results suggest that CRS-HIPEC may improve outcomes in a select group of PS patients.


Asunto(s)
Hipertermia Inducida , Sarcoma , Neoplasias de los Tejidos Blandos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada , Procedimientos Quirúrgicos de Citorreducción , Humanos , Quimioterapia Intraperitoneal Hipertérmica , Estudios Retrospectivos , Sarcoma/patología , Sarcoma/terapia , Tasa de Supervivencia
12.
Front Oncol ; 11: 795390, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34926311

RESUMEN

BACKGROUND: Peritoneal metastasis (PM) is a late-stage manifestation of intra-abdominal malignancies. The current standard of care indicates that cure can only be achieved with cytoreductive surgery (CRS) which is often indicated with concurrent adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC). However, the utility of HIPEC within subsets of PM is not fully understood. We seek to compare the effectiveness of HIPEC in improving peritoneal recurrence rates in PM of different origins. METHODS: We conducted a systematic review of trials on the PubMed, EMBASE, and Cochrane databases, last searched in August 2021. Biases were assessed using the Cochrane Collaboration's tool for assessing the risk of bias in randomized trials as well as the Methodological Index for Non-Randomized Studies (MINORS) framework. RESULTS: 7 gastric PM studies, 3 ovarian PM studies, and 3 colorectal PM studies were included. Recurrence-free survival was improved in the HIPEC + CRS cohort in 5 gastric trials but only 1 ovarian trial and none of colorectal origin. DISCUSSION: Our findings indicate decent effectiveness of HIPEC in gastric PM, but limited utility in ovarian and colorectal PM. Limitations in the current literature are attributed to the paucity of data available, a lack of homogeneity and consideration of novel and personalised treatment regimens. We implore for further studies to be conducted with a focus on patient selection and stratification, and suggest a reframing of approach towards modern molecular and targeted therapeutic options in future studies of HIPEC. SYSTEMATIC REVIEW REGISTRATION: https://www.researchregistry.com/browse-the-registry#registryofsystematicreviewsmeta-analyses/registryofsystematicreviewsmeta-analysesdetails/60c1ffff0c1b78001e8efbe3/, identifier reviewregistry1166.

13.
Sci Rep ; 11(1): 16829, 2021 08 19.
Artículo en Inglés | MEDLINE | ID: mdl-34413360

RESUMEN

Ovarian cancer is associated with poor prognosis. Platinum resistance contributes significantly to the high rate of tumour recurrence. We aimed to identify a set of molecular markers for predicting platinum sensitivity. A signature predicting cisplatin sensitivity was generated using the Genomics of Drug Sensitivity in Cancer and The Cancer Genome Atlas databases. Four potential biomarkers (CYTH3, GALNT3, S100A14, and ERI1) were identified and optimized for immunohistochemistry (IHC). Validation was performed on a cohort of patients (n = 50) treated with surgical resection followed by adjuvant carboplatin. Predictive models were established to predict chemosensitivity. The four biomarkers were also assessed for their ability to prognosticate overall survival in three ovarian cancer microarray expression datasets from The Gene Expression Omnibus. The extreme gradient boosting (XGBoost) algorithm was selected for the final model to validate the accuracy in an independent validation dataset (n = 10). CYTH3 and S100A14, followed by nodal stage, were the features with the greatest importance. The four gene signature had comparable prognostication as clinical information for two-year survival. Assessment of tumour biology by means of gene expression can serve as an adjunct for prediction of chemosensitivity and prognostication. Potentially, the assessment of molecular markers alongside clinical information offers a chance to further optimise therapeutic decision making.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Cisplatino/uso terapéutico , Aprendizaje Automático , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/cirugía , Línea Celular Tumoral , Cisplatino/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Neoplasias Ováricas/genética
14.
Cancers (Basel) ; 13(16)2021 Aug 18.
Artículo en Inglés | MEDLINE | ID: mdl-34439309

RESUMEN

Peritoneal carcinomatosis (PC) is often associated with malnutrition and an inability to tolerate enteral feeding. Although total parenteral nutrition (TPN) can be lifesaving for patients with no other means of nutritional support, its use in the management of PC patients remains controversial. Therefore, a systematic review and meta-analysis was performed to evaluate the benefit of TPN on the overall survival of PC patients, in accordance with PRISMA guidelines. A total of 187 articles were screened; 10 were included in this review and eight were included in the meta-analysis. The pooled median overall survival of patients who received TPN was significantly higher than patients who did not receive TPN (p = 0.040). When only high-quality studies were included, a significant survival advantage was observed in PC patients receiving TPN (p < 0.001). Subgroup analysis of patients receiving chemotherapy demonstrated a significant survival benefit (p = 0.008) associated with the use of TPN. In conclusion, TPN may improve survival outcomes in PC patients. However, further studies are needed to conclude more definitively on the effect of TPN.

15.
Cancers (Basel) ; 13(12)2021 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-34207401

RESUMEN

Up to 10% of well-differentiated liposarcoma (WDLS) progress to dedifferentiated liposarcoma (DDLS). We aimed to identify gene expression changes associated with dedifferentiation and whether these were informative of tumour biology of DDLS. We analysed datasets from the Gene Expression Omnibus (GEO, ID = GSE30929) database to identify differentially expressed genes between WDLS (n = 52) and DDLS (n = 39). We validated the signature on whole and laser-capture microdissected samples from patients with tumours consisting of mixed WDLS and DDLS components. A subset of this signature was applied to an independent dataset from The Cancer Genome Atlas (TCGA, n = 58 DDLS) database to segregate samples based on gene expression and compared for recurrence and overall survival (OS). A 15-gene signature consisting of genes with increased expression in DDLS compared to WDLS was generated. This signature segregated WDLS and DDLS samples from patients with mixed component tumours and across multiple recurrences. A further subset of this signature, consisting of five genes (AQP7, ACACB, FZD4, GPD1, LEP), segregated DDLS in a TCGA cohort with a significant difference in OS (p = 0.019) and recurrence-free survival (RFS) (p = 0.061). The five-gene model stratified DDLS into prognostic groups and outperformed clinical factors in existing models in retroperitoneal DDLS.

16.
J Surg Case Rep ; 2021(2): rjaa610, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33708376

RESUMEN

Retroperitoneal lymphangioma is an uncommon and benign mesodermal tumour that arises from the retroperitoneal lymphatics. Notably, it is a rare occurrence in adults, where <200 adult retroperitoneal lymphangioma cases have been published in the literature. Additionally, retroperitoneal lymphangioma is often difficult to diagnose preoperatively and formal diagnosis is frequently determined following surgical exploration. Here, we describe a rare case of retroperitoneal lymphangioma in a 74-year-old man who presented with a 6-month history of intermittent fresh per rectal bleeding with an incidental non-tender left iliac fossa firm mass on examination. Computed tomography scan established a retroperitoneal cystic lesion abutting the aorta and left common iliac vessels. Surgical exploration revealed a large cystic mass and a clean plane of dissection was performed, where the mass was completely excised with all the key structures preserved. Histology was consistent with a retroperitoneal lymphangioma.

17.
Ann Surg Oncol ; 28(11): 6625-6635, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-33655363

RESUMEN

BACKGROUND: The prognostic significance of inflammatory markers in solid cancers is well-established, albeit with considerable heterogeneity. This study sought to investigate the postoperative inflammatory marker trend in peritoneal carcinomatosis (PC), with a focus on colorectal PC (CPC), and to propose optimal surveillance periods and cutoffs. METHODS: Data were collected from a prospectively maintained database of PC patients treated at the authors' institution from April 2001 to March 2019. The platelet-lymphocyte ratio (PLR), the neutrophil-lymphocyte ratio (NLR), and the lymphocyte-monocyte ratio (LMR) were collected preoperatively and on postoperative days 0, 1 to 3, 4 to 7, 8 to 21, 22 to 56, and 57 to 90 as averages. Optimal surveillance periods and cutoffs for each marker were determined by maximally selected rank statistics. The Kaplan-Meier method and Cox proportional hazard regression models were used to investigate the association of inflammatory markers with 1-year overall survival (OS) and recurrence-free survival (RFS) using clinicopathologic parameters. RESULTS: The postoperative inflammatory marker trend and levels did not differ between the patients with and those without hyperthermic intraperitoneal chemotherapy (HIPEC). Low postoperative LMR (days 4-7), high postoperative NLR (days 8-21), and high postoperative PLR (days 22-56) were optimal for prognosticating poor 1-year OS, whereas high postoperative PLR and NLR (days 57-90) and low postoperative LMR (days 8-21) were associated with poor 1-year RFS. A composite score of these three markers was prognostic for OS in CPC. CONCLUSIONS: The reported cutoffs should be validated in a larger population of CPC patients. Future studies should account for the inflammatory response profile when selecting appropriate surveillance periods.


Asunto(s)
Neoplasias Colorrectales , Neoplasias Peritoneales , Neoplasias Colorrectales/cirugía , Humanos , Linfocitos , Neutrófilos , Pronóstico
19.
Oral Oncol ; 111: 105035, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33091845

RESUMEN

OBJECTIVES: We have previously identified and validated a panel of molecular prognostic markers (ATP13A3, SSR3, and ANO1) for Head and Neck Squamous Cell Carcinoma (HNSCC). The aim of this study was to investigate the consequence of ATP13A3 dysregulation on signaling pathways, to aid in formulating a therapeutic strategy targeting ATP13A3-overexpressing HNSCC. MATERIALS AND METHODS: Gene Set Enrichment Analysis (GSEA) was performed on HNSCC microarray expression data (Internal local dataset [n = 92], TCGA [n = 232], EMBL [n = 81]) to identify pathways associated with high expression of ATP13A3. Validation was performed using immunohistochemistry (IHC) on tissue microarrays (TMAs) of head and neck cancers (n = 333), staining for ATP13A3 and phosphorylated Aurora kinase A (phospho-T288). Short interfering RNA was used to knockdown ATP13A3 expression in patient derived HNSCC cell lines. Protein expression of ATP13A3 and Aurora kinase A was then assessed by immunoblotting. RESULTS: GSEA identified Aurora kinase pathway to be associated with high expression of ATP13A3 (p = 0.026). The Aurora kinase pathway was also associated with a trend towards poor prognosis and tumor aggressiveness (p = 0.086, 0.094, respectively). Furthermore, the immunohistochemical staining results revealed a significant association between Aurora kinase activity and high ATP13A3 expression (p < 0.001). Knockdown of ATP13A3 in human head and neck cell lines showed decrease in Aurora kinase A levels. CONCLUSION: Tumors with high ATP13A3 are associated with high Aurora kinase activity. This suggests a potential therapeutic role of Aurora kinase inhibitors in a subset of poor prognosis HNSCC patients with overexpression of ATP13A3.


Asunto(s)
Adenosina Trifosfatasas/metabolismo , Aurora Quinasa A/metabolismo , Neoplasias de Cabeza y Cuello/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Transducción de Señal , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Adenosina Trifosfatasas/genética , Aurora Quinasa A/antagonistas & inhibidores , Línea Celular Tumoral , Femenino , Silenciador del Gen , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Humanos , Inmunohistoquímica , Masculino , Proteínas de Transporte de Membrana/genética , Terapia Molecular Dirigida/métodos , Pronóstico , ARN Interferente Pequeño , Transducción de Señal/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Análisis de Matrices Tisulares
20.
Health Qual Life Outcomes ; 18(1): 270, 2020 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-32762683

RESUMEN

BACKGROUND: Retroperitoneal sarcoma represents 15% of sarcomas. The mainstay of treatment is surgery where a majority of patients require multi-visceral resections that may significantly impact their quality of life (QOL) following surgery. Studies in other cancers have shown that QOL may not be significantly impacted after radical or extensive surgery. However, there are limited studies examining the QOL specifically in patients with retroperitoneal sarcoma. In this pilot study, we retrospectively evaluated the QOL of patients with retroperitoneal sarcoma. METHODS: 32 out of 90 patients who underwent surgical intervention for retroperitoneal sarcoma in National Cancer Centre Singapore from January 1999 to August 2018 who were alive and on follow-up were included in this study. EORTC-QLQ-C30 was administered to the patients. RESULTS: The median age of our patients was 59 years (range, 35-84), and median time from surgery to the implementation of questionnaire was 2.5 years (range, 0.05-9.6). Younger patients had significantly better differences in global health, physical and role functioning scores as compared to older individuals. Female patients reported higher global health, physical, emotional and social functioning scores than males. Patients who were more than 2 years post-surgery exhibited better QOL scores as compared to those who had more recent surgery. Our patients had comparable global health and functioning scores compared to a reference group of outpatient cancer patients at our institution. CONCLUSIONS: Our pilot study investigating the QOL of patients with retroperitoneal sarcoma has shown that patients need to be followed up for at least 2 years following surgery to evaluate their QOL. In general, they achieved better functioning scores when compared with other cancer patients. These findings support the need for larger-scale prospective studies to further evaluate the QOL of these patients.


Asunto(s)
Calidad de Vida , Neoplasias Retroperitoneales/psicología , Sarcoma/psicología , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Neoplasias Retroperitoneales/cirugía , Estudios Retrospectivos , Sarcoma/cirugía , Singapur , Encuestas y Cuestionarios
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