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OBJECTIVE: The aim of this study was to compare surgical complexity, post-operative complications, and survival outcomes between patients with minimal residual disease (completeness of cytoreduction (CC) score) CC-1 at the time of primary debulking surgery and those with complete cytoreduction (CC-0) at the time of interval debulking surgery. METHODS: A retrospective multicenter study was conducted of patients with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage IIIC-IV) who underwent cytoreductive surgery achieving either minimal or no residual disease between January 2008 and December 2015. Patients underwent either primary or interval debulking surgery after receiving ≥3 cycles of neoadjuvant chemotherapy. The sub-group of patients with primary debulking surgery/CC-1 was compared with those with interval debulking surgery/CC-0. Overall survival and disease-free survival were estimated using the Kaplan-Meier method. RESULTS: A total of 549 patients were included, with upfront surgery performed in 175 patients (31.9%) and 374 patients (68.1%) undergoing interval debulking surgery. After primary debulking surgery, 157/175 (89.7%) had complete cytoreduction and 18/175 (10.3%) had minimal residual disease (primary debulking surgery/CC-1 group), while after interval debulking surgery, 324/374 (86.6%) had complete cytoreduction (interval debulking surgery/CC-0 group) and 50/374 (13.4%) had minimal residual disease. The rate of patients with peritoneal cancer index >10 was 14/17 (82.4%) for the primary debulking surgery/CC-1 group and 129/322 (40.1%) for the interval debulking surgery/CC-0 (p<0.001). The rate of patients with an Aletti score of ≥8 was 11/18 (61.1%) and 132/324 (40.7%), respectively (p=0.09) and the rate of major post-operative complications was 5/18 (27.8%) and 64/324 (19.8%), respectively (p=0.38). Overall median disease-free and overall survival were 19.4 months (95% CI 18.0 to 20.6) and 56.7 months (95%CI 50.2 to 65.8), respectively. Median disease-free survival for the primary debulking surgery/CC-1 group was 16.7 months (95% CI 13.6 to 20.0) versus 18.2 months (95% CI 16.4 to 20.0) for the interval debulking surgery/CC-0 group (p=0.56). Median overall survival for the primary debulking surgery/CC-1 group was 44.7 months (95% CI 34.3 to not reached) and 49.4 months (95% CI 46.2 to 57.3) for the interval debulking surgery/CC-0 group (p=0.97). CONCLUSIONS: Patients with primary debulking surgery with minimal residual disease and those with interval debulking surgery with no residual disease had similar survival outcomes. Interval surgery should be considered when achieving absence of residual disease is challenging at upfront surgery, given the lower tumor burden found during surgery.
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BACKGROUND: Cervical cancer's lymphatic spread primarily begins from the sentinel lymph nodes (SLNs), underlining their pivotal role in disease metastasis. However, these nodes' immune gene expression profiles and immunoregulation mechanisms have yet to be explored. METHODS: Our study aimed to elucidate the immune cell populations and their roles in the immune gene expression profile of negative SLNs compared with positive SLNs and non-SLNs using Nanostring RNA seq analysis. We performed a principal component analysis on the log2 normalized expression of 685 endogenous genes in the nCounter PanCancer Immune Profiling Panel, followed by an assessment of the differential expression of genes and immune cell type abundance. RESULTS: We found significant variations in gene expression among the groups, with negative SLNs displaying overexpression of genes related to tumor-infiltrating immune cells, specifically innate cell populations. They also demonstrated the upregulation of genes involved in antigen presentation and T-cell priming. In contrast, positive SLNs were enriched in regulatory networks, suggesting their potential role in immune evasion. A comparison of negative SLNs and non-SLNs revealed increased innate and adaptive immune cell types, underscoring the ongoing T cell response to tumor antigens. CONCLUSION: Our findings underscore a specific immunogenetic phenotype profile in negative SLNs, emphasizing their crucial role in the initial anticancer response, immunosurveillance, and the propagation of immune tolerance from the primary cervical tumor. These results highlight the potential of SLNs as a novel target for immunotherapy strategies and underscore the importance of new imaging methods for accurately identifying SLN status without removal. Future investigations are needed to understand further the immunological interplay within SLNs and their influence on cervical cancer progression.
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Ganglio Linfático Centinela , Neoplasias del Cuello Uterino , Humanos , Femenino , Neoplasias del Cuello Uterino/inmunología , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología , Ganglio Linfático Centinela/patología , Ganglio Linfático Centinela/inmunología , Inmunogenética/métodos , Persona de Mediana Edad , Metástasis Linfática , Biopsia del Ganglio Linfático Centinela/métodosRESUMEN
PURPOSE: The present knowledge about lymphatic drainage of the ovary is based on carcinological studies, but it has only rarely been studied under physiological conditions. However, it is one of the preferential routes of dissemination in ovarian cancer, and understanding it is therefore vital for optimal carcinological management.Our purpose was to evaluate the feasibility of an innovative technique to study the lymphatic drainage territories of the ovary using a recirculation module on the cadaveric model. METHODS: We injected patent blue into the cortex of twenty "revascularised" cadaver ovaries with the Simlife recirculation model. We observed the migration of the dye live and described the drainage territories of each ovary. RESULTS: We observed a staining of the lymphatic vessels and migration of the dye in all the subjects, systematically ipsilateral to the injected ovary. We identified a staining of the lumbo-aortic territory in 65% of cases, with a preferential lateral-caval involvement (60%) for the right ovary and lateral-aortic territory (40%) for the left ovary. A common iliac involvement was observed in only 10% of cases. In 57% of cases, the staining of the lumbo-aortic territory was associated with a staining of the suspensory ligament. The pelvic territory was involved in 50% of cases, with an external iliac staining in 25% of cases and internal in 20%. CONCLUSION: Our study provides for a better understanding of lymphatic drainage of the ovary using a new detection method, and allows the possibility of improving the teaching for operators with a realistic model. Continuation of this work could lead to considering more targeted and thus less morbid lymph node sampling for lymph node staging in early-stage ovarian cancer.
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Cadáver , Vasos Linfáticos , Neoplasias Ováricas , Ovario , Colorantes de Rosanilina , Humanos , Femenino , Ovario/anatomía & histología , Vasos Linfáticos/anatomía & histología , Colorantes , Estudios de Factibilidad , Metástasis LinfáticaRESUMEN
Purpose: Patient harm is often due to medication errors related to neuraxial and peripheral misconnection. We report a case of inadvertent injection of ciprofloxacin into the epidural space and discuss the strategies that could prevent such an incident. Summary: A 74-year-old woman presented a recurrence of an ovarian cancer. The recent discovery of an intrabdominal recurrence on CT-scan led us to propose a new surgical procedure. A thoracic epidural analgesia was performed prior to general anesthesia. Postoperative pain was controlled with patient-controlled epidural analgesia (PCEA) with ropivacaine-epinephrine. During the first night, abdominal pain appeared. During the second day, a nurse discovered that the bag connected to the pump contained ciprofloxacin and not ropivacaine. After aspiration of 2.5 ml sent to laboratory for analysis, the epidural catheter was removed. The investigation revealed the different causes leading to such an error. Three days after, the patient returned home, without any adverse symptoms. Conclusion: This is the first report of the inadvertent administration of ciprofloxacin into the epidural space via a patient-controlled epidural analgesia technique. As there is no effective treatment for such errors, we discuss the neurological risk of ciprofloxacin and prevention strategy mainly based on organizational and human factors.
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PURPOSE: This study investigates changes in CD8+ cells, CD8+/Foxp3 ratio, HLA I expression, and immune coregulator density at diagnosis and upon neoadjuvant chemotherapy (NACT), correlating changes with clinical outcomes. EXPERIMENTAL DESIGN: Multiplexed immune profiling and cell clustering analysis were performed on paired matched ovarian cancer samples to characterize the immune tumor microenvironment (iTME) at diagnosis and under NACT in patients enrolled in the CHIVA trial (NCT01583322). RESULTS: Several immune cell (IC) subsets and immune coregulators were quantified pre/post-NACT. At diagnosis, patients with higher CD8+ T cells and HLA I+-enriched tumors were associated with a better outcome. The CD8+/Foxp3+ ratio increased significantly post-NACT in favor of increased immune surveillance, and the influx of CD8+ T cells predicted better outcomes. Clustering analysis stratified pre-NACT tumors into four subsets: high Binf, enriched in B clusters; high Tinf and low Tinf, according to their CD8+ density; and desert clusters. At baseline, these clusters were not correlated with patient outcomes. Under NACT, tumors were segregated into three clusters: high BinfTinf, low Tinf, and desert. The high BinfTinf, more diverse in IC composition encompassing T, B, and NK cells, correlated with improved survival. PDL1 was rarely expressed, whereas TIM3, LAG3, and IDO1 were more prevalent. CONCLUSIONS: Several iTMEs exist during tumor evolution, and the NACT impact on iTME is heterogeneous. Clustering analysis of patients unravels several IC subsets within ovarian cancer and can guide future personalized approaches. Targeting different checkpoints such as TIM3, LAG3, and IDO1, more prevalent than PDL1, could more effectively harness antitumor immunity in this anti-PDL1-resistant malignancy.
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Linfocitos T CD8-positivos , Terapia Neoadyuvante , Neoplasias Ováricas , Microambiente Tumoral , Humanos , Femenino , Microambiente Tumoral/inmunología , Terapia Neoadyuvante/métodos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/mortalidad , Linfocitos T CD8-positivos/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Persona de Mediana Edad , Factores de Transcripción Forkhead/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Anciano , Adulto , Biomarcadores de Tumor , Receptor 2 Celular del Virus de la Hepatitis A/metabolismoRESUMEN
BACKGROUND: This study was a secondary analysis of the ROBOGYN-1004 trial conducted between 2010 and 2015. The study aimed to identify factors that affect postoperative morbidity after either robot-assisted laparoscopy (RL) or conventional laparoscopy (CL) in gynecologic oncology. METHODS: The study used two-level logistic regression analyses to evaluate the prognostic and predictive value of patient, surgery, and center characteristics in predicting severe postoperative morbidity 6 months after surgery. RESULTS: This analysis included 368 patients. Severe morbidity occurred in 49 (28 %) of 176 patients who underwent RL versus 41 (21 %) of 192 patients who underwent CL (p = 0.15). In the multivariate analysis, after adjustment for the treatment group (RL vs CL), the risk of severe morbidity increased significantly for patients who had poorer performance status, with an odds ratio (OR) of 1.62 for the 1-point difference in the WHO performance score (95 % CI 1.06-2.47; p = 0.027) and according to the type of surgery (p < 0.001). A focus on complex surgical acts showed significant more morbidity in the RL group than in the CL group at the less experienced centers (OR, 3.31; 95 % CI 1.0-11; p = 0.05) compared with no impact at the experienced centers (OR, 0.87; 95 % CI 0.38-1.99; p = 0.75). CONCLUSION: The findings suggest that the center's experience may have an impact on the risk of morbidity for patients undergoing complex robot-assisted surgical procedures.
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Neoplasias de los Genitales Femeninos , Laparoscopía , Complicaciones Posoperatorias , Procedimientos Quirúrgicos Robotizados , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Estudios de Seguimiento , Neoplasias de los Genitales Femeninos/cirugía , Procedimientos Quirúrgicos Ginecológicos/métodos , Procedimientos Quirúrgicos Ginecológicos/efectos adversos , Laparoscopía/efectos adversos , Laparoscopía/métodos , Procedimientos Quirúrgicos Mínimamente Invasivos/efectos adversos , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Morbilidad , Complicaciones Posoperatorias/etiología , Pronóstico , Procedimientos Quirúrgicos Robotizados/efectos adversos , Procedimientos Quirúrgicos Robotizados/métodosRESUMEN
BACKGROUND: Data suggest an association between positron emission tomography/CT (PET/CT) metabolic metrics and tumor microenvironment in several malignancies, and a potential role of PET/CT to monitor response to immunotherapy. OBJECTIVE: To evaluate the correlation between tumor loco-regional extension and tumor-infiltrating lymphocyte infiltration in locally advanced cervical cancer prior to concurrent chemo-radiotherapy.The secondary objective was to assess the association between tumor-infiltrating lymphocytes and PET/CT metabolic metrics. METHODS: Patients with locally advanced cervical cancer and negative para-aortic extensions on PET/CT were included. Two senior nuclear medicine physicians specializing in gynecologic oncology reviewed all PET/CT exams, and extracted tumor maximum standardized uptake value, metabolic tumor volume, and total lesion glycolysis, as well as pelvic lymph node involvement. One senior gynecologic oncology pathologist assessed intraepithelial tumor-infiltrating lymphocytes and stromal tumor-infiltrating lymphocytes. Intraepithelial tumor-infiltrating lymphocytes were categorized following previous studies as <1% and >1%. The cut-off for stromal tumor-infiltrating lymphocytes was chosen empirically: intermediate <60% and high >60%. RESULTS: 86 patients were included. Intraepithelial tumor-infiltrating lymphocytes were not significantly associated with tumor metabolic metrics. Intraepithelial tumor-infiltrating lymphocytes were not significantly associated with maximum standard uptake value (p=0.16), or metabolic tumor volume (p=0.19). Tumors with <1% intraepithelial tumor-infiltrating lymphocytes score were associated with a higher MRI tumor size (≥ median) (63.3% vs 39.3%, p=0.04). Patients with pelvic lymph node uptake were significantly more frequent in patients with high stromal tumor-infiltrating lymphocytes score (≥60%) (61.5% vs 31.7%, p=0.009). CONCLUSIONS: Poor or absent intraepithelial tumor-infiltrating lymphocytes were associated with more advanced disease at diagnosis and larger tumor size. Tumor-infiltrating lymphocytes were not associated with tumor metabolic activity. Intraepithelial and stroma tumor-infiltrating lymphocytes are not redundant and should be assessed separately. Further work is needed to evaluate the association between tumor metabolic profile and immune populations, including different T-cell subtypes for patient selection for immunotherapy strategies.
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Neoplasias de los Genitales Femeninos , Neoplasias del Cuello Uterino , Humanos , Femenino , Tomografía Computarizada por Tomografía de Emisión de Positrones , Linfocitos Infiltrantes de Tumor , Neoplasias del Cuello Uterino/diagnóstico por imagen , Neoplasias del Cuello Uterino/terapia , Neoplasias del Cuello Uterino/metabolismo , Neoplasias de los Genitales Femeninos/patología , Tomografía de Emisión de Positrones , Ganglios Linfáticos/patología , Estudios Retrospectivos , Fluorodesoxiglucosa F18 , Radiofármacos , Microambiente TumoralRESUMEN
Adult-type gynecological soft tissue and visceral sarcomas are rare tumors, with an estimated incidence of 13% of all sarcomas and 4% of all gynecological malignancies. They most often develop in the uterus (83%), followed by the ovaries (8%), vulva and vagina (5%), and other gynecological organs (2%). The objective of this review is to provide an overview of the current management of gynecological sarcomas, according to international guidelines. The management of gynecological sarcomas should follow the recommendations for the management of soft tissue and visceral sarcomas. Centralizing cases in expert centers improves patient survival, both for the diagnostic phase and for multidisciplinary therapeutic management. In the case of pelvic soft tissue sarcomas, a radiological biopsy is essential before any surgical decision is taken. In the case of a myometrial tumour which may correspond to a sarcoma, if conservative surgery such as myomectomy or morcellation is planned, an ultrasound-guided biopsy with pathological analysis including comparative genomic hybridization analysis must be carried out. In all cases, en bloc surgery, without rupture, is mandatory. Many rare histological subtypes require specific surgical management.
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Ginecología , Morcelación , Sarcoma , Adulto , Femenino , Humanos , Hibridación Genómica Comparativa , Sarcoma/cirugía , Biopsia Guiada por ImagenRESUMEN
OBJECTIVE: The purpose of this study was to establish a consensus on the surgical technique for sentinel lymph node (SLN) dissection in cervical cancer. METHODS: A 26 question survey was emailed to international expert gynecological oncology surgeons. A two-step modified Delphi method was used to establish consensus. After a first round of online survey, the questions were amended and a second round, along with semistructured interviews was performed. Consensus was defined using a 70% cut-off for agreement. RESULTS: Twenty-five of 38 (65.8%) experts responded to the first and second rounds of the online survey. Agreement ≥70% was reached for 13 (50.0%) questions in the first round and for 15 (57.7%) in the final round. Consensus agreement identified 15 recommended, three optional, and five not recommended steps. Experts agreed on the following recommended procedures: use of indocyanine green as a tracer; superficial (with or without deep) injection at 3 and 9 o'clock; injection at the margins of uninvolved mucosa avoiding vaginal fornices; grasping the cervix with forceps only in part of the cervix is free of tumor; use of a minimally invasive approach for SLN biopsy in the case of simple trachelectomy/conization; identification of the ureter, obliterated umbilical artery, and external iliac vessels before SLN excision; commencing the dissection at the level of the uterine artery and continuing laterally; and completing dissection in one hemi-pelvis before proceeding to the contralateral side. Consensus was also reached in recommending against injection at 6 and 12 o'clock, and injection directly into the tumor in cases of the tumor completely replacing the cervix; against removal of nodes through port without protective maneuvers; absence of an ultrastaging protocol; and against modifying tracer concentration at the time of re-injection after mapping failure. CONCLUSION: Recommended, optional, and not recommended steps of SLN dissection in cervical cancer have been identified based on consensus among international experts. These represent a surgical guide that may be used by surgeons in clinical trials and for quality assurance in routine practice.
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Neoplasias del Cuello Uterino , Femenino , Humanos , Neoplasias del Cuello Uterino/cirugía , Neoplasias del Cuello Uterino/patología , Metástasis Linfática/patología , Consenso , Escisión del Ganglio Linfático/métodos , Biopsia del Ganglio Linfático Centinela/métodos , Verde de Indocianina , Ganglios Linfáticos/patologíaRESUMEN
BACKGROUND: Retrospective data suggest that the incidence of parametrial infiltration is low in patients with early-stage low-risk cervical cancer, which raises questions regarding the need for radical hysterectomy in these patients. However, data from large, randomized trials comparing outcomes of radical and simple hysterectomy are lacking. METHODS: We conducted a multicenter, randomized, noninferiority trial comparing radical hysterectomy with simple hysterectomy including lymph-node assessment in patients with low-risk cervical cancer (lesions of ≤2 cm with limited stromal invasion). The primary outcome was cancer recurrence in the pelvic area (pelvic recurrence) at 3 years. The prespecified noninferiority margin for the between-group difference in pelvic recurrence at 3 years was 4 percentage points. RESULTS: Among 700 patients who underwent randomization (350 in each group), the majority had tumors that were stage IB1 according to the 2009 International Federation of Gynecology and Obstetrics (FIGO) criteria (91.7%), that had squamous-cell histologic features (61.7%), and that were grade 1 or 2 (59.3%). With a median follow-up time of 4.5 years, the incidence of pelvic recurrence at 3 years was 2.17% in the radical hysterectomy group and 2.52% in the simple hysterectomy group (an absolute difference of 0.35 percentage points; 90% confidence interval, -1.62 to 2.32). Results were similar in a per-protocol analysis. The incidence of urinary incontinence was lower in the simple hysterectomy group than in the radical hysterectomy group within 4 weeks after surgery (2.4% vs. 5.5%; P = 0.048) and beyond 4 weeks (4.7% vs. 11.0%; P = 0.003). The incidence of urinary retention in the simple hysterectomy group was also lower than that in the radical hysterectomy group within 4 weeks after surgery (0.6% vs. 11.0%; P<0.001) and beyond 4 weeks (0.6% vs. 9.9%; P<0.001). CONCLUSIONS: In patients with low-risk cervical cancer, simple hysterectomy was not inferior to radical hysterectomy with respect to the 3-year incidence of pelvic recurrence and was associated with a lower risk of urinary incontinence or retention. (Funded by the Canadian Cancer Society and others; ClinicalTrials.gov number, NCT01658930.).
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Carcinoma de Células Escamosas , Histerectomía , Neoplasias del Cuello Uterino , Femenino , Humanos , Canadá , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/cirugía , Histerectomía/efectos adversos , Histerectomía/métodos , Ganglios Linfáticos/patología , Recurrencia Local de Neoplasia/epidemiología , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Incontinencia Urinaria/etiología , Retención Urinaria/etiología , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/cirugíaRESUMEN
Peritoneal carcinomatosis is an unavoidable development of ovarian cancer, from the first treatment to relapses, and is the main cause of patients death. Hyperthermic intraperitoneal chemotherapy (HIPEC), is a hope for cure for patients with ovarian cancer. HIPEC is based on direct application of chemotherapy on the perioneum with high concentration of chemotherapy enhanced with specific effects of hyperthermia. Theoretically, HIPEC could be proposed at different steps of ovarian cancer development. But the hypothesis of efficiency of a new treatment must be assessed before being routinely applied. Numerous clinical series are already published about HIPEC used in primary treatment of ovarian cancer or for relapses. These series are mostly retrospectives and based on heterogeneous parameters as inclusion criteria of patients, intra peritoneal chemotherapy, concentration, temperature, duration of HIPEC. Taking into account this heterogeneity it is not possible to draw strong scientific conclusions about HIPEC efficiency to treat ovarian cancer patients. We proposed a review allowing a better understanding of current recommendations of the use of HIPEC in ovarian cancer patients.
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Hipertermia Inducida , Neoplasias Ováricas , Humanos , Femenino , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Quimioterapia Intraperitoneal Hipertérmica , Hipertermia Inducida/métodos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Terapia CombinadaRESUMEN
Recommendations for clinical practice Nice/Saint-Paul-de-Vence 2022-2023 : Management of advanced/relapsing endometrial cancer Since the first recommendations in 2020 concerning metastatic and/or relapsed endometrial cancer, new treatment options have shown a benefit on patients' life expectancy, justifying their update. In first line, the choice will be made between chemotherapy with carboplatin/paclitaxel or hormone therapy with progestin, depending on tumor characteristics (histological type, grade, expression of hormone receptors, rate of progression). In case of a dMMR tumors, the use of immunotherapy within the framework of a therapeutic trial is an option. Beyond first-line chemotherapy, current standard treatment consists of the combination of pembrolizumab and lenvatinib, regardless of MMR status. Close clinical and biological monitoring is however necessary given the potential toxicity. Chemotherapy retains its place either as monotherapy (paclitaxel or doxorubicin) in the event of failure or contraindication to pembrolizumab-lenvatinib, or in combination with carboplatin in the event of a long free interval and pMMR tumor. The numerous ongoing clinical trials evaluating new therapeutic targets or strategies adapted to molecular or histological types should allow further improvements the prognosis of patients with metastatic endometrial cancer.
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Neoplasias Endometriales , Femenino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/uso terapéutico , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/patología , Hormonas/uso terapéutico , Paclitaxel , Ensayos Clínicos como AsuntoRESUMEN
BACKGROUND: Ovarian adenocarcinoma (OVAD) frequently metastasizes to the peritoneal cavity and manifests by the formation of ascites, which constitutes a tumor-promoting microenvironment. In the peritoneal cavity, two developmentally, phenotypically and functionally distinct macrophage subsets, immunocompetent large peritoneal macrophages (LPM) and immunosuppressive small peritoneal macrophages (SPM), coexist. Because peroxisome proliferator-activated receptor γ (PPARγ) is a critical factor participating in macrophage differentiation and cooperates with CCAAT/enhancer binding protein ß (C/EBPß), a transcription factor essential for SPM-to-LPM differentiation, PPARγ could be also involved in the regulation of SPM/LPM balance and could be a promising therapeutic target. METHODS: To evaluate the 15(S)-hydroxyeicosatetraenoic acid (HETE), a PPARγ endogenous ligand, impact on ovarian tumor growth, we intraperitoneally injected 15(S)-HETE into a murine ovarian cancer model. This experimental model consists in the intraperitoneally injection of ID8 cells expressing luciferase into syngeneic C57BL/6 female mice. This ID8 orthotopic mouse model is a well-established experimental model of end-stage epithelial OVAD. Tumor progression was monitored using an in vivo imaging system. Peritoneal immune cells in ascites were analyzed by flow cytometry and cell sorting. To determine whether the impact of 15(S)-HETE in tumor development is mediated through the macrophages, these cells were depleted by injection of liposomal clodronate. To further dissect how 15(S)-HETE mediated its antitumor effect, we assessed the tumor burden in tumor-bearing mice in which the PPARγ gene was selectively disrupted in myeloid-derived cells and in mice deficient of the recombination-activating gene Rag2. Finally, to validate our data in humans, we isolated and treated macrophages from ascites of individuals with OVAD. RESULTS: Here we show, in the murine experimental model of OVAD, that 15(S)-HETE treatment significantly suppresses the tumor growth, which is associated with the differentiation of SPM into LPM and the LPM residency in the peritoneal cavity. We demonstrate that C/EBPß and GATA6 play a central role in SPM-to-LPM differentiation and in LPM peritoneal residence through PPARγ activation during OVAD. Moreover, this SPM-to-LPM switch is associated with the increase of the effector/regulatory T-cell ratio. Finally, we report that 15(S)-HETE attenuates immunosuppressive properties of human ovarian tumor-associated macrophages from ascites. CONCLUSION: Altogether, these results promote PPARγ as a potential therapeutic target to restrain OVAD development and strengthen the use of PPARγ agonists in anticancer therapy.
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Adenocarcinoma , Neoplasias Ováricas , PPAR gamma , Animales , Femenino , Humanos , Ratones , Ascitis , Carcinoma Epitelial de Ovario , Terapia de Inmunosupresión , Inmunosupresores , Macrófagos Peritoneales , Ratones Endogámicos C57BL , Neoplasias Ováricas/tratamiento farmacológico , Microambiente TumoralRESUMEN
BACKGROUND: Flap reconstruction is often required after pelvic tumor resection to reduce wound complications. The use of perforator flaps has been shown to reduce donor site morbidity. The purpose of this study was to evaluate the outcomes of pedicled deep inferior epigastric perforator (pDIEP) flap reconstruction. METHODS: This was a retrospective multicenter study of patients who underwent immediate pDIEP flap reconstruction for a pelvic or perineal defect after tumor resection between November 2012 and June 2022. The primary outcome was abdominal donor site morbidity, and the secondary outcome was perineal morbidity. RESULTS: Thirty-four patients (median age, 57.5 years) who underwent pelvic exenteration (n = 31), extralevator abdominoperineal excision (n = 2), or extended vaginal hysterectomy (n = 1) were included. The most common indications were recurrent cervical (n = 19) and anal (n = 4) squamous cell carcinoma. Twenty-nine patients (85%) had a history of radiotherapy. Only one patient (3%) had major (Clavien-Dindo ≥ III) donor site complications (surgical site infection due to tumor recurrence). Eleven patients (32%) had at least one major recipient site complication (surgical site infection [n = 1], total [n = 2] or partial [n = 1] flap loss, perineal dehiscence [n = 2], hematoma [n = 1], fistula [n = 5]). No incisional or perineal hernias were observed during follow-up. Ninety-day survival was 100%. CONCLUSION: Pedicled DIEP flap reconstructions performed by experienced surgical teams had good outcomes for perineal or vaginal reconstruction, with low abdominal morbidity, in patients with advanced pelvic malignancies who had undergone median laparotomy. The risks and benefits of this procedure should be carefully evaluated preoperatively using clinical and imaging data.
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Mamoplastia , Neoplasias Pélvicas , Colgajo Perforante , Procedimientos de Cirugía Plástica , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Pélvicas/cirugía , Infección de la Herida Quirúrgica/cirugía , Recurrencia Local de Neoplasia/cirugía , Colgajo Perforante/cirugía , Mamoplastia/efectos adversos , Perineo/cirugía , Estudios Retrospectivos , Complicaciones Posoperatorias/etiologíaRESUMEN
INTRODUCTION: Retroperitoneal liposarcoma (RPL) is a rare primary mesenchymal tumour that develops in retroperitoneal adipose tissue. Unlike the majority of published series, this homogeneous cohort focuses on RPL. The main purpose of this study is to evaluate the overall and recurrence-free survival of RPLs who underwent excision surgery and the prognostic factors involved. PATIENTS AND METHODS: A total of 82 patients from a single centre, who underwent curative surgery for histologically confirmed retroperitoneal liposarcoma between 2008 and 2020, were analysed in the study. Compartmental surgical excision was advised as per the guidelines. The primary endpoints were 5 years of overall survival and recurrence-free survival. Predictable tumour invasion of adjacent organs, based on a pre-operative CT scan, was also investigated to test the correlation between pre-operative imaging and pathological data. RESULTS: Median follow-up was 61.6 months. Five year overall survival was 71.9% [95% CI: 59.8; 80.9] and 5 year recurrence-free survival was 49% [95% CI: 36.4; 60.5]. Following multivariable analysis, the factors influencing overall survival were tumour rupture and onset of severe complications (Dindo-Clavien grade ≥3). Factors influencing recurrence-free survival were neoadjuvant radiotherapy and tumour rupture. A significant correlation (p < 0.05) was found between predicted invasion based on a CT scan of the colon, spleen, adrenal gland, posterior abdominal wall and diaphragm, and pathological invasion. CONCLUSIONS: Curative compartmental surgery remains the gold standard treatment for RPL. This study, highlights the fact that the quality of the surgical excision is a crucial factor in patient prognosis.
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Liposarcoma , Neoplasias Retroperitoneales , Humanos , Pronóstico , Liposarcoma/diagnóstico por imagen , Liposarcoma/cirugía , Neoplasias Retroperitoneales/diagnóstico por imagen , Neoplasias Retroperitoneales/cirugía , Análisis de Supervivencia , Recurrencia Local de Neoplasia/diagnóstico por imagen , Recurrencia Local de Neoplasia/cirugía , Estudios RetrospectivosRESUMEN
PURPOSE: To evaluate efficacy and feasibility of high-dose intensity-modulated radiotherapy (RT) with pre-operative helical tomotherapy, delivering 54 Gy/30 fractions in patients with retroperitoneal liposarcomas (RPLS). MATERIALS AND METHODS: Patients with operable, biopsy-proven, RPLS were included in this phase II multicenter study (ClinicalTrials.gov: NCT01841047). The primary objectives were to analyze loco-regional relapse free survival (LRFS), overall survival (OS) and toxicities, graded according to CTCAE V3.0. RESULTS: From April 2009 to September 2013, 48 patients were included. Histological types were: 20 well differentiated and 28 dedifferentiated liposarcomas. Median clinical target volume (CTV) was 2570 cc (range, 230-8734 cc). The radio-surgical schedule was completed as planned in all patients apart from one. A monobloc wide excision was achieved for all patients. Surgical margins were R0 (16; 34%), R1 (28; 60%), R2 (2; 4%) or missing (1, 2%).With a median follow-up of 5.5 years, 3-year LRFS rate was 74.2% (95%CI: [59.1%; 84.5%]). At 5 years, cumulative incidence of loco-regional relapse for well differentiated and dedifferentiated RPLS was 10% and 18%, respectively. The 5-year OS was 73.9% [95%CI: 58.7-84.3%]. During RT, the most common grade 3-4 adverse events were hematological (N = 20; 41.6%). After surgery and during follow-up, 17 patients (35.4%) presented a grade 3-4 toxicity. Two patients (4.1%) died due to a duodenal toxicity. Nine second cancers were observed. CONCLUSION: From this phase II trial of preoperative RT in RPLS patients, the dose level proposed cannot be considered safe, leading to non-negligible toxicity and second cancers rates. Our results, combined with STRASS-1 study, suggest that the ideal indication of RT for patients with RPLS still remains to be determined.
Asunto(s)
Liposarcoma , Neoplasias Primarias Secundarias , Radioterapia de Intensidad Modulada , Humanos , Radioterapia de Intensidad Modulada/efectos adversos , Radioterapia de Intensidad Modulada/métodos , Neoplasias Primarias Secundarias/etiología , Recurrencia Local de Neoplasia/patología , Liposarcoma/radioterapia , Liposarcoma/cirugía , Liposarcoma/etiologíaRESUMEN
Gynecologic carcinosarcomas (CS) are biphasic neoplasms composed of carcinomatous (C) and sarcomatous (S) malignant components. Because of their rarity and histologic complexity, genetic and functional studies on CS are scarce and the mechanisms of initiation and development remain largely unknown. Whole-genome analysis of the C and S components reveals shared genomic alterations, thus emphasizing the clonal evolution of CS. Reconstructions of the evolutionary history of each tumor further reveal that C and S samples are composed of both ancestral cell populations and component-specific subclones, supporting a common origin followed by distinct evolutionary trajectories. However, while we do not find any recurrent genomic features associated with phenotypic divergence, transcriptomic and methylome analyses identify a common mechanism across the cohort, the epithelial-to-mesenchymal transition (EMT), suggesting a role for nongenetic factors in inflicting changes to cellular fate. Altogether, these data accredit the hypothesis that CS tumors are driven by both clonal evolution and transcriptomic reprogramming, essential for susceptibility to transdifferentiation upon encountering environmental cues, thus linking CS heterogeneity to genetic, transcriptomic, and epigenetic influences. Significance: We have provided a detailed characterization of the genomic landscape of CS and identified EMT as a common mechanism associated with phenotypic divergence, linking CS heterogeneity to genetic, transcriptomic, and epigenetic influences.