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1.
Ther Adv Med Oncol ; 16: 17588359241277656, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39346117

RESUMEN

Background: In Part 1 of the phase III RUBY trial (NCT03981796) in patients with primary advanced or recurrent endometrial cancer (EC), dostarlimab plus carboplatin-paclitaxel (CP) significantly improved progression-free survival and overall survival compared with CP alone. Limited safety data have been reported for the combination of immunotherapies plus chemotherapy in this setting. Objectives: The objective of this analysis was to identify the occurrence of treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs) and to describe irAE management in Part 1 of the RUBY trial. Design: RUBY is a phase III, randomized, double-blind, multicenter study of dostarlimab plus CP compared with CP alone in patients with primary advanced or recurrent EC. Methods: Patients were randomized 1:1 to dostarlimab 500 mg, or placebo, plus CP every 3 weeks for 6 cycles, followed by dostarlimab 1000 mg, or placebo, every 6 weeks for up to 3 years. Adverse events (AEs) were assessed according to Common Terminology Criteria for Adverse Events, version 4.03. Results: The safety population included 487 patients who received ⩾1 dose of treatment (241 dostarlimab plus CP; 246 placebo plus CP). Treatment-emergent AEs were experienced by 100% of patients in both arms. TRAEs occurred in 97.9% of the dostarlimab arm and 98.8% of the placebo arm.The most common TRAEs occurred at similar rates between arms and were mostly low grade. IrAEs occurred in 58.5% of patients in the dostarlimab arm and 37.0% of patients in the placebo arm. Dostarlimab- or placebo-related irAEs were reported in 40.7% of patients in the dostarlimab arm and 16.3% of the placebo arm. Conclusion: The safety profile of dostarlimab plus CP was generally consistent with that of the individual components. Dostarlimab plus CP has a favorable benefit-risk profile and is a new standard of care for patients with primary advanced or recurrent EC. Trial registration: NCT03981796.


Safety of dostarlimab plus carboplatin-paclitaxel compared with carboplatin-paclitaxel in primary advanced or recurrent endometrial cancer For many years, patients with primary advanced or recurrent endometrial cancer were treated with chemotherapy, specifically with a combination of carboplatin and paclitaxel. Recently, new treatments called immune checkpoint inhibitors have been used to treat endometrial cancer. Dostarlimab, an immune checkpoint inhibitor, is being tested to treat many types of cancer, including endometrial cancer. In the RUBY trial, a combination of dostarlimab plus chemotherapy was compared with chemotherapy alone as treatment for primary advanced or recurrent endometrial cancer. Results showed that patients treated with dostarlimab plus chemotherapy had a lower risk of their cancer becoming worse and a lower risk of dying. Results in this article describe the safety of dostarlimab plus chemotherapy compared with chemotherapy alone. All patients in the RUBY trial experienced at least one adverse event (an undesired effect that happens while receiving treatment or shortly after stopping treatment); most were determined to be caused by the cancer treatments. No differences in the frequency of the overall cancer treatment-related adverse events were seen in patients who received dostarlimab plus chemotherapy compared with those patients who received chemotherapy alone. Some patients experienced an immune-related adverse event. These are a specific type of undesired effect that can occur when patients are treated with immune checkpoint inhibitors. Immune-related adverse events occurred more frequently in patients who received dostarlimab plus chemotherapy than in those who received chemotherapy alone. Physicians were generally able to treat the immune-related adverse events, and only a low percentage of patients discontinued treatment because they experienced an immune-related adverse event. The types of adverse events seen were similar to a combination of those seen in patients who received dostarlimab alone or patients who received chemotherapy alone as treatment for endometrial cancer. Dostarlimab plus chemotherapy is a new standard of care for patients with primary advanced or recurrent endometrial cancer.

2.
Front Oncol ; 14: 1432239, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39286024

RESUMEN

Introduction: Cervical cancer represents one of the main causes of female, cancer-related mortality worldwide. The majority of cancers are caused by human papillomaviruses such as HPV16 and HPV18. As chemotherapeutic resistance to first-line platinum treatment is still a predominant clinical challenge in advanced cervical cancer, novel treatment options including combinatorial therapies are urgently required to overcome chemotherapeutic resistance. Inhibition of A Disintegrin And Metalloproteinase (ADAM)-family members, heavily involved in tumour progression of a vast range of solid tumours, strongly improved response to chemotherapeutic treatment in other tumour entities including ovarian cancer. Methods: We established two- and three-dimensional models derived from three traditional cervical cancer cell lines and ectocervical cancer-derived organoids. Following characterisation, these models were used to investigate their response to cisplatin treatment in the absence and presence of ADAM inhibitors using viability assays and automated live cell imaging. Results: The pivotal role of the metalloprotease ADAM17 driving chemotherapy resistance was detectable in all ectocervical cultures irrespective of the model system used, whereas ADAM10 inhibition was predominantly effective only in loosely aggregated spheroids. We showed prominent differences regarding treatment responses between 2D monolayers compared to 3D spheroid and 3D organoid model systems. Particularly, the organoid system, regarded as the closest representation of primary tumours, exhibited reliably the combinatorial effect of ADAM17 inhibition and cisplatin in all three individual donors. Discussion: As two- and three-dimensional models of the same cell lines differ in their responses to chemotherapy it is essential to validate treatment strategies in more advanced model systems representing the patient situation more realistically. Ectocervical organoids showed reliable results regarding treatment responses closely mimicking the primary tumours and could therefore serve as an important tool for personalized medicine in cervical cancer. These findings strengthen the role of ADAM17 as a potential novel target for combinatorial treatments to overcome chemoresistance in cervical cancer.

3.
Biomedicines ; 12(6)2024 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-38927378

RESUMEN

Examinations of ovarian cancer cells require the ability to identify tumor cells. Array-based comparative genome hybridization (aCGH) on 30 ovarian carcinomas (OC) identified three genomic loci (8q24.23; 17p12; 18q22.3) over- or under-represented in OC. A fluorescence in situ hybridization (FISH) probe of these three loci is intended to identify tumor cells by their signal pattern deviating from a diploid pattern. Human DNA from these three loci is isolated from bacterial artificial chromosomes (BAC), amplified and labeled with fluorescent dyes. After a standard FISH procedure, 71 OC suspensions from primary tumors, three OC cell lines, three lymphocyte suspensions, and one mesenchymal cell line LP-3 are analyzed with a fluorescence microscope. On average, 15% of the lymphocytes deviate from the expected diploid signal pattern, giving a cut-off of 36%. If this value is exceeded, tumor cells are detected. The mesenchymal cell line LP-3 shows only 21% as a negative control. The OC cell lines as positive controls exceed this value at 38%, 67%, and 54%. Of the 71 OC primary cultures, four cases fell below this cut-off as false negatives. In the two-sample t-test, the percentages of conspicuous signal patterns differ significantly.

4.
Arch Gynecol Obstet ; 310(2): 1207-1213, 2024 08.
Artículo en Inglés | MEDLINE | ID: mdl-38789852

RESUMEN

OBJECTIVE: To investigate changes in surgical procedures and patient outcomes of patients diagnosed with endometrial cancer (EC) at a German university hospital between 1998 and 2014. METHODS: A monocentric, retrospective review was conducted to identify patients diagnosed and treated with EC during the aforementioned period at the Department of Gynecology and Obstetrics at the University Hospital Kiel, Germany. RESULTS: 303 patients were identified. Patient demographics, risk factors, histological subtypes and stages of EC remained consistent over time. The most common surgical procedure was total abdominal hysterectomy (TAH) (81.9%). In 2011, the institution carried out its first total laparoscopic hysterectomy (TLH) for EC, resulting in a significant increase in laparoscopic surgical procedures (2011-2014: N = 70; TAH 44.2%; TLH 51.4%). Although the total number of lymph node stagings remained consistent over time, there was a significant increase in the performance of simultaneous pelvic and para-aortic lymphonodectomy (LNE) compared to pelvic LNE alone (2.6 in 2001-2005 vs. 18.0% in 2011-2014, p ≤ 0.001). The duration of hospital stays significantly decreased over time, with a mean of 20.9 days in the first and 8.5 days in the last period. When comparing surgical procedures, TLHs resulted in significantly shorter postoperative stays with an average of 6.58 vs. 13.92 days for TAH. The surgical procedure performed did not affect 5-year overall survival rates in this study (84.9% for TAH and 85.3% for TLH, p = 0.85). CONCLUSIONS: Our retrospective single-center study demonstrates that laparoscopic surgery for endometrial cancer is oncologically safe and shortens hospital stays.


Asunto(s)
Neoplasias Endometriales , Histerectomía , Laparoscopía , Tiempo de Internación , Humanos , Femenino , Neoplasias Endometriales/cirugía , Neoplasias Endometriales/patología , Neoplasias Endometriales/mortalidad , Estudios Retrospectivos , Laparoscopía/estadística & datos numéricos , Laparoscopía/efectos adversos , Persona de Mediana Edad , Tiempo de Internación/estadística & datos numéricos , Anciano , Histerectomía/estadística & datos numéricos , Histerectomía/métodos , Escisión del Ganglio Linfático/estadística & datos numéricos , Alemania/epidemiología , Adulto , Estadificación de Neoplasias , Anciano de 80 o más Años , Resultado del Tratamiento
5.
Int J Mol Sci ; 24(24)2023 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-38139296

RESUMEN

Ovarian cancer (OC) cells with homologous recombination deficiency (HRD) accumulate genomic scars (LST, TAI, and LOH) over a value of 42 in sum. PARP inhibitors can treat OC with HRD. The detection of HRD can be done directly by imaging these genomic scars, or indirectly by detecting mutations in the genes involved in HR. We show that HRD detection is also possible using high-resolution aCGH. A total of 30 OCs were analyzed retrospectively with high-resolution arrays as a test set and 19 OCs prospectively as a validation set. Mutation analysis was performed by HBOC TruRisk V2 panel to detect HR-relevant mutations. CNVs were clustered with respect to the involved HR genes versus the OC cases. In prospective validation, the HRD status determined by aCGH was compared with external HRD assessments. Two BRCA mutation carriers did not have HRD. OC could approximately differentiate into two groups with characteristic CNV patterns with different survival rates. Mutation frequencies have a linear regression on the HRD score. Mutations in individual HR-relevant genes do not always indicate HRD. This may depend on the mutation frequency in tumor cells. The aCGH shows the genomic scars of an HRD inexpensively and directly.


Asunto(s)
Recombinación Homóloga , Neoplasias Ováricas , Humanos , Femenino , Estudios Retrospectivos , Hibridación Genómica Comparativa , Cicatriz/patología , Neoplasias Ováricas/patología , Fenotipo
6.
Eur J Cancer ; 195: 113390, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37890350

RESUMEN

BACKGROUND: Sentinel lymph node (SLN) status is a clinically important prognostic biomarker in breast cancer and is used to guide therapy, especially for hormone receptor-positive, HER2-negative cases. However, invasive lymph node staging is increasingly omitted before therapy, and studies such as the randomised Intergroup Sentinel Mamma (INSEMA) trial address the potential for further de-escalation of axillary surgery. Therefore, it would be helpful to accurately predict the pretherapeutic sentinel status using medical images. METHODS: Using a ResNet 50 architecture pretrained on ImageNet and a previously successful strategy, we trained deep learning (DL)-based image analysis algorithms to predict sentinel status on hematoxylin/eosin-stained images of predominantly luminal, primary breast tumours from the INSEMA trial and three additional, independent cohorts (The Cancer Genome Atlas (TCGA) and cohorts from the University hospitals of Mannheim and Regensburg), and compared their performance with that of a logistic regression using clinical data only. Performance on an INSEMA hold-out set was investigated in a blinded manner. RESULTS: None of the generated image analysis algorithms yielded significantly better than random areas under the receiver operating characteristic curves on the test sets, including the hold-out test set from INSEMA. In contrast, the logistic regression fitted on the Mannheim cohort retained a better than random performance on INSEMA and Regensburg. Including the image analysis model output in the logistic regression did not improve performance further on INSEMA. CONCLUSIONS: Employing DL-based image analysis on histological slides, we could not predict SLN status for unseen cases in the INSEMA trial and other predominantly luminal cohorts.


Asunto(s)
Neoplasias de la Mama , Aprendizaje Profundo , Linfadenopatía , Ganglio Linfático Centinela , Femenino , Humanos , Axila/patología , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/cirugía , Neoplasias de la Mama/genética , Escisión del Ganglio Linfático/métodos , Ganglios Linfáticos/patología , Metástasis Linfática/patología , Ganglio Linfático Centinela/patología , Biopsia del Ganglio Linfático Centinela/métodos
7.
J Extracell Vesicles ; 12(7): e12338, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37408115

RESUMEN

Ovarian cancer (OvCa) is the gynaecological disorder with the poorest prognosis due to the fast development of chemoresistance. We sought to connect chemoresistance and cancer cell-derived extracellular vesicles (EV). The mechanisms of how chemoresistance is sustained by EV remained elusive. One potentially contributing factor is A Disintegrin and Metalloprotease 17 (ADAM17)-itself being able to promote chemoresistance and inducing tumour cell proliferation and survival via the Epidermal Growth Factor Receptor (EGFR) pathway by shedding several of its ligands including Amphiregulin (AREG). We now demonstrate that upon chemotherapeutic treatment, proteolytically active ADAM17 is released in association with EV from OvCa cells. In terms of function, we show that patient-derived EV induce AREG shedding and restore chemoresistance in ADAM17-deficient cells. Confirming that ADAM17-containing EV transmit chemoresistance in OvCa, we propose that ADAM17 levels (also on EV) might serve as an indicator for tumour progression and the chemosensitivity status of a given patient.


Asunto(s)
Antineoplásicos , Vesículas Extracelulares , Neoplasias Ováricas , Humanos , Femenino , Proteínas ADAM/metabolismo , Receptores ErbB , Vesículas Extracelulares/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Proteína ADAM17
8.
Medicina (Kaunas) ; 59(5)2023 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-37241157

RESUMEN

Cervical cancer is still the fourth most common cancer in women throughout the world; an estimated 604,000 new cases were observed in 2020. Better knowledge of its pathogenesis, gained in recent years, has introduced new preventive and diagnostic approaches. Knowledge of its pathogenesis has made it possible to provide individualized surgical and drug treatment. In industrialized countries, cervical cancer has become a less frequent tumor entity due to the accessibility of the human papilloma virus vaccination, systematic preventive programs/early detection programs, health care infrastructure and the availability of effective therapy options. Nevertheless, globally, neither mortality nor morbidity has been significantly reduced over the past 10 years, and therapy approaches differ widely. The aim of this review is to address recent advances in the prevention, diagnostic investigation and treatment of cervical cancer globally, focusing on advances in Germany, with a view toward providing an updated overview for clinicians. The following aspects are addressed in detail: (a) the prevalence and causes of cervical cancer, (b) diagnostic tools using imaging techniques, cytology and pathology, (c) pathomechanisms and clinical symptoms of cervical cancer and (d) different treatment approaches (pharmacological, surgical and others) and their impact on outcomes.


Asunto(s)
Infecciones por Papillomavirus , Neoplasias del Cuello Uterino , Femenino , Humanos , Neoplasias del Cuello Uterino/terapia , Neoplasias del Cuello Uterino/prevención & control , Inmunización , Países Desarrollados , Prevalencia , Detección Precoz del Cáncer , Infecciones por Papillomavirus/prevención & control
9.
J Cell Mol Med ; 27(3): 379-391, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36625073

RESUMEN

Endometrial cancer (EC) is the most common gynaecological malignancy with increasing incidence in developed countries. As gold standard, hysteroscopy confirms only 30% of suspected ECs. The detection of EC cells in the vagina by fluorescence in situ hybridization (FISH) after a smear test could reduce invasive procedures in the future. Using array-based comparative genome hybridization (aCGH) on 65 endometrial carcinomas, most frequently imbalanced regions of the tumour genome were identified. Bacterial artificial chromosomes were used to generate FISH-probes homologue to these human regions. The FISH test was hybridized on swabs specimens collected from the vaginal cavity. Samples from six patients without EC were selected as a negative control and on 13 patients with known EC as a positive control. To distinguish between benign and EC cases, the cut-off value has been defined. A first validation of this EC-FISH Test was performed with swabs from 41 patients with suspected EC. The most common genomic imbalances in EC are around the CTNNB1, FBXW7 and APC genes. The cut-off is defined at 32% of analysed cells without diploid signal pattern. This differs significantly between the positive and negative controls (p < 0.001). In a first validation cohort of 41 patients with suspected EC, the EC-FISH Test distinguishes patients with and without EC with a sensitivity of 91% and a specificity of 83%. The negative predictive value is 96%. This is the first report of a non-invasive EC-FISH Test to predict EC in women with suspected EC.


Asunto(s)
Neoplasias Endometriales , Humanos , Femenino , Sensibilidad y Especificidad , Hibridación Fluorescente in Situ , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Valor Predictivo de las Pruebas , Vagina
10.
Front Immunol ; 14: 1286097, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38259448

RESUMEN

Ovarian carcinomas have the highest lethality amongst gynecological tumors. A problem after primary resection is the recurrence of epithelial ovarian carcinomas which is often associated with chemotherapy resistance. To improve the clinical outcome, it is of high interest to consider alternative therapy strategies. Due to their pronounced plasticity, γδ T cells are attractive for T-cell-based immunotherapy. However, tumors might escape by the release of lectin galectin-3, which impairs γδ T-cell function. Hence, we tested the effect of galectin-3 on the different γδ T-cell subsets. After coculture between ovarian tumor cells and Vδ1 or Vδ2 T cells enhanced levels of galectin-3 were released. This protein did not affect the cytotoxicity of both γδ T-cell subsets, but differentially influenced the proliferation of the two γδ T-cell subsets. While increased galectin-3 levels and recombinant galectin-3 inhibited the proliferation of Vδ2 T cells, Vδ1 T cells were unaffected. In contrast to Vδ1 T cells, the Vδ2 T cells strongly upregulated the galectin-3 binding partner α3ß1-integrin after their activation correlating with the immunosuppressive properties of galectin-3. In addition, galectin-3 reduced the effector memory compartment of zoledronate-activated Vδ2 T cells. Therefore, our data suggest that an activation of Vδ1 T-cell proliferation as part of a T-cell-based immunotherapy can be of advantage.


Asunto(s)
Galectina 3 , Neoplasias Ováricas , Femenino , Humanos , Galectina 3/genética , Carcinoma Epitelial de Ovario , Proliferación Celular , Técnicas de Cocultivo , Inmunosupresores , Neoplasias Ováricas/terapia
11.
Cancers (Basel) ; 14(23)2022 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-36497350

RESUMEN

Ovarian cancer is the third most common gynecological malignancy and has the highest mortality rate. Owing to unspecific symptoms, ovarian cancer is not detected until an advanced stage in about two-thirds of cases. Therefore, it is crucial to establish reliable biomarkers for the early stages to improve the patients' prognosis. The aim of this study is to investigate whether the ADAM17 substrates Nectin-4, Heparin-binding EGF-like growth factor (HB-EGF) and Amphiregulin (AREG) could function as potential tumor markers for ovarian cancer. In this study a set of 231 sera consisting of 131 ovarian cancer patients and 100 healthy age-matched controls were assembled. Nectin-4, HB-EGF and AREG levels of preoperatively collected sera were determined by enzyme-linked immunosorbent assay (ELISA). Our analysis revealed that Nectin-4 and HB-EGF were significantly increased compared to the age-matched control group (p < 0.0001, p = 0.016). Strikingly, significantly higher Nectin-4 and HB-EGF levels were detected in early-stage FIGO I/II (p <0.001; p = 0.025) compared to healthy controls. Eighty-four percent (16/19) of patients with low Ca-125 levels showed increased Nectin-4 levels. Our study proposes Nectin-4 and HB-EGF as promising blood-based biomarkers for the detection of early stages of ovarian cancer patients that would not have been detected by Ca-125.

12.
Cells ; 11(17)2022 08 29.
Artículo en Inglés | MEDLINE | ID: mdl-36078095

RESUMEN

Ectodomain shedding is an irreversible process to regulate inter- and intracellular signaling. Members of the a disintegrin and metalloprotease (ADAM) family are major mediators of ectodomain shedding. ADAM17 is involved in the processing of multiple substrates including tumor necrosis factor (TNF) α and EGF receptor ligands. Substrates of ADAM17 are selectively processed depending on stimulus and cellular context. However, it still remains largely elusive how substrate selectivity of ADAM17 is regulated. Tetraspanins (Tspan) are multi-membrane-passing proteins that are involved in the organization of plasma membrane micro-domains and diverse biological processes. Closely related members of the Tspan8 subfamily, including CD9, CD81 and Tspan8, are associated with cancer and metastasis. Here, we show that Tspan8 subfamily members use different strategies to regulate ADAM17 substrate selectivity. We demonstrate that in particular Tspan8 associates with both ADAM17 and TNF α and promotes ADAM17-mediated TNF α release through recruitment of ADAM17 into Tspan-enriched micro-domains. Yet, processing of other ADAM17 substrates is not altered by Tspan8. We, therefore, propose that Tspan8 contributes to tumorigenesis through enhanced ADAM17-mediated TNF α release and a resulting increase in tissue inflammation.


Asunto(s)
Proteínas ADAM , Desintegrinas , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Proteínas de la Membrana , Especificidad por Sustrato , Tetraspaninas/genética , Factor de Necrosis Tumoral alfa/metabolismo
13.
Int J Mol Sci ; 23(18)2022 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-36142413

RESUMEN

Although ovarian cancer is a rare disease, it constitutes the fifth leading cause of cancer death among women. It is of major importance to develop new therapeutic strategies to improve survival. Combining P8-D6, a novel dual topoisomerase inhibitor with exceptional anti-tumoral properties in ovarian cancer and compounds in preclinical research, and olaparib, a PARP inhibitor targeting DNA damage repair, is a promising approach. P8-D6 induces DNA damage that can be repaired by base excision repair or homologous recombination in which PARP plays a major role. This study analyzed benefits of combining P8-D6 and olaparib treatment in 2D and 3D cultures with ovarian cancer cells. Measurement of viability, cytotoxicity and caspase activity were used to assess therapy efficacy and to calculate the combination index (CI). Further DNA damage was quantified using the biomarkers RAD51 and γH2A.X. The combinational treatment led to an increased caspase activity and reduced viability. CI values partially show synergisms in combinations at 100 nM and 500 nM P8-D6. More DNA damage accumulated, and spheroids lost their membrane integrity due to the combinational treatment. While maintaining the same therapy efficacy as single-drug therapy, doses of P8-D6 and olaparib can be reduced in combinational treatments. Synergisms can be seen in some tested combinations. In summary, the combination therapy indicates benefits and acts synergistic at 100 nM and 500 nM P8-D6.


Asunto(s)
Neoplasias Ováricas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Caspasas/genética , Muerte Celular , Línea Celular Tumoral , Sinergismo Farmacológico , Femenino , Inestabilidad Genómica , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Ftalazinas/farmacología , Ftalazinas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Inhibidores de Topoisomerasa
14.
Cancers (Basel) ; 14(2)2022 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-35053582

RESUMEN

The need for pelvic treatment in patients with node-positive vulvar cancer (VSCC) and the value of pelvic lymphadenectomy (LAE) as a staging procedure to plan adjuvant radiotherapy (RT) is controversial. In this retrospective, multicenter analysis, 306 patients with primary node-positive VSCC treated at 33 gynecologic oncology centers in Germany between 2017 and 2019 were analyzed. All patients received surgical staging of the groins; nodal status was as follows: 23.9% (73/306) pN1a, 23.5% (72/306) pN1b, 20.4% (62/306) pN2a/b, and 31.9% (97/306) pN2c/pN3. A total of 35.6% (109/306) received pelvic LAE; pelvic nodal involvement was observed in 18.5%. None of the patients with nodal status pN1a or pN1b and pelvic LAE showed pelvic nodal involvement. Taking only patients with nodal status ≥pN2a into account, the rate of pelvic involvement was 25%. In total, adjuvant RT was applied in 64.4% (197/306). Only half of the pelvic node-positive (N+) patients received adjuvant RT to the pelvis (50%, 10/20 patients); 41.9% (122/291 patients) experienced recurrent disease or died. In patients with histologically-confirmed pelvic metastases after LAE, distant recurrences were most frequently observed (7/20 recurrences). Conclusions: A relevant risk regarding pelvic nodal involvement was observed from nodal status pN2a and higher. Our data support the omission of pelvic treatment in patients with nodal status pN1a and pN1b.

15.
Acad Radiol ; 29(2): 183-197, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-33293256

RESUMEN

RATIONALE AND OBJECTIVES: Adnexal masses detected incidentally at transvaginal ultrasound (TVUS) are a common and still challenging diagnostic problem. The primary goal of further imaging is an accurate tissue characterization so an optimal treatment plan can be devised including surgery only for lesions that are indeterminate or malignant. The aim of this prospective study was to evaluate the diagnostic utility of complementary multiparametric magnetic resonance imaging (mMRI) for treatment planning in patients with adnexal masses, and to assess how it ultimately correlates with subsequent histopathologic findings. MATERIAL AND METHODS: A total of 126 women (mean age: 54.6 years) with indeterminate adnexal masses underwent mMRI at 3T in addition to TVUS and testing to determine their CA-125 levels. The mMRI protocol consisted of a high-resolution T2-TSE in three planes, diffusion weighted images and dynamic contrast enhanced. First the character of the adnexal mass and the associated management decision (follow-up, laparoscopy or laparotomy) were assessed independently for each diagnostic method (TVUS + CA-125 and mMRI). All methods were then assessed in synopsis. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of each diagnostic method alone and in combination were calculated. The standard of reference was either final histology in women who underwent surgery or follow-up of at least 24 months in women who underwent follow-up. RESULTS: In 67.5% (85/126) of all patients, the adnexal mass was benign; a malignant tumor was diagnosed in 28.6% (36/126) and a borderline tumor in the remaining 4% (5/126) of patients. The diagnostic indices were as follows for TVUS + CA 125 alone, mMRI alone and all three methods combined: sensitivity 86% (31/36), 97% (35/36), and 100% (36/36); specificity 32% (29/90), 83% (75/90), and 80% (68/90); PPV 34% (31/91), 70% (35/50), and 74% (40/54); and NPV 65% (29/44), 98% (75/76), and 100% (72/72). Complementary use of mMRI changed the therapeutic management decision in 34% (41/126) of all patients. In 40.7% (37/91) of patients for whom surgery had been recommended based on TVUS + CA-125, MRI revealed a typical benign finding such that those patients underwent follow-up instead of surgery. None of the examined masses exhibited (tumor) progression or malignancy during the follow-up period. A laparotomy was performed instead of a laparoscopy in 8.7% (11/126) based on the mMRI result. CONCLUSION: MRI helps significantly improve sensitivity and specificity of diagnosis in patients with indeterminate adnexal masses detected at TVUS. Its diagnostic information revised the planned treatment in more than one-third of women.


Asunto(s)
Enfermedades de los Anexos , Imágenes de Resonancia Magnética Multiparamétrica , Enfermedades de los Anexos/diagnóstico por imagen , Enfermedades de los Anexos/terapia , Diagnóstico Diferencial , Femenino , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Estudios Prospectivos , Sensibilidad y Especificidad , Ultrasonografía
16.
Biol Chem ; 403(5-6): 545-556, 2022 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-34717050

RESUMEN

Natural killer group 2 member D (NKG2D) plays an important role in the regulation of natural killer (NK) cell cytotoxicity in cancer immune surveillance. With the aim of redirecting NK cell cytotoxicity against tumors, the NKG2D ligand UL-16 binding protein 2 (ULBP2) was fused to a single-chain fragment variable (scFv) targeting the human epidermal growth factor receptor 2 (HER2). The resulting bispecific immunoligand ULBP2:HER2-scFv triggered NK cell-mediated killing of HER2-positive breast cancer cells in an antigen-dependent manner and required concomitant interaction with NKG2D and HER2 as revealed in antigen blocking experiments. The immunoligand induced tumor cell lysis dose-dependently and was effective at nanomolar concentrations. Of note, ULBP2:HER2-scFv sensitized tumor cells for antibody-dependent cell-mediated cytotoxicity (ADCC). In particular, the immunoligand enhanced ADCC by cetuximab, a therapeutic antibody targeting the epidermal growth factor receptor (EGFR) synergistically. No significant improvements were obtained by combining cetuximab and anti-HER2 antibody trastuzumab. In conclusion, dual-dual targeting by combining IgG1 antibodies with antibody constructs targeting another tumor associated antigen and engaging NKG2D as a second NK cell trigger molecule may be promising. Thus, the immunoligand ULBP2:HER2-scFv may represent an attractive biological molecule to promote NK cell cytotoxicity against tumors and to boost ADCC.


Asunto(s)
Neoplasias de la Mama , Subfamilia K de Receptores Similares a Lectina de Células NK , Citotoxicidad Celular Dependiente de Anticuerpos , Neoplasias de la Mama/patología , Línea Celular Tumoral , Cetuximab/farmacología , Cetuximab/uso terapéutico , Femenino , Humanos , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Subfamilia K de Receptores Similares a Lectina de Células NK/uso terapéutico , Trastuzumab/farmacología , Trastuzumab/uso terapéutico
17.
Mol Cancer Ther ; 21(1): 70-78, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34725192

RESUMEN

P8-D6 is a novel dual inhibitor of human topoisomerase I (TOP1) and II (TOP2) with broad pro-apoptotic antitumor activity. NCI-60 screening revealed markedly improved cytotoxicity of P8-D6 against solid and leukemia cell lines compared with other single and dual topoisomerase inhibitors, for example, irinotecan, doxorubicin, or pyrazoloacridine. In this study, we investigated the capacity of P8-D6 to inhibit myeloma cell growth in vitro and in vivo Growth inhibition assays demonstrated significant anti-myeloma effects against different myeloma cell lines with IC50 values in the low nanomolar range. Freshly isolated plasma cells of patients with multiple myeloma were killed by P8-D6 with similar doses. P8-D6 activated caspase 3/7 and induced significant apoptosis of myeloma cells. Supportive effects of bone marrow stromal cells on IL6-dependent INA-6 myeloma cells were abrogated by P8-D6 and apoptosis occurred in a time- and dose-dependent manner. Of note, healthy donor peripheral blood mononuclear cells and human umbilical vein endothelial cells were not affected at concentrations toxic for malignant plasma cells. Treatment of myeloma xenografts in immunodeficient SCID/beige mice by intravenous and, notably, also oral application of P8-D6 markedly inhibited tumor growths, and significantly prolonged survival of tumor-bearing mice.


Asunto(s)
Mieloma Múltiple/tratamiento farmacológico , Naftalenos/uso terapéutico , Inhibidores de Topoisomerasa II/uso terapéutico , Animales , Línea Celular Tumoral , Humanos , Ratones , Ratones Desnudos , Ratones SCID , Mieloma Múltiple/patología , Naftalenos/farmacología , Inhibidores de Topoisomerasa II/farmacología
18.
Ther Adv Med Oncol ; 13: 17588359211059896, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34887943

RESUMEN

BACKGROUND: Ovarian cancer (OvCa) constitutes a rare and highly aggressive malignancy and is one of the most lethal of all gynaecologic neoplasms. Due to chemotherapy resistance and treatment limitations because of side effects, OvCa is still not sufficiently treatable. Hence, new drugs for OvCa therapy such as P8-D6 with promising antitumour properties have a high clinical need. The benzo[c]phenanthridine P8-D6 is an effective inductor of apoptosis by acting as a dual topoisomerase I/II inhibitor. METHODS: In the present study, the effectiveness of P8-D6 on OvCa was investigated in vitro. In various OvCa cell lines and ex vivo primary cells, the apoptosis induction compared with standard therapeutic agents was determined in two-dimensional monolayers. Expanded by three-dimensional and co-culture, the P8-D6 treated cells were examined for changes in cytotoxicity, apoptosis rate and membrane integrity via scanning electron microscopy (SEM). Likewise, the effects of P8-D6 on non-cancer human ovarian surface epithelial cells and primary human hepatocytes were determined. RESULTS: This study shows a significant P8-D6-induced increase in apoptosis and cytotoxicity in OvCa cells which surpasses the efficacy of well-established drugs like cisplatin or the topoisomerase inhibitors etoposide and topotecan. Non-cancer cells were affected only slightly by P8-D6. Moreover, no hepatotoxic effect in in vitro studies was detected. CONCLUSION: P8-D6 is a strong and rapid inductor of apoptosis and might be a novel treatment option for OvCa therapy.

19.
Cancers (Basel) ; 13(21)2021 Nov 06.
Artículo en Inglés | MEDLINE | ID: mdl-34771725

RESUMEN

Ovarian cancer has the highest mortality rate among gynecological tumors. This is based on late diagnosis and the lack of early symptoms. To improve early detection, it is essential to find reliable biomarkers. The metalloprotease ADAM17 could be a potential marker, as it is highly expressed in many solid tumors, including ovarian and breast cancer. The aim of this work is to evaluate the relevance of ADAM17 as a potential diagnostic blood-based biomarker in ovarian cancer. Ovarian cancer cell lines IGROV-1 and A2780, as well as primary patient-derived tumor cells obtained from tumor tissue and ascitic fluid, were cultured to analyze ADAM17 abundance in the culture supernatant. In a translational approach, a cohort of 117 well-characterized ovarian cancer patients was assembled and ADAM17 levels in serum and corresponding ascitic fluid were determined at primary diagnosis. ADAM17 was quantified by enzyme-linked immunosorbent assay (ELISA). In the present study, ADAM17 was detected in the culture supernatant of ovarian cancer cell lines and primary cells. In addition, ADAM17 was found in serum and ascites of ovarian cancer patients. ADAM17 level was significantly increased in ovarian cancer patients compared to an age-matched control group (p < 0.0001). Importantly early FIGO I/II stages, which would not have been detected by CA-125, were associated with higher ADAM17 concentrations (p = 0.007). This is the first study proposing ADAM17 as a serum tumor marker in the setting of a gynecological tumor disease. Usage of ADAM17 in combination with CA-125 and other markers could help detect early stages of ovarian cancer.

20.
J Clin Med ; 10(17)2021 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-34501212

RESUMEN

OBJECTIVE: The aim of the study was to perform a systematic assessment of disease-free survival (DFS), overall survival, and morbidity rates after open radical hysterectomy (ORH) and minimally invasive surgery (MIS) for early-stage cervical cancer and discuss with experts the consequences of the LACC trial (published by Ramirez et al. in 2018) on clinical routine. METHODS: A total of 5428 records were retrieved. After exclusion based on text screening, four records were identified for inclusion. Five experts from three independent large-volume medical centers in Europe were interviewed for their interpretation of the LACC trial. RESULTS: The LACC trial showed a significantly higher risk of disease progression with MIS compared to ORH (HR 3.74, 95% CI 1.63 to 8.58). This was not seen in one epidemiological study and was contradicted by one prospective cohort study reported by Greggi et al. A systematic review by Zhang et al. mentioned a similar DFS for robot-assisted radical hysterectomy (RRH) and LRH. Recurrence rates were significantly higher with MIS compared to ORH in the LACC trial (HR 4.26, 95% CI 1.44 to 12.60). In contrast, four studies presented by Greggi reported no significant difference in recurrence rates between LRH/RRH and ORH, which concurred with the systematic reviews of Zhang and Zhao. The experts mentioned various limitations of the LACC trial and stated that clinicians were obliged to provide patients with detailed information and ensure a shared decision-making process. CONCLUSIONS: The surgical treatment of early-stage cervical cancer remains a debated issue. More randomized controlled trials (RCT) will be needed to establish the most suitable treatment for this condition.

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