Platinum (PT)-resistant Epithelial Ovarian Cancer (EOC) grows as a metastatic disease, disseminating in the abdomen and pelvis. Very few options are available for PT-resistant EOC patients, and ...little is known about how the acquisition of PT-resistance mediates the increased spreading capabilities of EOC. Here, using isogenic PT-resistant cells, genetic and pharmacological approaches, and patient-derived models, we report that Integrin α6 (ITGA6) is overexpressed by PT-resistant cells and is necessary to sustain EOC metastatic ability and adhesion-dependent PT-resistance. Using in vitro approaches, we showed that PT induces a positive loop that, by stimulating ITGA6 transcription and secretion, contributes to the formation of a pre-metastatic niche enabling EOC cells to disseminate. At molecular level, ITGA6 engagement regulates the production and availability of insulin-like growth factors (IGFs), over-stimulating the IGF1R pathway and upregulating Snail expression. In vitro data were recapitulated using in vivo models in which the targeting of ITGA6 prevents PT-resistant EOC dissemination and improves PT-activity, supporting ITGA6 as a promising druggable target for EOC patients.
Synopsis
In EOC ITGA6 is overexpressed and secreted by PT-res cells favoring the formation of a pro-metastatic niche, adhesion and invasion of the mesothelium. ITGA6 inhibition prevents the activation of pro-invasive pathways, leading to decreased metastasis formation and increased response to PT.
PT treatment induces ITGA6 transcription and secretion, both in vitro and in vivo.
ITGA6 confers resistance to PT and higher adhesion and metastatic ability to EOC cells by upregulating Snail protein via IGFR1-Src activation.
Secreted ITGA6 favors EOC metastatic dissemination by modulating IGF1R signaling and Snail expression.
ITGA6 targeting in vivo is feasible, prevents dissemination and improves PT response.
In EOC ITGA6 is overexpressed and secreted by PT-res cells favoring the formation of a pro-metastatic niche, adhesion and invasion of the mesothelium. ITGA6 inhibition prevents the activation of pro-invasive pathways, leading to decreased metastasis formation and increased response to PT.
Serum p53 autoantibodies (p53-AAbs) are the product of an endogenous immune response against p53 overexpression driven by the ovarian tumour. The p53-AAbs are detectable only in a subset of patients. ...To date, the evidence of an association between the presence of p53-AAbs and ovarian cancer outcomes has been poorly investigated.
A systematic literature search was performed to identify eligible studies investigating the association of serum p53-AAbs and overall survival (OS) and disease free survival (DFS). Associations between presence of serum p53-AAbs and baseline tumour characteristics were also evaluated. Pooled hazard ratios (HRs) and corresponding 95% confidence intervals (CI) were computed to estimate the prognostic impact of serum p53-AAbs. Heterogeneity between studies was assessed.
A total of 583 patients (7 studies) for OS and 356 patients (4 studies) for DFS were included in the meta-analysis. Presence of p53-AAbs was not associated to OS (pooled uni- multivariate HR = 1.09; 95% CI: 0.55-2.16), and a large heterogeneity was found. When only multivariate HRs were pooled together (4 studies), presence of p53-AAbs was significantly associated to a better OS (pooled HR = 0.57; 95% CI: 0.40-0.81), and no significant heterogeneity was observed. A reduced DFS was associated to p53-AAbs (pooled uni- multivariate HR = 1.37; 95% CI: 0.83-2.25), though not significantly and with a moderate heterogeneity.
The prognostic significance of serum p53-AAbs in ovarian cancer was diverging according to uni or multivariate models used. Since the results of this work were based on only few investigations, large prospective studies are needed to better define the role of antibody immunity against p53.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Until recently, effective therapies for advanced endometrial cancer progressing to a platinum-based combination were lacking. In this setting, immunotherapy with anti PD-1/PDL-1 monoclonal antibodies ...is rising as a new paradigm in particular for patients with microsatellites instability/mismatch repair deficiency. In this case report, we describe an exceptional and rapid response to dostarlimab in a platinum refractory endometrial cancer patient with high disease burden harboring a mismatch repair deficiency.
Optimal debulking surgery is postulated to be useful in survival of ovarian cancer patients. Some studies highlighted the possible role of bowel surgery in this topic. We wanted to evaluate the role ...of bowel involvement in patients with advanced epithelial ovarian cancer who underwent optimal cytoreduction.
Between 1997 and 2004, 301 patients with advanced epithelial cancer underwent surgery at Department of Gynecological Oncology of Centro di Riferimento Oncologico (CRO) National Cancer Institute Aviano (PN) Italy. All underwent maximal surgical effort, including bowel and upper abdominal procedure, in order to achieve optimal debulking (R < 0.5 cm). PFS and OS were compared with residual disease, grading and surgical procedures.
Optimal cytoreduction was achieved in 244 patients (81.0%); R0 in 209 women (69.4.%) and R < 0.5 in 35 (11.6%). Bowel resection was performed in 116 patients (38.5%): recto-sigmoidectomy alone (69.8%), upper bowel resection only (14.7%) and both recto-sigmoidectomy and other bowel resection (15.5%). Pelvic peritonectomy and upper abdomen procedures were carried out in 202 (67.1%) and 82 (27.2%) patients respectively. Among the 284 patients available for follow-up, PFS and OS were significantly better in patients with R < 0.5. Among the 229 patients with optimal debulking (R < 0.5), 137 patients (59.8%) developed recurrent disease or progression. In the 229 R < 0.5 group, bowel involvement was associated with decreased PFS and OS in G1-2 patients whereas in G3 patients OS, but not PFS, was adversely affected. In the 199 patients with R0, PFS and OS were significantly better (p < 0.01) for G1-2 patients without bowel involvement whereas only significant OS (p < 0.05) was observed in G3 patients without bowel involvement versus G3 patients with bowel involvement.
Optimal cytoreduction (R < 0.5 cm and R0) is the most important prognostic factor for advanced epithelial ovarian cancer. In the optimally cytoreduced (R < 0.5 and R0) patients, bowel involvement is associated with dismal prognosis for OS both in patients with G1-2 grading and in patients with G3 grading. Bowel involvement in G3 patients, carries instead the same risk of recurrence for PFS.
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Background: As the prognosis of BRCA-related advanced ovarian cancer (AOC) continues to improve thanks to the introduction of targeted therapies like poly ADP-ribose polymerase inhibitors ...(PARPi) and bevacizumab, the occurrence of second primary tumors, in particular breast cancer (BC), is assumed to be more common. Despite this, data on the incidence of BC in this population are poor and guidelines for BC screening or risk reducing strategies are lacking. Methods: Published data from recent PARPi-based, phase III clinical trials involving germline BRCA mutated AOC were reviewed and analyzed. Only studies in which the incidence of at least one second primary solid tumor was reported were included. Cases of second primary BC cancers were pooled to calculate cumulative incidence according to the median follow-up period for each trial. 95% confidence interval (CI) was considered. Results: Four trials (SOLO1, PAOLA1, SOLO2 and SOLO3) involving 1186 germline BRCA 1-2 mutated AOC patients were included ( BRCA1, n = 816; BRCA2, n = 360; BRCA1 + BRCA2, n = 4; missing, n = 6). In all trials, patients were randomized to receive olaparib +/- bevacizumab (n = 788) versus placebo or standard therapies (n = 398). Median age at diagnosis of AOC was 56 years (range, 29-87). With a follow-up ranging from 3.9 months to 5 years, 16 new cases of BC were recorded, 10 in PARPi-based arms and 6 in control arms. Only two patients had a previous history of BC. The total cumulative incidence of BC was 1.37% (95% CI, 0.77-2.18), while cumulative incidences were 1.26% (95% CI, 0.61-2.31) and 1.51% (95% CI, 0.55-3.25) in PARPi-based arms and control arms, respectively. In a sensitivity analysis excluding the SOLO3 trial with the shortest follow-up, the total cumulative incidence was 1.63% (95% CI, 0.92-2.67). Other 20 cases of second primary solid tumors were registered, including 4 cases of non-small cell lung cancer. Conclusions: Patients with germline BRCA-related AOC receiving PARPi-based maintenance therapy can be reassured about the risk of second primary BC and intensive screening should be avoided at least in early treatment phase. More data with long term follow-up are needed.
The aim of this study was to add a new case of primary non-Hodgkin's malignant lymphoma of the vulva to the literature and to review the current literature.We searched the PubMed/MEDLINE databases ...for previous case reports using the key words "non-Hodgkin's malignant lymphoma of the vulva," "vulvar lymphoma," and "primary vulvar non-Hodgkin's lymphoma." We found 29 cases of primary vulvar non-Hodgkin's malignant lymphoma of the vulva reported until 2015. Among them, only 8 cases of diffuse large B-cell lymphoma (DLBCL), classified according to the most recent 2008 WHO classification, were reported.Moreover, only few studies reported the therapeutic management and clinical follow-up of patients affected by this condition.Due to its uncommon presentation, the primary non-Hodgkin's malignant lymphoma of the vulva can be undiagnosed; thus gynecologists, oncologists, and pathologists should be aware of this condition, as a correct diagnosis is essential for an appropriate therapeutic management.
Purpose
The purpose of this study was to evaluate patient-centered outcomes of decompressive percutaneous endoscopic gastrostomy (dPEG) in patients with malignant bowel obstruction due to advanced ...gynecological and gastroenteric malignancies.
Methods
This is a prospective analysis of 158 consecutive patients with small-bowel obstruction from advanced gynecological and gastroenteric cancer who underwent PEG or percutaneous endoscopic jejunostomy (PEJ) positioning for decompressive purposes from 2002 to 2012. All of them had previous abdominal surgery and were unfit for any other surgical procedures. Symptom relief, procedural complications, and post dPEG palliation were assessed. Global Quality of Life (QoL) was evaluated in the last 2 years (25 consecutive patients) before and 7 days after dPEG placement using the Symptom Distress Scale (SDS).
Results
d
PEG was successfully performed in 142 out of 158 patients (89.8 %). Failure of tube placement occurred in 16 patients (10.1 %). In 8/142 (5.6 %) patients, dPEG was guided by abdominal ultrasound. In 3/142 patients, dPEG was CT-guided. In 14 (9.8 %) patients, who had previously undergone total or subtotal gastrectomy, decompressive percutaneous endoscopic jejunostomy (dPEJ) was performed. In 1/14 patients, dPEJ was CT-guided. Out of 142 patients, 110 (77.4 %) experienced relief from nausea and vomiting 2 days after PEG.
Out of 142 patients, 116 (81.6 %) were discharged. The median postoperative hospital stay was 9 days (range 3–60). Peristomal infection (14 %) and intermittent obstruction (8.4 %) were the most frequent complications associated with PEG. Median survival time was 57 days (range 4–472) after PEG placement.
Twenty-five patients had QoL properly evaluated with SDS score before and 7 days after dPEG. Sixteen patients (64 %) out of 25 exhibited an improvement of QoL (
p
< 0.05), 7 (28 %) patients exhibited a non-significant worsening of QoL (
p
= 0.18), and in 2 (8 %) patients, it remained unmodified.
Conclusions
dPEG
is feasible, effective, relieves nausea and vomiting in patients with unremitting small-bowel obstruction from advanced gynecological and gastroenteric cancer, and improves QoL.
The objectives of this study were to evaluate whether the international recommendations on the management of uterine papillary serous carcinoma arising in a polyp are uniformly followed in Italian ...Oncologic Centers and whether the strategy adopted is effective.
Patients with uterine papillary serous carcinoma arising in a polyp and who had undergone a hysterectomy were identified in the 2003-2013 database of 7 Italian Gynecologic Oncology Centers. Clinical and pathologic characteristics and outcomes were compared between staging procedure types. Survival curves of the women were plotted using the Kaplan-Meier method and analyzed using Cox regression hazard model and the log-rank test. Associations between clinical parameters and the incidence of recurrence were assessed by generalized linear models and the Fisher test.
A total of 75 patients met the inclusion criteria. Recurrence-free survival was affected positively by type of surgical staging and negatively by preoperative diagnosis of hypertension. The association between surgical staging and recurrence-free survival resulted significant at univariate survival analysis (P=0.048 and 0.045) and maintained a trend of significance (P=0.070) in multivariate analysis, whereas hypertension was demonstrated to be the principal influencing factor.
The international recommendations on the management of uterine papillary serous carcinoma are not uniformly followed in daily practice, although the extension of the surgery seems to be associated with lower recurrence rates also when uterine papillary serous carcinoma is confined to a polyp or endometrial surface.
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