Abstract Objectives To assess the impact of muscle composition and sarcopenia on overall survival in advanced epithelial ovarian cancer (EOC) after primary debulking surgery (PDS). Methods Women with ...stage IIIC/IV EOC who underwent PDS with curative intent between 1/1/2006 and 12/31/2012 were included. Patient variables and vital status were abstracted. Body composition was evaluated in a semi-automated process using Slice-O-Matic software v4.3 (TomoVision). Skeletal muscle area and mean skeletal muscle attenuation were recorded. Associations with overall survival were evaluated using Cox proportional hazards models and recursive partitioning. Results We identified 296 patients and 132 (44.6%) were classified as sarcopenic. The average mean skeletal muscle attenuation of the entire cohort was 33.4 Hounsfield units (HU). A multivariate model of overall risk of death included histology, residual disease, and mean skeletal attenuation. Among patients without residual disease, overall survival, but not progression free survival was significantly different between patients with low versus high mean skeletal attenuation (median survival, 2.8 vs. 3.3 years). Among patients with residual disease, overall survival was significantly different between patients with low versus high mean skeletal attenuation ≥ 36.40 vs. < 36.40 HU (median survival, 2.0 vs. 3.3 years). Conclusions Sarcopenia and low mean skeletal muscle attenuation are common in women undergoing PDS for advanced EOC. These factors are associated with poorer outcomes, and can be used in preoperative risk stratification and patient counseling. Further research into body composition and whether this risk factor can be altered via nutrition or fitness in this population is warranted.
Edmonston vaccine strains of measles virus (MV) have significant antitumor activity in mouse xenograft models of ovarian cancer. MV engineered to express the sodium iodide symporter gene (MV-NIS) ...facilitates localization of viral gene expression and offers a tool for tumor radiovirotherapy. Here, we report results from a clinical evaluation of MV-NIS in patients with taxol- and platinum-resistant ovarian cancer. MV-NIS was given intraperitoneally every 4 weeks for up to 6 cycles. Treatment was well tolerated and associated with promising median overall survival in these patients with heavily pretreated ovarian cancer; no dose-limiting toxicity was observed in 16 patients treated at high-dose levels (10(8)-10(9) TCID50), and their median overall survival of 26.5 months compared favorably with other contemporary series. MV receptor CD46 and nectin-4 expression was confirmed by immunohistochemistry in patient tumors. Sodium iodide symporter expression in patient tumors after treatment was confirmed in three patients by (123)I uptake on SPECT/CTs and was associated with long progression-free survival. Immune monitoring posttreatment showed an increase in effector T cells recognizing the tumor antigens IGFBP2 and FRα, indicating that MV-NIS treatment triggered cellular immunity against the patients' tumor and suggesting that an immune mechanism mediating the observed antitumor effect. Our findings support further clinical evaluation of MV-NIS as an effective immunovirotherapy.
To evaluate the impact of an evidence-based triage algorithm to decide between primary debulking surgery (PDS) and neoadjuvant chemotherapy followed by interval debulking surgery (NACT/IDS) for ...advanced epithelial ovarian cancer (EOC).
Surgical morbidity and mortality (M/M) after PDS for stage IIIC-IV EOC at Mayo Clinic after implementation of the triage algorithm (contemporary cohort, 2012-July 2016) were compared to that of a historic PDS cohort (2003−2011).
Mean age of the 232 women who met inclusion criteria in the contemporary cohort was 63.9 years. We observed a 71% decrease in 90-day mortality from 8.9% to 2.6% (P = 0.002) between the contemporary and historic cohorts. Accordion grade 3+ postoperative complications within 30 days after surgery decreased from 22.3% to 18.3% (P = 0.19). Among those with a grade 3+ complication, 90-day mortality rates decreased from 28.3% in the historic cohort to 2.4% in the contemporary cohort (P < 0.001) suggesting patients were better able to tolerate complex surgery. When compared to the historic PDS cohort, oncologic outcomes were also improved in the contemporary PDS cohort. Complete as well as optimal (residual disease ≤1 cm) cytoreduction rates increased (45.5% vs. 62.5% and 84.5% vs. 95.3%, respectively, P < 0.001), and the proportion of women starting chemotherapy within 42 days of surgery increased (57.4% vs. 69.8%, P = 0.001). Three-year overall survival was 53% in the historic cohort and 66% in the contemporary cohort (P < 0.001).
Use of the Mayo triage algorithm for EOC was associated with reduced 90-day mortality after PDS and improved oncologic outcomes. Surgical risk assessment is a critical aspect of treatment planning in the primary management of EOC and should be incorporated into practice.
•Both primary debulking (PDS) & neoadjuvant chemotherapy (NACT) are ideal approaches for different ovarian cancer patients•Choice between NACT and PDS should be based on risk of surgical morbidity and mortality•Use of our triage algorithm to choose between PDS and NACT reduces 90 day mortality after PDS•Use of our triage algorithm also improved residual disease and ability to start chemotherapy within 42 days of surgery.
Abstract Objective Define subgroups of patients at highest risk for major morbidity and mortality after a traditional approach of maximal surgical efforts followed by chemotherapy for advanced ...ovarian cancer (AOC). Methods Preoperative health, intra-operative findings and outcomes were assessed in consecutive patients with primary AOC from 4 centers. Initial tumor dissemination was stratified into 3 groups based on volume of disease. Surgery was categorized using a previously described surgical complexity score (SCS). Statistical analysis was directed toward validating a multivariable risk-adjusted model. Results 576 patients with stage IIIC (N = 447, 77.6%) or IV AOC (N = 129, 22.4%) were analyzed. Age (HR (per year): 1.02; 95%CI: 1.01–1.03), high tumor dissemination (HTD) (HR: 1.73; 95%CI: 1.19–2.56), residual disease (RD) > 1 cm (HR: 2.46; 95%CI: 1.74–3.53), and stage IV (HR: 1.93; 95% CI: 1.51–2.45), independently correlated with OS. We identified a small subgroup of patients who comprised a high-risk group (N = 38, 6.6%) characterized by all of the following characteristics: high initial tumor dissemination (HTD) or stage IV plus poor performance or nutritional status plus age ≥ 75. In this group, high SCS to achieve low RD was associated with morbidity of 63.6% and limited survival benefit. Conclusions Optimal management of AOC requires accurate, risk-adjusted predictors of outcomes allowing a tailored approach starting with primary therapy. Complex surgical procedures to render low RD improve survival, and in the majority of cases, the benefits of such surgery appear to outweigh the morbidity. However careful analysis identifies a subgroup of patients in whom an alternative approach may be the better strategy.
Residual disease after initial surgery for ovarian cancer is the strongest prognostic factor for survival. However, the extent of surgical resection required to achieve optimal cytoreduction is ...controversial. Our goal was to estimate the effect of aggressive surgical resection on ovarian cancer patient survival.
A retrospective cohort study of consecutive patients with International Federation of Gynecology and Obstetrics stage IIIC ovarian cancer undergoing primary surgery was conducted between January 1, 1994, and December 31, 1998. The main outcome measures were residual disease after cytoreduction, frequency of radical surgical resection, and 5-year disease-specific survival.
The study comprised 194 patients, including 144 with carcinomatosis. The mean patient age and follow-up time were 64.4 and 3.5 years, respectively. After surgery, 131 (67.5%) of the 194 patients had less than 1 cm of residual disease (definition of optimal cytoreduction). Considering all patients, residual disease was the only independent predictor of survival; the need to perform radical procedures to achieve optimal cytoreduction was not associated with a decrease in survival. For the subgroup of patients with carcinomatosis, residual disease and the performance of radical surgical procedures were the only independent predictors. Disease-specific survival was markedly improved for patients with carcinomatosis operated on by surgeons who most frequently used radical procedures compared with those least likely to use radical procedures (44% versus 17%, P < .001).
Overall, residual disease was the only independent predictor of survival. Minimizing residual disease through aggressive surgical resection was beneficial, especially in patients with carcinomatosis.
II-2.
Ovarian cancer is the eighth most frequent cancer in women and is the most lethal gynecologic malignancy worldwide. The majority of ovarian cancer patients are newly diagnosed presenting with ...advanced-stage disease. Primary cytoreductive surgery and adjuvant taxane- and platinum-based combination chemotherapy are the standard treatment for advanced ovarian cancer. A number of studies have consistently shown that successful cytoreductive surgery and the resultant minimal residual disease are significantly associated with survival in patients with this disease. Much has been written and even more debated regarding the competing perspectives of biology of ovarian cancer versus the value of aggressive surgical resection. This review will focus on the current evidences and outcomes supporting the positive impact of aggressive surgical effort on survival in the primary management of ovarian cancer.
During the past decade, the age-adjusted mortality rate for endometrial cancer (EC) increased 1.9% annually with TP53 mutant (TP53-mu) EC disproportionally represented in advanced disease and deaths. ...Therefore, we aimed to assess pivotal molecular parameters that differentiate clinical outcomes in high- and low-risk EC. Using the Cancer Genome Atlas, we analyzed EC specimens with available DNA sequences and quantitative gene-specific RNA expression data. After polymerase ɛ (POLE)-mutant specimens were excluded, differential gene-specific mutations and mRNA expressions were annotated and integrated. Consequent to TP53-mu failure to induce p21, derepression of multiple oncogenes harboring promoter p21 repressive sites was observed, including CCNA2 and FOXM1 (P < .001 compared with TP53 wild type TP53-wt). TP53-wt EC with high CCNA2 expression (CCNA2-H) had a targeted transcriptomic profile similar to that of TP53-mu EC, suggesting CCNA2 is a seminal determinant for both TP53-wt and TP53-mu EC. CCNA2 enhances E2F1 function, upregulating FOXM1 and CIP2A, as observed in TP53-mu and CCNA2-H TP53-wt EC (P < .001). CIP2A inhibits protein phosphatase 2A, leading to AKT inactivation of GSK3β and restricted oncoprotein degradation; PPP2R1A and FBXW7 mutations yield similar results. Upregulation of FOXM1 and failed degradation of FOXM1 is evidenced by marked upregulation of multiple homologous recombination genes (P < .001). Integrating these molecular aberrations generated a molecular biomarker panel with significant prognostic discrimination (P = 5.8×10-7); adjusting for age, histology, grade, myometrial invasion, TP53 status, and stage, only CCNA2-H/E2F1-H (P = .0003), FBXW7-mu/PPP2R1A-mu (P = .0002), and stage (P = .017) were significant. The generated prognostic molecular classification system identifies dissimilar signaling aberrations potentially amenable to targetable therapeutic options.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PD-0332991 is a selective inhibitor of the CDK4/6 kinases with the ability to block retinoblastoma (Rb) phosphorylation in the low nanomolar range. Here we investigate the role of CDK4/6 inhibition ...in human ovarian cancer.
We examined the effects of PD-0332991 on proliferation, cell-cycle, apoptosis, and Rb phosphorylation using a panel of 40 established human ovarian cancer cell lines. Molecular markers for response prediction, including p16 and Rb, were studied using gene expression profiling, Western blot, and array CGH. Multiple drug effect analysis was used to study interactions with chemotherapeutic drugs. Expression of p16 and Rb was studied using immunohistochemistry in a large clinical cohort of ovarian cancer patients.
Concentration-dependent antiproliferative effects of PD-0332991 were seen in all ovarian cancer cell lines, but varied significantly between individual lines. Rb-proficient cell lines with low p16 expression were most responsive to CDK4/6 inhibition. Copy number variations of CDKN2A, RB, CCNE1, and CCND1 were associated with response to PD-0332991. CDK4/6 inhibition induced G0/G1 cell cycle arrest, blocked Rb phosphorylation in a concentration-and time-dependent manner, and enhanced the effects of chemotherapy. Rb-proficiency with low p16 expression was seen in 97/262 (37%) of ovarian cancer patients and was independently associated with poor progression-free survival (adjusted relative risk 1.49, 95% CI 1.00-2.24, P = 0.052).
PD-0332991 shows promising biologic activity in ovarian cancer cell lines. Assessment of Rb and p16 expression may help select patients most likely to benefit from CDK4/6 inhibition in ovarian cancer.
OBJECTIVE:To evaluate the association of hysterectomy on ovarian function by comparing antimüllerian hormone, a marker of ovarian reserve, before and after hysterectomy.
METHODS:The Prospective ...Research on Ovarian Function study prospectively followed 1) premenopausal women undergoing ovary-sparing hysterectomy for benign indications, and 2) a referent cohort with similar age distributions and intact reproductive organs; they reported that women undergoing hysterectomy became menopausal 1.9 years earlier than referents. In a planned secondary analysis, baseline antimüllerian hormone levels and the absolute change and percentage change in antimüllerian hormone levels between baseline and 1-year follow-up were compared between groups.
RESULTS:Baseline median antimüllerian hormone levels were similar between the hysterectomy group (n=148) and the referent group (n=172). After 1 year, patients undergoing hysterectomy had a significantly greater median percentage decrease (−40.7% compared with −20.9%; P<.001), had a higher proportion with undetectable antimüllerian hormone (12.8% compared with 4.7%; P=.02), and had on average 0.77 times the antimüllerian hormone level (P=.001) compared with referents. These differences were attenuated among white women but remained significant among black women. Comparisons of women stratified by low or high ovarian reserve at baseline or among propensity score-matched cohorts showed similar findings; however, the absolute median change in antimüllerian hormone levels was similar between groups (−0.3 compared with −0.2; P=.31).
CONCLUSION:Women undergoing hysterectomy had similar antimüllerian hormone levels at baseline and experienced a greater percentage decrease in levels after 1 year compared with referents, suggesting that hysterectomy may lead to ovarian damage that is unrelated to baseline ovarian reserve.
•Positive margins after primary surgery for EMPD conferred higher recurrence risk.•Compared to MMS, WLE was significantly more likely to result in positive margins.•With negative margins, there is a ...trend toward higher recurrence risk after WLE compared to MMS.•Males were more likely than females to undergo MMS for EMPD.
To determine surgical and pathologic variables associated with recurrence in extramammary Paget's disease (EMPD).
Medical records of patients seeking care for EMPD from 1/1992–9/2015 were reviewed. Follow-up was restricted to 5years following primary surgery. Recurrence-free survival (RFS) was estimated using the Kaplan-Meier method. Risk factors were evaluated for an association with recurrence and positive margins, respectively, using Cox proportional hazards regression and logistic regression.
Of 154 patients, 90 (58.4%) were female and 65 (41.6%) were male. Treatment consisted of wide local excision (WLE, includes WLE or radical vulvectomy, 77.3%), Mohs micrographic surgery (MMS, 19.5%), and abdominoperineal resection (3.2%). RFS at 1, 3, and 5years was 84.5% (95% confidence interval (CI), 78.2–91.4%), 66.1% (95% CI, 57.5–75.9%), and 56.1% (95% CI, 46.9–67.1%), respectively. Positive surgical margins were univariately associated with higher risk of recurrence (HR 3.55, 95% CI 1.74, 7.24). Margin status significantly correlated with procedure type (33.3% vs. 3.4% had positive margins with WLE vs. MMS, p=0.01). Among patients with negative margins, there was a 2.5 fold increased risk of recurrence after WLE compared to MMS (95% CI, 0.57–10.9, p=n.s.).
Inclusion of males allowed us to examine the influence of a different surgical approach (MMS) on margin status and recurrence rates in EMPD. In contrast to prior studies including solely vulvar EMPD, we observed strong association between margin status and recurrence risk. Risk of positive margins was significantly higher after WLE compared to MMS. MMS should be explored to improve outcomes in gynecologic patients with EMPD.
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