Is the sarcomatous component (homologous vs heterologous) the prognostic "driving force" in early-stage uterine carcinosarcomas? A retrospective multicenter study.

PURPOSE: Uterine carcinosarcomas (UCSs) are aggressive biphasic malignancies, with a carcinomatous/epithelial component and a sarcomatous/mesenchymal counterpart. The aim of this study was to evaluate the impact of the sarcomatous component (homologous vs heterologous) on the overall survival (OS) and progression-free survival (PFS). METHODS: This is a multicenter observational retrospective study conducted in patients with stage I and II UCSs. RESULTS: Ninety-five women with histological diagnosis of early-stage UCSs were retrieved: 60 (63.2%) had tumors with homologous sarcomatous components, and 35 (36.8%) with heterologous. At univariate analysis, a stromal invasion ≥ 50%, the presence of clear cell, serous or undifferentiated carcinomatous component, the heterologous sarcomatous component and FIGO stage IB and II were shown to be variables with a statistically significant negative impact on PFS. Similarly, a depth of invasion ≥ 50%, the heterologous sarcomatous component and FIGO stage IB and II were statistically negative prognostic factors also concerning OS. At multivariate analysis, only the heterologous sarcomatous component was confirmed to be a statistically significant negative prognostic factor both on PFS (HR 2.362, 95% CI 1.207-4.623, p value = 0.012) and on OS (HR 1.950, 95% CI 1.032-3.684, p = 0.040). CONCLUSION: Carcinomatous and sarcomatous components both played a role in tumor progression and patients' survival. However, only the sarcomatous component retained a statistical significance at the multivariable model suggesting its preeminent prognostic role in early-stage UCSs.

Minimally Invasive Approaches in Locally Advanced Cervical Cancer Patients Undergoing Radical Surgery After Chemoradiotherapy: A Propensity Score Analysis.

PURPOSE: Chemoradiation (CT/RT) followed by radical surgery (RS) may play a role in locally advanced cervical cancer (LACC) patients with suboptimal response to CT/RT or in low-income countries with limited access to radiotherapy. Our aim is to evaluate oncological and surgical outcomes of minimally invasive radical surgery (MI-RS) compared with open radical surgery (O-RS). PATIENTS AND METHODS: Data for stage IB2-IVA cervical cancer patients managed by CT/RT and RS were retrospectively analyzed. RESULTS: Beginning with 686 patients, propensity score matching resulted in 462 cases (231 per group), balanced for FIGO stage, lymph node status, histotype, tumor grade, and clinical response to CT/RT. The 5-year disease-free survival (DFS) was 73.7% in the O-RS patients and 73.0% in the MI-RS patients (HR 1.034, 95% CI 0.708-1.512, p = 0.861). The 5-year locoregional recurrence rate was 12.5% (O-RS) versus 15.2% (MI-RS) (HR 1.174, 95% CI 0.656-2.104, p = 0.588). The 5-year disease-specific survival (DSS) was 80.4% in O-RS patients and 85.3% in the MI-RS group (HR 0.731, 95% CI 0.438-1.220, p = 0.228). Estimated blood loss was lower in the MI-RS group (p < 0.001), as was length of hospital stay (p < 0.001). Early postoperative complications occurred in 77 patients (33.3%) in the O-RS group versus 88 patients (38.1%) in the MI-RS group (p = 0.331). Fifty-six (24.2%) patients experienced late postoperative complications in the O-RS group, versus 61 patients (26.4%) in the MI-RS group (p = 0.668). CONCLUSION: MI-RS and O-RS are associated with similar rates of recurrence and death in LACC patients managed by surgery after CT/RT. No difference in early or late complications was reported.

Definition of a dynamic laparoscopic model for the prediction of incomplete cytoreduction in advanced epithelial ovarian cancer: proof of a concept.

OBJECTIVE: To develop an updated laparoscopy-based model to predict incomplete cytoreduction (RT>0) in advanced epithelial ovarian cancer (AEOC), after the introduction of upper abdominal surgery (UAS). PATIENTS AND METHODS: The presence of omental cake, peritoneal extensive carcinomatosis, diaphragmatic confluent carcinomatosis, bowel infiltration, stomach and/or spleen and/or lesser omentum infiltration, and superficial liver metastases was evaluated by staging laparoscopy (S-LPS) in a consecutive series of 234 women with newly diagnosed AEOC, receiving laparotomic PDS after S-LPS. Parameters showing a specificity≥75%, PPV≥50%, and NPV≥50% received 1 point score, with an additional one point in the presence of an accuracy of ≥60% in predicting incomplete cytoreduction. The overall discriminating performance of the LPS-PI was finally estimated by ROC curve analysis. RESULTS: No-gross residual disease at PDS was achieved in 135 cases (57.5%). Among them, UAS was required in 72 cases (53.3%) for a total of 112 procedures, and around 25% of these patients received bowel resection, excluding recto-sigmoid resection. We observed a very high overall agreement between S-LPS and laparotomic findings, which ranged from 74.7% for omental cake to 94.8% for stomach infiltration. At a LPS-PIV≥10 the chance of achieving complete PDS was 0, and the risk of unnecessary laparotomy was 33.2%. Discriminating performance of LPS-PI was very high (AUC=0.885). CONCLUSIONS: S-LPS is confirmed as an accurate tool in the prediction of complete PDS in women with AEOC. The updated LPS-PI showed improved discriminating performance, with a lower rate of inappropriate laparotomic explorations at the established cut-off value of 10.

Laparoscopic radical hysterectomy in cervical cancer as total mesometrial resection (L-TMMR): a multicentric experience.

OBJECTIVE: To analyze the feasibility of total mesometrial resection by laparoscopy (L-TMMR) in a multicentric series of early stage cervical cancer. METHOD: We prospectively evaluated a consecutive series of cervical cancer patients with pre-operative FIGO stages IA2-IB1 at the Catholic University in Rome and in Campobasso and the Charitè University in Berlin. All cases were assessed at pre-operative MRI scan and clinically confirmed by investigation under anesthesia, adhering strictly to the FIGO criteria. The surgical and post-surgical data were collected. RESULTS: 104 women with cervical cancer were admitted between July 2013 and August 2014 and among them 71 patients with pre-operative FIGO stages IA2-IB1 were treated with L-TMMR. One laparotomic conversion was registered. The median operative time was 260min (120-670min), estimated blood loss was 100cm(3) (25-900cm(3)), and the median length of hospital stay was 6days (2-26days). We observed 8 intra-operative complications including a vascular injury of the left internal iliac vein that caused conversion, 6 vesical injuries and 1 ureteral injury managed laparoscopically. Two vescico-vaginal fistula and one hemoperitoneum were observed as major post-operative complications (4.2%). CONCLUSION: L-TMMR can be safely performed in selected cervical cancer patients. Further larger prospective trials are needed to evaluate the oncological outcome of patients undergoing this surgical procedure.

Clinical outcome of recurrent locally advanced cervical cancer (LACC) submitted to primary multimodality therapies.

OBJECTIVES: Recurrence of disease represents a clinical challenge in cervical cancer patients, especially when all available treatment modalities have been used in the primary setting. The aim of this study was to analyze the patterns of recurrence and their association with clinical outcome in locally advanced cervical cancer (LACC) patients submitted to primary chemoradiation (CTRT) followed by radical surgery (RS). METHODS: This study was conducted on 364 LACC patients treated with CTRT plus RS since January 1996 to July 2012. For each relapse, information on date of clinical/pathological recurrence, and pattern of disease presentation were retrieved. Post-relapse survival (PRS) was recorded from the date of recurrence to the date of death for disease or last seen. Survival probabilities were compared by the log rank test. Cox's regression model with stepwise variable selection was used for multivariate prognostic analysis for PRS. RESULTS: Within a median follow-up of 42months, 75 recurrences (20.6%) and 54 disease-associated deaths (14.8%) were recorded. By analysing the pattern of relapse, most of the recurrences were outside the irradiated field (n=43, 57.3%) and the most frequently observed site was visceral (n=16, 21.3%). Among the parameters of the recurrence associated with PRS including the pattern of recurrence, the size of recurrence, SCC-Ag serum levels at recurrence, and secondary radical surgery, only the last one retained an independent predictive role in reducing the risk of death (p=0.037). CONCLUSIONS: The feasibility of secondary radical resection positively impacts on PRS of LACC patients submitted to multimodality primary treatments.

Fertility-sparing surgery in ovarian cancer extended beyond the ovaries: a case report and review of the literature.

BACKGROUND: Much attention has been recently focused on the role of fertility-sparing surgery in patients with ovarian cancer. However, few data are currently available on the feasibility of conservative approaches in women with disease extending beyond the ovaries. AIM: This review article aims at summarizing the oncologic and obstetric outcome of patients with stage II-III ovarian cancer treated with fertility-sparing surgery. We also describe a successful conservative management of a stage IIC endometrioid ovarian carcinoma. METHODS: A literature search through Medline was carried out to locate published articles using the following keywords for selection: 'Fertility-sparing surgery and ovarian cancer'. From every single case series, we retrieved data on patients with stage II-III disease submitted to conservative surgery. RESULTS: We identified 21 patients with stage II-III disease receiving fertility-sparing surgery. Recurrent disease was observed in 9 women (42.8%), and 5 (23.8%) of them died of disease. In contrast, a successful obstetric outcome has been reported in 3 cases (14.2%). CONCLUSIONS: Radical surgical staging remains the standard of care for all women with stage II-III disease. A fertility-sparing approach may be considered only in the presence of a favorable histology and a very strong fertility desire.

Effect of oxidation and mutation on the conformational dynamics and fibril assembly of amyloidogenic peptides derived from apolipoprotein C-II.

The oxidation of methionine residues in proteins can inhibit the self-assembly of proteins to form amyloid fibrils. For human apolipoprotein (apo) C-II the oxidation of methionine at position 60 inhibits fibril formation by the mature protein and by the core peptides apoC-II(56-76) and apoC-II(60-70). To investigate the molecular nature of these effects, we carried out fully solvated, all-atom molecular dynamics simulations of the structural changes in apoC-II(56-76) associated with substitutions of oxidized methionine (Met ox) at position 60. The results with apoC-II(56-76) (Met ox) showed less flexibility in structure, leading to a perturbation of the hydrophobic core. Valine substitution at position 60 showed an increased tendency to explore a wide range of conformational space, whereas the behavior of the Gln substitution mutant was similar to the wild-type peptide. These simulations are consistent with kinetic measurements which showed that a Met60Gln substitution within apoC-II(56-76) had little effect on the rate of fibril formation whereas substitution of Met ox or Val at position 60 lead to significant inhibition of peptide fibril formation. The effects of amino acid modification and substitutions on the kinetics of peptide fibril formation differ from the effects observed with full-length apoC-II inferring that additional mechanisms are involved in fibril formation by mature apoC-II.

Advances in surgical management of cervical cancer.

Cervical cancer (CC) remains an important health problem representing the second most frequent malignancy in women, with 470 000 new cases/year and 280 000 deaths, 80% of which occur in developing countries. In the last few years, new theoretical developments and advances in technology resulted in novel surgical approaches aimed at improving the therapeutic efficacy and/or reducing treatment related side effects. In particular, the authors focused their attention on the most relevant novelties related to the laparoscopic approach to CC treatment, and on the issue of modulation of surgical radicality. Moreover, the possible perspectives of sentinel lymph node concept and robotic surgery, as well as clinical issues related to conservative procedures including ''nerve sparing'' and ''fertility sparing'' strategies, have been evaluated.

Systematic comparison of empirical forcefields for molecular dynamic simulation of insulin.

The use of atomistic simulation methodologies based on empirical forcefields has enhanced our understanding of many physical processes governing protein structure and dynamics. However, the forcefields used in classical modeling studies are often designed for a particular class of proteins and rely on continuous improvement and validation by comparison of simulations with experimental data. We present a comprehensive comparison of five popular forcefields for simulating insulin. The effect of each forcefield on the conformational evolution and structural properties of the peptide is analyzed in detail and compared with available experimental results. In this study we observed that different forcefields favor different structural trends. However, the all-atom forcefield CHARMM27 and the united-atom forcefield GROMOS 43A1 delivered the best representation of the experimentally observed dynamic behavior of chain B of insulin.

Comparative study of insulin chain-B in isolated and monomeric environments under external stress.

We have conducted a series of theoretical simulations of insulin chain-B under different electric field conditions. This work extends our previous studies of the isolated chain-B by including chain-A and revealing the effects of chemical stress. For this complete protein, we observed increased stability under ambient conditions and under the application of thermal stress, compared to isolated chain-B. On the other hand, the presence of chain-A enhanced the effects of the applied electric field. Under the static field, the presence of chain-A lowered the strength of the field necessary to stretch the protein. Under the oscillating fields, there was relatively less stretching due to the competitive alignment process of the three helical regions with respect to the field. At high field strengths, we observed that the high frequency oscillating field caused less secondary structure disruption than a lower frequency field of the same strength.

Molecular dynamics simulations of a fibrillogenic peptide derived from apolipoprotein C-II.

The pathway to amyloid fibril formation in proteins involves specific structural changes leading to the combination of misfolded intermediates into oligomeric assemblies. Recent NMR studies showed the presence of "turns" in amyloid peptides, indicating that turn formation may play an important role in the nucleation of the intramolecular folding and possible assembly of amyloid. Fully solvated all-atom molecular dynamics simulations were used to study the structure and dynamics of the apolipoprotein C-II peptide 56 to 76, associated with the formation of amyloid fibrils. The peptide populated an ensemble of turn structures, stabilized by hydrogen bonds and hydrophobic interactions enabling the formation of a strong hydrophobic core which may provide the conditions required to initiate aggregation. Two competing mechanisms discussed in the literature were observed. This has implications in understanding the mechanism of amyloid formation in not only apoC-II and its fragments, but also in other amyloidogenic peptides.

Preoperative concomitant chemoradiotherapy in locally advanced cervical cancer: safety, outcome, and prognostic measures.

OBJECTIVES: To evaluate the morbidity, and the therapeutic value of surgery after chemoradiation in a large series of locally advanced cervical cancers (LACC). The prognostic role of different clinico-pathological factors has been also evaluated. METHODS: Between October 1997 and October 2006, 161 LACC patients were treated at both the Gynecologic Oncology Units of the Catholic University of Rome and Campobasso. Radiotherapy was administered to the whole pelvic region in combination with cisplatin and 5-fluorouracil. Radical surgery was performed 5-6 weeks after the end of the treatment. RESULTS: A clinical complete/partial response was observed in 153 patients and radical surgery was performed in 152 cases. The overall rate of surgical complications was 33% with 15 (10%) patients experiencing severe toxicities. At pathological examination 111 of 152 patients (73%) showed absent/microscopic residual disease. With a median follow-up of 28 months, the 5-year disease free-survival (DFS) was 83% and the 5-year overall survival (OS) 90%. Advanced FIGO (Federation Internationale de Gynecolgie et d'Obstetrique) stage, pathological response and lymph node involvement were found significantly associated with clinical outcome. CONCLUSIONS: We confirmed in a larger series the safety and efficacy of this multimodal approach in the treatment of LACC. The pathological assessment of response can allow not only a tailored surgery in selected patients, but also the identification of patients with higher risk of recurrence to be submitted to adjuvant therapies.

Effect of frequency on insulin response to electric field stress.

There are many unanswered questions regarding the precise way in which proteins respond to external stress. Since the function of proteins is critically linked to their three-dimensional structures, exposure to any form of stress which may induce changes in conformation can potentially initiate severe cellular dysfunction. This is particularly relevant with regard to the increasing presence of electromagnetic devices in today's environment and the possible effects on human health. Previously, we investigated the effect of electric field of various strengths on insulin chain-B under static and oscillating conditions. This paper expands on our previous work by subjecting the peptide to an oscillating electric field of different frequencies. We observed a frequency-dependent effect where the application of lower-frequency oscillating fields resulted in static-field-like behavior of the peptide, whereby the intrinsic flexibility of the protein is constrained, thus potentially restricting access to the protein's active state.

Participation of patients with gynecological cancer in phase I clinical trials: two years experience in a major cancer center.

OBJECTIVES: This study aims at analyzing the clinico-demographic features that influence the recruitment of gynecological cancer (GC) patients to phase I trials. The possible clinical benefit to patients resulting from the participation in these trials has been also investigated. METHODS: We performed a retrospective analysis of GC patients referred to the Phase I Unit of the Royal Marsden Hospital in Sutton (Surrey, UK), over 2 years. RESULTS: Overall 68 GC patients were referred, and subsequently 32 (47.1%) enrolled. The percentage of patients enrolled increased as the distance to travel between the patient's residence and the hospital shortened (8.3% through 47.8% to 60.8%, for travel time >2, 1-2 or < or =1 h, respectively; p=0.008). Better performance status (PS) was found to be associated with higher enrollment rate with percentages increasing from 0 through 51.2 to 58.8 in cases with PS> or =2, PS=1, PS=0, respectively (p=0.015). Among the biochemical parameters, only hepatobiliary dysfunction was found to be associated with lower enrollment (p=0.012). Minimal response/disease stabilization was observed in 11 patients (34.4%). An increased median survival following the first visit was observed in patients enrolled compared to those not enrolled (8 versus 4 months, respectively, p=0.0055). In the multivariate analysis, only PS and enrollment in trials retained an independent prognostic role (p=0.031 and p=0.040, respectively). CONCLUSIONS: This study, suggesting liver function and PS as important factors influencing the recruitment of GC patients to phase I trials could guide referral of patients to phase I Units. Moreover, the practical limitations imposed by long distance travel, together with the potential clinical benefit due to the participation to these trials, should encourage more investigators to develop phase I units in major cancer centers.

From bio-molecular and technology innovations to clinical practice: focus on ovarian cancer.

Ovarian cancer (OC) still represents the most lethal of gynecological malignancies with the chance for death in 5 years exceeding the chance for life. In recent years, the development of knowledge in molecular biology of OC coupled with the new technologies offers enormous opportunity to learn about aetiology of OC, and also give us a powerful tool for early diagnosis, prognosis and treatment of this disease. In particular, small cancer specimens from patients have become extremely informative thanks to techniques such as laser capture microdissection (LCM), tissue lysate arrays (TLAs), reverse trascriptase polymerase chain reaction (RT-PCR), and mass spectrometry. All of this coupled with advancements in bioinformatics have allowed the explosion of genomics, transcriptomics and proteomics. This paper focusses on the influence that advancement in the "-omics" bio-technology will reserve in OC diagnosis, prognostic characterization, and treatment.

Protein flexibility: multiple molecular dynamics simulations of insulin chain B.

Multiple molecular dynamics simulations totaling more than 100 ns were performed on chain B of insulin in explicit solvent at 300 K and 400 K. Despite some individual variations, a comparison of the protein dynamics of each simulation showed similar trends and most structures were consistent with NMR experimental values, even at the elevated temperature. The importance of packing interactions in determining the conformational transitions of the protein was observed, sometimes resulting in conformations induced by localized hydrophobic interactions. The high temperature simulation generated a more diverse range of structures with similar elements of secondary structure and populated conformations to the simulations at room temperature. A broad sampling of the conformational space of insulin chain B illustrated a wide range of conformational states with many transitions at room temperature in addition to the conformational states observed experimentally. The T-state conformation associated with insulin activity was consistently present and a possible mechanism of behavior was suggested.

Survivin expression in ovarian cancer and its correlation with clinico-pathological, surgical and apoptosis-related parameters.

We investigated the association of survivin expression with prognosis and other apoptosis-related biological factors in 110 primary ovarian cancer patients admitted to the Division of Gynecologic Oncology, Catholic University of Rome. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded sections by using polyclonal antibody ab469 for survivin, and mouse monoclonal antibodies (clone 124 and DO-7), for bcl-2 and p53, respectively. Cytoplasmic survivin immunoreaction was observed in 84.5% cases, while nuclear survivin immunostaining was observed in 29.1% cases. We failed to find any relationship between cytoplasmic survivin positivity rate and any of the parameters examined. Serous tumours showed a lower percentage of nuclear survivin positivity with respect to other histotypes (20.5 vs 48.6%, respectively; P-value=0.004). The percentage of nuclear survivin positivity was higher in cases subjected to primary tumour cytoreduction (43.5%), with respect to patients subjected to exploratory laparotomy (20%) (P=0.024). Bcl-2 and p53 were, respectively, expressed in 27.3 and 60.0% of the cases and their expression was not correlated with survivin status. During the follow-up period, progression and death of disease were observed in 68 (61.8%) and 53 (48.2%) cases, respectively. There was no difference in time to progression and overall survival according to survivin status in ovarian cancer patients. In conclusion, in our experience, the immunohistochemical assessment of survivin status does not seem to be helpful in the prognostic characterisation of ovarian cancer. A more in depth investigation of the complex physiology of divergent survivin variants is needed in order to clarify the biological and the clinical role of differentially located survivin isoforms.

Electric field effects on insulin chain-B conformation.

The response of proteins to different forms of stress continues to be a topic of major interest, especially with the proliferation of electromagnetic devices conjectured to have detrimental effects on human health. In this paper, we have performed molecular dynamics simulations on insulin chain-B under the influence of both static and oscillating electric fields, ranging from 10(7) to 10(9) V/m. We have found that both variants have an effect on the normal behavior of the protein, with oscillating fields being more disruptive to the structure as compared to static fields of similar effective strength. The application of a static field had a stabilizing effect on the secondary structure, restricting the inherent flexibility that is crucial for insulin's biological activity.