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The expression of placental alkaline phosphatase in 116 ovarian epithelial tumours was examined in formalin-fixed tissues used for routine histopathologic examination. In the total material, 51 % of the tumours displayed positive immunoreactivity, as described by the monoclonal anti-placental alkaline phosphatase antibody C2, with similar incidence (46-67%) in the four major groups of the adenocarcinomas, i.e., serous, mucinous, endometrioid and mesonephric tumours. By use of a histochemical staining index the mucinous and mesonephric tumours demonstrated a more intense staining (2.1 and 2.6) compared to the serous and endometrioid tumours (0.9 and 1.5). The relevance of the findings is discussed in relation to the use of monoclonal antibody technologies for radioimmunolocalization and radioimmunotherapy. Copyright © 1989 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background:The peak in incidence of ovarian cancer occurs around 65 years and concurrent increasing risk by age for a number of diseases strongly influence treatment and prognosis. The aim was to explore prevalence and incidence of co-morbidity in ovarian cancer patients compared with the general population.Methods:The study population was patients with ovarian cancer in Sweden 1993-2006 (n=11 139) and five controls per case (n=55 687). Co-morbidity from 1987 to 2006 was obtained from the Swedish Patient Register. Prevalent data were analysed with logistic regression and incident data with Cox proportional hazards models.Results:Women developing ovarian cancer did not have higher overall morbidity than other women earlier than 3 months preceding cancer diagnosis. However, at time of diagnosis 11 of 13 prevalent diagnosis groups were more common among ovarian cancer patients compared with controls. The incidence of many common diagnoses was increased several years following the ovarian cancer and the most common diagnoses during the follow-up period were thromboembolism, haematologic and gastrointestinal complications.Conclusion:Women developing ovarian cancer do not have higher overall morbidity the years preceding cancer diagnosis. The incidence of many common diagnoses was increased several years following the ovarian cancer. It is crucial to consider time between co-morbidity and cancer diagnosis to understand and interpret associations. [ABSTRACT FROM AUTHOR]

Copyright of Die Pathologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Introduction: Gynecological cancers account for a large number of cancer-related deaths in women. Endometrial cancer is the most prevalent, while ovarian cancer is the deadliest gynecological cancer worldwide. To overcome the clinical need for easy and rapid testing, there is a growing interest in cancer detection in non-invasive modalities. With a growing field of liquid biopsy, urine became interesting source of cancer biomarkers. Objectives: The aim of this manuscript is to provide an overview on the origin, analysis and the clinical significance of urine microRNAs in gynecological cancers, with a focus on ovarian and endometrial cancer. MicroRNAs, a class of small non-coding nucleic acids, are emerging as a non-invasive biomarkers due to the feasibility and the extreme stability in body fluids. Specific miRNA expression signatures have been previously identified in ovarian and endometrial cancer. Results: The aim of this manuscript is to provide an overview on the origin, analysis and the clinical significance of urine microRNAs in gynecological cancers, with the focus on ovarian and endometrial cancer. Conclusion: The advantages and limitations of urine microRNA utility and technologies are discussed. Previously detected microRNA from urine of the patients are summarized to evaluate their potential as non-invasive clinical biomarkers in gynecological oncology. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OC) is an aggressive disease, primarily diagnosed in late stages with only 20% of patients surviving more than 5 years. Liquid biopsy markers have great potential to improve current diagnostic and prognostic methods. Here, we compared miRNAs and DNA methylation in matched plasma, whole blood and tissues as a surrogate marker for OC. We found that while both cfDNA and cf-miRNAs levels were upregulated in OC compared to patients with benign lesions or healthy controls, only cf-miRNA levels were an independent prognosticator of survival. Following on our previous work, we found members of the miR-200 family, miR-200c and miR-141 to be upregulated in both plasma and matched tissues of OC patients which correlated with adverse clinical features. We could also show that the upregulation of miR-200c and -141 correlated with promoter DNA hypomethylation in tissues, but not in plasma or matched whole blood samples. As cf-miRNAs are more easily obtained and very stable in blood, we conclude that they might serve as a more appropriate surrogate liquid biopsy marker than cfDNA for OC. [ABSTRACT FROM AUTHOR]

Five to 10% of patients with stage IA, grade 1 or 2, endometrioid adenocarcinoma subsequently develop locoregional or distant recurrence. These patients have significantly reduced 5-year survival rates and salvage therapy success rates as low as 40%. The aim of this review is to highlight knowledge gaps that could further refine the risk categories of endometrial carcinoma (EC) and guide future randomized trials of adjuvant therapy for low-risk EC. A systematic search of the literature on PubMed and Medline was conducted using the following search terms: endometrial cancer, endometrial adenocarcinoma, endometrioid adenocarcinoma, low grade, early stage, stage IA, low risk, locoregional recurrence, and relapse. Relevant primary studies were extracted and included in this review. Risk factors for recurrence of low-risk EC were epidemiological (age, body mass index, ethnicity), molecular (DNA MMR, MSI, TP53 mutation and P53 defect, CTNNB1 mutation, PTEN and POLE mutation, L1CAM expression), pathological (positive peritoneal cytology, lymphovascular invasion, tumor size), and others like Ki67-percentage, micro-RNA expression, and hormonal receptor expression. CTNNB1 mutation, L1CAM expression, lymphovascular invasion, and tumor size were identified as significant risk factors for recurrence in low-risk EC. There are subsets of low-risk EC patients at high risk of recurrence and should be suspected when having the following risk factors: positive molecular markers, large tumor size, and lymphovascular invasion. A novel scoring system and randomized controlled trials should be conducted to identify these patients who will benefit most from adjuvant therapy to avoid recurrence. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the clinical benefit of dose-dense paclitaxel plus carboplatin (TC) with bevacizumab therapy for advanced ovarian, fallopian tube, and primary peritoneal cancer patients in the neoadjuvant setting. Methods: Ovarian, fallopian tube or primary peritoneal cancer patients with stage III–IV disease received neoadjuvant chemotherapy (NAC) every 3 weeks consisting of paclitaxel (80 mg/m2) on days 1, 8, and 15; carboplatin (AUC 6.0 mg/mL × min.) on day 1; and bevacizumab (15 mg/kg) on day 1. Interval debulking surgery (IDS) was performed after 3 cycles of dose-dense TC-bevacizumab therapy. The primary endpoint was the rate of complete resection by IDS. Secondary endpoints were treatment completion rate, treatment exposure, response rate to NAC, adverse events, and perioperative complications. Results: Twenty-four patients were included in this study. The median age was 55.5 years (37–80 years), and most patients had high-grade serous carcinoma accounted (n = 18). IDS was performed in all patients with complete resection achieved in 75% (95% confidence interval: 57.7–92.3%). The lower limit exceeded the preset threshold rate of 55%. The response rate to NAC was 79%, and serum CA125 levels were in the normal range after NAC in 57% of patients. Grade 4 hematological toxicities and grade 3/4 non-hematological toxicities occurred in 29% and 17% of patients during NAC, respectively. Grade 3/4 perioperative complications were seen in 29% of patients, but no gastrointestinal perforations or treatment-related deaths occurred. Conclusions: Neoadjuvant dose-dense TC-bevacizumab therapy was well tolerated, and a satisfactory rate of complete resection by IDS was achieved. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GCs) are commonly used topical treatments for skin diseases but are associated with both local and systemic side effects. In this study, we describe a selective non-steroidal glucocorticoid receptor (GR) agonist for topical use, LEO 134310, which is rapidly deactivated in the blood resulting in low systemic exposure and a higher therapeutic index in the TPA-induced skin inflammation mouse model compared with betamethasone valerate (BMV) and clobetasol propionate (CP). Selectivity of LEO 134310 for GR was confirmed within a panel of nuclear receptors, including the mineralocorticoid receptor (MR), which has been associated with induction of skin atrophy. Topical treatment with LEO 134310 in minipigs did not result in any significant reduction in epidermal thickness in contrast to significant epidermal thinning induced by treatment with BMV and CP. Thus, the profile of LEO 134310 may potentially provide an effective and safer treatment option for skin diseases compared with currently used glucocorticoids. [ABSTRACT FROM AUTHOR]

Purpose: To develop and validate a radiomic nomogram based on arterial phase of CT to discriminate the primary ovarian cancers (POCs) and secondary ovarian cancers (SOCs). Methods: A total of 110 ovarian cancer patients in our hospital were reviewed from January 2010 to December 2018. Radiomic features based on the arterial phase of CT were extracted by Artificial Intelligence Kit software (A.K. software). The least absolute shrinkage and selection operation regression (LASSO) was employed to select features and construct the radiomics score (Rad-score) for further radiomics signature calculation. Multivariable logistic regression analysis was used to develop the predicting model. The predictive nomogram model was composed of rad-score and clinical data. Nomogram discrimination and calibration were evaluated. Results: Two radiomic features were selected to build the radiomics signature. The radiomics nomogram that incorporated 2 radiomics signature and 2 clinical factors (CA125 and CEA) showed good discrimination in training cohort (AUC 0.854), yielding the sensitivity of 78.8% and specificity of 90.7%, which outperformed the prediction model based on radiomics signature or clinical data alone. A visualized differential nomogram based on the radiomic score, CEA, and CA125 level was established. The calibration curve demonstrated the clinical usefulness of the proposed nomogram. Conclusion: The presented nomogram, which incorporated radiomic features of arterial phase of CT with clinical features, could be useful for differentiating the primary and secondary ovarian cancers. [ABSTRACT FROM AUTHOR]

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Ovarian cancer (OC) is the fourth most common cancer among Pakistani, Scottish and Chinese women. The aim of the present study was to determine the association of potential risk factors with OC and analysis of Cancer Antigen 125 (CA125) in its monitoring and diagnosis. A total of 200 patients diagnosed with OC were included in this study. All the patients were interviewed and 54 OC patients (case group) and 35 age-matched healthy subjects (control group) gave their blood for analysis of CA125. The blood of case and control groups was subjected to an ELISA test for the evaluation of CA125 levels. Majority of the patients were of 40–50 years of age and most of the patients were diagnosed at this period of life. The majority of the patients experienced their first menarche and menopause at the age of 13–14 and 40–50 years respectively. There is no significant association between early menarche and OC family history, nor between late menopause and OC family history. There is a significant association between family history of breast cancer (BC) and age of menarche (P = 0.005). An OC patient with an age of menarche of 13 years or younger has 2.8 times the odds of having a family history of BC than those whose age of menarche is more than 13 years. Eleven percent of patients diagnosed with OC received no intervention. All other patients underwent treatment options including hysterectomy (69.5%), radiotherapy (39%) and chemotherapy (95%). The profiles of the patients showed that those who had a family history of OC were more likely to provide blood samples (OR = 3.87, P = 0.025), and similarly for those with a history of breast cancer (OR = 2.83, P = 0.022) in comparison to those who were not willing to provide blood for testing of biomarker. The distribution of CA125 for OC patients and control group showed that CA125 values were significantly higher (P = 0.034) in the case patients compared with the control group. The decrease in CA125 levels indicated the positive response to treatment, whereas increase in CA125 values showed resistant and disease progression. 52% of the patients with OC were correctly diagnosed as having OC (based on the optimal cut-point of CA125), while 83% of those without OC were also correctly diagnosed (with 48% of OC patients and 17% of non-OC patients incorrectly diagnosed). We concluded that there is significant association between family history of breast cancer and OC history and use of CA125 as a biomarker is not an ideal diagnostic and monitoring test as it has low sensitivity and high specificity. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this article is to review the most commonly used tumor markers in abdominal and pelvic tumors, describe their limitations and explain how to use them in the context of known cancer in order to optimize multidisciplinary care of oncologic patients. Conclusion: Tumor markers are important for the diagnosis, staging, monitoring of treatment and detection of recurrence in many cancers. This knowledge is crucial in the daily interpretation of images of oncologic and non-oncologic patients. However, radiologists should also be aware of the limitations of the most commonly used tumor markers and they should not be used solely, but interpreted in conjunction with diagnostic imaging, clinical history and physical examination that will help optimize the multidisciplinary care and management of oncologic patients. [ABSTRACT FROM AUTHOR]

Breast cancer (BCa) is a heterogeneous disease with different histological, prognostic and clinical aspects. Therefore, the need for identification of novel biomarkers for diagnosis, prognosis and monitoring of disease, as well as treatment outcome prediction remains at the forefront of research. The search for circulating elements, obtainable by simple peripheral blood withdrawal, which may serve as possible biomarkers, constitutes still a challenge. In the present study, we have evaluated the expression of 6 circulating miRNAs, (miR-16, miR-21, miR-23α, miR-146α, miR-155 and miR-181α), in operable BCa patients, with non-metastatic, invasive ductal carcinoma, not receiving neoadjuvant chemotherapy. These miRNAs, known to be involved in both tumor cell progression and immune pathways regulation, were analyzed in relation to circulating cytokines, tumor immune-cell infiltration and established prognostic clinicopathological characteristics. We have identified three different clusters, with overall low (C1), moderate (C2) or high (C3) expression levels of these six circulating miRNAs, which define three distinct groups of non-metastatic BCa patients characterized by different clinicopathological and immune-related characteristics, with possibly different clinical outcomes. Our data provide the proof-of-principle to support the notion that, up- or down-regulation of the same circulating miRNA may reflect different prognosis in BCa. Nonetheless, the prognostic and/or predictive potential of these three "signatures" needs to be further evaluated in larger cohorts of BCa patients with an, at least, 5-year clinical follow-up. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to reveal the efficacy of weekly administration of paclitaxel and carboplatin for advanced ovarian cancer patients with poor performance status (PS).Methods: FIGO stage III/IV ovarian cancer or fallopian tube cancer patients who underwent interval debulking surgery (IDS) followed by neoadjuvant chemotherapy (NAC) were analyzed retrospectively. Patients were divided into two groups based on NAC: weekly paclitaxel and carboplatin (W-TC) and 3 weeks of paclitaxel and carboplatin (TW-TC). Toxicity, efficacy of NAC, surgery outcome, and prognosis were assessed by comparing the two groups.Results: Twenty patients treated with W-TC and 18 patients treated with TW-TC were analyzed. All of the W-TC patients were poor PS (PS ≥ 2), and all of the TW-TC patients were good PS (PS ≤ 1). The overall clinical response rates were 70% in W-TC and 83.4% in TW-TC. In the W-TC group, Grade 3/4 anemia and thrombocytopenia and greater than grade 2 neuropathy were significantly reduced compared to TW-TC patients. A frequency of treatment delay greater than 7 and 14 days, G-CSF support, blood transfusion, and dose reduction or regimen change were also significantly reduced in the W-TC group. The rate of IDS, optimal debulking surgery, complications during operation, and blood transfusion were similar between the W-TC and TW-TC groups. Progression-free survival and overall survival were also similar between the two groups.Conclusion: Our study suggested that NAC with W-TC for poor PS patients with non-treated ovarian cancer reduced the toxicity of chemotherapy and had the same efficacy as TW-TC. [ABSTRACT FROM AUTHOR]

Copyright of Der Schmerz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Der Onkologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Purpose: Cancer antigens (CA) 15-3 and 27.29 are used in the clinical management of many breast cancer patients. Given that immunoassays for CA 15-3 and CA 27.29 target epitopes on the same glycoprotein—Mucin 1 (MUC1)—the present analysis was conducted to evaluate the potential concordance of tumor marker results when both tests were ordered by providers on the same specimens.Methods: A retrospective limited dataset of paired CA 15-3 (Roche Diagnostics) and CA 27.29 (Siemens Diagnostics) test results was obtained from a national clinical reference laboratory. Concordance according to reference interval (RI) status and percent (%) change between consecutive test results was analyzed.Results: 37,652 paired results from 12,470 distinct patients were obtained. The correlation between CA 15-3 and CA 27.29 results was high (correlation coefficient: Pearson, 0.967), although across the dataset a significant difference between CA 15-3 and CA 27.29 results was observed (P < 0.05). RI concordance between CA 15-3 and CA 27.29 results was observed in 93.7% of pairs (35,280 of 37,652). Correlation was also observed in the % change of CA 15-3 and CA 27.29 results between consecutive specimens for individual patients. Using doubling or halving thresholds (i.e., 100% increase or 50% decrease), concordance in % change was observed between CA 15-3 and CA 27.29 in approximately 90% of cases. Individual patient results trended similarly across both markers over time.Conclusion: While generally concordant, CA 15-3 and CA 27.29 results should not be used interchangeably. The present report provides no evidence for added value in performing both tests routinely for individual patients. [ABSTRACT FROM AUTHOR]

Epithelial ovarian cancer is typically diagnosed at an advanced stage. Current state-of-the-art surgery and chemotherapy result in the high incidence of complete remissions; however, the recurrence rate is also high. For most patients, the disease eventually becomes a continuum of symptom-free periods and recurrence episodes. Different targeted treatment approaches and biological drugs, currently under development, bring the promise of turning ovarian cancer into a manageable chronic disease. In this review, we discuss the current standard in the therapy for ovarian cancer, major recent studies on the new variants of conventional therapies, and new therapeutic approaches, recently approved and/or in clinical trials. The latter include anti-angiogenic therapies, polyADP-ribose polymerase (PARP) inhibitors, inhibitors of growth factor signaling, or folate receptor inhibitors, as well as several immunotherapeutic approaches. We also discuss cost-effectiveness of some novel therapies and the issue of better selection of patients for personalized treatment. [ABSTRACT FROM AUTHOR]

Platelets seem to play a role in the development of ovarian cancer. Platelet count (PLT) is an ubiquitous available parameter. We analyzed retrospectively data of 756 patients with primary adnexal tumors: 584 benign and 172 malignant (148 invasive and 24 borderline) cases. We compared the diagnostic accuracy of CA125, PLT, and a combination of CA125 and PLT. The cutoff values for CA125 and PLT were 35 U/ml and 350/nl, respectively. The median age of patients with benign and malignant tumors was 45 and 64 years, respectively. A total of 77/172 (44.8 %) malignant and 50/584 (8.6 %) benign cases presented with thrombocytosis (PLT ≥350/nl). The median PLT differed between benign and malignant cases (257/nl vs. 330/nl; p < 0.001), similarly as CA125 did (17 vs. 371 U/ml; p < 0.001). In the multivariate analysis, age, CA125, and thrombocytosis predicted independently the presence of malignancy. The results of CA125 were false positive in 21 % and false negative in 13 %. If considered together, thrombocytosis + CA125 were false positive only in 9 %, whereas the false negative rate was 12 %. The sensitivity and specificity of CA125, thrombocytosis, and thrombocytosis + CA125 for detecting adnexal malignancy were 0.88/0.78, 0.45/0.91, and 0.81/0.94, respectively. The positive predictive value (PPV) of CA125, thrombocytosis, and thrombocytosis + CA125 was 0.79, 0.61, and 0.91, respectively. In conclusion, PLT is an ubiquitously available parameter that could be useful in the diagnostic evaluation of pelvic mass. Considering thrombocytosis additionally to CA125 improves the specificity and PPV and reduces the false positive rate in detecting adnexal malignancy. [ABSTRACT FROM AUTHOR]

Background: Cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) is an established therapy for pseudomyxoma peritonei (PMP). However, the role of IPC is unclear. By ex vivo assessment of PMP tumor cell sensitivity to cytotoxic drugs, we investigated the basis for IPC drug selection and the role of IPC in the management of PMP. Methods: Tumor cells were prepared by collagenase digestion of tumor tissue from 133 PMP patients planned for CRS and IPC. Tumor cell sensitivity to oxaliplatin, 5FU, mitomycin C, doxorubicin, irinotecan, and cisplatin was assessed in a 72-h cell-viability assay. Drug sensitivity was correlated to progression-free survival (PFS) and overall survival (OS). Results: Samples from 92 patients were analyzed successfully. Drug sensitivity varied considerably between samples. Peritoneal mucinous carcinomatosis (PMCA), compared with PMCA intermediate or disseminated peritoneal adenomucinosis, was slightly more resistant to platinum and 5FU and tumor cells from patients previously treated with chemotherapy were generally less sensitive than those from untreated patients. Multivariate analysis showed patient performance status and completeness of CRS to be prognostic for OS. Among patients with complete CRS ( n = 61), PFS tended to be associated with sensitivity to mitomycin C and cisplatin ( p ≈ 0.06). At the highest drug concentration tested, the hazard ratio for disease relapse increased stepwise with drug resistance for all drugs. Conclusions: Ex vivo assessment of drug sensitivity in PMP provides prognostic information. The results suggest a role for IPC as therapeutic adjunct to CRS and for individualization of IPC by pretreatment assessment of drug sensitivity. [ABSTRACT FROM AUTHOR]

Cancer vaccines as a modality of immune-based cancer treatment offer the promise of a non-toxic and efficacious therapeutic alternative for patients. Emerging data suggest that response to vaccination largely depends on the magnitude of the type I immune response generated, epitope spreading and immunogenic modulation of the tumor. Moreover, accumulating evidence suggests that cancer vaccines will likely induce better results in patients with low tumor burden and less aggressive disease. To induce long-lasting clinical responses, vaccines will need to be combined with immunoregulatory agents to overcome tumor-related immune suppression. Immunotherapy, as a treatment modality for prostate cancer, has received significant attention in the past few years. The most intriguing characteristics that make prostate cancer a preferred target for immune-based treatments are (1) its relative indolence which allows sufficient time for the immune system to develop meaningful antitumor responses; (2) prostate tumor-associated antigens are mainly tissue-lineage antigens, and thus, antitumor responses will preferentially target prostate cancer cells. But, also in the event of eradication of normal prostate epithelium as a result of immune attack, this will have no clinical consequences because the prostate gland is not a vital organ; (3) the use of prostate-specific antigen for early detection of recurrent disease allows for the initiation of vaccine immunotherapy while tumor burden is still minimal. Finally, for improving clinical outcome further to increasing vaccine potency, it is imperative to recognize prognostic and predictive biomarkers of clinical benefit that may guide to select the therapeutic strategies for patients most likely to gain benefit. [ABSTRACT FROM AUTHOR]

The ultrashort-acting dihydropyridine calcium channel antagonist clevidipine (Cleviprex) has a rapid onset and offset of effect and reduces blood pressure (BP) by decreasing arteriolar resistance without affecting venous capacitance vessels. This article reviews the clinical efficacy and tolerability of intravenous clevidipine when used to manage BP in perioperative and intensive care settings, as well as summarizing its pharmacological properties. Intravenous clevidipine effectively treated preoperative and postoperative hypertension in patients undergoing cardiac surgery, according to the results of the randomized, multicentre, double-blind, phase III ESCAPE-1 and ESCAPE-2 trials. The randomized, open-label, multicentre, phase III ECLIPSE trials indicated that in terms of keeping systolic BP within the target range, clevidipine was more effective than nitroglycerin or sodium nitroprusside perioperatively and had similar efficacy to nicardipine postoperatively in cardiac surgery patients. In small, double-blind trials in patients undergoing coronary artery bypass graft surgery, perioperative clevidipine was noninferior to nitroglycerin, and postoperative clevidipine had similar efficacy to sodium nitroprusside. Noncomparative studies demonstrated that clevidipine provided rapid BP control in patients with acute neurological injuries (including intracerebral haemorrhage, subarachnoid haemorrhage and acute ischaemic stroke), and was not associated with 'overshoot' in the vast majority of patients. Intravenous clevidipine was generally well tolerated and was usually associated with no reflex tachycardia or only very modest increases in heart rate. In conclusion, intravenous clevidipine is a valuable agent for the management of BP in perioperative and intensive care settings. [ABSTRACT FROM AUTHOR]

Mucinous tumors of the ovary represent a spectrum of neoplastic disorders, including benign mucinous cystadenoma, pseudomyxoma peritonei, mucinous tumors of low malignant potential (borderline), and invasive mucinous ovarian carcinoma. These tumors are related closely to each other and are distinct from other histologic subtypes of epithelial ovarian neoplasms from a clinical, histologic, and molecular standpoint. A continuum appears to be present from benign to borderline to malignant, which is different from other types of epithelial ovarian cancer. Mutational profiles are also distinct, as KRAS mutations are common, but p53 and BRCA mutations are infrequent. These characteristics lead to specific biologic behavior and guide both clinical management and research efforts in patients with mucinous ovarian tumors. [ABSTRACT FROM AUTHOR]

Peritoneal carcinomatosis (PC) is a common form of tumour metastasis stemming from gastrointestinal and colorectal cancers. For a long time, PC has been considered a terminal clinical condition treated only with palliative systemic chemotherapy and associated with very limited results. During the last decade, the treatment of advanced colorectal disease has greatly improved with the emergence of new chemotherapy drugs and biological agents. However, the median survival rates still do not surpass 24 months, even though most of these studies correspond to groups of patients with metastatic disease to the liver and/or lung. The approach and development of cytoreductive radical surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC) are based on performing radical surgery of the entire visible tumour within the abdomen/peritoneum, followed immediately by HIPEC, which acts upon microscopic tumour that remains present after surgery and which is responsible for the persistence or relapse of peritoneal disease. Peritonectomy procedures are demanding surgical techniques that permit elimination of the tumour present in the peritoneal lining and any other organs and/or structures that are infiltrated. The synergistic effect of hyperthermia and chemotherapy has been well documented. Hyperthermia increases the cytotoxicity of some cytostatic agents and increases the penetration of certain drugs into the neoplastic cells. The prognosis for patients with PC who undergo combined treatment correlates with the volume of PC (tumour burden) measured as the Peritoneal Cancer Index (PCI) and the ability to perform a CRS, to completely eliminate the gross tumour. At least one phase III study and an important number of phase II studies have shown that CRS + HIPEC provides important survival benefits for patients with PC of colorectal origin. The combination of CRS + HIPEC is indicated for patients with good general health, a low PCI, absence of extra-abdominal metastasis and who can, technically, undergo CRS. The early identification of this group of patients, rapid referral to centres specialised in CRS + HIPEC, together with the correct application of this treatment, are key in achieving the best results. [ABSTRACT FROM AUTHOR]

To inform clinical management of glioblastoma patients, we estimated the relative prevalence (present at glioblastoma diagnosis) and incidence (newly diagnosed) of comorbid conditions among these patients and their matched controls. We identified 2,424 glioblastoma patients registered in the Swedish National Cancer Registry between 1993 and 2006. Next, 12,120 randomly sampled population-based controls were individually matched to cases on age, sex and calendar year of diagnosis. We then evaluated patient discharge data for selected potential comorbid conditions. Seizures (odds ratio (OR) 31.6, 95 % confidence interval (CI) 24.7-40.3) and cerebral edema (OR 25.0, 95 % CI 5.5-114) were the most prevalent conditions at diagnosis. Beginning 30 days after diagnosis, increased risks of incident deep vein thrombosis (hazard ratio (HR) 119.7, 95 % CI 60.8-211.0) and pulmonary embolism (HR 92.4, 95 % CI 48.3-176.6) were observed. Risks of incident cardiovascular diseases including heart failure (HR 4.0, 95 % CI 2.6-6.1), coronary artery disease (HR 2.3, 95 % CI 1.7-3.2), and myocardial infarction (HR 1.9, 95 % CI 1.1-3.4) were also elevated among glioblastoma patients. In this first population-based study of both prevalent and incident comorbid conditions among glioblastoma patients, we have quantified risk of those conditions related to the tumor and its treatment-based on nationwide registry data. However, for incident conditions we cannot distinguish between the effects of the tumor and the effects of treatment. A novel finding was the elevated risk of cardiovascular disease among glioblastoma patients; glioblastoma patients should be monitored for signs of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background:Radical hysterectomy is recommended for endometrial adenocarcinoma patients with suspected gross cervical involvement. However, the efficacy of operative procedure has not been confirmed.Methods:The patients with endometrial adenocarcinoma who had suspected gross cervical involvement and underwent hysterectomy between 1995 and 2009 at seven institutions were retrospectively analysed (Gynecologic Oncology Trial and Investigation Consortium of North Kanto: GOTIC-005). Primary endpoint was overall survival, and secondary endpoints were progression-free survival and adverse effects.Results:A total of 300 patients who underwent primary surgery were identified: 74 cases with radical hysterectomy (RH), 112 patients with modified radical hysterectomy (mRH), and 114 cases with simple hysterectomy (SH). Median age was 47 years, and median duration of follow-up was 47 months. There were no significant differences of age, performance status, body mass index, stage distribution, and adjuvant therapy among three groups. Multi-regression analysis revealed that age, grade, peritoneal cytology status, and lymph node involvement were identified as prognostic factors for OS; however, type of hysterectomy was not selected as independent prognostic factor for local recurrence-free survival, PFS, and OS. Additionally, patients treated with RH had longer operative time, higher rates of blood transfusion and severe urinary tract dysfunction.Conclusion:Type of hysterectomy was not identified as a prognostic factor in endometrial cancer patients with suspected gross cervical involvement. Perioperative and late adverse events were more frequent in patients treated with RH. The present study could not find any survival benefit from RH for endometrial cancer patients with suspected gross cervical involvement. Surgical treatment in these patients should be further evaluated in prospective clinical studies. [ABSTRACT FROM AUTHOR]

In this review article we discuss the evolution of second-line treatment options for patients with metastatic colorectal cancer (mCRC). The benefits of second-line chemotherapy have been established for some time, but in the last decade a number of trials have evaluated combinations of irinotecan- and oxaliplatin-based chemotherapy with molecular-targeted agents; e.g., vascular endothelial growth factor (VEGF)-targeting agents (bevacizumab, aflibercept), epidermal growth factor receptor antibodies (cetuximab, panitumumab), and tyrosine kinase inhibitors (vatalanib). Recent developments include the availability of the new VEGF-targeted agent aflibercept and the new concept of continuing bevacizumab after failure of first-line bevacizumab, which is likely to become a new treatment option in the second-line setting. Choosing the most appropriate second-line treatment regimen for mCRC patients remains a complex issue. All of the currently available molecular-targeted agents seem to be active even after patients have received a bevacizumab-based first-line regimen. Overall, the selection of second-line treatment for mCRC depends on several variables and should be determined taking into account the patient's performance and disease status. [ABSTRACT FROM AUTHOR]

Objective: Aflibercept (Zaltrap) is a novel antiangiogenic agent that binds to vascular endothelial growth factor (VEGF) and inhibits VEGF-dependent tumor growth. We aimed to characterize the population pharmacokinetics (PK) of free and bound aflibercept in patients with solid tumors to examine the influence of covariates on their PK and to evaluate the proposed dosing regimens by simulation. Methods: Data from 9 clinical trials with 1,506 cancer patients receiving aflibercept (2-9 mg/kg every 2 or 3 weeks; 1 h IV infusion) as a monotherapy or in combination with various chemotherapies were included. Free and bound aflibercept concentrations were analyzed using a non-linear mixed-effects modeling approach with MONOLIX 4.1.2. Results: An approximation of a target-mediated drug disposition model with irreversible binding of free aflibercept to VEGF adequately described the PK of free and bound aflibercept. The typical estimated clearances for free (CL) and bound aflibercept (CL) were 0.88 and 0.19 L/day, respectively. The volumes of distribution for free ( V) and bound ( V) aflibercept were similar (~4 L). CL and V increased with body weight and were lower in women. Patients with low albumin (ALB) or high alkaline phosphatase (ALK) had faster CL compared to a typical patient. Pancreatic cancer may be associated with changes in binding of aflibercept to VEGF. Simulations of different dosing regimens showed that adequate saturation of circulating VEGF was achieved with a dose of 4 mg/kg every 2 weeks. Conclusions: Aflibercept kinetics was most affected by gender, body weight, ALB, ALK and pancreatic cancer. Simulations supported the rationale for the recommended dose of 4 mg/kg every 2 weeks for aflibercept. [ABSTRACT FROM AUTHOR]

Plasma profiling of patients treated with antiangiogenic agents may identify markers that correlate with toxicity. Objectives were to correlate changes in cytokine and angiogenic factors as potential markers of toxicity to aflibercept. Circulating cytokine and angiogenic factors were measured in 28 patients with recurrent glioblastoma in a single-arm phase II study of aflibercept. Plasma samples were analyzed at baseline, 24 h, and 28 days using multiplex assays or ELISA. We evaluated log-transformed baseline biomarker expressions with Cox proportional hazard regression models to assess the effect of markers on any grade II-IV (Gr II-IV) toxicity, on-target toxicity (hypertension, proteinuria, thromboembolism), and fatigue. All tests were two sided with a statistical significance level of p = 0.05. Among 28 pts, there were 116 Gr II-IV events. Changes in IL-13 from baseline to 24 h predicted on-target toxicities. Increases in IL-1b, IL-6, and IL-10 at 24 h were significantly associated with fatigue. Progression-free survival was 14.9 months for patients in the all-toxicity group and 9.0 months for patients in the on-target toxicity group compared to 4.3 months for those who did not develop any Gr II-IV toxicity ( p = 0.002 and p = 0.045, respectively). Toxicity from antiangiogenic therapy remains an important cause of antiangiogenic treatment discontinuation and patient morbidity. Changes in IL6, IL10, and IL13 were repeatedly correlated with toxicity. Profiling of IL-13 as a surrogate for endothelial dysfunction could individualize patients at risk during antiangiogenic therapy, as could identifying those at higher risk for fatigue using IL-6 and IL-10. [ABSTRACT FROM AUTHOR]

Treatment of epithelial ovarian cancer involves surgical management with staging or debulking surgery and chemotherapy with a platinum and taxane-containing regimen. Despite achieving a 70-80 % complete remission, patients often will recur. Novel therapies are needed to improve the treatment of ovarian cancers. Tumor angiogenesis is a critical process involved in the growth and metastasis of ovarian cancer. Numerous phase II trials with angiogenesis inhibitors have been reported and have led to the development and completion of several recent phase III trials in both upfront and recurrent ovarian cancers. Future studies will need to focus on how and when to incorporate angiogenesis inhibitors in the treatment armamentarium for ovarian cancers. [ABSTRACT FROM AUTHOR]

We report on the immunogenicity and clinical effects in a phase I/II dose escalation trial of a DNA fusion vaccine in patients with prostate cancer. The vaccine encodes a domain (DOM) from fragment C of tetanus toxin linked to an HLA-A2-binding epitope from prostate-specific membrane antigen (PSMA), PSMA. We evaluated the effect of intramuscular vaccination without or with electroporation (EP) on vaccine potency. Thirty-two HLA-A2 patients were vaccinated and monitored for immune and clinical responses for a follow-up period of 72 weeks. At week 24, cross-over to the immunologically more effective delivery modality was permitted; this was shown to be with EP based on early antibody data, and subsequently, 13/15 patients crossed to the +EP arm. Thirty-two HLA-A2 control patients were assessed for time to next treatment and overall survival. Vaccination was safe and well tolerated. The vaccine induced DOM-specific CD4 and PSMA-specific CD8 T cells, which were detectable at significant levels above baseline at the end of the study ( p = 0.0223 and p = 0.00248, respectively). Of 30 patients, 29 had a measurable CD4 T-cell response and PSMA-specific CD8 T cells were detected in 16/30 patients, with or without EP. At week 24, before cross-over, both delivery methods led to increased CD4 and CD8 vaccine-specific T cells with a trend to a greater effect with EP. PSA doubling time increased significantly from 11.97 months pre-treatment to 16.82 months over the 72-week follow-up ( p = 0.0417), with no clear differential effect of EP. The high frequency of immunological responses to DOM-PSMA vaccination and the clinical effects are sufficiently promising to warrant further, randomized testing. [ABSTRACT FROM AUTHOR]

Purpose: Clevidipine is a rapidly-acting intravenous dihydropyridine antihypertensive acting via calcium channel blockade. This was a randomized, single-blind, parallel-design study of a 72-h continuous clevidipine infusion. Method: Doses of 2, 4, 8, or 16.0 mg/h or placebo were evaluated in 61 subjects with mild to moderate essential hypertension. IV clevidipine or placebo was initiated at 2.0 mg/h and force-titrated in doubling increments every 3 min to target dose, then maintained for 72 h. Blood pressure and heart rate were measured during infusion, and for 4, 6 and 8 h after termination of infusion, although oral therapy could be restarted at 4 h. Clevidipine blood levels were obtained during infusion and for 1 hour after termination. Results: Rapid onset of drug effect occurred at all clevidipine dose levels, with consistent pharmacokinetics and rapid offset after 72-h infusion. No evidence of tolerance to the clevidipine drug effect was observed at any dose level over the 72-h infusion. No evidence of rebound hypertension was found for either 4 or 6 h after termination of the clevidipine infusion. At 8 h following cessation of clevidipine, blood pressure was not significantly higher than at baseline. Placebo-treated subjects had blood pressures lower than baseline at 8 h following infusion termination; hence, placebo-adjusted blood pressures tended to be slightly higher than baseline. Conclusion: This study supports the use of up to 72 h of IV clevidipine therapy for the management of blood pressure, with consistent pharmacokinetic/pharmacodynamic characteristics and context insensitive half-life across the dose ranges evaluated. [ABSTRACT FROM AUTHOR]

Background: In recent years, evidence is accumulating that cancer cells develop strategies to escape immune recognition. HLA class I HC down-regulation is one of the most investigated. In addition, different HLA haplotypes are known to correlate to both risk of acquiring diseases and also prognosis in survival of disease or cancer. We have previously shown that patients with serous adenocarcinoma of the ovary in advanced surgical stage disease have a particularly poor prognosis if they carry the HLA-A02* genotype. We aimed to study the relationship between HLA-A02* genotype in these patients and the subsequent HLA class I HC protein product defects in the tumour tissue. Materials and methods: One hundred and sixty-two paraffin-embedded tumour lesions obtained from Swedish women with epithelial ovarian cancer were stained with HLA class I heavy chain (HC) and β-microglobulin (β-m)-specific monoclonal antibodies (mAb). Healthy ovary and tonsil tissue served as a control. The HLA genotype of these patients was determined by PCR/sequence-specific primer method. The probability of survival was calculated using the Kaplan-Meier method, and the hazard ratio (HR) was estimated using proportional hazard regression. Results: Immunohistochemical staining of ovarian cancer lesions with mAb showed a significantly higher frequency of HLA class I HC and β-m down-regulation in patients with worse prognosis (WP) than in those with better prognosis. In univariate analysis, both HLA class I HC down-regulation in ovarian cancer lesions and WP were associated with poor survival. In multivariate Cox-analysis, the WP group (all with an HLA-A02* genotype) had a significant higher HR to HLA class I HC down-regulation. Conclusions: HLA-A02* is a valuable prognostic biomarker in epithelial ovarian cancer. HLA class I HC loss and/or down-regulation was significantly more frequent in tumour tissues from HLA-A02* positive patients with serous adenocarcinoma surgical stage III-IV. In multivariate analysis, we show that the prognostic impact is reasonably correlated to the HLA genetic rather than to the expression of its protein products. [ABSTRACT FROM AUTHOR]

The peritoneal metastatic route of cancer dissemination is shared by cancers of the ovary and gastrointestinal tract. Once initiated, peritoneal metastasis typically proceeds rapidly in a feed-forward manner. Several factors contribute to this efficient progression. In peritoneal metastasis, cancer cells exfoliate into the peritoneal fluid and spread locally, transported by peritoneal fluid. Inflammatory cytokines released by tumor and immune cells compromise the protective, anti-adhesive mesothelial cell layer that lines the peritoneal cavity, exposing the underlying extracellular matrix to which cancer cells readily attach. The peritoneum is further rendered receptive to metastatic implantation and growth by myofibroblastic cell behaviors also stimulated by inflammatory cytokines. Individual cancer cells suspended in peritoneal fluid can aggregate to form multicellular spheroids. This cellular arrangement imparts resistance to anoikis, apoptosis, and chemotherapeutics. Emerging evidence indicates that compact spheroid formation is preferentially accomplished by cancer cells with high invasive capacity and contractile behaviors. This review focuses on the pathological alterations to the peritoneum and the properties of cancer cells that in combination drive peritoneal metastasis. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis which drives endothelial cell survival, proliferation, and migration while increasing vascular permeability. Playing an important role in the physiology of normal ovaries, VEGF has also been implicated in the pathogenesis of ovarian cancer. Essentially by promoting tumor angiogenesis and enhancing vascular permeability, VEGF contributes to the development of peritoneal carcinomatosis associated with malignant ascites formation, the characteristic feature of advanced ovarian cancer at diagnosis. In both experimental and clinical studies, VEGF levels have been inversely correlated with survival. Moreover, VEGF inhibition has been shown to inhibit tumor growth and ascites production and to suppress tumor invasion and metastasis. These findings have laid the basis for the clinical evaluation of agents targeting VEGF signaling pathway in patients with ovarian cancer. In this review, we will focus on VEGF involvement in the pathophysiology of ovarian cancer and its contribution to the disease progression and dissemination. [ABSTRACT FROM AUTHOR]

Depletion of cellular nicotinamide adenine dinucleotide (NAD) by inhibition of its synthesis is a new pharmacological principle for cancer treatment currently in early phases of clinical development. We present new and previously published data on the safety and efficacy of these drugs based on early clinical trials. A phase I clinical trial of CHS 828 in patients with advanced solid tumours was performed. Published clinical trials on NAD depleting drugs for cancer treatment were summarised for safety and efficacy. Seven patients with previously treated solid tumours received oral administration of CHS 828 in the dose range 20–80 mg once weekly for 3 weeks in 4 weeks cycles. Toxicity was dominated by gastrointestinal symptoms including nausea, vomiting, diarrhoea, constipation, subileus and gastric ulcer. One patient had thrombocytopenia grade 2. There were two cases each of grade 3–4 hyperuricemia and hypokalemia. Safety and efficacy of the NAD depleting drugs CHS 828 and FK866 have been reported from four phase I clinical trials, including a total of 97 patients with previously treated solid tumours. Outstanding toxicity reported was thrombocytopenia and various gastrointestinal symptoms. No objective tumour remission has been observed in the total of 104 patients treated in the above early trials. Critical toxicity from NAD depleting cancer drugs to consider in future trials seems to be thrombocytopenia and various gastrointestinal symptoms. Efficacy of NAD depleting drugs when used alone is expected to be low. [ABSTRACT FROM AUTHOR]

We have previously demonstrated an association of the human leukocyte antigen (HLA), HLA-A2 allele with ovarian and prostate cancer mortality as well as a segregation of the ancestral HLA haplotype (AHH) 62.1 [(A2) B15 Cw3 DRB1*04] in patients with stage III–IV serous ovarian cancer. The objective of the present study was to determine the role of the HLA phenotype on the prognosis in stage III–IV malignant melanoma patients. A cohort of metastatic malignant melanoma patients ( n = 91), in stage III ( n = 26) or IV ( n = 65) were analysed for HLA-A, -B, -Cw and -DRB1 types by PCR/sequence-specific primer method. The frequencies of HLA alleles in the patients were compared to that of healthy Swedish bone marrow donors. The effect of HLA types on prognosis was defined by Kaplan–Meier and Cox analysis. The presence of the AHH 62.1 in clinical stage IV patients was significantly and independently associated with the worst survival rate recorded from the appearance of metastasis (HR = 2.14; CI = 1.02–4.4; P = 0.04). In contrast, the period from the primary diagnosis to metastasis was the longest in patients with this haplotype (HR = 0.40; CI = 0.17–0.90; P = 0.02). Melanoma patients in our cohort with 62.1 AHH which is associated with autoimmune diseases have an initial strong anti-tumour control with longer metastasis-free period. These patients have rapid progression after the appearance of metastasis, responding poorly to chemo- or/and immunotherapy. This apparently paradoxical clinical process could be due to the interplay between tumour clones escape and immune surveillance ending up with a rapid disease progression. [ABSTRACT FROM AUTHOR]

Clevidipine (Cleviprex™), a late-generation dihydropyridine calcium channel antagonist available as a lipid emulsion for intravenous infusion, is approved in the US for the reduction of blood pressure (BP) when oral therapy is not feasible or desirable. Intravenous clevidipine is effective in the treatment of both acute preoperative and postoperative hypertension in adult cardiac surgery patients, and with a rapid onset and short duration of action the drug can be easily titrated for predictable BP control. Moreover, in terms of controlling acutely elevated BP in this patient population, clevidipine is more effective than sodium nitroprusside or nitroglycerin in the perioperative setting, and has an efficacy no different from that of nicardipine in the postoperative setting. Data from a noncomparative study also indicate that intravenous clevidipine is effective in the treatment of adults with acute severe hypertension. Clevidipine is generally well tolerated in these patient populations, and has a safety profile generally similar to that of sodium nitroprusside, nitroglycerin, or nicardipine in cardiac surgery patients. Additional comparative data are required to definitively position clevidipine with respect to other agents, particularly in patients with acute severe hypertension, and there is potential for its use to be investigated in other appropriate clinical settings requiring acute BP control. In the meantime, the clinical data currently available indicate that intravenous clevidipine has potential as an option for the treatment of acute perioperative hypertension during cardiac surgery and hypertensive emergencies in adults. [ABSTRACT FROM AUTHOR]

Retinoids have previously been reported to inhibit proliferation of melanoma cell lines in vitro. However, the relative antimetastatic efficacy of various retinoids on melanoma in vivo is unknown. Therefore, we investigated the effects of different retinoids on the invasion and metastasis of murine melanoma B16-F10 cells in vitro and in vivo. Based on the findings, the antitumor effects of a selected retinoid either alone or in combination with cisplatin were also investigated in a preclinical mouse melanoma model. Cell proliferation and invasion analyses of murine melanoma B16-F10 cells were assessed in the presence of different retinoids, either alone or in combination with cisplatin (CDDP) or 5-fluorouracil (5-FU). Experimental lung metastasis assay was performed in this study to investigate the antimetastatic efficacy of retinoids. Additionally, a mouse melanoma model was used to assess the antitumor efficacy of a selected retinoid in combination with cisplatin. Retinoids showed significant antiproliferation and anti-invasion effects on murine melanoma B16-F10 cells. Pretreatment with retinoids increased the sensitivity to CDDP but not to 5-FU in in-vitro. Moreover, the number of metastatic colonies formed in the lungs of mice injected intravenously with B16-F10 cells was significantly reduced by injecting the respective retinoid once a day for 10 days. Treatment with a combination of cisplatin and 13- cis-retinoic acid resulted in a significant reduction in primary tumor size and the number of lung metastatic nodules in melanoma-bearing mice. These results suggest that retinoids not only exhibit antimetastatic effect, but also enhance the antitumor activity of cisplatin in vivo. [ABSTRACT FROM AUTHOR]

Approximately 72 million people in the US experience hypertension. Worldwide, hypertension may affect as many as 1 billion people and be responsible for ≈7.1 million deaths per year. It is estimated that ≈1% of patients with hypertension will, at some point, develop a hypertensive crisis. Hypertensive crises are further defined as either hypertensive emergencies or urgencies, depending on the degree of blood pressure elevation and presence of end-organ damage. Immediate reduction in blood pressure is required only in patients with acute end-organ damage (i.e. hypertensive emergency) and requires treatment with a titratable, short-acting, intravenous antihypertensive agent, while severe hypertension without acute end-organ damage (i.e. hypertensive urgency) is usually treated with oral antihypertensive agents.The primary goal of intervention in a hypertensive crisis is to safely reduce blood pressure. The appropriate therapeutic approach of each patient will depend on their clinical presentation. Patients with hypertensive emergencies are best treated in an intensive care unit with titratable, intravenous, hypotensive agents. Rapid-acting intravenous antihypertensive agents are available, including labetalol, esmolol, fenoldopam, nicardipine and sodium nitroprusside. Newer agents, such as clevidipine and fenoldopam, may hold considerable advantages to other available agents in the management of hypertensive crises. Sodium nitroprusside is an extremely toxic drug and its use in the treatment of hypertensive emergencies should be avoided. Similarly, nifedipine, nitroglycerin and hydralazine should not to be considered first-line therapies in the management of hypertensive crises because these agents are associated with significant toxicities and/or adverse effects. [ABSTRACT FROM AUTHOR]