Malnutrition and clinical outcome in gynecologic patients.

OBJECTIVES: An association between malnutrition and poor patient outcome has been established in various medical fields, but there is a general lack of data on the prevalence of malnutrition among gynecologic patients. Therefore an assessment of malnutrition is needed to detect malnourished patients in gynecology and initiate nutritional therapy if needed. STUDY DESIGN: Between 2011 and 2012 at our Gynecologic Department of a German University Hospital, 397 patients were evaluated regarding the risk of malnutrition and occurrence of complications during the time of hospitalization. The Nutritional Risk Screening (NRS) 2002 system was used to estimate the risk level for malnutrition. Of the 397 patients, 336 received surgery and 61 were treated conservatively. Patients were included independently of surgical intervention or age. The parameters for the clinical outcome were complications and time of hospitalization. RESULTS: A severe risk of malnutrition was diagnosed in 142 patients (35.8%) according to an NRS score of ≥3. Furthermore, a significantly higher complication rate among those patients who were at risk for malnutrition (NRS 1-2) (7.8%) or who were malnourished (NRS ≥3) (22.8%) was found (p<0.001 χ(2)). Regarding the length of stay (LOS) in hospital, the medial hospitalization time increased from 7 to 10 days when patients were malnourished (NRS score ≥3) (p<0.001). CONCLUSIONS: Malnutrition occurs frequently among gynecologic patients. Adequate perioperative nutritional supportive therapy should be considered in malnourished patients to improve their clinical outcome.

Human epididymis protein 4 (HE4) in benign and malignant diseases.

BACKGROUND: Human epididymis protein 4 (HE4) is described as a useful new biomarker in ovarian cancer. As HE4 is neither tumor nor organ specific, we intensively investigated the occurrence of this protein in female and male patients with various benign and malignant diseases in order to avoid misinterpretation and to identify potential additional clinical relevance. METHODS: We retrospectively investigated HE4(ARCHITECT R , Abbott Diagnostics, US) in the sera of 205 healthy individuals, 654 patients with benign disorders and 720 patients with cancer before initial treatment. RESULTS: The lowest concentrations of HE4 were observed in healthy men (median 26.2 pmol/L) followed by healthy women (median 40.4 pmol/L). In benign diseases, highest HE4 concentrations were seen in both women and men with renal failure (women, median 1041 pmol/L; men, median 1368pmol/L). In women, the highest HE4 levels in malignant diseases were observed in ovarian cancer (median 242 pmol/l),whereas the highest HE4 concentrations in men occurred in lung cancer (median 89.2 pmol/L). The area under the curve(AUC) of HE4 in women was highest in ovarian cancer and borderline tumors as compared to benign gynecological disorders(88.9 % ), with a sensitivity of 67.4 % at 95 % specificity.Also, significantly elevated concentrations of HE4 with reference to the respective group of benign diseases were observed in uterus corpus and breast cancer as well as in lung cancer for men and women. CONCLUSIONS: HE4 has the highest relevance in ovarian cancer but can be elevated in a variety of benign and malignant diseases.

The diagnostic accuracy of two human epididymis protein 4 (HE4) testing systems in combination with CA125 in the differential diagnosis of ovarian masses.

BACKGROUND: Cancer antigen 125 (CA125) is the best known single tumor marker for ovarian cancer (OC). We investigated whether the additional information of the human epididymis protein 4 (HE4) improves diagnostic accuracy. METHODS: We retrospectively analyzed preoperative sera of 109 healthy women, 285 patients with benign ovarian masses (cystadenoma: n=78, leimyoma: n=66, endometriosis: n=52, functional ovarian cysts: n=79, other: n=10), 16 low malignant potential (LMP) ovarian tumors and 125 OC (stage I: 22, II: 15, III: 78, IV: 10). CA125 was analyzed using the ARCHITECT system, HE4 using the ARCHITECT(a) system and EIA(e) technology additionally. RESULTS: The lowest concentrations of CA125 and HE4 were observed in healthy individuals, followed by patients with benign adnexal masses and patients with LMP tumors and OC. The area under the curve (AUC) for the differential diagnosis of adnexal masses of CA125 alone was not significantly different to HE4 alone in premenopausal (CA125: 86.7, HE4(a): 82.6, HE4(e): 81.6% p>0.05) but significantly different in postmenopausal [CA125: 93.4 vs. HE4(a): 88.3 p=0.023 and vs. HE4(e): 87.8% p=0.012] patients. For stage I OC, HE4 as a single marker was superior to CA125, which was the best single marker in stage II-IV. The combination of CA125 and HE4 using risk of malignancy algorithm (ROMA) gained the highest sensitivity at 95% specificity for the differential diagnosis of adnexal masses [CA125: 70.9, HE4(a): 67.4, HE4(e): 66.0, ROMA(a): 76.6 and ROMA(e): 74.5%], especially in stage I OC [CA125: 27.3, HE4(a): 40.9, HE4(e): 40.9, ROMA(a): 45.5 and ROMA(e): 45.5%]. CONCLUSIONS: CA125 is still the best single marker in the diagnosis of OC. HE4 alone and even more the combined analysis of CA125 and HE4 using ROMA improve the diagnostic accuracy of adnexal masses, especially in early OC.

Cetuximab monotherapy in advanced cervical cancer: a retrospective study with five patients.

OBJECTIVE: Effective cytotoxic treatment options for advanced cervical cancer are exceedingly limited. Therefore, interest has increased in targeted therapeutics for the treatment of cervical cancer. Cetuximab, a monoclonal antibody, binds specifically to the epidermal growth factor receptor (EGFR) and competitively inhibits the binding of epidermal growth factor and other ligands. In cervical cancer the expression of EGFR is reported in up to 85% of the tumour cells. Therefore, Cetuximab monotherapy could be a new option in the treatment of patients with advanced cervical cancer. STUDY DESIGN: Five patients with advanced cervical cancer were treated with Cetuximab monotherapy as third- to fifth-line therapy between 2005 and 2008 in our institution. The tumour stage at the time of diagnosis ranged between IIB and IVB. Cetuximab was applied with an initial loading dose of 400 mg/m(2) followed by a dose of 250 mg/m(2) weekly. RESULTS: Only one patient (20%) had a stable disease, and the other four a progressive disease during Cetuximab monotherapy, after the RECIST criteria. Four out of five patients (80%) developed an acneiform rash as a common observed side effect of Cetuximab therapy. The median survival time from the beginning of the Cetuximab therapy was 8.6 months. CONCLUSION: No advantage could be found in the treatment with Cetuximab monotherapy in patients with advanced cervical cancer in this study. Further studies are necessary to evaluate the significance of Cetuximab in the treatment of advanced cervical cancer.

Predictive value of CA 125 and CA 72-4 in ovarian borderline tumors.

BACKGROUND: The aim of this study was to assess the prognostic value of cancer antigen (CA) 125 and CA 72-4 in patients with ovarian borderline tumor (BOT). METHODS: All women diagnosed and treated for BOT at our institution between 1981 and 2008 were included into this retrospective study (n=101). Preoperatively collected serum samples were analyzed for CA 125 (Architect, Abbott and Elecsys, Roche) and CA 72-4 (Elecsys, Roche) with reference to clinical data and compared to healthy women (n=109) and ovarian cancer patients (n=130). RESULTS: With a median of 34.7 U/mL (range 18.1-385.0 U/mL) for CA 125 and 2.3 U/mL (range 0.2-277.0 U/mL) for CA 72-4, serum tumor markers in BOT patients were significantly elevated as compared to healthy women with a median CA 125 of 13.5 U/mL (range 4.0-49.7 U/mL) and median CA 72-4 of 0.8 U/mL (range 0.2-20.6 U/mL). In addition, there was a significant difference compared with ovarian cancer patients who showed a median CA 125 of 401.5 U/mL (range 12.5-35,813 U/mL), but no difference was observed for CA 72-4 (median 3.9 U/mL, range 0.3-10,068 U/mL). Patients with a pT1a tumor stage had significantly lower values of CA 125 but not of CA 72-4 compared with individuals with higher tumor stages (median CA 125 29.9 U/mL for pT1a vs. 50.9 U/mL for >pT1a; p=0.014). There was a trend for increased concentrations of CA 125 but not of CA 72-4 in the presence of ascites, endometriosis or peritoneal implants at primary diagnosis. With respect to the prognostic value of CA 125 or CA 72-4, CA 125 was significantly higher at primary diagnosis in patients who later developed recurrence (251.0 U/mL vs. 34.65 U/mL, p=0.012). CONCLUSIONS: Serum CA 125 and CA 72-4 concentrations in BOT patients differ from healthy controls and patients with ovarian cancer. CA 125, but not CA 72-4, at primary diagnosis correlates with tumor stage and tends to be increased in the presence of ascites, endometriosis or peritoneal implants. Moreover, CA 125 at primary diagnosis appears to have prognostic value for recurrence.

Inhibition of intraperitoneal tumor growth of human ovarian cancer cells by bi- and trifunctional inhibitors of tumor-associated proteolytic systems.

Several proteolytic systems are involved in (anti)adhesive, migratory, and proteolytic processes, necessary for tumor progression and metastasis. We analyzed whether multifunctional inhibitors of different tumor-associated proteolytic systems reduce tumor growth and spread of human ovarian cancer cells in vivo. Bifunctional inhibitors are composed of the N-terminal domain of either the human matrix metalloproteinase inhibitors TIMP-1 or TIMP-3 and the cysteine protease inhibitor chicken cystatin (chCysWT); trifunctional inhibitors are composed of N-TIMP-1 or -3 and a chicken cystatin variant harboring the uPAR binding site of uPA, chCys-uPA19-31, which in addition to its inhibitory activity toward cysteine proteases interferes with the interaction of the serine protease uPA with its receptor. OV-MZ-6#8 cancer cells, stably transfected with plasmids expressing the multifunctional inhibitors, displayed similar proliferative and adhesive features as the vector-transfected control, but showed significant reduction in their invasive behavior in vitro. The cell lines expressing the multifunctional inhibitors were inoculated into the peritoneum of nude mice. Expression of three of the four inhibitor variants (N-hTIMP-1-chCysWT, N-hTIMP-1-chCys-uPA19-31, and N-hTIMP-3-chCysWT) resulted in a significant reduction of tumor burden compared to the vector-control cell line. These compact and small inhibitors may represent promising agents for gene therapy of solid malignant tumors.

Soluble tissue actor interferes with angiostatin-mediated inhibition of endothelial cell proliferation by lysine-specific interaction with plasminogen kringle domains.

Experimental and clinical data suggest that tissue factor (TF), the major initiator of blood coagulation cascade, as well as proteases and components of the fibrinolytic system are involved in tumor growth at least in some solid tumors via effects on angiogenesis. Whereas the pro- and anti-angiogenic effects of the plasminogen/plasmin system and plasminogen kringle domains, respectively, are well characterized, the pathways responsible for the pro-angiogenic properties of TF remain poorly understood. To learn more about the biological significance of the recently described binding of plasminogen to the extracellular domain of TF, we examined the effects of soluble TF (sTF) on angiostatin-inhibited proliferation of endothelial cells. In solid phase binding assays, we found that sTF binds specifically to plasminogen, to the plasminogen kringle domains K1-3, K1-5, K4, as well as to mini-plasminogen. Inhibition of binding of plasminogen and its kringle domains to sTF by the lysine analog 6-aminohexanoic acid (AHA) suggests that lysine-binding sites are involved in plasminogen interaction with TF. Moreover, in the presence of sTF, the inhibitory effect of K1-5 on bFGF-mediated HUVEC proliferation was dose-dependently and saturably abolished. This suggests that TF can interfere with the antagonistic effect of K1-5 on endothelial cell proliferation. In contrast, sTF by itself had no effect on the endothelial cell proliferation. Whereas the interference of TF with K1-5-mediated effect was prevented by AHA, this lysine analog did not abolish the proliferation inhibition of K1-5. In conclusion, the binding of sTF to the plasminogen fragment K1-5 seems to antagonize the anti-angiogenic effects of this plasminogen fragment.