H. Kölbl

The Humoral Immune System Has a Key Prognostic Impact in Node-Negative Breast Cancer

Estrogen receptor (ER) expression and proliferative activity are established prognostic factors in breast cancer. In a search for additional prognostic motifs, we analyzed the gene expression patterns of 200 tumors of patients who were not treated by systemic therapy after surgery using a discovery approach. After performing hierarchical cluster analysis, we identified coregulated genes related to the biological process of proliferation, steroid hormone receptor expression, as well as B-cell and T-cell infiltration. We calculated metagenes as a surrogate for all genes contained within a particular cluster and visualized the relative expression in relation to time to metastasis with principal component analysis. Distinct patterns led to the hypothesis of a prognostic role of the immune system in tumors with high expression of proliferation-associated genes. In multivariate Cox regression analysis, the proliferation metagene showed a significant association with metastasis-free survival of the whole discovery cohort [hazard ratio (HR), 2.20; 95% confidence interval (95% CI), 1.40-3.46]. The B-cell metagene showed additional independent prognostic information in carcinomas with high proliferative activity (HR, 0.66; 95% CI, 0.46-0.97). A prognostic influence of the B-cell metagene was independently confirmed by multivariate analysis in a first validation cohort enriched for high-grade tumors (n = 286; HR, 0.78; 95% CI, 0.62-0.98) and a second validation cohort enriched for younger patients (n = 302; HR, 0.83; 95% CI, 0.7-0.97). Thus, we could show in three cohorts of untreated, node-negative breast cancer patients that the humoral immune system plays a pivotal role in metastasis-free survival of carcinomas of the breast.

Hyperemesis Gravidarum Associated With Helicobacter pylori Seropositivity

Objective To test the hypothesis that infection with Helicobacter pylori is associated with hyperemesis gravidarum. Methods From January 1995 to November 1996 we enrolled 105 patients with hyperemesis gravidarum in a prospective study. The Helicobacter serum Immunoglobulin (Ig) G concentrations in these patients were compared with those in asymptomatic gravidas matched for week of gestation. Results Positive serum IgG concentrations were found in 95 of the 105 hyperemesis patients (90.5%) compared with 60 of 129 controls (46.5%). A χ2 test showed statistical significance (P < .001). The mean (± standard deviation) index percentages of the IgG titers were 74.2 ± 23.6% in the hyperemesis group and 24.3 ± 4.4% in the control group (P < .01, Student t test). Conclusion Infection with H pylori may cause hyperemesis gravidarum.

Prognostic value of immunohistochemically detected CD44 isoforms CD44v5, CD44v6 and CD44v7–8 in human breast cancer

We investigated the expression of CD44 isoforms containing variant exons v5, v6 and v7-8 in 115 human breast cancer specimens by means of immunohistochemistry. CD44 isoforms CD44v5, CD44v6 and CD44v7-8 were detected in 56% (n = 64), 24% (n = 28) and 15% (n = 17), respectively. In 36 specimens of axillary lymph node metastasis, expression of CD44v5, CD44v6 and CD44v7-8 was found in 94% (n = 34), 92% (n = 33) and 89% (n = 32), respectively. Five year survival rates with or without CD44v5 and CD44v6 expression were 71% versus 86% (log-rank test, P = 0.02) and 62% versus 81% (log-rank test, P = 0.001), respectively. For disease-free survival, expression of CD44v5, CD44v6 and CD44v7-8 showed a prognostic impact (log-rank test, P = 0.004, P = 0.0001 and P = 0.0001, respectively). However, multivariate analysis revealed that all investigated CD44 isoforms failed to be independent predictors of the patients outcome.

Recommendations for the handling and oncologic pathology report of lymph node specimens submitted for evaluation of metastatic disease in gynecologic malignancies

ZusammenfassungDer Lymphknotenstatus ist einer der wichtigsten Prognosefaktoren bei gynäkologischen Malignomen und oft Grundlage für das Management von Patientinnen in der adjuvanten Situation. Die Zahl der entfernten Lymphknoten ist ein wesentlicher Parameter der operativen Radikalität und der Qualitätssicherung. In dieser Übersicht wird zur histopathologischen Aufarbeitung und Befundung von Lymphadenektomiepräparaten bei Karzinomen des weiblichen Genitaltrakts (ausgenommen Mammakarzinom) Stellung genommen. Im Besonderen wird eingegangen auf die Bearbeitung von Lymphknoten im Schnellschnitt sowie von Sentinel-Lymphknoten.Der Befundbericht sollte die Zahl der metastatisch befallenen, im Verhältnis zur Zahl der entfernten Lymphknoten, die Metastasengröße sowie eine eventuelle paranodale Infiltration beinhalten. Beim Nachweis von isolierten Tumorzellen und Mikrometastasen, insbesondere in Sentinel-Lymphknoten, sollte die Detektionsmethode genannt werden. Bei unbekannten Primärtumoren (sogenanntes CUP-Syndrom) sollte — ggf. nach immunhistochemischer Analyse — zum möglichen Primärtumor Stellung genommen werden.AbstractThe nodal status is one of the strongest prognostic factors in gynecologic malignancies. Metastatic involvement of regional and distant lymph nodes represents the selection basis for adjuvant therapy in a large number of solid neoplasms. The number of resected lymph nodes is one of the most important parameters in the quality control of the surgical procedure, in particular with respect to radicality. The present paper provides recommendations for gross dissection, laboratory procedures and reporting for lymph node biopsies, lymph node dissections and sentinel lymph node biopsies (SLN) for cancers of the vulva, vagina, uterine cervix, endometrium, Fallopian tubes and the ovaries, submitted for the evaluation of metastatic disease.The pathologic oncology report should include information about the number and size of resected lymph nodes, the number of involved lymph nodes with the maximum size of metastases and the presence of paranodal infiltration. In addition, the detection of isolated tumor cells should be reported, particularly with respect to the detection method (immunostains or molecular methods). In cases of metastatic disease and carcinoma of unknown primary (CUP-syndrome), information should be given regarding the primary tumor.

Serum proteome profiling of primary breast cancer indicates a specific biomarker profile

Non-invasive biomarkers for early breast cancer detection are urgently needed, as the risk of recurrent morbidity and mortality is closely related to the stage of the disease at the time of primary surgery. Currently, there are no established clinical biomarkers for breast cancer. Evaluation of protein expression patterns in body fluids using proteomic technologies can be used to discover new biomarkers for the detection of breast cancer. The aim of this study was to identify a biomarker signature identifying primary non-metastatic breast cancer and healthy controls. We screened 91 serum samples including 45 breast cancer patients and 46 healthy women using a proteomic approach. We found 14 biomarkers whose combination detects breast cancer patients from non-cancer controls with a sensitivity of 89% and specificity of 67%. Five biomarkers were comparable with previously identified proteins from published data using similar approaches. This biomarker panel allows accurate discrimination between breast cancer and healthy individuals. In addition, it could distinguish subgroups of breast cancer based on patterns of several specific biomarkers. Further validation of biomarkers could potentially facilitate the early diagnosis of breast cancer as an aid to imaging diagnostics.

IMMUNOHISTOCHEMICAL DIFFERENTIATION BETWEEN OVARIAN GRANULOSA CELL TUMORS AND OVARIAN CARCINOMAS

SummaryDifferential diagnosis is a major problem in histopathology of ovarian tumors. Difficulties may arise if the tumor is a poorly differentiated carcinoma or a granulosa cell tumor of the sarcomatoid type. It was the aim of the present study to evaluate the usefulness of immunohistochemistry in differentiating between granulosa cell tumors of the ovary and ovarian carcinomas. We investigated 56 ovarian malignancies (13 granulosa cell tumors, 17 serous, 14 mucinous and 12 poorly differentiated carcinomas) and performed immunohistochemical detection of Vimentin, Keratin, CA125, CA19-9, CEA, S100 and Ber-EP4. Expression of Vimentin was highest and expression of Keratin was lowest in granulosa cell tumors in contrast to carcinomas. CA125 and CA19-9 were not expressed in granulosa cell tumors, whereas the detection rate in carcinomas (except for CA125 in mucinous carcinomas) was high. CEA, S100 and Ber-EP4 do not seem to be useful markers in differential diagnosis. A marker profile of Vimentin, Keratin, CA125 and CA19-9 allows a quite strict differentiation between poorly differentiated ovarian carcinomas and granulosa cell tumors of the ovary.

Antibody microarray analysis of the serum proteome in primary breast cancer patients.

Noninvasive biomarkers are urgently needed for detecting breast cancer as early as possible since the risk of recurrence, morbidity, and mortality is closely related to disease stage at the time of primary surgery. There are currently no such biomarkers in clinical use as a diagnostic tool. Proteomic analysis of protein expression patterns in body fluids has potential for use in identifying biomarkers of breast cancer. The aim of this study was to compare protein expression levels in the sera of primary breast cancer patients and healthy controls. An antibody microarray tool with 23 antibodies immobilized on nitrocellulose slides was used to determine the levels of acute phase proteins, interleukins, and complement factors in the sera of 101 study participants (49 women with primary breast cancer and 52 healthy age-matched controls). Statistical analysis of reaction intensities identified 6 proteins that showed significantly (p < 0.05) different levels in breast cancer patients vs. healthy subjects. The neural network distinguished cancer patients from controls with a sensitivity of 69% and a specificity of 76%. Thus, antibody microarray analysis could be used as a tool for the development of improved diagnostics and biomarker discovery for breast cancer patients. Further validation of the results and de novo screening of new biomarkers could facilitate the early diagnosis of breast cancer.

Could we treat more unruptured ectopic pregnancies with intramuscular methotrexate

The main reason for the restricted use of methotrexate in the treatment of ectopic pregnancy (EP) obviously is the fear of tubal rupture in patients with lower abdominal pain after the administration of methotrexate. Therefore, we wanted to find out if patient characteristics at first presentation, such as age, pretreatment β-hCG level, adnexal mass as visualized by transvaginal ultrasonography, or history of prior EP, would identify patients at risk for tubal rupture if they were hemodynamically stable and showed no signs of peritoneal irritation. We examined whether more patients could have been treated medically with methotrexate, because tubal rupture was unforeseeable at first presentation and inclusion criteria for methotrexate treatment were fulfilled. From January 1996 to August 1998, 122 patients diagnosed as having EP were treated at the Gynecologic Department of the University Hospital of Vienna. Inclusion criteria for medical treatment with intramuscular methotrexate (50 mg/ m2 body surface area) were (1) hemodynamic stability, (2) an unruptured ectopic mass ≤5 cm at the greatest dimension demonstrated at transvaginal ultrasonography; (3) β-hCG level ≤5,000 mIU/ml; (4) no cardiac activity of the extrauterine embryo; (5) wish of future fertility, and (6) informed consent. Patients with hemodynamic instability, severe abdominal pain, an ectopic mass ≥5 cm at the greatest dimension, β-hCG levels ≥5,000 mIU/ml, cardiac activity of the extrauterine embryo, and no wish of future fertility, or disagreement with methotrexate treatment, primarily underwent surgery. Despite the fact that none of the above patient characteristics at first presentation identified patients at risk for tubal rupture, only 60/122 patients (49%) actually underwent medical treatment whereas our inclusion criteria would have granted medical treatment in 101/122 patients (83%). We determined the actual and maximal possible percentages of patients with unruptured EP eligible for medical treatment of EP with intramuscular single-dose methotrexate 50 mg/m2 body surface area. Our data show that tubal rupture in hemodynamically stable patients is not foreseeable and should not lead to a restricted use of medical treatment in patients preferring methotrexate.

CD44-Splice-Varianten als Prognosefaktoren beim invasiven Zervixkarzinom

Fragestellung: Eine aberrante Expression von spezifischen Isoformen (Splice-Varianten) des Adhasionsmolekuls CD44 wurde in verschiedenen malignen Tumoren des Menschen nachgewiesen. Wir wollten abklare

Pain perception during outpatient cystoscopy: a prospective controlled study

OBJECTIVE Rigid cystoscopy is a common diagnostic tool in the assessment of lower urinary tract symptoms, but it is an invasive procedure which can cause distress. Data exist about pain perception during cystoscopy in male patients but only a few data are available in women. The purpose of this study was to investigate pain perception in urogynecologic patients during cystoscopy and compare it with pain perception during urodynamics. We also investigated the difference between anticipated and actual pain perception. STUDY DESIGN A cooperative, non-randomized cohort study was performed including 109 women with pelvic floor dysfunction scheduled for outpatient cystoscopy or urodynamic testing. Patients completed a questionnaire and a visual analog scale (VAS, 0-10 cm) before and after examination. Patients were called one day after examination and asked about pain and their general state of health. According to power calculation, a sample size of 52 patients per group was needed to detect a 2 cm difference in pain scores on the VAS - judged as a clinically significant - with 95% power and a two-sided significance level of 0.05. RESULTS In 57 patients undergoing cystoscopy versus 52 patients undergoing urodynamics, the main pain scores on VAS were 1.9 cm for cystoscopy and 1.2 cm for urodynamics (p=0.03). Patients in both groups anticipated more pain than they actually experienced: 2.7±2.4 before versus 1.9±1.8 after cystoscopy (p<0.01) and 2.1±2.4 before versus 1.2±1.6 after urodynamics (p<0.01). CONCLUSION Patients experience cystoscopy as more painful than urodynamics. Patients anticipate both cystoscopy and urodynamics to be more painful than they actually are.