Prediction of clinical response to drugs in ovarian cancer using the chemotherapy resistance test (CTR-test)

Background In order to validate if the test result of the Chemotherapy Resistance Test (CTR-Test) is able to predict the resistances or sensitivities of tumors in ovarian cancer patients to drugs, the CTR-Test result and the corresponding clinical response of individual patients were correlated retrospectively. Results were compared to previous recorded correlations. Methods The CTR-Test was performed on tumor samples from 52 ovarian cancer patients for specific chemotherapeutic drugs. Patients were treated with monotherapies or drug combinations. Resistances were classified as extreme (ER), medium (MR) or slight (SR) resistance in the CTR-Test. Combination treatment resistances were transformed by a scoring system into these classifications. Results Accurate sensitivity prediction was accomplished in 79% of the cases and accurate prediction of resistance in 100% of the cases in the total data set. The data set of single agent treatment and drug combination treatment were analyzed individually. Single agent treatment lead to an accurate sensitivity in 44% of the cases and the drug combination to 95% accuracy. The detection of resistances was in both cases to 100% correct. ROC curve analysis indicates that the CTR-Test result correlates with the clinical response, at least for the combination chemotherapy. Those values are similar or better than the values from a publication from 1990. Conclusions Chemotherapy resistance testing in vitro via the CTR-Test is able to accurately detect resistances in ovarian cancer patients. These numbers confirm and even exceed results published in 1990. Better sensitivity detection might be caused by a higher percentage of drug combinations tested in 2012 compared to 1990. Our study confirms the functionality of the CTR-Test to plan an efficient chemotherapeutic treatment for ovarian cancer patients

Inflammatory bowel disease (IBD)-like disease in a case of a 33-year old man with glycogenosis 1b

Background Inflammatory bowel disease (IBD)-like conditions in glycogen storage disease (GSD) type Ib have been predominantly described in children. Signs and symptoms of GSD type Ib are hypoglycemia, pancytopenia and hepatosplenomegaly. Based on few published cases, there is evidence that granulocyte-colony stimulating factor (G-CSF) in patients with glycogenosis–related pancytopenia might ameliorate the IBD-like disease through leukocyte increase. Case presentation Here we firstly describe a case of an adult 33-year-old Caucasian male patient with GSD type Ib accompanied with IBD-like disease with persistent pancytopenia despite moderate-dose G-CSF treatment. Recent vomiting and abdominal discomfort were due to a high-grade stenosis in the transverse colon. A dose increase of the G-CSF successfully normalized his leukocyte count. However, the stenosis worsened and surgical therapy was needed. Conclusion We suggest that symptomatic patients with GSD type Ib should undergo endoscopic examination in order to detect IBD-like disease and to initiate early treatment

The role of human epididymis protein 4 (HE4) in borderline tumors of the ovary (BOT) and in relapsed epithelial ovarian cancer (EOC)

Einleitung: Humanes Epididymis Protein 4 (HE4) ist ein sekretorisches Glykoprotein, was in serösen epithelialen Ovarialkarzinomen (EOC) überexprimiert wird. HE4 hat im Vergleich zum etablierten Cancer Antigen 125 (CA125) eine höhere Sensitivität und Spezifität bezüglich der Erkennung eines EOC und bezüglich der Unterscheidung benigner und maligner ovarieller Raum- forderungen (RF) eine höhere Spezifität. Ferner gibt es Hinweise, dass low- grade-EOC aus serösen Borderline-Tumoren des Ovars (BOT) entstehen. Diese Erkenntnisse führten dazu, die Korrelation der HE4-Gewebeexpression mit klinisch-pathologischen Para¬metern bei BOT ohne invasive Implantate (non-inv BOT) sowie die Rolle von HE4 in der prä¬operativen Unterscheidung benigner versus maligner RF und zur Vorhersage von BOT mit in¬vasiven Implantaten (inv BOT) zu untersuchen. Zudem untersuchten wir den Stellenwert von HE4 in der ersten Rezidivsituation bei EOC-Patientinnen. Methodik: Es wurden klinisch- patho¬logische Daten, Gewebe- und Blutproben innerhalb des Projektes „Tumor Bank Ovarian Cancer“ gesammelt. Die HE4-Gewebeexpression wurde anhand von gruppierten Immunoreak¬tivitätsscore (IRS) mit klinisch-pathologischen Parametern korreliert. Anhand von Receiver-Operating Charac¬teristics (ROC)-Kurvenanalysen wurde die Vorhersagekraft von im Serum bestimmten HE4, CA125 und dem Risk of Ovarian Malignancy Algorithm (ROMA) bezüglich der Unterscheidungs¬fähigkeit von non-inv BOT oder benignen RF zu inv BOT ermittelt. Im dritten Teil wurden Assoziationen zwischen HE4-Konzentrationen und klinisch-pathologischen Parametern unter¬sucht und anhand von Kaplan- Meier-Kurven Überlebenszeitraten sowie die jeweiligen 95%-Konfidenzintervalle geschätzt. Ergebnisse: Bei den 25 untersuchten BOT-Patientinnen ergaben sich zwischen grup¬pierten IRS und histologischem Subtyp, Alter, CA125-Konzentration und FIGO-Stadium keine signifikanten Korrelationen. In der zweiten Studie hatten von 167 Patientinnen 15 inv BOT, 104 benigne RF und 48 non-inv BOT. CA125 war HE4 und ROMA bezüglich der Unterscheidungs¬fähigkeit von inv BOT zu benignen RF und non-inv BOT überlegen. Im dritten Teil wurden 73 Patientinnen mit erstem EOC-Rezidiv eingeschlossen. Bei einem HE4-Cut-Off- Wert von 250 pmol/L konnte mit einer Sensitivität von 52% und einer Spezifität von 93,8% (p=0,001) eine totale makroskopische Tumorfreiheit für die erste Rezidivoperation hervorgesagt werden. Die HE4-Konzentration war ein unabhängiger pro¬gnostischen Faktor für das Gesamtüberleben (OS) (p<0,001) und prädiktiv für das chirurgische Outcome (p=0,036). Schlussfolgerung: Die Rolle von HE4 bei BOT bleibt weiterhin unklar. Allerdings scheinen sowohl HE4 als auch CA125 keine verlässlichen Biomarker für die Vor-hersage von inv BOT zu sein. Aufgrund niedriger Fall¬zahlen sind zukünftig prospektive multizentrische Studien notwendig. Bezüglich der ersten Rezidiv¬situation beim EOC konnte erstmalig gezeigt werden, dass HE4 ein unabhängiger prognostischer bzw. prädiktiver Marker für das OS und das chirurgische Outcome ist.Introduction: Human Epididymis Protein 4 (HE4) is a secretory glycoprotein which is over-expressed in serous epithelial ovarian cancer (EOC). HE4 offers a higher sensitivity and speci¬ficity in the prediction of EOC and a higher specificity in the differentiation between benign and malignant ovarian masses compared to the established Cancer Antigen 125 (CA125). Further¬more, it is suggested that low-grade EOC derive from serous borderline tumors of the ovary (BOT). These findings prompted us to investigate the correlation of HE4 tissue expression and clinical-pathological parameters of BOT without invasive implants (non-inv BOT), to ana¬lyze the role of preoperative HE4 in discriminating benign versus malignant masses and in pre¬dicting the presence of BOT with invasive implants (inv BOT). Furthermore, we investigated the role of HE4 in EOC patients with first relapse. Methods: Clinical-pathological data, tissue and blood samples were collected within the project „Tumor Bank Ovarian Cancer“. HE4 tissue expres¬sion was correlated with clinical- pathological parameters using grouped immuoreactivity scores (IRS). Receiver- Operating Characteristics (ROC) curve analysis was performed to eva¬luate the predictive accuracy of HE4, CA125 and the Risk of Ovarian Malignancy Algorithm (ROMA) for discriminating patients with non-inv BOT or benign masses from inv BOT. In the third study, associations between HE4 blood levels and clinical- pathological parameters were investigated. Survival and 95% confidence intervals rates were estimated according to Kaplan-Meier curves. Results: Among the 25 BOT patients no signi¬ficant correlations between grouped IRS and histological subtype, age, CA125 levels and FIGO stage were found. In the second study, out of 167 patients 104 had benign masses, 48 had non-inv BOT and 15 had inv BOT. CA125 was superior to HE4 and ROMA in discriminating inv BOT from patients with benign masses and non-inv BOT. In the third study, 73 patients with first relapse were included. At a HE4 cut-off value of 250 picomol/L, a sensitivity of 52% and a specificity of 93.8% (p=0.001) were reached in predicting total macroscopic tumor clearance. HE4 concentration was an inde¬pendent prognostic and predictive factor for overall survival (OS) (p<0.001) and surgical out¬come (p=0.036), respectively. Conclusion: The role of HE4 in BOT remains unclear. Both HE4 and CA125 are not reliable biomarkers for the prediction of inv BOT. Due to the low number of cases prospective multicentric studies are needed. Regarding patients with a first EOC relapse, we could show that HE4 is an independent prognostic and predictive marker for OS and surgical outcome, respectively

Preoperative HE4 and ROMA values do not improve the CA125 diagnostic value for borderline tumors of the ovary (BOT) - a study of the TOC Consortium

BACKGROUND: Borderline tumors of the ovary (BOT) are a distinct entity of ovarian tumors, characterized by lack of stromal invasion. Recent studies postulated that the presence of invasive implants, incomplete staging, fertility sparing surgery and residual tumor after surgery are major prognostic factors for BOT. There are no biomarkers that can predict BOT or the presence of invasive implants. OBJECTIVE: The aim of our study was to assess the value of CA125 and HE4 alone, or within ROMA score for detecting BOT, and for predicting the presence of invasive implants. METHODS: Retrospective, monocentric study on 167 women diagnosed with BOT or benign ovarian masses. Serum HE4, CA125 levels and ROMA were assessed preoperatively. Due to low number of BOT with invasive implants, we performed an unmatched analysis (consecutive patients) and a matched analysis (according to age and histology) to compare BOT with invasive implants, BOT without invasive implants and benign disease. RESULTS: There were no significant differences in the HE4 and CA125 expressions in the three groups of patients (p = 0.984 and p = 0.141, respectively). The ROC analysis showed that CA125 alone is superior to ROMA and HE4 in discriminating patients with BOT with invasive implants from patients with benign diseases and BOT without invasive implants. A newly established score, ROMABOT, did not perform better than ROMA. The analysis of the matched groups revealed similar results as the analysis of all samples. CONCLUSIONS: Both HE4 and CA125 are not reliable biomarkers for the diagnosis of BOT or for predicting the presence of invasive implants

Frequency of Positive Familial Criteria in Patients with Adenocarcinoma of the Esophageal-Gastric Junction and Stomach: First Prospective Data in a Caucasian Cohort

Objectives: Current prospective studies investigating the frequency of hereditary criteria in a Caucasian population for adenocarcinoma of the esophagogastric junction (AEG) and stomach (GC) are missing. Genetic testing criteria (screening criteria) for hereditary diffuse gastric cancer (HDGC) were updated in 2020, but do not address patients with intestinal histology (familial intestinal gastric cancer FIGC). Thus, we prospectively screened patients residing in Berlin newly diagnosed with AEG or GC for hereditary criteria to gain insights into the frequency of HDGC. Methods: Prospective documentation of familial/clinical parameters in patients residing in Berlin with AEG or GC over three years was conducted. Besides HDGC criteria from 2015 and revised 2020, we also documented patients fulfilling these criteria but with intestinal type gastric cancer (FIGC). Statistical analysis was performed using X2-test. Results: One hundred fifty-three patients were finally included (92 GC; male: 50 (n.s.); 61 AEG; male: 47; p = 0.007). Hereditary criteria for HDGC were detected in 9/92 (9.8%) (2015 criteria) and in 14/92 (15.2%) (2020 criteria) of GC patients (AEG: 2015 criteria 3/61 (4.9%) versus 4/61 according to 2020 criteria (6.5%)). Patients fulfilling hereditary criteria but with intestinal histology (FIGC) increased from 8.7% (2015) to 14.1%, respectively (2020) (AEG: 3.2% (2015) versus 6.6% (2020)). Hereditary criteria including intestinal histology were found in 29.3% (GC) and 13.1% (AEG) (p = 0.03) according to the 2020 criteria. Conclusions: HDGC criteria were found in 15.2% of GC patients according to the 2020 criteria. Percentage increased to 29.3% including patients with intestinal histology among the GC group, and was 13.1% in cases with AEG. These data indicate that family history seems to be of utmost importance in GC to further detect potential hereditary genetic risks. This equally applies for patients with intestinal subtype GC

Role of IGF-I in Primary Ovarian Cancer - A Study of the OVCAD European Consortium

IGF-I (insulin growth factor 1) is crucially involved in cellular proliferation. Moreover, deregulation of IGF-I has been shown to be relevant in the carcinogenesis of various tumor entities. However, the impact of IGF-I in epithelial ovarian cancer (EOC) is unclear. In the present study, we investigated the predictive and prognostic role of circulatory IGF-I in primary EOC patients.status: publishe

Additional file 1: of Prediction of clinical response to drugs in ovarian cancer using the chemotherapy resistance test (CTR-test)

Percentage of viable cells and tumor cells. The percentage of viable cells and tumor cells of the different patient samples (Responder or Non-Responder for Monotherapy, Monotherapy plus Avastin or Combination Chemotherapy) is presented. (PDF 29 kb