Anne Kirstine Møller

18F-FDG PET/CT as a Diagnostic Tool in Patients with Extracervical Carcinoma of Unknown Primary Site: A Literature Review

BACKGROUNDnCarcinoma of unknown primary (CUP) represents a heterogeneous group of metastatic malignancies for which no primary tumor site can be identified after extensive diagnostic workup. Failure to identify the primary site may negatively influence patient management. The aim of this review was to evaluate (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) as a diagnostic tool in patients with extracervical CUP.nnnMATERIALS AND METHODSnA comprehensive literature search was performed and four publications were identified (involving 152 patients) evaluating (18)F-FDG PET/CT in CUP patients with extracervical metastases. All studies were retrospective and heterogeneous in inclusion criteria, study design, and diagnostic workup prior to (18)F-FDG PET/CT.nnnRESULTSn(18)F-FDG PET/CT detected the primary tumor in 39.5% of patients with extracervical CUP. The lung was the most commonly detected primary tumor site (∼50%). The pooled estimates of sensitivity, specificity, and accuracy of (18)F-FDG PET/CT in the detection of the primary tumor site were 87%, 88%, and 87.5%, respectively.nnnCONCLUSIONSnThe present review of currently available data indicates that (18)F-FDG PET/CT might contribute to the identification of the primary tumor site in extracervical CUP. However, prospective studies with more uniform inclusion criteria are required to evaluate the exact value of this diagnostic tool.

Efficient Identification of miRNAs for Classification of Tumor Origin

Carcinomas of unknown primary origin constitute 3% to 5% of all newly diagnosed metastatic cancers, with the primary source difficult to classify with current histological methods. Effective cancer treatment depends on early and accurate identification of the tumor; patients with metastases of unknown origin have poor prognosis and short survival. Because miRNA expression is highly tissue specific, the miRNA profile of a metastasis may be used to identify its origin. We therefore evaluated the potential of miRNA profiling to identify the primary tumor of known metastases. Two hundred eight formalin-fixed, paraffin-embedded samples, representing 15 different histologies, were profiled on a locked nucleic acid-enhanced microarray platform, which allows for highly sensitive and specific detection of miRNA. On the basis of these data, we developed and cross-validated a novel classification algorithm, least absolute shrinkage and selection operator, which had an overall accuracy of 85% (CI, 79%-89%). When the classifier was applied on an independent test set of 48 metastases, the primary site was correctly identified in 42 cases (88% accuracy; CI, 75%-94%). Our findings suggest that miRNA expression profiling on paraffin tissue can efficiently predict the primary origin of a tumor and may provide pathologists with a molecular diagnostic tool that can improve their capability to correctly identify the origin of hitherto unidentifiable metastatic tumors and, eventually, enable tailored therapy.

Paclitaxel, cisplatin and gemcitabine in treatment of carcinomas of unknown primary site, a phase II study

Abstract Background. The present study was conducted to evaluate the efficacy and toxicity of a combination of paclitaxel, cisplatin and gemcitabine in patients with carcinoma of unknown primary site (CUP). Patients and methods. Patients with CUP, ECOG performance status 0–1 and age between 18 and 65 years old were treated with paclitaxel 175 mg/m2 day 1, cisplatin 75 mg/m2 day 1 and gemcitabine 1000 mg/m2 day 1 and 8 in a three-week schedule. Results. Ninety-eight patients were enrolled between 1998 and 2008. Ninety-one patients had target lesions according to the RECIST guidelines. The overall response rate was 42.9% (39 patients), including five complete responses (5.5%) and 34 partial responses (37.4%). The median survival time was 10.7 months, and the survival rates at one and two years were 42% and 14%, respectively. The most frequent grade 3 or more adverse events were neutropenia and thrombocytopenia. There were 3 treatment-related deaths. Conclusions. Combination of paclitaxel, cisplatin and gemcitabine is an active regimen in patients with CUP with response and survival rates at least similar to other platinum- and taxane-containing regimens. The treatment was well tolerated by most patients although neutropenia and thrombocytopenia were relatively common. The present regimen represents an attractive regimen in younger CUP patients with a good performance status.

Capecitabine and oxaliplatin as second-line treatment in patients with carcinoma of unknown primary site

Abstract Background. Treatment of patients with carcinoma of unknown primary site (CUP) remains a challenge, and no effective second-line treatment has been identified. In CUP patients who are non-responsive or relapse early after first-line platinum/taxane-based regimens, it is likely that gastrointestinal (GI) tract tumours may be overrepresented. These patients could be candidates for GI tract-directed therapy. We here report the results obtained with oxaliplatin and capecitabine as second-line therapy in 25 recurrent/refractory CUP patients following first-line treatment with paclitaxel, cisplatin and gemcitabine. Patients and methods. Patients received capecitabine orally (1000 mg/m2) twice daily, days 1–14, and oxaliplatin (130 mg/m2) intravenously on day 1 in a three-week schedule. Results. Twenty-five CUP patients received a median of three cycles of capecitabine and oxaliplatin as second-line treatment. Histopathological assessments suggested the primary site to be of GI tract origin in the majority of the patients (76%). We found an objective response rate of 13%, a median progression-free survival and overall survival rate of 2.3 and 3.9 months, respectively, and 32% of patients alive at one year after initiation of second-line therapy. The regimen was well tolerated by most patients. Conclusions. This study, demonstrates that there is still a significant need for improved second-line therapy in CUP patients.

Comparison of a gene expression profiling strategy to standard clinical work-up for determination of tumour origin in cancer of unknown primary (CUP)

Abstract CupPrint® is a genomic signature able to identify 47 different cancer types. The aim of our study was to compare the accuracy of this genomic signature to that of a full clinical work-up in diagnosing the primary tumour site. Patients with newly diagnosed, untreated metastatic tumours were eligible for this trial. The clinical work-up and gene expression profiling on a biopsy from a metastatic site were started at the same time. The study was planned using a one-stage Fleming design. Patients in whom no primary site was diagnosed by the clinical work-up were excluded. Out of the 67 patients registered, the primary site was identified by clinical work-up in 36 patients, and diagnosis with CupPrint was obtained in 53. There were 31 evaluable patients with both clinical and CupPrint diagnoses, and out of these a similar diagnosis was obtained in 11 patients, i.e. the concordance rate was 35% (95% confidence interval: 19–55%). The median time to diagnosis through the clinical work-up was 48 days, and 10 days with CupPrint (P<0·001). We concluded that in patients with newly diagnosed metastatic tumours, CupPrint has low accuracy in diagnosing the primary cancer site.

Development and validation of a microRNA based diagnostic assay for primary tumor site classification of liver core biopsies

Identification of the primary tumor site in patients with metastatic cancer is clinically important, but remains a challenge. Hence, efforts have been made towards establishing new diagnostic tools. Molecular profiling is a promising diagnostic approach, but tissue heterogeneity and inadequacy may negatively affect the accuracy and usability of molecular classifiers. We have developed and validated a microRNA‐based classifier, which predicts the primary tumor site of liver biopsies, containing a limited number of tumor cells. Concurrently we explored the influence of surrounding normal tissue on classification. MicroRNA profiling was performed using quantitative Real‐Time PCR on formalin‐fixed paraffin‐embedded samples. 278 primary tumors and liver metastases, representing nine primary tumor classes, as well as normal liver samples were used as a training set. A statistical model was applied to adjust for normal liver tissue contamination. Performance was estimated by cross‐validation, followed by independent validation on 55 liver core biopsies with a tumor content as low as 10%. A microRNA classifier developed, using the statistical contamination model, showed an overall classification accuracy of 74.5% upon independent validation. Two‐thirds of the samples were classified with high‐confidence, with an accuracy of 92% on high‐confidence predictions. A classifier trained without adjusting for liver tissue contamination, showed a classification accuracy of 38.2%. Our results indicate that surrounding normal tissue from the biopsy site may critically influence molecular classification. A significant improvement in classification accuracy was obtained when the influence of normal tissue was limited by application of a statistical contamination model.

Variations in Oncology Consultations: How Dictation Allows Variations to be Documented in Standardized Ways

In-between 2016 and 2017 a new hospital information system (HIS) was introduced at several hospitals in Denmark radically changing the core work practices for a majority of the healthcare professionals. Promptly, the new HIS began to receive criticism from healthcare professionals for failing to live up to proclaimed expectations. To fully understand the problems experienced by the healthcare professionals we need to understand the fundamental nature of the work prior to the implementation. In this paper, we investigate patient consultations as they were performed prior to the implementation of the HIS at an oncology department. Reporting from a 1.5xa0year-long study, we find patient consultations were organized in three sequential activities: review, interaction, and documentation. Further, we find that the dictaphone served as a key artifact allowing physicians to enact flexibility in documentation while simultaneously providing them with the capability to communicate and coordinate with the medical secretaries. Our empirical findings suggest that the medical secretaries are critical for structured documentation of variations in health data and are the cornerstones that allow physicians to enact sentimental efforts when interacting with patients. These insights prove important in understanding the criticism aimed at the new HIS implementation since the implementation removed the dictaphone as a key artifact and instead introduced a new organizational structure where documentation was assumed accomplished in parallel with patient interaction. The transformation consequently shifted work, previously performed by the medical secretaries, to the physicians.

Abstract LB-357: Efficient identification of tumor of unknown primary origin by its microRNA profile

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DCnnBackground: Carcinomas of unknown primary origin (CUP) constitute 3-5% of all newly diagnosed metastatic cancers, the primary source of which is hard to classify with current histological methods, often because CUPs are poorly differentiated. Since effective cancer treatment depends on early and proper identification of the tumor, CUP patients have poor prognosis and short survival rates. Increasing evidence suggests that microRNAs play an important role in the initiation and progression of cancer, and because the expression of microRNAs is highly tissue specific, the microRNA profile of an unknown tumor can be used to identify its tissue of origin. Here, we present a microRNA based classifier, which based on a samples microRNA profile, can predict its tissue origin with high accuracy.nnMethods: Total RNA was extracted from 1115 formalin fixed paraffin embedded (FFPE) samples, and subjected to expression analysis on an LNA (Locked Nucleic Acid) enhanced microarray platform, which allows for very sensitive and specific detection of 2090 microRNAs. Based on the microRNA expression profiles, we tested and cross-validated several classification algorithms, including KNN (K nearest neighbors), LDA (linear discriminant analysis), SVM (support vector machines) and LASSO (least absolute shrinkage and selection operator) to assess, which method is best suited for the current multiclass classification task.nnResults: The currently best classifier for tumors of unknown primary origin is based on the LASSO algorithm, which consistently is able to identify 15 different tumor histologies with 90% or higher accuracy based on a small set of microRNAs. We are currently assessing the classifiers performance on true unknown primary tumors, where the correct diagnosis has been obtained at autopsy.nnCitation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-357.