Objective: The incidence rate and mortality of breast cancer are increasing in Taiwan during recent years. The incidence rate of breast cancer is ranked number one among top ten female cancers, and the mortality of breast cancer is ranked fourth among cause of death for female cancer sufferers. The most common age group for breast cancer is between 40 and 50 years old. Breast cancer causes huge disease burdens for individual, family and society. The breast sonography and fine needle aspiration cytology (FNAC) are common screening methods for breast cancer diagnosis. Nevertheless, little study has focused on the benefits of combing these two methods in clinical application. This study aims to fill such research gap. Method: This study conducted medical chart reviews and collected 2,776 observations that were under breast sonography and FNAC examination from a regional hospital locates in southern Taiwan. The diagnosis categories for sonography include: malignant, benign, and probably benign tumor. The diagnosis categories for FNAC include: malignant, benign, and suspicious for malignant. Results: Among 2,776 observations, there were 555 observations (20%) had operation in the studied hospital. The operation results indicated that 205 (36.9%) observations were with malignant status, and 350 (63.1%) observations were with benign status. The diagnosis categories of both sonography and FNAC were significantly associated with the operation results (p<0.001). The FNAC had specificity in 100%, false positive ratio in zero, and positive predictive value in 100%. The Odds ratios for sonography diagnosis categories, age groups, and tumor sizes were OR=4.132 (95%CI: 1.5¡V11.6), OR=31.957 (95% CI: 3.7¡V272.4), OR=0.457 (95% CI: 0.1¡V1.5), respectively. When combining sonography and FNAC in parallel tests, the diagnosis accuracy was 89.2%, sensitivity was 90.2%, specificity was 88.6%, positive predictive value was 82.2%, and negative predictive value was 93.9%. When combining sonography and FNAC in serial testing, the diagnosis accuracy was 88.1%, sensitivity was 67.8%, specificity was 100%, positive predictive value was 100%, and negative predictive value was 84.1%. Conclusion: Combining sonography and FNAC in breast cancer diagnosis can increase the accuracy, decrease false positive ratio and false negative ratio. These two methods can be conducted during outpatient visit and are fast, accurate and cost-effective tools for breast cancer diagnosis. These two methods particularly appropriate for younger female patients for early screening, early intervention, and may increase the survival rates.

In this study, meta-analysis of diagnostic tests, Summary Receiver Operating Characteristic (SROC) curve, bivariate random effects and Hierarchical Summary Receiver Operating Characteristic (HSROC) curve theories have been discussed and accuracy in literature of Fine Needle Aspiration (FNA) biopsy that is used in the diagnosis of masses in breast cancer (malignant or benign) has been analyzed. FNA Cytological (FNAC) examination in breast tumor is, easy, effective, effortless, and does not require special training for clinicians. Because of the uncertainty related to FNAC&lsquo / s accurate usage in publications, 25 FNAC studies have been gathered in the meta-analysis. In the plotting of the summary ROC curve, the logit difference and sums of the true positive rates and the false positive rates included in the meta-analysis&lsquo / s codes have been generated by SAS. The formula of the bivariate random effects model and hierarchical summary ROC curve is presented in context with the literature. Then bivariate random effects implementation with the new SAS PROC GLIMMIX is generated. Moreover, HSROC implementation is generated by SAS PROC HSROC NLMIXED. Curves are plotted with RevMan Version 5 (2008). It has been stated that the meta-analytic results of bivariate random effects are nearly identical to the results from the HSROC approach. The results achieved through both random effects meta-analytic methods prove that FNA Cytology is a diagnostic test with a high level of distinguish over breast tumor.

Background: Reported results for thyroid nodule fine-needle aspiration (FNA) cytology mainly originate from tertiary centers. However, thyroid nodule FNA cytology is mainly performed in primary care settings for which the distribution of FNA Bethesda categories and their respective malignancy rates are largely unknown. Therefore, this study investigated FNA cytology malignancy rates of a large primary care setting to determine to what extent current evidence-based strategies for the malignancy risk stratification of thyroid nodules are applied and applicable in such primary care settings. Methods: In a primary care setting, 9460 FNAs of thyroid nodules were retrospectively analyzed from 8380 patients evaluated by one cytologist (I.R.) during a period of two years. The 8380 FNA cytologies were performed by 64 physicians in different private practices throughout Germany in primary care settings. Results: The cytopathologic results were classified according to theBethesda Systemas non-diagnostic in 19%, cyst/ cystic nodule in 21%, benign (including thyroiditis) in 48%, atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) in 6%, follicular neoplasms/suspicious for follicular neoplasm (FN/SFN) in 4%, suspicious for malignancy (SFM) in 1%, and malignant in 1%. The proportion of patients proceeding to surgery or with a follow-up of at least one year and the observed risks of malignancy were 22%/8% for AUS/FLUS, 69%/ 17% for FN/SFN, 78%/86% for SFM, and 71%/98% for malignant. For 112 cytologically suspicious and malignant FNAs, there were 102 true positives and 10 false positives, considering histology as gold standard. Conclusion: At variance with other data mostly originating from tertiary centers, these data demonstrate low percentages for malignant, SFM, FN/SFN, and AUS/FLUS, and high percentages for cysts/cystic nodules in this primary care setting in Germany. The risks of malignancy for malignant, SFM, AUS/FLUS, and FN/SFN FNA cytologies are according to Bethesda recommendations.:1 ABKÜRZUNGSVERZEICHNIS ............................................................................................................... 1 2 EINFÜHRUNG .......................................................................................................................................... 2 2.1 DAS ORGAN SCHILDDRÜSE ................................................................................................................................ 3 2.1.1 Anatomie der Schilddrüse ......................................................................................................................... 3 2.1.2 Funktion der Schilddrüse .......................................................................................................................... 3 2.2 SCHILDDRÜSENKNOTEN ..................................................................................................................................... 4 2.2.1 Epidemiologie der Schilddrüsenknoten .............................................................................................. 4 2.2.2 Ätiologie der Schilddrüsenknoten ......................................................................................................... 4 2.2.3 Jodversorgung in Deutschland ................................................................................................................ 5 2.2.4 Symptomatik der Schilddrüsenknoten ................................................................................................ 5 2.2.5 Diagnostik von Schilddrüsenknoten ..................................................................................................... 6 2.2.6 Die Feinnadelaspirationszytologie (FNA) ......................................................................................... 9 2.2.7 Therapeutisches Management ............................................................................................................ 11 2.3 DIE ABLEITUNG DER RATIONALE .................................................................................................................. 13 3 PUBLIKATIONSMANUSKRIPT ........................................................................................................ 14 4 ZUSAMMENFASSUNG ......................................................................................................................... 22 4.1 SCHLUSSFOLGERUNG ....................................................................................................................................... 26 5 LITERATURVERZEICHNIS ................................................................................................................ 28 6 ANLAGEN ............................................................................................................................................... 33 6.1 TABELLE 1: MALIGNITÄTSRISIKO NACH SONOGRAPHISCHEM ERSCHEINUNGSBILD UND FNA INDIKATION FÜR SCHILDDRÜSENKNOTEN (36) ........................................................................................................... 33 6.2 TABELLE 2: DAS BETHESDA SYSTEM FOR REPORTING THYROID CYTHOPATHOLOGY. DIAGNOSTISCHE KATEGORIEN UND MALIGNITÄTSRISIKEN (36) ........................................................................................................... 34 6.3 ABBILDUNG 1: ALGORITHMUS FÜR PATIENTEN MIT SCHILDDRÜSENKNOTEN NACH DER AMERICAN THYROID ASSOCIATION (36) .......................................................................................................................................... 35 6.4 DARSTELLUNG DES EIGENEN BEITRAGS AN DER PUBLIKATION ............................................................... 36 6.5 ERKLÄRUNG ÜBER DIE EIGENSTÄNDIGE ABFASSUNG DER ARBEIT .......................................................... 54 6.6 LEBENSLAUF ..................................................................................................................................................... 55 6.7 VERZEICHNIS WISSENSCHAFTLICHER VERÖFFENTLICHUNGEN ................................................................ 56 6.8 DANKSAGUNG ................................................................................................................................................... 57

Introduction: Effusion cytology can be performed for the purpose of diagnosis, treatment, and prognosis of malignant disease. A common analysis of effusion cytology samples is the May Grunwald Giemsa stain.    Aim: The aim of the study was to compare May Grunwald Giemsa stain and May Grunwald Giemsa Quick Stain in order to determine the best quality stain and suggest ways to improve the current staining protocol.     Materials and Methods: The methods used in this study are the routine laboratory’s standard procedures for  May-Grunwald Giemsa stain and May-Grunwald Giemsa Quick Stain but with adapted washing steps that investigates the effect of tap water, distilled water, and phosphate buffer on stain quality. Two pleural effusion samples were stained in the initial experiment and two pleural effusions and one ascites sample in the second experiment.    Results and Conclusion: All samples gave a greater score when stained with May-Grunwald Giemsa Quick Stain compared to traditional May-Grunwald Giemsa stain. For the traditional May-Grunwald Giemsa, the use of any of the three phosphate buffers scores higher than the routine washing where tap water is used. In conclusion, it would be of benefit to further investigate and implement phosphate buffer in traditional staining or proceed with the May-Grunwald Quick Stain for all pleural and ascites effusions.

Hinsichtlich einer effizienten Nachsorge von Melanompatienten existieren entsprechende Empfehlungen, aber auch widersprüchliche Stellungnahmen hinsichtlich Intervalllänge und Umfang der Nachsorge. Das Melanom ist einer der malignen Tumoren mit den am schnellsten steigenden Inzidenzraten, was auch eine Steigerung der Mortalität bedingt. In der vorliegenden Arbeit werden neue diagnostische Strategien geprüft und in ein vorbestehendes Melanomnachsorgeschema aufgenommen, um Patientenbetreuung, die frühe Entdeckung von Metastasen, aber auch die Raten an rezidivfreiem - und Gesamtüberleben zu verbessern. In einer großen prospektiven Studie von 4 Jahren Dauer konnte der Ultraschall von Lymphknoten, Weichteilgewebe und in transit Strecken eher als die rein klinische Untersuchung Metastasen entdecken und führte auf diese Weise zu einer Verbesserung des rezidivfreien- und des Gesamtüberlebens. Die Feinnadelaspirationszytologie (FNAC) wurde in einer weltweit, zahlenmäßig führenden Studie durchgeführt um die verdächtigten Läsionen tatsächlich zu diagnostizieren. Dies geschah hierbei nahezu nicht-invasiv. Hohe Zahlen an Sensitivität und Spezifität dieser Methode konnten erreicht werden und eine Diagnose konnte auch in sehr kleinen Läsionen oder solchen in einer schwierigen Position etabliert werden. Bei letzteren Läsionen erwies sich auch die Hinzunahme einer ultraschallgesteuerten Drahtmarkierung als nützliches Procedere. Auf diese Weise konnte die Exzision dieser Läsionen in komplizierter Lage vereinfacht werden. Eine weitere Studie untersuchte die begleitende Anwendung der Untersuchung einer seriellen reverse Transskriptase Polymerasekettenreaktion (RT-PCR) zum Nachweis von Tyrosinase aus peripherem Blut von Hochrisikomelanompatienten. Patienten, die im Blut mindestens einmal positiv getestet wurden, zeigten ein signifikant höheres Risiko, krankheitsspezifisch am Melanom zu versterben, als Patienten, die stets ein negatives Resultat aufwiesen. Die Tyrosinase RT-PCR Untersuchungen konnten auch an geringen Mengen Material wie Feinnadelaspiraten oder dem Feinnadelpunktaten des Sentinel Node erfolgreich durchgeführt werden. Alle aufgezeigten Methoden erwiesen sich als effektiv und wurden deswegen in das bestehende Nachsorgeprogramm der Melanompatienten an der Charité, Berlin aufgenommen. / There exist recommendations but also controversies about the necessity and effectiveness of a distinctive melanoma follow-up programme. Melanoma is one of the fastest increasing malignant tumours with increasing rates of incidence and mortality. In this work new strategies are implemented in a pre-existing melanoma follow-up schedule in order to ameliorate the care for patients, the detection of metastases and the relapse-free and overall survival rates. In a large prospective study taking four years the ultrasound of lymph nodes, soft tissues and in transit distances was shown to earlier detect recurrences than the clinical examination thus significantly enhancing recurrence-free and overall survival. Fine needle aspiration cytology (FNAC) has been performed in a large, worldwide leading study to verify the suspected lesions in a nearly non-invasive way. High percentages in sensitivity and specificity could be achieved also in small lesions or lesions in an unfavourable localization. The latter lesions have been shown to be better detectable by a marking procedure. An anchor wire has been sonographically placed within such a lesion to improve the successful excision. A further study examined the value of serial RT-PCR testing from peripheral blood in melanoma patients. Patients, who have been tested at least once positive, had a higher risk ratio to die disease-specifically from melanoma. This result has been highly significant. RT-PCR examinations could also be applied in small amounts of material such as fine needle aspirations or material of FNA C of the sentinel node. All modalities could be proven to be effective and therefore are included in the melanoma follow-up programme of the Charité, Humboldt University of Berlin.

Immunhistokemi (IHC) och immuncytokemi (ICC) är viktiga verktyg inom cancerdiagnostik för att fastställa diagnoser. Både histologiskt och cytologiskt material kan användas för immunokemisk analys men kräver olika förberedelser. Den preanalytiska fasen påverkar epitop och antigenens tillgänglighet samt immunoreaktivitet, vilket gör valet av pre- och postfixering och hur de påverkar cytologiskt material, viktiga att förstå. ICC tillämpas vanligen på cytologiskt material som preparerats enligt cellblockteknik (CBT) men ibland saknas extraherat material för analys. Antikroppar kan användas för att differentiera tumörursprung, tumörsubtyper och inflammatoriska tillstånd, vilket är avgörande för klinisk diagnostik och behandlingsbeslut för individen. Vid klinisk patologi och cytologi i Kalmar är ett återkommande problem bristen på cellmaterial för CBT-preparering vid punktionscytologi. Syftet med denna studie var att validera antikroppar (kalretinin, CD45, CK5, CK7, SOX-10, EpCAM och TTF-1) på cytologiskt material (pleuraexsudat från 10 patienter) som preparerats enligt ThinPrep™- metoden (TP-metoden). Studien syftade även till att undersöka effekterna av post-fixering i 4 % formalin, 96% etanol eller ingen post-fixering inför ICC-analys för att se om valet av post-fixeringsmedel påverkar antikropparnas färgningsmönster (nukleärt, cytoplasmatiskt eller membranöst). CD45, CK5, CK7 och TTF-1 kunde valideras i studien. Det fanns inte någon signifikant skillnad (p &gt; 0,05) i bedömningskategorierna (bakgrund, inmärkning och cellantal) mellan olika post-fixeringsmedel. Det fanns heller inga indikationer som visade att en särskild post-fixering gynnande ett särskilt färgningsmönster. Fler studier behövs för att förstå den preanalytiska fasens påverkan på ICC- analys av cytologiskt material. I samband med punktionscytologi skulle preparering enligt TP-metoden säkerställa tillgången på cellmaterial för ICC-analys. / Immunohistochemistry (IHC) and immunocytochemistry (ICC) are crucial tools in cancer diagnostics for establishing diagnosis. Both histological and cytological materials can be used for immunochemical analysis, but they require different preparations. The pre-analytical phase affects the epitope and antigen availability as well as immunoreactivity, making the choice of pre- and post-fixation and their impact on cytological material important to understand. ICC is usually applied to cytological material prepared using the cell block technique (CBT), but sometimes there is a lack of extracted material for analysis. Antibodies can differentiate tumor origins, subtypes, and inflammatory conditions, which is essential for clinical diagnostics and treatment decisions. In clinical pathology and cytology in Kalmar, a recurring issue is the lack of cell material for CBT preparation in fine-needle aspiration cytology. This study aimed to validate antibodies (calretinin, CD45, CK5, CK7, SOX-10, EpCAM, and TTF-1) on cytological material (n=10 pleural effusions) prepared using the ThinPrep™ method (TP method). The study also aimed to study the effects of post-fixation in 4% formalin, 96% ethanol, or without fixation medium before ICC analysis to see if the choice of post-fixation medium affects the staining patterns of the antibodies (nuclear, cytoplasmic, or membranous). CD45, CK5, CK7, and TTF-1 were validated in the study. There was no significant difference (p &gt; 0.05) in the assessment categories (background, staining, and cell count) between different post-fixation media. There were also no indications that a particular post-fixation medium favored a specific staining pattern. Further studies are needed to understand the pre-analytical phase's impact on ICC analysis of cytological material. In fine-needle aspiration cytology, preparation using the TP method would ensure the availability of cell material for ICC analysis.