Thesis (M.A.)--Boston University / The standardized uptake value (SUV) is increasingly being used for diagnosis, staging, and monitoring disease in clinical oncology. Comparing tumor SUV to background SUV is an attractive way to minimize variability and ensure the quality of scans across different institutions. The liver has been identified as a potential source for background normalization, however no studies have compared the liver to other background sites for a variety of cancers. The purpose of this study was to evaluate the use of liver uptake for the standardization of FDG PET/CT imaging. Scans from 145 patients were prospectively reviewed under the supervision of a radiologist with board certification in nuclear medicine (R.M.S. , 3 years of experience). Liver SUV values were correlated to mediastinum SUV values in lung and breast cancer patients, and internal jugular vein (IJV) SUV values in head and neck cancer patients. The independent t-test was used to determine if there was a statistically significant affect of the amount of incubation time or use of intravenous contrast on the SUV. For the lung and breast cancer patients, a strong correlation was observed between the mediastinum SUVmean and liver SUVmean (r = 0.89), whereas for the head and neck cancer patients, a weaker correlation was observed between the IJV SUVmean and the liver SUVmean (r = 0.69). Neither the amount of incubation time nor the use of IV contrast demonstrated a significant affect on the SUV. We conclude that liver SUVmean may be used to standardize FOG PET/CT studies in cancers of the lung, breast and head and neck. However, additional studies in other cancers as well as the affects of age, gender, benign disease and use of chemotherapy are still desired before widespread adoption of this standard.

The aim of this thesis was to develop and validate prognostic and predictive biomarkers in order to better identify among patients with metastatic colorectal cancer those at high-risk of early death or progression. The interest in developing such biomarkers is that their subsequent use in clinical practice would avoid exposing a patient for months to the toxic side effects of ineffective and expensive treatments, and thus to limit the financial impact of these treatments on our healthcare systems.The projects carried out in the framework of this thesis have shown that:The biomarker WB-MATV (metabolically active tumor volume of the whole body) measured before the start of the last line treatment has a high prognostic value, higher than the general clinical parameters commonly used. This biomarker was then validated in first line treatment and was shown to have a high prognostic value, also higher than the general clinical parameters.The biomarker cfDNA (circulating DNA) also representing the tumor load was then investigated to assess its value added to the previously validated WB-MATV. We showed that the presence of high levels of cfDNA before starting the last-line treatment is significantly associated with poor prognosis and that these two biomarkers are prognostically complementary, each providing an added value.The biomarker of early metabolic response to last line treatment has a high negative predictive value (95%). This biomarker was then validated as a predictive biomarker independent of WB-MATV and clinical factors in first-line treatment setting.In conclusion, the results of this thesis strongly support the clinical use of these prognostic and predictive biomarkers in patients with metastatic colorectal cancer. Allowing a more accurate stratification of patients, the use of the combination of these biomarkers should become an essential tool to help oncologists in tailoring therapeutic strategies according to the patients’ individual risk. / Doctorat en Sciences médicales (Médecine) / info:eu-repo/semantics/nonPublished

No description available.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22739号 / 医博第4657号 / 新制||医||1046(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 佐藤 俊哉, 教授 椛島 健治 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

Background: Breast cancer is the second most common cancer in adults and the most frequent cancer diagnosed in women. In South Africa, breast cancer accounts for 38.5% of cancers diagnosed in women. Since the presence, extent and location of distant metastases is one important prognostic factor in locally advanced breast cancer (LABC), accurate staging at diagnosis is crucial to ensure patients receive the appropriate treatment. Increasing evidence shows that the use of 18F-FDG PET/CT for disease staging of LABC may improve diagnostic sensitivity. Aim: To prospectively assess the difference in diagnostic accuracy between whole-body PET/PET-CT and conventional imagine (CI) for staging LABC. Methods: A total of 42 participants with clinical stage III and a select few stage II breast cancer underwent both 18F-FDG PET/CT and CI. Results: 18F-FDG PET/CT found significantly more (p=0.0077) distant metastatic sites than CI (36% vs. 21%). 18F-FDG PET/CT upstaged 9 (21.4%) of patients from clinical stage IIIa to stage IIIc, and changed management of 54% of patients. Thirty-eight percent (38%) of the patients had their clinical stage unchanged. One of 5 suspected metastatic sites 18F FDG PET/CT was positive for malignancy on biopsy. Conclusion: The 18F-FDG PET/CT is useful for staging locally advanced non-inflammatory infiltrating ductal carcinoma of the breast. Use of 18F-FDG PET/CT was superior to conventional imaging in assessing metastatic mediastinal lymphadenopathy, but with a poor specificity. The use of 18F-FDG PET/CT in LABC is useful, with the biopsy of isolated suspicious lesions for metastasis increasing its accuracy.

Malignant melanoma (MM) is the deadliest skin cancer with an ever-increasing incidence. New treatments have improved the prognosis for patients with advanced MM. Still, most patients do not respond, and the side effects can be severe, underlining the need for better therapies. The overall aim of this thesis was to evaluate new means to improve the treatment for patients with advanced MM. Immunostimulatory gene therapy (AdCD40L) was evaluated in a clinical study and BRAF-inhibitory treatment in rare cases of BRAF-mutated MM. Due to its immunogenicity, MM is an attractive target for immunostimulatory gene therapy. AdCD40L is an adenovirus carrying the human gene for CD40 ligand, which in different ways can stimulate the immune system to combat cancer. We conducted a Phase I/IIa study with AdCD40L in patients with metastatic MM having received established treatments. In cohort 1 (n=6), four weekly, intratumoural AdCD40L injections were given. In cohort 2 (n=9), low dose cyclophosphamide was added to increase the immune response. Since irradiation may act synergistically with immunotherapy, patients in cohort 3 (n=9) also received a single fraction of radiotherapy (8 Gy). This fraction was given towards the lesion selected for injections. The primary objectives were to assess the feasibility and safety of AdCD40L-treatment and secondarily its anti-tumour effects. Patients were thoroughly assessed for toxicity. The anti-tumour response was evaluated by imaging techniques (FDG-PET/CT, DW-MRI scans), tumour biopsies and blood tests. Plasma protein markers were measured with a multiplex platform. Another objective was to evaluate the potential of DW-MRI and FDG-PET/CT for prediction of AdCD40L treatment response, in terms of overall survival (OS). AdCD40L was well tolerated with mild transient reactions. Local and distant responses in PET/CT scans along with a significantly better 6-month survival in the cohorts that received cyclophosphamide conditioning were observed. Effector lymphocyte responses were elicited. All patients had an increased T effector/T regulatory-cell ratio and death receptors were significantly up-regulated post therapy. Inflammatory cytokines and other plasma proteins were altered in favourable ways by the AdCD40L treatment. The analyses support that the functional DWI parameters may be better early predictors of OS than the established metabolic and morphologic criteria of FDG-PET/CT and CT/MRI, respectively. In conclusion, the stimulation of the CD40 pathway to initiate anti-tumour immunity is a promising treatment alternative for MM patients. However, further studies with developed treatment schemes are warranted. In the first report ever on treatment of a pregnant patient with a BRAF-inhibitor, the therapy was initiated in the second trimester. The treatment with vemurafenib enabled prolonged gestation, hence reducing the risk of immaturity-related complications. Further, we report the first case worldwide of a patient with metastatic conjunctival melanoma who benefitted from treatment with vemurafenib. Additional studies are needed to assess the efficacy of BRAF -inhibitors in the different subtypes of ocular melanoma.

A 28-year-old female patient with active and difficult-to-treat systemic lupus erythematosus (SLE) was diagnosed with liver-dominant diffused large B-cell lymphoma. Repeated response 18F-FDG-PET studies showed persistently high, and, despite intensified immunochemotherapy, further increasing metabolic activity of one of the hepatic lymphoma residuals, whereas all other initial lymphoma manifestations had achieved complete metabolic remission. As biopsy of the 18F-FDG-PET-positive liver residual turned out to be inconclusive, complete resection was performed. Subsequent histopathological examination, however, revealed only necrotic tissue. Thus, no further lymphoma treatment was scheduled. The patient undergoes regular surveillance and is disease-free 13 months after resection. Similarly, treatment of SLE is no longer required due to lack of activity already after the first two cycles of lymphoma treatment. The case shows how closely SLE and diffused large B-cell lymphoma can be connected and stresses the importance of interdisciplinary treatment approaches. In the future, artificial intelligence may help to further classify 18F-FDG-PET-positive lymphoma residuals. This could lead to an increase of the positive predictive value of interim- and end-of-treatment 18F-FDG-PET. The patient’s point of view enables another instructive perspective on the course of treatment, which often remains hidden to treating physicians due to lack of time in clinical routine.

C. burnetii est une bactérie intracellulaire strcite. Récemment, un milieu axénique, nommé ACCM 2 a été développé, et permet la culture de cette bactérie en atmosphère microaérophile. Nous avons testé si l’ajout d’acide urique dans le milieu de culture pouvait permettre une culture en milieu aérobie. Nous avons observé une croissance de C. burnetii incubée en conditions aérobies dans le milieu ACCM2 enrichi en acide urique. A Cayenne, en Guyane Française, les pneumopathies causées par C. burnetii sont fréquentes et sévères. Nous avons analysé le génome d’une souche isolée à Cayenne. Ce travail a mis en évidence une délétion de 6105 pb intéressant le gène du système de sécrétion de type 1 (T1SS). Cette réduction de génome est probablement impliquée dans l’hypervirulence des souches de Cayenne. Enfin, nous avons testé la sensibilité aux antibiotiques de 6 souches isolées à partir de patients vivant à Cayenne. Ces souches étaient toutes sensibles à la doxycycline et résistantes aux macrolides. Dans une troisième partie nous avons analysé l’apport du TEP scanner dans le diagnostic des infections à C. burnetii. 167 patients atteints d’infections à C. burnetii ont bénéficié d’un TEP scanner. Nous avons retrouvé une proportion élevée de fixations ostéo-articulaires (21) et ganglionnaires (27), et nous avons proposé de nouvelles définitions pour ces localisations. Nous avons ensuite étudié l’impact du traitement chirurgical chez les patients atteints d’infections vasculaires. Une analyse rétrospective de 86 patients atteints d’infections vasculaires a montré que la chirurgie était associée à une diminution de la mortalité à 2,5 ans et à une meilleure évolution sérologique / C. burnetii is an intracellular bacterium. Recently, an axenic medium, named ACCM 2, has been developed and allows the culture of this bacterium in a microaerophilic atmosphere. We tested if the addition of uric acid in the medium could allow an aerobic culture. We observed growth of C. burnetii incubated under aerobic conditions in the ACCM2 medium enriched with uric acid. In Cayenne, French Guiana, pneumonia caused by C. burnetii are frequent and severe. We analyzed the genome of a strain from Cayenne. This work revealed a 6105 bp deletion in the gene of the type 1 secretion system (T1SS). This genome reduction is probably involved in the hypervirulence of Cayenne strains. Finally, we tested the antibiotic suceptibility of 6 strains isolated from patients living in Cayenne. These strains were all susceptible to doxycycline and resistant to macrolides. In a third part we analyzed the contribution of PET scanner in the diagnosis of C. burnetii infections. 167 patients with C. burnetii infections benefited from a PET scan. We found a high proportion of osteo-articular (21) and lymphadenitis (27) fixations, and we proposed new definitions for these locations. We then investigated the impact of surgical treatment in patients with vascular infections. A retrospective analysis of 86 patients with vascular infections showed that surgery was associated with a lower mortality at 2.5 years and a better serological outcome

Background: Hibernomas are rare benign soft-tissue tumours arising from brown fat tissue. Although imaging characteristics are not specific certain imaging features, common locations and patient demographics may suggest hibernoma as a differential diagnosis. Case presentation: We report on two 48-year-old male patients with hibernoma. The tumour presented with local swelling of the inguinal region in the first patient and was an incidental imaging finding in the second patient. Imaging included magnetic resonance imaging in both patients and computed tomography as well as 18 F-fluorodeoxyglucose positron emission tomography-computed tomography in the second patient. In both cases histological diagnosis was initially based on excisional and needle core biopsy, respectively. Complete surgical resection confirmed the diagnosis of hibernoma thereafter. Conclusion: In soft tissue tumours with fatty components hibernoma may be included into the differential diagnosis. Because of the risk of sampling errors in hibernoma-like tissue components of myxoid and well-differentiated liposarcoma, complete resection is mandatory. This article also reviews the current imaging literature of hibernomas.

Background: Hibernomas are rare benign soft-tissue tumours arising from brown fat tissue. Although imaging characteristics are not specific certain imaging features, common locations and patient demographics may suggest hibernoma as a differential diagnosis. Case presentation: We report on two 48-year-old male patients with hibernoma. The tumour presented with local swelling of the inguinal region in the first patient and was an incidental imaging finding in the second patient. Imaging included magnetic resonance imaging in both patients and computed tomography as well as 18 F-fluorodeoxyglucose positron emission tomography-computed tomography in the second patient. In both cases histological diagnosis was initially based on excisional and needle core biopsy, respectively. Complete surgical resection confirmed the diagnosis of hibernoma thereafter. Conclusion: In soft tissue tumours with fatty components hibernoma may be included into the differential diagnosis. Because of the risk of sampling errors in hibernoma-like tissue components of myxoid and well-differentiated liposarcoma, complete resection is mandatory. This article also reviews the current imaging literature of hibernomas.