Brain 18 F-FDG-PET and an optimized cingulate island ratio to differentiate Lewy body dementia and Alzheimer's disease.

BACKGROUND AND PURPOSE: The diagnosis of Dementia with Lewy Bodies (DLB) is challenging due to various clinical presentations and clinical and neuropathological features that overlap with Alzheimer's disease (AD). The use of 18 F-Fluorodeoxyglucose-PET (18 F-FDG-PET) can be limited due to similar patterns in DLB and AD. However, metabolism in the posterior cingulate cortex is known to be relatively preserved in DLB and visual assessment of the "cingulate island sign" became a helpful tool in the analysis of 18F-FDG-PET. The aim of this study was the evaluation of visual and semiquantitative 18F-FDG-PET analyses in the diagnosis of DLB and the differentiation to AD as well as its relation to other dementia biomarkers. METHODS: This retrospective study comprises 81 patients with a clinical diagnosis of DLB or AD that underwent 18 F-FDG-PET/CT. PET scans were analyzed visually and semiquantitatively and results were compared to clinical data, cerebrospinal fluid results, dopamine transporter scintigraphy, and 18F-Florbetaben-PET. Furthermore, different cingulate island ratios were calculated to analyze their diagnostic accuracy. RESULTS: Visual assessment of 18F-FDG-PET showed an accuracy of 62%-77% in differentiating between DLB and AD. Standard uptake values were significantly lower in the primary visual cortex and the lateral occipital cortex of DLB patients compared to AD patients. The cingulate island ratio was significantly higher in the DLB group compared to the AD group and the ratio posterior cingulate cortex to visual cortex plus lateral occipital cortex showed the highest diagnostic accuracy to discriminate between DLB and AD at 81%. CONCLUSIONS: Semiquantitative 18F-FDG-PET imaging and especially the use of an optimized cingulate island ratio are valuable tools to differentiate between DLB and AD.

The Role of PSMA PET/CT in the Primary Diagnosis and Follow-Up of Prostate Cancer-A Practical Clinical Review.

The importance of PSMA PET/CT in both primary diagnostics and prostate cancer recurrence has grown steadily since its introduction more than a decade ago. Over the past years, a vast amount of data have been published on the diagnostic accuracy and the impact of PSMA PET/CT on patient management. Nevertheless, a large heterogeneity between studies has made reaching a consensus difficult; this review aims to provide a comprehensive clinical review of the available scientific literature, covering the currently known data on physiological and pathological PSMA expression, influencing factors, the differences and pitfalls of various tracers, as well as the clinical implications in initial TNM-staging and in the situation of biochemical recurrence. This review has the objective of providing a practical clinical overview of the advantages and disadvantages of the examination in various clinical situations and the body of knowledge available, as well as open questions still requiring further research.

Development of high-affinity fluorinated ligands for cannabinoid subtype 2 receptor, and in vitro evaluation of a radioactive tracer for imaging.

The development of neurodegenerative diseases is associated with cerebral inflammation, which activates resident immune cells of the central nervous system (CNS), namely microglial cells that show an up-regulation of the cannabinoid subtype 2 receptor (CB2R) expression. Therefore our work aimed to design and synthesize a radiotracer for the detection of CB2R expression by positron emission tomography (PET) allowing an early diagnosis of neurodegenerative diseases. For the development of such a PET tracer, N-alkyl-substituted indole-3-yl-tetramethylcyclopropylketones served as lead structures due to their high CB2R potency and selectivity, allowing radiolabeling on the N-alkyl chain. To this end, eight novel fluorinated N-alkyl-indole-3-yl-tetramethylcyclopropylketones were synthesized, investigated in radioligand binding studies, and structure-activity relationships were evaluated. The most promising candidate was (1-(4-fluoropropyl)-1H-indole-3-yl)(2,2,3,3-tetramethyl-cyclopropyl)methanone (Ki: 7.88 nM at the CB2R, 3430 nM at cannabinoid subtype 1 receptor (CB1R)). A precursor was synthesized, radiofluorinated with no-carrier-added [18F]F- by nucleophilic substitution of a tosyl group, and the resulting PET ligand was purified, all being performed on a fully automated synthesis module. The tracer was produced in 34 ± 6% radiochemical yield within 2 h and with molar activities of up to 1500 GBq/µmol. A first preclinical evaluation was carried out including determination of logP, metabolic stability by liver microsomes, and autoradiography. The novel PET tracer for imaging CB2R showed promising results warranting subsequent clinical evaluation.

Liver Enzyme Elevation After 177Lu-PSMA Radioligand Therapy for Metastasized Castration-Resistant Prostate Cancer.

177Lu-PSMA radioligand therapy is a promising new option for patients with metastasized castration-resistant prostate cancer, and the spectrum of adverse events with this treatment has to be evaluated. Here, we describe the case of a patient with M1c disease (metastasis to the mediastinum, lungs, bones, and liver) who presented with elevated liver enzyme levels after receiving 177Lu-PSMA radioligand therapy for castration-resistant prostate cancer. Pretreatment 68Ga-PSMA PET/CT showed at least 4 liver lesions with low uptake. Overall, the liver uptake was inhomogeneous. Liver biopsy was performed subsequently.

Mesorectal Lymph Node Metastases as Index Lesion in 68Ga-PSMA-PET/CT Imaging for Recurrent Prostate Cancer.

Purpose: Several studies have demonstrated an advantage of 68Ga-PSMA-PET/CT as staging modality for detection of prostate cancer (PCa) metastases. Data concerning metastatic manifestation and impact on PCa development of mesorectal lymph nodes (MLN) is limited. Our investigation describes MLN metastases as index lesion in 68Ga-PSMA PET/CT imaging for recurrent PCa. Methods: Twelve PCa patients with biochemical recurrence (BCR) after primary therapy who prospectively underwent a baseline 68Ga-PSMA-PET/CT initially showed MLN metastases. Eight of these patients received a follow-up 68Ga-PSMA-PET/CT to evaluate treatment response and further evolution. Prostate-specific antigen (PSA)-levels, changes in PSMA-uptake of MLN metastases and further 68Ga-PSMA PET/CT findings were recorded. Results: Median PSA at the first 68Ga-PSMA-PET/CT was 5.39 ng/ml. In all patients therapeutic management changed after the first 68Ga-PSMA-PET/CT. Androgen deprivation therapy (ADT) was initiated in seven of eight patients, one patient restarted initial ADT. Three patients additionally received salvage radiation therapy (sRT) including the prostatic lodge and docetaxel chemotherapy was started in one case. At follow-up, a decrease of PSA-level was detected in all patients (median 2.05 ng/ml) after median 10 months. In six of eight patients we observed a decrease or complete regress of PSMA-uptake in MLN in the follow-up 68Ga-PSMA-PET/CT. Conclusion: MLN metastases detected by 68Ga-PSMA-PET/CT seem to be a relevant localization of tumor manifestation and may serve as index lesion in the treatment of recurrent PCa. Besides the known oncological benefits of ADT and sRT, in case of sole MLN metastases individualized therapy like salvage lymphadenectomy or RT with a defined radiation field could be options for these patients.

Enhancing PSMA-uptake with androgen deprivation therapy - a new way to detect prostate cancer metastases?

ABSTRACT Purpose: 68Ga-PSMA PET/CT imaging is a promising modality for the staging of recurrent prostate cancer (PCa). Current evidence suggests limited diagnostic value of the 68Ga-PSMA PET/CT in PSA-levels ≤0.3ng/mL. Experimental data have demonstrated an increase in PSMA-expression in PCa metastases by androgen deprivation in vitro. The aim of the current study was to investigate a possible enhancing effect of PSMA with low-dose androgen deprivation in patients with BCR and low PSA-levels. Materials and Methods: Five patients with PCa and BCR, following radical prostatectomy, underwent 68Ga-PSMA PET/CT. A consecutive 68Ga-PSMA PET/CT was performed 6 to 11 days after injection of 80mg of Degarelix (Firmagon®). We recorded PSA and testosterone serum-levels and changes of PSMA-uptake in 68Ga-PSMA PET/CT images. Results: Median PSA prior 68Ga-PSMA PET/CT was 0.27ng/mL. All patients had a decrease in testosterone serum levels from median 2.95μg/l to 0.16μg/l following Degarelix injection. We observed an increase in the standardized uptake value (SUV) in PSMA-positive lymphogenous and osseous lesions in two patients following androgen deprivation. In another two patients, no PSMA positive signals were detected in either the first or the second scan. Conclusion: Our preliminary results of this feasibility assessment indicate a possible enhancing effect of PSMA-imaging induced by low-dose ADT. Despite several limitations and the small number of patients, this could be a new approach to improve staging by 68Ga-PSMA PET/CT in PCa patients with BCR after primary therapy. Further prospective studies with larger number of patients are needed to validate our findings.

Impact of rs12917 MGMT Polymorphism on [18F]FDG-PET Response in Pediatric Hodgkin Lymphoma (PHL).

PURPOSE: The enzyme O6-methylguanine-DNA methyltransferase (MGMT) is an important component of the DNA repair machinery. MGMT removes O6-methylguanine from the DNA by transferring the methyl group to a cysteine residue in its active site. Recently, we detected the single nucleotide polymorphism (SNP) rs12917 (C/T) in the MGMT sequence adjacent to the active site in Hodgkin lymphoma (HL) cell line KM-H2. We now investigated whether this SNP is also present in other HL cell lines and patient samples. Furthermore, we asked whether this SNP might have an impact on metabolic response in 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography ([18F]FDG-PET), and on overall treatment outcome based on follow-up intervals of at least 34 months. PROCEDURES: We determined the frequency of this MGMT polymorphism in 5 HL cell lines and in 29 pediatric HL (PHL) patients. The patient cohort included 17 female and 12 male patients aged between 4 and 18 years. After characterization of the sequence, we tested a possible association between rs12917 and age, gender, Ann Arbor stage, treatment group, metabolic response following two courses of OEPA (vincristine, etoposide, prednisone, and doxorubicin) chemotherapy, radiotherapy indication, and relapse status. RESULTS: We detected the minor T allele in four of five HL cell lines. 11/29 patients carried the minor T allele whereas 18/29 patients showed homozygosity for the major C allele. Interestingly, we observed significantly better metabolic response in PHL patients carrying the rs12917 C allele resulting in a lower frequency of radiotherapy indication. CONCLUSION: MGMT polymorphism rs12917 seems to affect chemotherapy response in PHL. The prognostic value of this polymorphism should be investigated in a larger patient cohort.

Enhancing PSMA-uptake with androgen deprivation therapy - a new way to detect prostate cancer metastases?

PURPOSE: 68Ga-PSMA PET/CT imaging is a promising modality for the staging of recurrent prostate cancer (PCa). Current evidence suggests limited diagnostic value of the 68Ga-PSMA PET/CT in PSA-levels ≤0.3ng/mL. Experimental data have demonstrated na increase in PSMA-expression in PCa metastases by androgen deprivation in vitro. The aim of the current study was to investigate a possible enhancing effect of PSMA with low-dose androgen deprivation in patients with BCR and low PSA-levels. MATERIALS AND METHODS: Five patients with PCa and BCR, following radical prostatectomy, underwent 68Ga-PSMA PET/CT. A consecutive 68Ga-PSMA PET/CT was performed 6 to 11 days after injection of 80mg of Degarelix (Firmagon®). We recorded PSA and testosterone serum-levels and changes of PSMA-uptake in 68Ga-PSMA PET/CT images. RESULTS: Median PSA prior 68Ga-PSMA PET/CT was 0.27ng/mL. All patients had a decrease in testosterone serum levels from median 2.95µg/l to 0.16µg/l following Degarelix injection. We observed an increase in the standardized uptake value (SUV) in PSMA-positive lymphogenous and osseous lesions in two patients following androgen deprivation. In another two patients, no PSMA positive signals were detected in either the fi rst or the second scan. CONCLUSION: Our preliminary results of this feasibility assessment indicate a possible enhancing effect of PSMA-imaging induced by low-dose ADT. Despite several limitations and the small number of patients, this could be a new approach to improve staging by 68Ga-PSMA PET/CT in PCa patients with BCR after primary therapy. Further prospective studies with larger number of patients are needed to validate our findings.

[Incidence and Predictive Factors for Bilaterality in Patients with Papillary Thyroid Carcinoma]. / Inzidenz und prädiktive Faktoren des bilateralen papillären Schilddrüsenkarzinoms.

BACKGROUND: The optimal extent of thyroidectomy for papillary thyroid cancer (PTC) ≥ 10 mm und < 10 mm is still controversial. Therefore, the purpose of this study was to investigate factors predictive for bilaterality in patients with papillary thyroid carcinoma (PTC). MATERIAL AND METHODS: We retrospectively reviewed 123 PTC patients in a single centre study who underwent either completion or total thyroidectomy and analysed the predictive value of tumour size, histological parameters, multifocality, and lymph node metastases with primary tumour size of ≥ 10 mm and < 10 mm as well as for ≥ 7 mm and < 7 mm. RESULTS: Out of 123 patients, 26 exhibited bilateral PTC. This was significantly more frequent in patients with a primary tumour size of ≥ 10 mm (77%) compared to a tumour size of < 10 mm (23%) (p = 0.004). Multifocality was found to be an independent predictive factor for bilaterality (p = 5.022e-18). Metachronous lymph node metastases showed a trend for bilateral PTCs (p = 0.0691). These findings were reproducible for the comparison between the ≥ 7 mm and < 7 mm group. CONCLUSION: The presence of bilateral PTC appears to be related to the size of the primary tumour ≥ 10 mm. Multifocality is a positive predictor for bilaterality. When multifocality, even with a primary tumour size of < 10 mm, is observed in patients with PTC, total thyroidectomy or completion thyroidectomy may be considered. If lobectomy is performed in patients with PTC, meticulous follow-up is needed to detect hidden malignancies in the contralateral lobe.

18F-FDG-PET Detects Drastic Changes in Brain Metabolism in the Tg4-42 Model of Alzheimer's Disease.

The evaluation of new therapeutic strategies in Alzheimer's disease (AD) relies heavily on in vivo imaging and suitable animal models that mimic the pathological changes seen in patients. 18F-Fluorodeoxyglucose (18F-FDG)-positron-emission tomography (PET) is a well-established non-invasive imaging tool for monitoring changes in cerebral brain glucose metabolism in vivo. 18F-FDG-PET is used as a functional biomarker for AD as patients show an early and progressive reduction of cerebral glucose metabolism. However, earlier studies in preclinical models of AD showed conflicting results. The aim of this study was the evaluation of cerebral glucose metabolism in the Tg4-42 mouse model of AD using 18F-FDG-PET/magnetic resonance imaging (MRI). Tg4-42 mice show an age-dependent reduction in glucose metabolism together with severe neuron loss and memory deficits. Similar to AD patients early decrease in 18F-FDG uptake was already detected in young (3 months) Tg4-42 mice. The altered glucose metabolism coupled with age- and disease related cognitive decline of Tg4-42 mice make it a well-suited model for preclinical testing of AD-relevant therapeutics.

Partial Response to First-Line Crizotinib in an Elderly Male Patient with ROS1 Translocation-Positive Lung Cancer.

We report on a 90-year-old male patient with a ROS1-translocated adenocarcinoma of the lung who was treated with crizotinib as first-line therapy. After 11 months of treatment, we noticed complete metabolic response as measured by (18)F-FDG-PET/CT scan and a partial response according to RECIST criteria. This patient indicates that ROS1 translocations are not restricted to young age, female gender and low stage. Furthermore, this case illustrates exemplarily that crizotinib therapy is effective and manageable even as first-line treatment in elderly patients with comorbidities. Based on our findings, we recommend to include elderly patients with advanced pulmonary adenocarcinomas in molecular screening approaches for ROS1 translocations.

See the unseen: Mesorectal lymph node metastases in prostate cancer.

BACKGROUND: Our study is the first evaluation of nodal metastatic prostate cancer (PCa) to mesorectal lymph nodes (MLN) detected by (68) Ga-PSMA-PET/CT. METHODS: We retrospectively analyzed 76 consecutive PCa patients who underwent (68) Ga-PSMA-PET/CT: 61 PCa patients with biochemical recurrence (BCR) after curative treatment and 15 high-risk PCa before primary therapy. We assessed PET-positive MLN, which are indicative for PCa. RESULTS: We detected PET-positive lesions for PCa in (68) Ga-PSMA-PET/CT in 66 of 76 (87%) patients. Nodal disease was imaged in 47 of 66 (71%) patients. Indicative mesorectal nodal lesions for PCa were detected in 12 of 76 (15.8%) patients. The median number of PET-positive MLN was one per patient. Seven of twelve patients had recurrent PCa after radical prostatectomy with a median PSA value of 1.84 ng/ml (range 0.31-13). Five of twelve patients had untreated first diagnosed high-risk PCa with median PSA value of 90 ng/ml (range 4.6-93) at PET/CT, respectively. For all PET positive MLN a morphological correlate was found in CT (shortest diameter median 4 mm [range 4-21]; longest diameter median 7.5 mm [range 5-25]). After PET/CT, four patients with recurrent PCa received hormonal therapy, one patient was treated with directed radiation therapy of MLN, one patient received chemotherapy, and one patient was treated with pelvic lymph node dissection. Three high-risk PCa patients received hormonal therapy, and two patients were treated with adjuvant hormonal therapy after radical prostatectomy. CONCLUSIONS: Detection and exact location of nodal metastasis for PCa is crucial for the choice of treatment and the patient's prognosis. (68) Ga-PSMA-PET/CT seems to improve the detection of nodal metastasis in PCa, especially concerning mesorectal lymph nodes.

Biphasic 68Ga-PSMA-HBED-CC-PET/CT in patients with recurrent and high-risk prostate carcinoma.

PURPOSE: Binding of (68)Ga-PSMA-HBED-CC ((68)Ga-PSMA) at prostate cancer (PC) cells increases over time. A biphasic protocol may help separating benign from tumor lesions. The aim of this study was the retrospective evaluation of a diagnostic incremental value of a dual-time point (biphasic) (68)Ga-PSMA-PET/CT in patients with prostate cancer. METHODS: Retrospective analysis of 35 consecutive patients (49-78 years, median 71) with newly diagnosed PC (12/35) or recurrence of PC (23/35). PET/CT (Gemini TF16, Philips) was acquired 1 h and 3 h p. i. of 140-392 MBq (300 MBq median) (68)Ga-PSMA, followed by a diagnostic contrast CT. PET findings were correlated with histology or unequivocal CT findings. Semiquantitative PET data (SUVmax, SUV mean) were acquired and target-to-background-ratios (T/B-ratio) were calculated for benign and malign lesions for both time points. Size of lymph nodes (LN) on diagnostic CT was recorded. Statistical analysis was performed for assessment of significant changes of semiquantitative PET-parameters over time and for correlation of size and uptake of lymph nodes. RESULTS: One hundred and four lesions were evaluated. Sixty lesions were referenced by histology or unequivocal CT findings, including eight (13.3 %) histopathologically benign lymph nodes, 12 (20 %) histopathologically lymph node metastases, 12 (20 %) primary tumors, three (5 %) local recurrences, and 25 (41.7 %) bone metastases. Forty-four lesions were axillary LN with normal CT-appearance. Benign lesions had significantly lower SUVmax and T/B-ratios compared with malignant findings. Malign lesions showed a significant increase of both parameters over time compared to benign findings. There was no correlation between LN size and SUVmax. The sensitivity, specificity, the positive predictive value and negative predictive value of PET/CT regarding pelvic LN was 94 %, 99 %, 89 %, and 99.5 %, respectively. CONCLUSIONS: In contrast to benign tissues, the uptake of proven tumor lesions increases on (68)Ga-PSMA-PET/CT over time. A biphasic PET-study may lead to a better detection of tumor lesions in unequivocal findings.

The impact of nodal tumour burden on lymphoscintigraphic imaging in patients with melanomas.

PURPOSE: To retrospectively study the influence of nodal tumour burden on lymphoscintigraphic imaging in 509 consecutive patients with melanomas. METHODS: Bidirectional lymphatic drainage, the clear depiction of an afferent lymphatic vessel, time to depiction of the first sentinel lymph node (SLN) and number of depicted and excised nodes were recorded. Nodal tumour load was classified as SLN-negative, SLN micrometastases or macrometastases. RESULTS: In the overall population, using multivariate regression analysis, a short SLN depiction time was significantly associated with the depiction of a greater number of radioactive nodes, a short distance between the primary tumour site and the nodal basin, younger age and lower nodal tumour burden. The proportion of patients with clear depiction of an afferent lymphatic vessel depended on the nodal tumour load (46% in SLN-negative patients, 57% in SLN positive patients, and 69% in patients with macrometastases; P = 0.009). Macrometastasis was significantly associated with delayed depiction of the first radioactive node and a greater number of depicted hotspots. In patients with clinically nonsuspicious nodes, i.e. the classical target group for SLN biopsy, clear depiction of an afferent vessel was significantly associated with a higher number of SLNs during dynamic acquisition, SLN micrometastasis and a higher overall number of metastatic lymph nodes after SLN biopsy plus completion lymphadenectomy. The excision of more than two SLNs did not increase the metastasis detection rate. In patients with bidirectional or tridirectional lymphatic drainage, the SLN positivity rates for the first, second and third basin were 25.4%, 11.7% and 0.0 %, respectively (P = 0.002). CONCLUSION: In patients with clinically nonsuspicious lymph nodes, clear depiction of an afferent lymph vessel may be a sign of micrometastasis. Macrometastasis is associated with prominent afferent vessels, delayed depiction of the first radioactive node and a higher number of depicted hotspots.

Long-lasting complete response of metastatic melanoma to ipilimumab with analysis of the resident immune cells.

Even though ipilimumab is a promising antibody used for stage IV melanoma therapy, the response varies and is difficult to predict. We here report on a case of successful treatment with ipilimumab in dacarbazine-resistant metastatic malignant melanoma, including a review of the literature on the long-term treatment results. A 62-year-old patient with a history of a resected lentigo-maligna melanoma 5 years earlier and parotideal metastasis 1 year before was admitted with a newly detected 3.5 cm liver metastasis. Atypical liver resection was performed (R1). Immunohistochemically, CD3+ T-lymphocytes and CD68+ macrophages were detected at the tumour margins and within the parotideal and hepatic melanoma metastases. A sub-analysis of the liver metastasis showed scattered FOX-P3+ regulatory T-lymphocytes as well as multiple CD8+ effector T-cells. Chemotherapy with dacarbazine 1,000 mg/m(2)/day was administered at 4-weeks intervals for 3 months. A follow-up positron-emission computed tomography and liver biopsy revealed melanoma metastases in the liver, lungs, and mediastinum. Compassionate use of ipilimumab was administered at 3 mg/kg every 3 weeks for a total of four doses. After an initial increase in tumour size, most lesions responded, but progressive axillary and cervical lymphadenopathy was observed before complete remission was achieved. Side effects included fatigue, dyspnoea, cough, upper abdominal pain with diarrhoea, and gingival hyperplasia. Now, 36 months after ipilimumab therapy and 8 years after the initial melanoma diagnosis, the tumour did not recur. It would be challenging to hypothesize that long intervals between diagnosis and need for treatment, clinical side effects, an initial increase in tumour size and the presence of intra-tumoural T-cells and macrophages might predict tumour response.