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Breast cancer is the most common cancer in females worldwide. Nuclear medicine plays an important role in patient management, not only in initial staging, but also during follow-up. Radiopharmaceuticals to study breast cancer have been used for over 50 years, and several of these are still used in clinical practice, according to the most recent guideline recommendations. In this critical review, an overview of nuclear medicine procedures used during the last decades is presented. Current clinical indications of each of the conventional nuclear medicine and PET/CT examinations are the focus of this review, and are objectively provided. Radionuclide therapies are also referred, mainly summarising the methods to palliate metastatic bone pain. Finally, recent developments and future perspectives in the field of nuclear medicine are discussed. In this context, the promising potential of new radiopharmaceuticals not only for diagnosis, but also for therapy, and the use of quantitative imaging features as potential biomarkers, are addressed. Despite the long way nuclear medicine has gone through, it looks like it will continue to benefit clinical practice, paving the way to improve healthcare provided to patients with breast cancer.

Introduction and objectives To evaluate the migration of 99mTc-tilmanocept from the injection site (IS) as well as the uptake in sentinel nodes (SNs) and non-SNs for lymphatic mapping in patients with breast cancer and melanoma, scheduled for SN biopsy after interstitial tracer administration. Materials and methods For 29 primary tumours in 28 patients (mean age: 62y, range: 45–81y) scheduled for SN biopsy planar images were acquired 10 and 120 min after administration of 74 MBq 99mTc-tilmanocept, in order to evaluate lymphatic drainage as well as uptake ratios between injection site (IS), SN and non-SN. SPECT-CT was performed immediately after delayed planar images to enable anatomical lymph node localization. Results SNs were visualized in all patients (100%) with drainage to 34 basins. Uptake in non-SNs was perceived in 16 basins (47%). Number of SNs was concordant between early and delayed images in all basins excepting five (86%). In 24 patients tracer migrated to one lymph node basin (LNB), in three to 2 and in one to 4. When IS was included (N = 29) on image, IS/SN ratio could be measured per LNB. The IS/SN ratio at 2 h compared to 15 min decreased with an average of 66% (range: 15–96%). SN/non-SN 2 h ratio in LNBs with visible non-SNs averaged 6.6 (range: 2.3–15.6). In 9 patients with two SNs SN1/SN2 ratio averaged 1.9 on delayed images. At histopathology, SNs were found to be tumour positive in 7 basins (20%). Conclusion 99mTc-tilmanocept appears to meet the requirements for improved SN imaging in breast cancer and melanoma on the basis of early and persistent SN visualization frequently accompanied by no or markedly less non-SN uptake. This is associated to rapid migration from the injection site together with increasing SN uptake and retention as expressed by decreasing IS/SN and persistently high SN/non-SN ratios. Further head-to-head comparison of 99mTc-tilmanocept with standard SN radiotracers in larger series of patients is necessary.

Resumen Introduccion y objetivos Evaluar la migracion de 99mTc-tilmanocept desde el punto de inyeccion (PI), asi como la captacion de los ganglios centinela (GC) y no-GC para el mapeo linfatico en pacientes con cancer de mama y melanoma, programados para la biopsia de GC despues de la administracion del trazador intersticial. Materiales y metodos En 29 tumores primarios de 28 pacientes (edad media: 62 anos, intervalo: 45-81 anos) programados para biopsia de GC, se obtuvieron imagenes planares 10 y 120 minutos despues de la administracion de 74 MBq 99mTc-tilmanocept, a fin de evaluar el drenaje linfatico, asi como las relaciones de captacion entre el lugar de la inyeccion, el GC y el no-GC. La SPECT/TC se realizo inmediatamente despues de las imagenes planares tardias para permitir la localizacion anatomica de los ganglios linfaticos. Resultados Se visualizaron GC en todos los pacientes (100%) con drenaje a 34 estaciones. La captacion de los no-GC, se percibio en 16 estaciones (47%). El numero de GC fue concordante entre las imagenes precoces y tardias en todas las estaciones, excepto en cinco (86%). En 24 pacientes, el trazador migro a un ganglio linfatico (LNB), en tres a dos y en uno a cuatro. Cuando se incluyo el PI (n = 29) en la imagen, se pudo medir la proporcion PI/GC por LNB. La proporcion PI/GC a las dos horas, en comparacion con los 15 minutos disminuyo con un promedio del 66% (rango: 15-96%). La proporcion GC/no-GC a las dos horas en LNB con no-GC visibles promedio 6,6 (rango: 2,3-15,6). En nueve pacientes con dos GC, la proporcion media GC1/GC2 1,9 en imagenes tardias. En la histopatologia, se encontro que los GC eran positivos para el tumor en siete estaciones (20%). Conclusion El 99mTc-tilmanocept parece cumplir los requisitos para mejorar las imagenes de GC en el cancer de mama y el melanoma sobre la base de una visualizacion temprana y persistente de GC, frecuentemente acompanada de una captacion nula o marcadamente menor de no -GC. Esto se asocia con una rapida migracion desde el lugar de la inyeccion, junto con una mayor captacion y retencion de GC, expresada mediante la disminucion del IS/SN y la persistencia de altas proporciones de GC/no-GC. Es necesario realizar una comparacion mas detallada entre el radiotrazador de 99mTc-tilmanocept y el radiotrazador de GC estandar en series mas grandes de pacientes.

To report the first experience of our multidisciplinary team with functional imaging usingIn eighteen patients with prolactinoma, referred to our tertiary referral centre because of intolerance or resistance for dopamine agonists (DA), Met-PET/MRIMet-PET/MRIMet-PET/MRI

TO THE EDITOR: In The Netherlands, the residency training programs for nuclear medicine and radiology were merged in 2015. This integrated residency training program was born from the vision that clinicians should not have to deal with multiple imaging specialists who are modality-based and

To investigate the time and effort needed to perform vertebral morphometry, as well as inter-observer agreement for identification of vertebral fractures on vertebral fracture assessment (VFA) images.Ninety-six images were retrospectively selected, and three radiographers independently performed semi-automatic 6-point morphometry. Fractures were identified and graded using the Genant classification. Time needed to annotate each image was recorded, and reader fatigue was assessed using a modified Simulator Sickness Questionnaire (SSQ). Inter-observer agreement was assessed per-patient and per-vertebra for detecting fractures of all grades (grades 1-3) and for grade 2 and 3 fractures using the kappa statistic. Variability in measured vertebral height was evaluated using the intraclass correlation coefficient (ICC).Per-patient agreement was 0.59 for grades 1-3 fracture detection, and 0.65 for grades 2-3 only. Agreement for per-vertebra fracture classification was 0.92. Vertebral height measurements had an ICC of 0.96. Time needed to annotate VFA images ranged between 91 and 540 s, with a mean annotation time of 259 s. Mean SSQ scores were significantly lower at the start of a reading session (1.29; 95% CI: 0.81-1.77) compared to the end of a session (3.25; 95% CI: 2.60-3.90; p 0.001).Agreement for detection of patients with vertebral fractures was only moderate, and vertebral morphometry requires substantial time investment. This indicates that there is a potential benefit for automating VFA, both in improving inter-observer agreement and in decreasing reading time and burden on readers.

We review recent technological advances and new clinical indications for sentinel node (SN) and radioguided surgery in order to delineate future tendencies of interventional nuclear medicine in this field. A literature research was performed in PubMed to select relevant articles to be used as key references for analysis of the current approaches and tendencies in SN and radioguided surgery, as well as the evolving contribution of nuclear medicine intervention techniques to the various clinical applications. For classic indications such as melanoma and breast cancer, the incorporation of the SN approach based on the combined use of existing and new preoperative and intraoperative technologies in high-risk patient categories is becoming an emerging area of clinical indication. For SN biopsy staging in other malignancies with more complex lymphatic drainage, the incorporation of sophisticated tools is most helpful. The consecutive use of PET/CT and the SN procedure is increasing as a potential combined approach for the management of specific areas such as the axilla and the pelvis in patients at high risk of regional dissemination. Also, for the management of locoregional metastasis and oligometastatic disease, interventional nuclear medicine techniques are becoming valuable alternatives. The extended experience with SN biopsy is leading to technological advances facilitating the incorporation of this procedure to stage other malignancies with complex lymphatic drainage. New nuclear medicine-based approaches, incorporating SPECT/CT and PET/CT to guide resection of SNs and occult metastases, have recently been gaining ground.

To evaluate the migration ofFor 29 primary tumours in 28 patients (mean age: 62y, range: 45-81y) scheduled for SN biopsy planar images were acquired 10 and 120min after administration of 74MBqSNs were visualized in all patients (100%) with drainage to 34 basins. Uptake in non-SNs was perceived in 16 basins (47%). Number of SNs was concordant between early and delayed images in all basins excepting five (86%). In 24 patients tracer migrated to one lymph node basin (LNB), in three to 2 and in one to 4. When IS was included (N=29) on image, IS/SN ratio could be measured per LNB. The IS/SN ratio at 2h compared to 15min decreased with an average of 66% (range: 15-96%). SN/non-SN 2h ratio in LNBs with visible non-SNs averaged 6.6 (range: 2.3-15.6). In 9 patients with two SNs SN1/SN2 ratio averaged 1.9 on delayed images. At histopathology, SNs were found to be tumour positive in 7 basins (20%).

Aims/hypothesis: Brown adipose tissue (BAT) improves energy metabolism by combusting glucose and lipids into heat. Agonism of the glucagon-like peptide-1 receptor (GLP-1R) within the central nervous system activates BAT in mice. Moreover, in patients with type 2 diabetes, GLP-1R agonism lowers body weight and improves glucose and lipid levels, possibly involving BAT activation. Interestingly, people from South Asian descent are prone to develop cardiometabolic disease. We studied the effect of GLP-1R agonism on BAT in humans, specifically in South Asians and Europids without obesity or type 2 diabetes. Methods: Twelve Dutch South Asian and 12 age- and BMI-matched Europid nondiabetic men received 12 weeks extended-release exenatide (Bydureon) in this single-arm prospective study. Before and after treatment, BAT was visualized by a cold-induced [18F]FDG-PET/CT scan and a thermoneutral MRI scan, and resting energy expenditure (REE), substrate oxidation, body composition and fasting plasma glucose and serum lipids were determined. Appetite was rated using a visual analogue scale. Results: Since the effect of exenatide on metabolic parameters did not evidently differ between ethnicities, data of all participants were pooled. Exenatide decreased body weight (−1.5 ± 0.4 kg, p < 0.01), without affecting REE or substrate oxidation, and transiently decreased appetite ratings during the first weeks. Exenatide also lowered triglycerides (−15%, p < 0.05) and total cholesterol (−5%, p < 0.05), and tended to lower glucose levels. Notably, exenatide increased BAT metabolic volume (+28%, p < 0.05) and mean standardized uptake value (+11%, p < 0.05) ([18F]FDG-PET/CT), without affecting supraclavicular adipose tissue fat fraction (MRI). Conclusions/interpretation: We show for the first time that GLP-1R agonism increases [18F]FDG uptake by BAT in South Asian and Europid men without obesity or type 2 diabetes. Trial registry: Clinicaltrials.gov NCT03002675.

The axillary lymph node status remains a major prognostic factor in early-stage breast cancer, providing information that is important for tailoring postsurgical treatment. Sentinel lymph node biopsy (SLNB) has radically altered the management of the axilla for patients with early breast cancer, resulting in fewer complications and better quality of life than de novo axillary lymph node dissection. Although SLNB is widely performed in patients with breast cancer, several technical issues such as the choice of the optimal radiopharmaceutical, the site and mode of radiocolloid injection, and the type of preoperative imaging remain a matter of discussion. With optimal preoperative lymphatic mapping high identification rates are achieved, especially when the radiocolloid is combined with blue dye. The performance of SLNB can be further improved with the intraoperative use of portable imaging devices and hybrid approaches, especially in cases of complex drainage. The SLNB procedure is indicated in patients with early-stage breast cancer (cT1-2 tumors) without cytological or histological evidence of axillary lymph node metastases. Controversies remain concerning the application of SLNB in patients with large or multifocal tumors, ductal carcinoma in situ, and recurrent disease. In addition, no consensus exists about the importance of identification and treatment of metastasis in lymph nodes of the internal mammary chain. With the increasing use of neoadjuvant chemotherapy for breast-sparing surgery in patients with locally advanced breast cancer, a new dilemma has arisen concerning appropriate timing of the SLNB procedure in the neoadjuvant setting. The abovementioned issues are discussed in detail in this chapter. In addition, the chapter considers the clinical impact of the SLNB procedure in breast cancer, including the ongoing paradigm shift in axillary management.

PurposeRecent developments in iterative image reconstruction enable absolute quantification of SPECT/CT studies by incorporating compensation for collimator-detector response, attenuation, and scatter as well as resolution recovery into the reconstruction process (Evolution; Q.Metrix package; GE Healthcare, Little Chalfont, UK). The aim of this experimental study is to assess its quantitative accuracy for potential clinical Tc-99m-sestamibi (MIBI)-related SPECT/CT application in neoadjuvant chemotherapy response studies in breast cancer.MethodsTwo phantoms were filled with MIBI and acquired on a SPECT/CT gamma camera (Discovery 670 Pro; GE Healthcare), that is, a water cylinder and a NEMA body phantom containing six spheres that were filled with an activity concentration reflecting clinical MIBI uptake. Subsequently, volumes-of-interest (VOI) of each sphere were drawn (semi)automatically on SPECT using various isocontour methods or manually on CT. Finally, prone MIBI SPECT/CT scans were acquired 5 and 90 min p.i. in a locally advanced breast cancer patient.ResultsActivity concentration in the four largest spheres converged after nine iterations of evolution. Depending on the count statistics, the accuracy of the reconstructed activity concentration varied between -4.7 and -0.16% (VOI covering the entire phantom) and from 6.9% to 10% (8.8 cm ? cylinder VOI placed in the center of the phantom). Recovery coefficients of SUVmax were 1.89 0.18, 1.76 +/- 0.17, 2.00 +/- 0.38, 1.89 +/- 0.35, and 0.90 +/- 0.26 for spheres with 37, 28, 22, 17, and 13 mm ?, respectively. Recovery coefficients of SUVmean were 1.07 +/- 0.06, 1.03 +/- 0.09, 1.17 +/- 0.21, 1.10 +/- 0.20, and 0.52 +/- 0.14 (42% isocontour); 1.10 +/- 0.07, 1.02 +/- 0.09, 1.13 +/- 0.19, 1.06 +/- 0.19, and 0.51 +/- 0.13 (36% isocontour with local background correction); and 0.96, 1.09, 1.03, 1.03, and 0.29 (CT). Patient study results were concordant with the phantom validation.ConclusionsAbsolute SPECT/CT quantification of breast studies using MIBI seems feasible (

Breast cancer (BC) is the most common cancer in women worldwide. In the last years, the contribution of nuclear medicine has grown based on the use of dedicated molecular breast devices for diagnosis and biopsy. Recent technical improvements have been achieved in order to increase the detection of smaller breast lesions using lower doses of radiotracers as well as to facilitate accurate biopsy sampling. Furthermore, new prototypes have been developed combining anatomic and functional imaging. Although the gamma-emitting 99m Tc-sestamibi ( 99m Tc-MIBI) and the positron-emitting 18 F-fluorodeoxyglucose ( 18 F-FDG) are the most widely used radiotracers, several new tracers have been investigated to target more specific biologic features of BC like proliferation, angiogenesis and tumour receptor status. Dedicated molecular breast devices have been introduced as an adjunct imaging tool to mammography (MG) and ultrasound (US) in the clinical work-up for BC. Additionally, due to the increased interest in molecular tumour subtype analysis and ribonucleic acid (RNA)-based gene expression profiling tests in the routine clinical practice, a possible new clinical application of dedicated breast imaging concerns locally advanced BC, principally in order to visualise intra-tumour metabolic heterogeneity enabling selection of areas with highest tracer uptake (vital tissue) for core needle biopsy. Hence, it will be possible to more adequately tailor the individual treatment, also enabling therapy response monitoring. This review evaluates the current and future perspectives as well as the shortcomings of breast imaging using dedicated nuclear medicine devices.

Purpose: To investigate the clinical utility of molecular breast imaging (MBI) in patients with proven invasive breast cancer scheduled for breast-conserving surgery (BCS). Methods: Following approval by the institutional review board and written informed consent, records of patients with newly diagnosed breast cancer scheduled for BCS who had undergone MBI for local staging in the period from March 2012 till December 2014 were retrospectively reviewed. Results: A total of 287 women (aged 30–88 years) were evaluated. MBI showed T stage migration in 26 patients (9%), with frequent detection of in situ carcinoma around the tumor. Surgical management was adjusted in 14 of these patients (54%). In 17 of 287 patients (6%), MBI revealed 21 proven additional lesions in the ipsilateral, contralateral breast or both. In 18 of these additional foci (86%), detected in 15 patients, malignancy was found. Thirteen of these 15 patients had ipsilateral cancer and 2 patients bilateral malignancy. In total, MBI revealed a larger tumor extent, additional tumor foci or both in 40 patients (14%), leading to treatment adjustment in 25 patients (9%). Conclusion: MBI seems to be a useful imaging modality with a high predictive value in revealing ipsilateral and bilateral disease not visualized by mammography and ultrasound. It may play an important role in delineating the extent of the index lesion during preoperative planning. Incorporation of MBI in the clinical work-up as an adjunct modality to mammography and ultrasound may lead to better selection of patients who could benefit from BCS.

OBJECTIVE. The purpose of this study is to evaluate a new device using molecular breast imaging (MBI) for 99mTc-sestamibi-guided stereotactic lesion localization as a complementary biopsy tool. MATERIALS AND METHODS. From December 2012 to May 2016, a total of 38 consecutive women (mean age, 59 years; range, 41-77 years) underwent 99mTc-sestamibi-guided biopsy using a new MBI-based device and were retrospectively reviewed. The biopsy modality used five steps: Stereotactic localization of the 99mTc-sestamibi-avid lesion, calculation of coordinates of the lesion location using dedicated software, placement of the needle, verification of the correct needle position, and tissue sampling with a vacuum-assisted device followed by placement of a radiologic marker at the biopsy site and ex vivo measurement of the biopsy specimens. RESULTS. The procedure was technically successful in all 38 lesions. In all cases, biopsy samples were radioactive and adequate for histopathologic analysis. Nineteen lesions (50%) were found to be malignant, and the remaining lesions were found to be benign. The mean procedure time was 71 minutes (range, 44-112 minutes). The radiologic marker was successfully deployed in 37 lesions (97%). Two hematomas and three vasovagal reactions were observed. CONCLUSION. Technetium-99m sestamibi-guided biopsy performed using a dedicated MBI-based device is technically feasible and represents a valuable complementary biopsy tool in breast lesion diagnosis.

Background Marking the axilla with radioactive iodine seed and sentinel lymph node (SLN) biopsy have been proposed for axillary staging after neoadjuvant systemic therapy in clinically node‐positive breast cancer. This study evaluated the identification rate and detection of residual disease with combined excision of pretreatment‐positive marked lymph nodes (MLNs) together with SLNs. Methods This was a multicentre retrospective analysis of patients with clinically node‐positive breast cancer undergoing neoadjuvant systemic therapy and the combination procedure (with or without axillary lymph node dissection). The identification rate and detection of axillary residual disease were calculated for the combination procedure, and for MLNs and SLNs separately. Results At least one MLN and/or SLN(s) were identified by the combination procedure in 138 of 139 patients (identification rate 99·3 per cent). The identification rate was 92·8 per cent for MLNs alone and 87·8 per cent for SLNs alone. In 88 of 139 patients (63·3 per cent) residual axillary disease was detected by the combination procedure. Residual disease was shown only in the MLN in 20 of 88 patients (23 per cent) and only in the SLN in ten of 88 (11 per cent), whereas both the MLN and SLN contained residual disease in the remainder (58 of 88, 66 per cent). Conclusion Excision of the pretreatment‐positive MLN together with SLNs after neoadjuvant systemic therapy in patients with clinically node‐positive disease resulted in a higher identification rate and improved detection of residual axillary disease., Replacing axillary lymph node dissection with less invasive axillary staging procedures in patients with clinically node‐positive breast cancer treated with neoadjuvant systemic therapy is debated. Implementation of several different less invasive procedures is ongoing at some centres. In this cohort, the identification rate and detection of residual disease of combined excision of the pretreatment‐positive marked lymph node with the sentinel lymph nodes were evaluated, and compared with excising only the marked lymph node or the sentinel lymph nodes alone. Combination superior

Brown adipose tissue (BAT) improves energy metabolism by combusting glucose and lipids into heat. Agonism of the glucagon-like peptide-1 receptor (GLP-1R) within the central nervous system activates BAT in mice. Moreover, in patients with type 2 diabetes, GLP-1R agonism lowers body weight and improves glucose and lipid levels, possibly involving BAT activation. Interestingly, people from South Asian descent are prone to develop cardiometabolic disease. We studied the effect of GLP-1R agonism on BAT in humans, specifically in South Asians and Europids without obesity or type 2 diabetes.Twelve Dutch South Asian and 12 age- and BMI-matched Europid nondiabetic men received 12 weeks extended-release exenatide (Bydureon) in this single-arm prospective study. Before and after treatment, BAT was visualized by a cold-induced [Since the effect of exenatide on metabolic parameters did not evidently differ between ethnicities, data of all participants were pooled. Exenatide decreased body weight (-1.5 ± 0.4 kg, p 0.01), without affecting REE or substrate oxidation, and transiently decreased appetite ratings during the first weeks. Exenatide also lowered triglycerides (-15%, p 0.05) and total cholesterol (-5%, p 0.05), and tended to lower glucose levels. Notably, exenatide increased BAT metabolic volume (+28%, p 0.05) and mean standardized uptake value (+11%, p 0.05) ([We show for the first time that GLP-1R agonism increases [Clinicaltrials.gov NCT03002675.

This case highlights the use of lymphoscintigraphy with SPECT/CT in patients with previous chest and/or axillary surgery. A 67-year-old woman with a history of left breast carcinoma treated with lumpectomy and radiotherapy, and a second lumpectomy of the ipsilateral breast for a second breast carcinoma, underwent a lymphoscintigraphy for a new left breast lesion. Planar images visualized an alternative lymphatic drainage to the contralateral axilla and to the left paravertebral area. SPECT/CT confirmed sentinel nodes in both stations.

This study investigated whether radiomic features derived from preoperative PET images could predict both tumor biology and prognosis in women with invasive squamous cell carcinoma of the vulva. Methods: Patients were retrospectively included if they had a unifocal primary cancer at least 2.6 cm in diameter, received a preoperative 18F-FDG PET/CT scan followed by surgery, and had at least 6 mo of follow-up data. 18F-FDG PET images were analyzed by semiautomatically drawing a volume of interest on the primary tumor in each PET image, followed by extraction of 83 radiomic features. Unique radiomic features were identified by principal-component analysis (PCA), after which they were compared with histopathology using nonpairwise group comparison and linear regression. Univariate and multivariate Cox regression analyses were used to correlate the identified features with progression-free survival (PFS) and overall survival (OS). Survival curves were estimated using the Kaplan–Meier method. Results: Forty women were included. PCA revealed 4 unique radiomic features, which were not associated with histopathologic characteristics such as grade, depth of invasion, lymph-vascular space invasion, and metastatic lymph nodes. No statistically significant correlation was found between the identified features and PFS. However, Moran’s I, a feature that identifies global spatial autocorrelation, correlated with OS (P = 0.03). Multivariate Cox regression analysis showed that extracapsular invasion of the metastatic lymph nodes and Moran’s I were independent prognostic factors for PFS and OS. Conclusion: Our data show that PCA is usable to identify specific radiomic features. Although the identified features did not correlate strongly with tumor biology, Moran’s I was found to predict patient prognosis. Larger studies are required to establish the clinical relevance of the observed findings.

This study investigated whether radiomic features derived from preoperative PET images could predict both tumor biology and prognosis in women with invasive squamous cell carcinoma of the vulva. Methods: Patients were retrospectively included if they had a unifocal primary cancer at least 2.6 cm in diameter, received a preoperative (18)F-FDG PET/CT scan followed by surgery, and had at least 6 mo of follow-up data. (18)F-FDG PET images were analyzed by semiautomatically drawing a volume of interest on the primary tumor in each PET image, followed by extraction of 83 radiomic features. Unique radiomic features were identified by principal-component analysis (PCA), after which they were compared with histopathology using nonpairwise group comparison and linear regression. Univariate and multivariate Cox regression analyses were used to correlate the identified features with progression-free survival (PFS) and overall survival (OS). Survival curves were estimated using the Kaplan–Meier method. Results: Forty women were included. PCA revealed 4 unique radiomic features, which were not associated with histopathologic characteristics such as grade, depth of invasion, lymph-vascular space invasion, and metastatic lymph nodes. No statistically significant correlation was found between the identified features and PFS. However, Moran’s I, a feature that identifies global spatial autocorrelation, correlated with OS (P = 0.03). Multivariate Cox regression analysis showed that extracapsular invasion of the metastatic lymph nodes and Moran’s I were independent prognostic factors for PFS and OS. Conclusion: Our data show that PCA is usable to identify specific radiomic features. Although the identified features did not correlate strongly with tumor biology, Moran’s I was found to predict patient prognosis. Larger studies are required to establish the clinical relevance of the observed findings.

In breast cancer, interest in technetium-99m (Tc-99m) sestamibi-based therapy monitoring is increasing owing to the growing use of Tc-99m-sestamibi-based molecular breast imaging. In the present meta-analysis of 529 patients, Tc-99m-sestamibi planar imaging showed low sensitivity for predicting a pathologic nonresponse to neoadjuvant chemotherapy. In contrast, Tc-99m-sestamibi imaging performed during treatment seemed highly sensitive for the prediction of nonresponse. New tools incorporating quantitative single photon emission computed tomography/computed tomography need to be explored.Background: Interest in technetium-99m (Tc-99m)-sestamibi imaging for neoadjuvant chemotherapy (NAC) response monitoring in locally advanced breast cancer (LABC) is increasing but remains matter of discussion. The present study conducted a meta-analysis of the diagnostic performance of Tc-99m-sestamibi to predict pathologic nonresponse to NAC for primary LABC. Materials and Methods: A systematic data search was performed. Studies with a minimum of 10 LABC patients that had evaluated Tc-99m-sestamibi imaging for NAC nonresponse using conventional planar scintimammography, breast-specific gamma-imaging, and/or single photon emission computed tomography/computed tomography (SPECT/CT) were included. The histopathologic findings were the reference standard. The meta-analysis was performed using a mixed logistic regression model. Results: The search revealed 14 eligible studies with 529 patients. Of the 14 studies, 11 had evaluated scintimammography and 3 breast-specific gamma-imaging. No studies examining SPECT or SPECT/CT were found. The overall estimated pooled sensitivity, specificity, and positive and negative likelihood ratios of Tc-99m-sestamibi imaging to predict nonresponsiveness to NAC were 70.3% (95% confidence interval [CI], 56.5%-81.3%%), 90.1% (95% CI, 77.5%-96.0%), 7.13 (95% CI, 3.08-16.53), and 0.33 (95% CI, 0.22-0.49), respectively. Only 3 studies (107 patients) evaluated Tc-99m-sestamibi imaging during NAC, reported an estimated pooled sensitivity of 87% (95% CI, 72%-100%) and specificity of 93% (95% CI, 85%-100%). Conclusion: Only planar Tc-99m-sestamibi imaging has been investigated for NAC nonresponse in LABC but showed low sensitivity to predict pathologic nonresponse. However, most studies focused on the prediction of pathologic complete response after NAC. Although experience is limited, Tc-99m-sestamibi uptake during NAC seems highly sensitivity for the prediction of nonresponsiveness. Features such as SPECT/CT imaging, standardized quantification, relation to tumor subtypes, and proper timing have been insufficiently evaluated and require further investigation. (C) 2017 Elsevier Inc. All rights reserved.

The aim of this study was to evaluate the effect of sitagliptin on glucose tolerance, plasma lipids, energy expenditure and metabolism of brown adipose tissue (BAT), white adipose tissue (WAT) and skeletal muscle in overweight individuals with prediabetes (impaired glucose tolerance and/or impaired fasting glucose). One participant from the sitagliptin group was excluded from analysis, due to a distribution error, leaving 29 participants for further analysis. Sitagliptin, but not placebo, lowered glucose excursion (−40%; p < 0.003) during OGTT, accompanied by an improved insulinogenic index (+38%; p < 0.003) and oral disposition index (+44%; p < 0.003). In addition, sitagliptin lowered serum concentrations of triacylglycerol (−29%) and very large (−46%), large (−35%) and medium-sized (−24%) VLDL particles (all p < 0.05). Body weight, body composition and energy expenditure did not change. In skeletal muscle, sitagliptin increased mRNA expression of PGC1β (also known as PPARGC1B) (+117%; p < 0.05), a main controller of mitochondrial oxidative energy metabolism. Although the primary endpoint of change in BAT volume and activity was not met, sitagliptin increased [18F] FDG uptake in subcutaneous WAT (sWAT; +53%; p < 0.05). Reported side effects were mild and transient and not necessarily related to the treatment. Twelve weeks of sitagliptin in overweight, Europid men with prediabetes improves glucose tolerance and lipid metabolism, as related to increased [18F] FDG uptake by sWAT, rather than BAT, and upregulation of the mitochondrial gene PGC1β in skeletal muscle. Studies on the effect of sitagliptin on preventing or delaying the progression of prediabetes into type 2 diabetes are warranted., This work was supported in part by a research grant to PCNR fromthe Investigator Initiated Studies Programof Merck Sharp&Dohme Corp (IIS no. 51292). PCNR is an Established Investigator of the Dutch Heart Foundation (grant 2009T038). MRB is supported by a Dutch Diabetes Research Foundation Fellowship (grant 2015.81.1808). This collaboration project is also supported in part by the Ministry of Economic Affairs by means of the PPP Allowance made available by the Top Sector Life Sciences & Health to stimulate public–private partnerships. BMT and JRR are supported by University of Granada, Plan Propio de Investigacion 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES). This work was also supported by the Netherlands CardioVascular Research Initiative: ‘the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organisation for Health Research and Development and the Royal Netherlands Academy of Sciences’ for the GENIUS-II project ‘Generating the best evidence-based pharmaceutical targets for atherosclerosis’ (CVON2017-20).

Human brown adipose tissue (BAT) is commonly assessed by cold-induced 18F-fluorodeoxyglucose (FDG) PET-CT using several quantification criteria. Uniform criteria for data analysis became available recently (BARCIST 1.0). We compared BAT volume and activity following BARCIST 1.0 criteria against the most commonly used criteria [Hounsfield Units (HU):-250, -50, standardized uptake value (SUV):2.0; HU: Not applied, SUV:2.0 and HU:-180, -10, SUV:1.5] in a prospective study using three independent cohorts of men including young lean adults, young overweight/obese adults and middle-aged overweight/obese adults. BAT volume was the most variable outcome between criteria. While BAT volume calculated using the HU: NA; SUV: 2.0 criteria was up to 207% higher than the BAT volume calculated based on BARCIST 1.0 criteria, it was up to 57% lower using the HU: -250, -50; SUV: 2.0 criteria compared to the BARCIST 1.0. Similarly, BAT activity (expressed as SUVmean) also differed between different thresholds mainly because SUVmean depends on BAT volume. SUVpeak was the most consistent BAT outcome across the four study criteria. Of note, we replicated these findings in three independent cohorts. In conclusion, BAT volume and activity as determined by 18F-FDG-PET/CT highly depend on the quantification criteria used. Future human BAT studies should conduct sensitivity analysis with different thresholds in order to understand whether results are driven by the selected HU and/or SUV thresholds. The design of the present study precludes providing any conclusive threshold, but before more definitive thresholds for HU and SUV are available, we support the use of BARCIST 1.0 criteria to facilitate interpretation of BAT characteristics between research groups.

Introduction Brown adipose tissue (BAT) recently emerged as a potential therapeutic target in the treatment of obesity and associated disorders due to its fat-burning capacity. The current gold standard in assessing BAT activity is [18F]FDG PET-CT scan, which has severe limitations including radiation exposure, being expensive, and being labor-intensive. Therefore, indirect markers are needed of human BAT activity and volume. Objective We aimed to identify metabolites in serum that are associated with BAT volume and activity in men. Methods We assessed 163 metabolites in fasted serum of a cohort of twenty-two healthy lean men (age 24.1 (21.7–26.6) years, BMI 22.1 (20.5–23.4) kg/m2) who subsequently underwent a cold-induced [18F]FDG PET-CT scan to assess BAT volume and activity. In addition, we included three replication cohorts consisting of in total thirty-seven healthy lean men that were similar with respect to age and BMI compared to the discovery cohort. Results After correction for multiple testing, fasting concentrations of lysophosphatidylcholine-acyl (LysoPC-acyl) C16:1, LysoPC-acyl C16:0 and phosphatidylcholine-diacyl C32:1 showed strong positive correlations with BAT volume (β= 116 (85–148) mL, R2 = 0.81, p = 4.6 × 10−7 ; β = 79 (93–119) mL, R2 = 0.57, p = 5.9 × 10−4 and β= 91 (40–141) mL, R2 = 0.52, p = 1.0 × 10−3, respectively) as well as with BAT activity (β= 0.20 (0.11–0.29) g/mL, R2 = 0.59, p = 1.9 × 10−4; β = 0.15 (0.06–0.23) g/mL, R2 = 0.47, p = 2.0 × 10−3 and β= 0.13 (0.01–0.25) g/mL, R2 = 0.28, p = 0.04, respectively). When tested in three independent replication cohorts (total n = 37), the association remained significant between LysoPC-acyl C16:0 and BAT activity in a pooled analysis (β= 0.15 (0.07–0.23) g/mL, R2 = 0.08, p = 4.2 × 10−4). Conclusions LysoPC-acyl C16:0 is associated with BAT activity in men. Since BAT is regarded as a promising tool in the battle against obesity and related disorders, the identification of such a noninvasive marker is highly relevant. Electronic supplementary material The online version of this article (doi:10.1007/s11306-017-1185-z) contains supplementary material, which is available to authorized users.

The purpose of this study is to evaluate a new device using molecular breast imaging (MBI) forFrom December 2012 to May 2016, a total of 38 consecutive women (mean age, 59 years; range, 41-77 years) underwentThe procedure was technically successful in all 38 lesions. In all cases, biopsy samples were radioactive and adequate for histopathologic analysis. Nineteen lesions (50%) were found to be malignant, and the remaining lesions were found to be benign. The mean procedure time was 71 minutes (range, 44-112 minutes). The radiologic marker was successfully deployed in 37 lesions (97%). Two hematomas and three vasovagal reactions were observed.Technetium-99m sestamibi-guided biopsy performed using a dedicated MBI-based device is technically feasible and represents a valuable complementary biopsy tool in breast lesion diagnosis.

Purpose This review aims to discuss the methodological aspects of dedicated molecular breast imaging (MBI) using 99mTc-sestamibi as radiotracer to guide biopsy of occult or unclear breast lesions on mammography (MG) and ultrasound (US) that are suspicious on MBI (BI-RADS criteria 4 and 5), including its advantages, limitations and future clinical applications. Methods Literature search was performed using the PubMed/MEDLINE database and “99mTc-sestamibi”, “biopsy” and “breast cancer” as keywords. The search was restricted to English language. Results There are few studies on 99mTc-sestamibi guided biopsy methods; to our knowledge, no full studies have yet been reported on clinical validation of this new biopsy procedure. This review describes technical aspects of 99mTc-sestamibi guided biopsy and discusses the advantages and limitations of this procedure in comparison with MG, US and MRI-guided biopsy. Conclusions MBI-guided biopsy appears to be a complementary modality and is principally indicated in the case of occult or unclear breast lesions on MG/US, that are suspicious on MBI. The future indication is in targeted biopsies in patients with large heterogeneous tumours. Further studies are needed to define the accuracy of this biopsy procedure.

Breast-specific gamma imaging (BSGI) is a new technique in nuclear medicine for the diagnosis of breast cancer. After intravenous injection of the radioactive substance 99mTc-sestamibi the breasts are imaged with a gamma camera. The radionuclide assimilates into intracellular mitochondria, which are present in greater numbers in breast cancer cells than in normal cells. This causes a relatively high uptake of the radionuclide in tumours. Along with mammography and ultrasound, MRI is the current gold standard in breast imaging diagnostics. However, MRI is a complex and expensive procedure and has low specificity leading to high false-positive rates. BSGI has equally high sensitivity but is more specific, cheaper and much simpler to interpret. BSGI could replace MRI as a complementary technique to show, exclude or indicate the extent of breast cancer.

Introduction.18F-FDG-PET visualises inflammation. Both atherosclerosis and giant cell arteritis cause vascular inflammation, but distinguishing the two may be difficult. The goal of this study was to assess interobserver agreement and diagnostic accuracy of18F-FDG-PET for the detection of large artery involvement in giant cell arteritis (GCA).Methods. 3118F-FDG-PET/CT scans were selected from 2 databases. Four observers assessed vascular wall18F-FDG uptake, initially without and subsequently with predefined observer criteria (i.e., vascular wall18F-FDG uptake compared to liver or femoral artery18F-FDG uptake). External validation was performed by two additional observers. Sensitivity and specificity of18F-FDG-PET were determined by comparing scan results to a consensus diagnosis.Results. The highest interobserver agreement (kappa: 0.96 in initial study and 0.79 in external validation) was observed when vascular wall18F-FDG uptake higher than liver uptake was used as a diagnostic criterion, although agreement was also good without predefined criteria (kappa: 0.68 and 0.85). Sensitivity and specificity were comparable for these methods. The criterion of vascular wall18F-FDG uptake equal to liver18F-FDG uptake had low specificity.Conclusion. Standardization of image assessment for vascular wall18F-FDG uptake promotes observer agreement, enables comparative studies, and does not appear to result in loss of diagnostic accuracy compared to nonstandardized assessment.

In sports medicine, foot disorders present a significant clinical challenge due to the complex anatomy and function of the foot. Injuries are complex involving soft tissue as well as bony structures. Bone scintigraphy is a sensitive technique, which provides essential functional information which correlates better with clinical symptoms and treatment response than anatomical abnormalities. It is a useful tool to detect conditions affecting the bony structures of the foot in an early phase, but can also be helpful in the initial evaluation of soft tissue injuries. MRI though remains better in delineating most soft tissue injuries. The emergence of SPECT-CT has increased the accuracy of bone scintigraphy. This is particularly true for the recently developed hybrid systems, which are capable of acquiring high-resolution multislice CT images. Bone SPECT-CT has shown to have incremental value in orthopedic conditions and sports injuries. However, one should be aware of the fact that available evidence concerning the clinical value of bone SPECT-CT in sports injuries in the foot is scarce; especially the specificity of the technique needs to be further elucidated.

OBJECTIVE Most patients with differentiated thyroid carcinoma (DTC) undergo total thyroidectomy followed by routine radioiodide thyroid remnant ablation. Most centres that routinely perform radioiodide ablation prescribe a low-iodide diet (LID) to increase the radioiodide accumulation in thyroid remnants. The efficacy of an LID on thyroid remnant ablation, however, has never been demonstrated convincingly. DESIGN AND METHODS In a retrospective study, we studied two groups of DTC patients without distant metastases, who had received either a standard diet or an LID during ablation (LID group, n = 59, and control group, n = 61). Both groups were compared for radioiodide uptake in thyroid remnants during ablation and efficacy parameters of remnant ablation, 6 months after ablation. A subgroup without extrathyroidal tumour growth was analysed separately (stages T1-3, NO). RESULTS In the total group, the LID during ablation decreased the 24-h urinary iodide excretion to 26.6 μg compared with 158.8 μg in controls whereas radioiodide uptake in thyroid remnants was increased by 65% (P < 0.001). Six months after ablation, patients were investigated after thyroid hormone withdrawal. In the total group, no significant effects of the LID during ablation were observed on thyroglobulin (Tg) or the percentage of patients with persistent neck activity after 185 MBq 131 I. However, in the LID group, 65% of patients without Tg antibodies had undergone successful ablation (defined by absent neck activity and Tg

Summary introduction Depot preparations of long-acting somatostatin analogues are being used increasingly in the treatment of GH hypersecretion in patients with acromegaly, either as primary treatment or as secondary treatment following incomplete surgery. In 60% of these patients, Sandostatin long-acting release (LAR), the depot preparation of octreotide, achieves effective suppression of serum GH (

BackgroundBrown adipose tissue (BAT) has emerged as a novel player in energy homeostasis in humans and is considered a potential new target for combating obesity and related diseases. The current 'gold standard' for quantification of BAT volume and activity is cold-induced 18F-FDG uptake in BAT. However, use of this technique is limited by cost and radiation exposure. Given the fact that BAT is a thermogenic tissue, mainly located in the supraclavicular region, the aim of the current study was to investigate whether cold-induced supraclavicular skin temperature and core body temperature may be alternative markers of BAT activation in humans.Subjects/methodsBAT volume and activity were measured in 24 healthy lean adolescent males (mean age 24.1±0.8 years), using cold-induced 18F-FDG uptake with PET-CT. Core body temperature was measured continuously in the small intestine with use of an ingestible telemetric capsule and skin temperature was measured by eighteen wireless iButtons attached to the skin following ISO-defined locations.ResultsProximal and distal (hand/feet) skin temperatures markedly decreased upon cold exposure, while supraclavicular skin temperature significantly increased (35.2±0.1 vs. 35.5±0.1°C, p = 0.001). Furthermore, cold-induced supraclavicular skin temperature positively correlated with both total (R2 = 0.28, P = 0.010) and clavicular BAT volume (R2 = 0.20, P = 0.030) and clavicular SUVmax (R2 = 0.27, P = 0.010), while core body temperature did not.ConclusionsSupraclavicular skin temperature as measured by iButtons may have predictive value for BAT detection in adult humans. This is highly desirable considering the increasing interest in pharmacological interventions to stimulate BAT in human subjects.Trial registrationNTR 2473.

BACKGROUND: Individuals of south Asian origin have a very high risk of developing type 2 diabetes compared with white Caucasians. We aimed to assess volume and activity of brown adipose tissue (BAT), which is thought to have a role in energy metabolism by combusting fatty acids and glucose to produce heat and might contribute to the difference in incidence of type 2 diabetes between ethnic groups. METHODS: We enrolled Dutch nationals with south Asian ancestry and matched Caucasian participants at The Rijnland Hospital (Leiderdorp, Netherlands). Eligible participants were healthy lean men aged 18-28 years, and we matched groups for BMI. We measured BAT volume and activity with cold-induced (18)F-fluorodeoxyglucose ((18)F-FDG) PET CT scans, and assessed resting energy expenditure, non-shivering thermogenesis, and serum parameters. This study is registered with the Netherlands Trial Register, number 2473. FINDINGS: Between March 1, 2013, and June 1, 2013, we enrolled 12 participants in each group; one Caucasian participant developed hyperventilation after (18)F-FDG administration, and was excluded from all cold-induced and BAT measurements. Compared with Caucasian participants, south Asian participants did not differ in age (mean 23.6 years [SD 2.8] for south Asians vs 24.6 years [2.8] for Caucasians) or BMI (21.5 kg/m(2) [2.0] vs 22.0 kg/m(2) [1.6]), but were shorter (1.74 m [0.06] vs 1.85 m [0.04]) and lighter (65.0 kg [8.5] vs 75.1 kg [7.2]). Thermoneutral resting energy expenditure was 1297 kcal per day (SD 123) in south Asian participants compared with 1689 kcal per day (193) in white Caucasian participants (difference -32%, p=0.0008). On cold exposure, shiver temperature of south Asians was 2.0 degrees C higher than Caucasians (p=0.0067) and non-shivering thermogenesis was increased by 20% in white Caucasians (p

In healthy subjects, basal endogenous glucose production is partly regulated by paracrine intrahepatic factors. It is currently unknown whether paracrine intrahepatic factors also influence the increased basal endogenous glucose production in patients with type 2 diabetes mellitus. Administration of indomethacin to patients with type 2 diabetes mellitus stimulates endogenous glucose production and inhibits insulin secretion. Our aim was to evaluate whether this stimulatory effect on glucose production is solely attributable to inhibition of insulin secretion. In order to do this, we administered indomethacin to 5 patients with type 2 diabetes during continuous infusion of somatostatin to block endogenous insulin and glucagon secretion and infusion of basal concentrations of insulin and glucagon in a placebo-controlled study. Endogenous glucose production was measured 3 hours after the start of the somatostatin, insulin and glucagon infusion, for 4 hours after administration of placebo/indomethacin, by primed, continuous infusion of [6,6-(2)H(2)] glucose. At the time of administration of placebo or indomethacin, there were no significant differences in plasma glucose concentrations and endogenous glucose production rates between the two experiments (16.4 +/- 2.09 mmol/l vs. 16.6 +/- 1.34 mmol/l and 17.7 +/- 1.05 micromol/kg/min and 17.0 +/- 1.06 micromol/kg/min), control vs. indomethacin). Plasma glucose concentration did not change significantly in the four hours after indomethacin or placebo administration. Endogenous glucose production in both experiments was similar after both placebo and indomethacin. Mean plasma C-peptide concentrations were all below the detection limit of the assay, reflecting adequate suppression of endogenous insulin secretion by somatostatin. There were no differences in plasma concentrations of insulin (76 +/- 5 vs. 74 +/- 4 pmol/l) and glucagon (69 +/- 8 vs. 71 +/- 6 ng/l) between the studies with levels remaining unchanged in both experiments. Plasma concentrations of cortisol, epinephrine, and norepinephrine were similar in the two studies and did not change significantly. We conclude that indomethacin stimulates endogenous glucose production in patients with type 2 diabetes mellitus by inhibition of insulin secretion.

In healthy subjects, paracrine factors partly regulate insulin secretion and basal endogenous glucose production. Administration of pentoxifylline, an adenosine receptor antagonist, inhibits transiently endogenous glucose production in healthy humans without any changes in glucoregulatory hormone concentrations. To evaluate the modulatory role of adenosine on endogenous glucose production and basal insulin secretion in type 2 diabetes, aminophylline, a potent adenosine receptor antagonist, was administered intravenously to 5 patients with type 2 diabetes mellitus in a saline-controlled study. Endogenous glucose production was measured before and during 6 hours after administration of aminophylline/saline by primed, continuous infusion of [6,6-2H2]glucose. During both experiments, the decrease in plasma glucose concentration was similar (16% v 18% from basal, not significant [NS]). After aminophylline administration, basal endogenous glucose production was transiently inhibited within 15 minutes to 70% from basal, whereas it did not change significantly in the control experiment (P = .02). The inhibition of glucose production coincided with stimulation of insulin secretion to 144% from basal 90 minutes after the administration of aminophylline (P = .008). In the control experiment insulin secretion decreased gradually by 29% during 6 hours. We conclude that aminophylline inhibits endogenous glucose production in type 2 diabetes by stimulation of insulin secretion. Paracrine factors, such as adenosine, may be involved in the regulation of basal insulin secretion in type 2 diabetes mellitus.

The rising incidence of tuberculosis worldwide means an increasing burden on diagnostic facilities, so tests simpler than Ziehl-Neelsen staining are needed. Such tests should be objective, reproducible, and have at least as good a detection limit as 10 4 bacteria/ml. A capture enzyme-linked immunosorbent assay (ELISA) was developed for detection of lipoarabinomannan (LAM) in human sputum samples. As a capture antibody, we used a murine monoclonal antibody against LAM, with rabbit antiserum against Mycobacterium tuberculosis as a source of detector antibodies. The sensitivity of the capture ELISA was evaluated by using purified LAM and M. tuberculosis whole cells. We were able to detect 1 ng of purified LAM/ml and 10 4 M. tuberculosis whole cells/ml. LAM could also be detected in culture filtrate of a 3-week-old culture of M. tuberculosis . The culture filtrate contained approximately 100 μg of LAM/ml. The detection limit in sputum pretreated with N -acetyl- l -cysteine and proteinase K was 10 4 M. tuberculosis whole cells per ml. Thirty-one (91%) of 34 sputum samples from 18 Vietnamese patients with tuberculosis (32 smear positive and 2 smear negative) were positive in the LAM detection assay. In contrast, none of the 25 sputum samples from 21 nontuberculous patients was positive. This specific and sensitive assay for the detection of LAM in sputum is potentially useful for the diagnosis of tuberculosis.

Objective: Whole body hyperthermia (WBH) in combination with chemotherapy is a relatively new promising treatment modality for patients with cancer. The objective of this report is to present the development of an acute systemic inflammatory response syndrome (SIRS) with multiple organ dysfunction syndrome (MODS) following WBH in combination with chemotherapy. Although WBH can also induce cytokine production, MODS has not been described before in association with WBH. Design: Case report. The patient was treated with WBH (core temperature 41.8 °C using a radiant heat device (Aquatherm) ) in combination with polychemotherapy (ifosfamide, carboplatin and etoposide (ICE) ) in the context of a clinical trial for metastatic sarcomas. Setting: Department of Medical Oncology and Intensive Care Unit of a university hospital. Patient: A 58-year-old Caucasian woman treated for disseminated leiomyosarcoma of the uterus, who developed SIRS with brain dysfunction, hypotension, respiratory failure and renal dysfunction following WBH/ICE. Interventions: She was successfully treated in the Intensive Care Unit by mechanical ventilation, inotropics and antibiotics. Measurements and results: There was a remarkable recovery within 2 days: she regained full conciousness, could be extubated, inotropic support was stopped and creatinine levels returned to pre-treatment levels. All cultures remained sterile. After almost complete recovery, 5 days later a second episode of fever during neutropenia occurred and, despite antibiotic treatment, she died of Bacteroides distasonis sepsis. Conclusion: WBH should be added as a new cause to the already known list of physical-chemical insults which can result in MODS.

Buruli ulcers have not been previously described in China, and only once at higher latitudes on the northern hemisphere. A patient who travelled in the Shan Dong Province in the People's Republic of China developed an ulcer which was proven to be a Buruli ulcer. The clinical picture and histopathological findings from biopsy specimens are characteristic for a Buruli ulcer, and also the growth in culture (Coletsos medium) at a restricted temperature of 30 degrees C. A multiplex polymerase chain reaction (PCR) based on the amplification of the gene encoding for 16S ribosomal RNA and a nested PCR based on the Mycobacterium ulcerans specific repeated sequence 2404 were performed. These PCR investigations identified the bacteria as M. ulcerans, subspecies shinshuense. The patient was initially treated with clarithromycin and rifampicin, which was changed to ciprofloxacin and rifabutin when rifampicin resistance of the first isolate was established. There were no signs of reactivation of the disease 6 months after the end of treatment. M. ulcerans infection occurs above 30 degrees latitude on the northern hemisphere in China and is caused by M. ulcerans, subspecies shinshuense. This case appears to be cured by chemotherapy alone, in contrast to the general experience that surgical treatment is indicated. The granulomatous reaction with only fragments of acid-fast bacteria in the biopsy at the end of treatment many indicate the development of an adequate cell-mediated immune response leading to resistance to the infection.

Summary We studied whether serum interferon (IFN)-γ or interleukin (IL)-10 levels and their corresponding functional polymorphic genotypes are associated with partial remission of type 1 diabetes (T1D). A multi-centre study was undertaken in patients with newly diagnosed T1D and matched controls. T1D patients were followed for 3 months and characterized for remission status. Partial clinical remission was defined as a daily insulin dose ≤ 0.38 units/kg/24 h with an HbA1c ≤ 7.5%. Thirty-three patients and 32 controls were phenotyped for serum concentrations of IFN-γ and IL-10 and genotyped for functional polymorphisms of the IFN-γ and IL-10 genes. Sixteen of 25 informative patients (63%) remitted. Serum IFN-γ concentrations were significantly decreased in remitters but increased in non-remitters compared to controls, and did not change over time in any group. IFN-γ genotypes corresponded with serum levels in controls and non-remitters, but not in remitters who displayed the lowest serum IFN-γ levels despite more often carrying high-producing IFN-γ genotypes. Neither the frequency of IL-10 genotypes nor serum IL-10 concentration differed between patients and controls. The combination of high-producing IFN-γ genotype together with low serum IFN-γ concentration at the time of diagnosis provided a strong positive predictive value for remission. Serum IFN-γ concentrations predicted by genotype and observed serum levels were discordant in remitters, suggestive of regulation overruling genetic predisposition. Although high-producing genotypes were less frequent in remitters, they were predictive of remission in combination with low serum IFN-γ levels. These data imply that remission is partially immune-mediated and involves regulation of IFN-γ transcription.