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Introduction Suppression of physiological myocardial FDG activity is vital in patients undergoing PET/CT for assessment of known or suspected cardiac sarcoidosis. This study aims to evaluate the efficacy of physiological myocardial FDG suppression following a protocol change to a 24-h high fat very low carbohydrate (HFVLC) diet and prolonged fast. Methods A retrospective review of patients undergoing FDG PET/CT for the evaluation of cardiac sarcoidosis was performed. Prior to June-2018, patients were prepared with a single very high-fat low carbohydrate meal followed by a 12-18 h fast (group 1). After June-2018, a protocol change was initiated with patients prepared with a HFVLC diet for 24-h followed by a 12-18 h fast (group 2). Focal myocardial activity was classified as positive, absent activity as negative and diffuse/focal on diffuse activity as indeterminate. Results A total of 94 FDG PET/CT scans were included with 46 scans in group 1 and 48 scans in group 2. Studies were classified as positive, negative or indeterminate in 25 (54%), 7 (15%) and 14 (30%) scans in group 1 and in 13 (27%), 33 (69%) and 2 (4%) scans in group 2, respectively. In scans classified as negative, myocardial FDG activity was less than mediastinal blood pool activity in 5/7 (71%) scans in group 1 and 33/33 (100%) scans in group 2. Conclusion Excellent myocardial FDG suppression can be achieved using a 24-h HFVLC diet and prolonged fast, resulting in a very low indeterminate scan rate in patients with known or suspected cardiac sarcoidosis.

Lu-177-labeled prostate-specific membrane antigen (PSMA) radioligand therapy using PSMA-617 and PSMA-I&T ligands (Lu-177-PRLT) is an emerging treatment in metastatic castration-resistant prostate cancer (mCRPC). This retrospective study evaluates clinical outcomes of Lu-177-PRLT in earlier and later phases of mCRPC grouped by previous taxane chemotherapy. Methods: A retrospective analysis was performed on 167 patients with mCRPC who underwent Lu-177-PRLT between March 2013 and December 2016. Patients were classified as either taxane chemotherapy pretreated (T-pretreated) or naive (T-naive) depending on whether they had received taxane-based chemotherapy prior to Lu-177-PRLT. Clinical outcome for T-pretreated and T-naive patients was assessed by overall survival (OS), radiographic progression-free survival, and prostate-specific antigen (PSA) response rate. Univariate and multivariable analyses were performed for both T-pretreated and T-naive patients to determine predictors of outcome. Toxicity was categorized by the Common Terminology Criteria for Adverse Events (version 4.03). Results: Of the 167 patients treated with Lu-177-PRLT, 83 were T-pretreated and 84 were T-naive. At baseline, T-pretreated patients had overall poorer performance status, a higher prevalence of bone metastases, higher PSA levels, lower hemoglobin levels, higher alkaline phosphatase (ALP) levels and had received more additional therapies compared with T-naive patients. Median OS was 10.7 mo for T-pretreated patients and 27.1 mo for T-naive patients. Median radiographic progression-free survival was 6.0 mo for T-pretreated patients and 8.8 mo for T-naive patients. PSA response assessment was evaluable in 132 patients and seen in 25 of 62 (40%) T-pretreated patients and 40 of 70 (57%) T-naive patients. Significant determinates of inferior OS in multivariable analysis for T-pretreated patients were poorer performance status, lower cumulative administered activity, and lower baseline hemoglobin. Higher baseline alkaline phosphatase was the only significant determinate of inferior OS in multivariable analysis for T-naive patients. Overall Lu-177-PRLT was safe, with minimal adverse effects evident during follow-up in both T-pretreated and T-naive patients. Conclusion: Lu-177-PRLT is a promising therapy in mCRPC, with encouraging outcomes and minimal associated toxicity seen in both our T-naive and heavily pretreated patient cohorts.

Increasing brown adipose tissue (BAT) activity is a possible therapeutic strategy to increase energy expenditure and glucose and lipid clearance to ameliorate obesity and associated comorbidities. The thiazolidinedione (TZD) class of glucose-lowering drugs increase BAT browning in preclinical experimental models but whether these actions extend to humans in vivo is unknown. The aim of this study was to determine the effect of pioglitazone treatment on adipocyte browning and adaptive thermogenesis in humans.We first examined whether pioglitazone treatment of cultured human primary subacromioclavicular-derived adipocytes induced browning. Then, in a blinded, placebo-controlled, parallel trial, conducted within the Baker Institute clinical research laboratories, 14 lean male participants who were free of cardiometabolic disease were randomised to receive either placebo (lactose; n = 7, age 22 ± 1 years) or pioglitazone (45 mg/day, n = 7, age 21 ± 1 years) for 28 days. Participants were allocated to treatments by Alfred Hospital staff independent from the study via electronic generation of a random number sequence. Researchers conducting trials and analysing data were blind to treatment allocation. The change in cold-stimulated BAT activity, assessed before and after the intervention by [Pioglitazone significantly increased in vitro browning and adipogenesis of adipocytes. In the clinical trial, cold-induced BAT maximum standardised uptake value was significantly reduced after pioglitazone compared with placebo (-57 ± 6% vs -12 ± 18%, respectively; p 0.05). BAT total glucose uptake followed a similar but non-significant trend (-50 ± 10% vs -6 ± 24%, respectively; p = 0.097). Pioglitazone increased total and lean body mass compared with placebo (p 0.05). No other changes between groups were detected.The disparity in the actions of pioglitazone on BAT between preclinical experimental models and our in vivo human trial highlight the imperative to conduct human proof-of-concept studies as early as possible in BAT research programmes aimed at therapeutic development. Our clinical trial findings suggest that reduced BAT activity may contribute to weight gain associated with pioglitazone and other TZDs.ClinicalTrials.gov NCT02236962 FUNDING: This work was supported by the Diabetes Australia Research Program and OIS scheme from the Victorian State Government.

Background Macrophage migration inhibitory factor ( MIF ) is a key regulator of inflammatory responses, including in the heart. Plasma MIF is elevated early in the course of acute myocardial infarction. In this study, we hypothesized that plasma MIF may also be increased in acute myocardial ischemia. Methods and Results Patients undergoing cardiac stress test (stress nuclear myocardial perfusion scan or stress echocardiography) were recruited. Twenty‐two patients had a stress test indicative of myocardial ischemia and were compared with 62 patients who had a negative stress test. Plasma MIF was measured by ELISA before and after the stress test. MIF was also measured in patients with peripheral arterial occlusive disease before and after exercise causing claudication. Gene and protein expression of MIF was measured in mouse cardiac and skeletal muscle tissue by real‐time polymerase chain reaction and western blot, respectively. Plasma MIF was elevated at 5 and 15 minutes after stress (relative to before stress) in patients with a positive test, compared with those with a negative test. In contrast, high‐sensitivity troponin T and C‐reactive protein were not altered after stress in either group. MIF was not altered after exercise in PAOD patients, despite the occurrence of claudication, suggesting that plasma MIF is not a marker for skeletal muscle ischemia. This may be explained by a lower gene and protein expression of MIF in skeletal muscle than the heart. Conclusions Our results suggest that plasma MIF is an early marker for acute myocardial ischemia.

Background It is unclear how to predict which patients will respond to Y-90 radiosynoviorthesis. The aim of this study is to correlate clinical outcomes following Y-90 radiosynoviorthesis with bremsstrahlung and Y-90 PET/CT imaging findings. Methods Fifty-one joints underwent bremsstrahlung planar and Y-90 PET/CT imaging following Y-90 radiosynoviorthesis. The Y-90 distribution pattern on bremsstrahlung planar imaging was classified as diffuse or non-diffuse and compared with the intra or extra-articular location of activity on Y-90 PET/CT. Treatment response was assessed by patients and clinicians at 6 months. In patients who underwent bremsstrahlung SPECT, side-by-side comparison with PET was performed with image quality/resolution scored using a five-point-scale. Findings Bremsstrahlung planar images were classified as diffuse in 33/51 (65 %) and non-diffuse in 18/51 (35 %) scans. There was no association between treatment response and the bremsstrahlung planar imaging pattern. PET/CT confirmed an intra-articular location in all 33/33 (100 %) diffuse scans and an extra-articular location in 3/18 (17 %) non-diffuse scans. Of the three joints with extra-articular activity, none had any treatment response. Excluding these three joints, there remained no association between the bremsstrahlung planar imaging pattern and treatment response. Of the 42 joints imaged with SPECT, PET image quality/resolution was classified as superior in 40 (95 %). In one patient with extra-articular activity on PET/CT, SPECT/CT was unable to definitively localise the activity to the intra or extra-articular space. Conclusions The distribution pattern on bremsstrahlung planar imaging did not correlate with clinical outcome following Y-90 radiosynoviorthesis in our study population. However, in patients with non-diffuse planar imaging patterns, Y-90 PET/CT should be considered to exclude extra-articular activity with PET providing superior image quality compared to SPECT.

The baseline insulin data given in Table 1 for the placebo group were incorrectly reported as 51 ± 10 pmol/l instead of 48 ± 10 pmol/l. This mistake also impacts on data reported in Table 4. The authors also note an error in the reported change in noradrenaline levels, from pre- to post-pioglitazone treatment (Table 4). The relevant rows from Tables 1 and 4 are reproduced here, with corrected data shown in bold. These corrections do not change the statistical significance of any comparison. (Table presented.).

Testosterone therapy for osteoporosis has not been studied extensively in women because of its potential to cause virilization. Female-to-male transsexuals are genetic females who suffer from gender dysphoria and thus take supra-physiologic doses of testosterone to change from the female to male phenotype. The aim of this study is to examine the effects of testosterone treatment on the genetic female skeleton.A group of 15 female-to-male transsexuals was prospectively enrolled for observation over a 2-year period. The subjects had a mean age of 37.0 +/- 3.0 years. All of the subjects self-administered testosterone esters intramuscularly at a mean dose of 70.7 +/- 4.5 mg weekly.The subjects had measurements of bone mineral density (BMD) by dual X-ray absorptiometry (DXA) of the femoral neck and spine (L2-L4) at 12-month intervals. They had determinations of serum oestradiol, testosterone, soluble RANKL (sRANKL), osteoprotegerin (OPG) and urine N-telopeptide (NTX) at the date of enrolment and at the end of 2 years. results There was a significant positive increase in mean BMD of 7.8% at the femoral neck and a nonsignificant increase in mean BMD of 3.1% at the spine over 2 years. The levels of testosterone reached the upper normal range for males and the levels of oestradiol declined to near the postmenopausal range. sRANKL levels decreased significantly in female-to-male transsexuals who newly initiated testosterone therapy. There was no significant change in urine NTX or serum OPG during the study.We conclude that supra-physiologic testosterone therapy increases BMD at the hip while maintaining BMD at the spine in female-to-male transsexuals. The effects of testosterone may be the result of testosterone hormone directly acting on the bone or indirectly through aromatization to oestradiol. Lower RANKL levels coupled with unchanged OPG levels results in an increased OPG/RANKL ratio, which may be beneficial to the bone by inhibiting osteoclastogenesis.

The morbidity and mortality conference (M&MC) appears to have sprung from the efforts of physicians to improve practice through the examination of medical errors and bad outcomes. The modern M&MC has had limited examination (and almost none outside surgery and anesthesia), but may be straying from the precepts from which it evolved. Learning from one's errors is important, but confronting them is difficult and is particularly delicate when done in conference. If the effort is successful, it can serve as a model. If unsuccessful, it can instead convey the lesson that attempting to learn from error is at best unproductive and at worst unpleasant. Thus, the M&MC is a double-edged sword, and particular attention should be given to the way that it is conducted. The authors review the historical roots and current literature on the M&MC, discusses relevant literature on medical error, and offers a definition, guiding principles, and a set of guidelines for a modern internal medicine M&MC. The ideas are presented not as a blueprint, but rather to stimulate a debate on the merits of establishing a framework for a working model, in order to refocus on the tradition of self-analysis and critical thinking in a manner that is productive for all participants.

OBJECTIVE To determine the effectiveness and costs of prophylaxis for disseminated Mycobacterium avium complex (MAC) infection in patients with AIDS. DESIGN A decision analysis model was constructed to compare rifabutin (300 mg/day), azithromycin (1200 mg/week), and clarithromycin (500 mg twice per day) with no prophylaxis. Sensitivity analysis was done on all model parameters, including initial CD4 count for beginning prophylaxis. SETTING The setting was hypothetical for the cost-effectiveness model. Clinical data were taken from published prospective randomized controlled trials. MAIN OUTCOME MEASURES Outcomes were measured in terms of projected life expectancy, quality-adjusted life expectancy, direct medical costs, and cost-effectiveness in U.S. dollars per quality-adjusted life-year saved ($/QALY). RESULTS For patients with AIDS and those having CD4 counts

The aim of this study is to evaluate the incremental staging information, management impact, and prognostic stratification of PET/CT in the primary staging of esophageal cancer in a cohort of patients with mature survival data.Between July 2002 and June 2005, 139 consecutive patients with newly diagnosed esophageal cancer underwent conventional staging investigations (CSI), followed by PET/CT. Disease stage was classified according to the American Joint Committee on Cancer staging system (6th edition) and grouped as stage I-IIA, stage IIB-III, and stage IV reflecting broad groupings that determine therapeutic choice. Validation of results was performed when PET/CT and CSI stage groups were discordant and in those patients where PET/CT changed management. Management impact was determined by comparing prospectively recorded pre-PET/CT management plans with post-PET/CT management plans. Survival after follow-up of at least 5 y in patients was analyzed using the Kaplan-Meier product limit method and the Cox proportional hazards regression model.PET/CT changed the stage group in 56 of 139 (40%) patients and changed management in 47 of 139 (34%) patients. In 22 patients, therapy was changed from curative to palliative and in 3 from palliative to curative; in 11, treatment modality was changed without a change in treatment intent, and in 11 the delivery of therapy or diagnostic procedure was changed. Of the 47 patients with management change, imaging results could be validated in 31 patients, and PET/CT correctly changed management in 26 (84%) of these. Of the remaining 5 patients, CSI stage was also incorrect in 4 and correct in 1. Median survival was 23 mo. PET/CT stages I-IIA, IIB-III, and IV had a 5-y survival of 40%, 38%, and 6%, respectively. Post-PET/CT stage group and treatment intent were both strongly associated with survival (P0.001).PET/CT provides incremental staging information compared with CSI, changes management in one third of patients, and has powerful prognostic stratification in the primary staging of esophageal cancer.

Invasive infection with organisms of the Mycobacterium avium complex (MAC) is common among patients with advanced human immunodeficiency virus infection. In previous studies, we analyzed multiple individual colonies of MAC isolated from specimens obtained at the same time and observed that 14 to 20% of patients are simultaneously infected with more than one strain. In this study, we examined sequential isolates from 12 patients with AIDS who had two or more MAC isolates available from clinical specimens collected more than 1 week apart; the intervals between the first and last specimens ranged from 8 to 192 (median, 46) days. For each isolate, restriction digests of genomic DNA were analyzed by pulsed-field gel electrophoresis; DNA was prepared by using a protocol, described here in detail, which had been optimized for conditions of bacterial growth and lysis. The pulsed-field gel electrophoresis analysis identified four patients (33%) infected with two different MAC strains. Both M. avium and M. intracellulare were cultured from blood specimens from two patients. In each of the four patients, the second strain was identified from a culture taken within 14 days of the initial study isolate, and in three of these patients, the first strain was detected again in a subsequent culture. These observations suggest that the presence of two different strains among isolates from sequential cultures may reflect ongoing polyclonal infection. We conclude that polyclonal infection with MAC is common among patients with AIDS. The identification of such infections may be critical in the development of effective treatments.

Ventilation-perfusion (V/Q) scintigraphy is established for regional assessment of lung function in a variety of diseases, including pulmonary embolism (PE). PET/CT may further improve the accuracy and utility of V/Q imaging because of its superior technical characteristics. This pilot study assessed the feasibility of performing V/Q PET/CT and compared diagnostic utility with conventional V/Q imaging in patients with clinical suspicion of PE.Ten patients undergoing conventional V/Q imaging were prospectively recruited. PET/CT V/Q imaging was performed after inhalation of (68)Ga-carbon nanoparticles ("Galligas") and administration of (68)Ga-macroaggregated albumin. Blinded to the results of the other study, SPECT/CT (n = 9) or SPECT (n = 1) images and PET/CT images were graded by a predefined scoring system for scan quality. The number of matched or unmatched defects and diagnosis were also measured and compared with a final diagnosis.PET image quality was equivalent or superior to SPECT in all patients, with more homogeneous radiotracer distribution for both ventilation and perfusion studies (P0.01). Based on conventional V/Q imaging, the diagnosis was acute PE in 2 patients and no PE in 7 patients, and the imaging results were nondiagnostic in 1 patient. The PET/CT diagnosis was concordant in 8 patients, and these studies demonstrated a similar number and distribution of matched and unmatched defects. In 1 discordant case, a patient with a SPECT/CT study that was nondiagnostic because of severe airway disease showed no PE on PET/CT. In another, the diagnosis of PE established on SPECT/CT was not reported on PET/CT 2 d later, possibly because of interval clot lysis or migration.This intraindividual comparative study demonstrated that V/Q PET/CT with (68)Ga-labeled radiotracers can be performed in clinical practice. Compared with conventional V/Q imaging, advantages include higher-resolution, fully tomographic images with potentially better regional quantitation of lung function. The short half-life of (68)Ga also enables more flexible acquisition protocols with the option of performing ventilation studies selectively on patients with abnormal perfusion. On the basis of our results, further studies are indicated to assess whether V/Q PET/CT can improve diagnostic algorithms for patients with suspected PE.

Skin tests with 0.1 mL of intermediate-strength Mycobacterium tuberculosis purified protein derivative (PPD) and 0.1 mL of Mycobacterium avium sensitin were conducted on 484 healthy subjects from diverse geographic sites. Reactions ofor = 5 mm to one antigen that exceeded the reaction to the other byor = 3 mm were considered M. avium- or PPD-dominant. PPD-dominant reactions were more frequent at sites where routine Bacille Calmette-Guérin immunization is done or where there are high rates of tuberculosis: New Hampshire, 2%; Boston, 7%; Finland, 14%; Trinidad, 26%; and Kenya, 28%. However, rates of M. avium-dominant reactions ranged from 7% to 12% at all sites. Analysis of dominant reactions based on a more stringent 10-mm minimum reaction size showed similar trends. These data suggest that exposure to MAC is similar in developed and developing countries but that broad mycobacterial immunity is greater in developing countries and may contribute to the lower rates of disseminated MAC infections in AIDS in these areas.

To define the genetic diversity among Mycobacterium avium isolates from human immunodeficiency virus-infected patients, specimens were cultured prospectively, and isolates obtained from 14 patients (4 with positive blood, stool, and sputum; 6 with positive blood and stool; 3 with positive blood only; and 1 with positive stool only) were studied. Both serotyping and ribotyping had limited ability to discriminate among isolates from different patients, whereas the distinctive restriction fragment profiles resolved by pulsed-field gel electrophoresis indicated that each patient was infected by a unique strain. Of the 13 bacteremic patients, 2 were bacteremic concurrently with 2 distinct strains. The fact that M. avium isolates from AIDS patients exhibit considerable genetic diversity supports the hypothesis that the infection is acquired from various environmental sources. Further, individual patients are not infrequently bacteremic with > 1 strain simultaneously, which may need to be considered in protocols for the diagnosis and management of M. avium disease.

Study Objective: To determine if Mycobacterium gordonae is an opportunistic respiratory tract pathogen in patients infected with human immunodeficiency virus, type 1 (HIV-1). Design: Retrospective review of medical records of all patients with positive cultures for M gordonae from 1987 to 1989. Patients: Fifteen patients had positive sputum cultures for M gordonae: five patients had AIDS or had HIV-1 infections with ≤180 CD4 cells/cu mm, and ten patients had no clinical evidence of HIV-1 infection. Results: Three of the five HIV-1 infected patients had clinical, roentgenographic, and microbiologic evidence of pulmonary infection due to M gordonae that responded to antimycobacterial therapy. One of the two remaining HIV-1 infected patients had disseminated M tuberculosis and possible coinfection with M gordonae, and the other was lost to follow-up. None of the ten patients without evidence of HIV-1 infection was considered to have M gordonae respiratory tract infection. Conclusions: Sputum isolates of M gordonae should be considered potential opportunistic respiratory tract pathogens in patients with advanced HIV-1 infection and with otherwise unexplained pulmonary infection. (Chest; 100:716-20)

The sensitivity and specificity of dual mycobacterial skin testing were assessed in an unblinded study of 22 patients with culture-confirmed Mycobacterium avium complex (MAC) infection and 20 patients with culture-confirmed Mycobacterium tuberculosis infection. Intradermal skin tests were performed with 0.1 mL of M. avium sensitin, 0.1 mL of PPD (purified protein derivative), and two control antigens (mumps and Candida). All patients with M. tuberculosis infection reacted to the skin tests; the mean reaction size was 19.7 +/- 1.4 mm when PPD was administered and 10.3 +/- 1.5 mm when M. avium sensitin was administered. Four patients with MAC were anergic; for the remaining 18, mean reactions of 15.2 +/- 1.4 mm to M. avium sensitin and 4.3 +/- 1.3 to PPD were noted. A skin test was defined as M. avium-dominant or PPD (M. tuberculosis)-dominant if there was a minimum reaction size of > or = 5 mm to the given species, and the reaction to the given species was > or = 3 mm greater than the reaction to the heterologous species. Dominant skin test reactions were present in 18 (90%) of 20 patients with M. tuberculosis and 15 (83%) of 18 nonanergic patients with MAC. The specificity of dominant skin tests was 100% for infection with M. tuberculosis and 100% for infection with MAC. M. avium-dominant skin tests identify subjects with prior MAC infection and distinguish them from patients with M. tuberculosis infection.

A 43-year-old woman underwent sentinel lymph node localisation prior to a left mastectomy and sentinel node biopsy for recurrent multifocal left-sided breast cancer. Previous treatment included a wide local excision and left axillary nodal clearance 15 months ago. Following one peri-areolar intradermal injection of 15 MBq of Tcantimony colloid in the upper inner quadrant of the left breast, dynamic planar imaging failed to identify a sentinel node. SPECT/CT imaging demonstrated a lymphatic channel extending from the left subpectoral region through the lingula of the left lung into the mediastinum posterior to the pulmonary trunk and terminating in the subcarinal nodal station (arrow). This unusual pattern of breast lymphatic drainage via the pulmonary lymphatic system is attributed to opening of collateral lymphatic channels following the previous left axillary nodal clearance. A left internal mammary sentinel lymph node (arrowhead) was also demonstrated and confirmed intraoperatively. While it is commonly believed that spread of breast cancer beyond the regional lymph nodes is haematogenous, it is also increasingly being recognised that traditional anatomical descriptions of lymphatic anatomy do not necessarily reflect observed variations in lymphatic pathways [1, 2]. Given that breast cancer is one of the known extrathoracic malignancies that metastasise to mediastinal nodes [3–5], this finding of a direct communication of breast lymphatic drainage with the intrapulmonary lymphatic system provides a potential mechanism for this pattern of spread. This case highlights how the combination of functional and anatomical information provided by SPECT/CT in lymphoscintigraphy continues to improve our understanding of potential paths of cancer spread.

In the 1980s, nosocomial pneumonia became the second most common nosocomial infection in the United States. Gram-negative bacilli and Staphylococcus aureus were the most frequently isolated bacteria. Methods to improve the diagnostic sensitivity and specificity included transtracheal aspirates and bronchoscopy with protected specimen brush or bronchoalveolar lavage. Multivariate analysis was used to identify independent risk factors for pneumonia and fatality in different subsets of high-risk patients. Gastric pH and colonization were evaluated as risk factors for pneumonia in mechanically ventilated patients. Colonized respiratory therapy equipment and contaminated tubing condensate and in-line medication nebulizers were suggested as possible sources of nosocomial pathogens. Staff education programs, the use of barrier precautions, and selective decontamination of the digestive tract were associated with reduced rates of lower respiratory tract infection. Despite a decade of progress in our understanding of nosocomial pneumonia, progress in the 1990s will undoubtedly include molecular epidemiologic techniques, appropriate application of risk factor data, and the use of new methods for the diagnosis of pneumonia. Prevention strategies should focus on more effective infection control techniques, improved invasive devices/equipment, and the judicious use of antibiotics for treatment and prophylaxis.