Targeted ultrasound and fine-needle aspiration cytology for sentinel node diagnostics in early-stage melanoma: a validation study.

Ultrasound-guided fine-needle aspiration cytology (US-FNAC) is used to evaluate the involvement of lymph nodes in various malignant diseases. Its value in detecting sentinel lymph node (SN) metastasis preoperatively in melanoma patients is controversial and is the subject of this study. In this prospective validation study, 91 consecutive patients with melanoma clinical stage I (n=64) and II (n=27) were examined with US-FNAC before SN biopsy from 2012 to 2014 at a tertiary center. All patients underwent lymphoscintigraphy before the US-FNAC. Lymph nodes that showed any of the Berlin morphologic criteria on ultrasonography were examined using FNAC. The median Breslow thickness of the melanomas was 1.22 mm (range: 0.47-11.5 mm). Twenty-two percent of the patients had metastases in their SNs, 90% of which were smaller than 2 mm in largest diameter. The percentages of metastases with a size more than 1 mm were 50 and 29%, respectively, in the true-positive and false-negative US groups. The sensitivity, specificity, positive predictive value, and negative predictive value for overall US examination were 30, 81, 24, and 83%, respectively. None of the FNACs contained conclusive malignant cells. The specificity of the FNAC was 76%. Our results show that US-FNAC was not a useful diagnostic tool in our setting as it did not add significantly to the staging and management of patients with mainly thin cutaneous melanomas, perhaps because of the often small size of the SN metastases. It may be useful in the early diagnosis of lymph node metastases in a subgroup of melanoma patients with larger metastases.

Effect of Liraglutide Treatment on Prediabetes and Overweight or Obesity in Clozapine- or Olanzapine-Treated Patients With Schizophrenia Spectrum Disorder: A Randomized Clinical Trial.

Importance: Compared with the general population, patients with schizophrenia have a 2- to 3-fold higher mortality rate primarily caused by cardiovascular disease. Previous interventions designed to counteract antipsychotic-induced weight gain and cardiometabolic disturbances reported limited effects. Objectives: To determine the effects of the glucagon-like peptide-1 receptor agonist liraglutide added to clozapine or olanzapine treatment of schizophrenia spectrum disorders. Design, Setting, and Participants: This randomized clinical double-blind trial enrolled participants at 2 clinical sites in Denmark. Of 214 eligible participants with a schizophrenia spectrum disorder, 103 were randomized to liraglutide or placebo. Participants received stable treatment with clozapine or olanzapine, were overweight or obese, and had prediabetes. Data were collected from May 1, 2013, through February 25, 2016. Interventions: Treatment for 16 weeks with once-daily subcutaneous injection of liraglutide or placebo. Trial drug therapy was titrated during the first 2 weeks of the study. Main Outcomes and Measures: The primary end point was change in glucose tolerance estimated by a 75-g oral glucose tolerance test result. Secondary end points included change in body weight and cardiometabolic parameters. Results: Of the 103 patients undergoing randomization (60 men [58.3%] and 43 women [41.7%]), 97 were included in the efficacy analysis, with a mean (SD) age of 42.5 (10.5) years and mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) of 33.8 (5.9). The liraglutide and placebo groups had comparable characteristics (mean [SD] age, 42.1 [10.7] vs 43.0 [10.5] years; 30 men in each group; mean [SD] body mass index, 33.7 [5.1] vs 33.9 [6.6]). A total of 96 randomized participants (93.2%) completed the trial. Glucose tolerance improved in the liraglutide group compared with the placebo group (P < .001). Altogether, 30 liraglutide-treated participants (63.8%) developed normal glucose tolerance compared with 8 placebo-treated participants (16.0%) (P < .001; number needed to treat, 2). Body weight decreased with liraglutide compared with placebo (-5.3 kg; 95% CI, -7.0 to -3.7 kg). Reductions in waist circumference (-4.1 cm; 95% CI, -6.0 to -2.3 cm), systolic blood pressure (-4.9 mm Hg; 95% CI, -9.5 to -0.3 mm Hg), visceral fat (-250.19 g; 95% CI, -459.9 to -40.5 g), and low-density lipoprotein levels (-15.4 mg/dL; 95% CI, -23.2 to -7.7 mg/dL) occurred with liraglutide compared with placebo. Adverse events with liraglutide affected mainly the gastrointestinal tract. Conclusions and Relevance: Liraglutide significantly improved glucose tolerance, body weight, and cardiometabolic disturbances in patients with schizophrenia spectrum disorders treated with clozapine or olanzapine. Trial Registration: clinicaltrials.gov Identifier: NCT01845259.

Radioactive Seed Localization or Wire-guided Localization of Nonpalpable Invasive and In Situ Breast Cancer: A Randomized, Multicenter, Open-label Trial.

OBJECTIVE: To compare the rate of positive resection margins between radioactive seed localization (RSL) and wire-guided localization (WGL) after breast conserving surgery (BCS). BACKGROUND: WGL is the current standard for localization of nonpalpable breast lesions in BCS, but there are several difficulties related to the method. METHODS: From January 1, 2014 to February 4, 2016, patients with nonpalpable invasive breast cancer or DCIS visible on ultrasound were enrolled in this randomized, multicenter, open-label clinical trial, and randomly assigned to RSL or WGL. The primary outcome was margin status after BCS. Secondary outcomes were duration of the surgical procedure, weight of surgical specimen, and patients' pain perception. Analyses were performed by intention-to-treat (ITT) and per protocol. RESULTS: Out of 444 eligible patients, 413 lesions representing 409 patients were randomized; 207 to RSL and 206 to WGL. Twenty-three did not meet inclusion criteria, chose to withdraw, or had a change in surgical management and were excluded. The remaining 390 lesions constituted the ITT population. Here, resection margins were positive in 23 cases (11.8%) in the RSL group compared with 26 cases (13.3%) in the WGL group (P = 0.65). The per-protocol analysis revealed no difference in margin status (P = 0.62). There were no significant differences in the duration of the surgical procedure (P = 0.12), weight of the surgical specimen (P = 0.54) or the patients' pain perception (P = 0.28). CONCLUSION: RSL offers a major logistic advantage, as localization can be done several days before surgery without any increase in positive resection margins compared with WGL.

Renal deterioration after spinal cord injury is associated with length of detrusor contractions during cystometry-A study with a median of 41 years follow-up.

AIMS: To investigate which urodynamic parameters are associated with renal deterioration over a median of 41 years follow-up after traumatic spinal cord injury. METHODS: Medical records of patients with a traumatic spinal cord injury sustained 1944-1975 were reviewed from time of injury until 2012. Patients who attended regular renography and/or renal clearance examinations and had minimum one cystometry and pressure-flow study were included. Renal deterioration was diagnosed as split renal function ≤30% in one kidney or relative glomerular filtration rate ≤51% of expected according to age and gender. Detrusor function, presence of detrusor sphincter dyssynergia, maximum detrusor pressure, post-void residual volume, and cystometric bladder capacity were obtained. In patients with detrusor overactivity, a detrusor overactivity/cystometry ratio was calculated using duration of detrusor contraction(s) during filling cystometry divided by total duration of filling cystometry. RESULTS: A total of 73 patients were included in the study, and the median follow-up time was 41 years after injury (range 24-56). Sixty-four patients (88%) used reflex triggering or bladder expression as bladder emptying method for the longest period after injury. During follow-up 60% changed to clean intermittent catheterization. The majority of the patients (68%) had neurogenic detrusor overactivity. In 35 patients, a detrusor-overactivity/cystometry ratio could be calculated and a detrusor overactivity/cystometry ratio > 0.33 was significantly associated with renal deterioration (P < 0.02). No significant association was found between maximum detrusor pressure or other urodynamic parameters and renal deterioration. CONCLUSIONS: Duration of detrusor overactivity longer than one third of the duration of cystometry is associated with renal deterioration after spinal cord injury.

Automated Bone Scan Index as a quantitative imaging biomarker in metastatic castration-resistant prostate cancer patients being treated with enzalutamide.

BACKGROUND: Having performed analytical validation studies, we are now assessing the clinical utility of the upgraded automated Bone Scan Index (BSI) in metastatic castration-resistant prostate cancer (mCRPC). In the present study, we retrospectively evaluated the discriminatory strength of the automated BSI in predicting overall survival (OS) in mCRPC patients being treated with enzalutamide. METHODS: Retrospectively, we included patients who received enzalutamide as a clinically approved therapy for mCRPC and had undergone bone scan prior to starting therapy. Automated BSI, prostate-specific antigen (PSA), hemoglobin (HgB), and alkaline phosphatase (ALP) were obtained at baseline. Change in automated BSI and PSA were obtained from patients who have had bone scan at week 12 of treatment follow-up. Automated BSI was obtained using the analytically validated EXINI Bone(BSI) version 2. Kendall's tau (τ) was used to assess the correlation of BSI with other blood-based biomarkers. Concordance index (C-index) was used to evaluate the discriminating strength of automated BSI in predicting OS. RESULTS: Eighty mCRPC patients with baseline bone scans were included in the study. There was a weak correlation of automated BSI with PSA (τ = 0.30), with HgB (τ = -0.17), and with ALP (τ = 0.56). At baseline, the automated BSI was observed to be predictive of OS (C-index 0.72, standard error (SE) 0.03). Adding automated BSI to the blood-based model significantly improved the C-index from 0.67 to 0.72, p = 0.017. Treatment follow-up bone scans were available from 62 patients. Both change in BSI and percent change in PSA were predictive of OS. However, the combined predictive model of percent PSA change and change in automated BSI (C-index 0.77) was significantly higher than that of percent PSA change alone (C-index 0.73), p = 0.041. CONCLUSIONS: The upgraded and analytically validated automated BSI was found to be a strong predictor of OS in mCRPC patients. Additionally, the change in automated BSI demonstrated an additive clinical value to the change in PSA in mCRPC patients being treated with enzalutamide.

Radionuclide leakage monitoring during hyperthermic isolated limb perfusion for treatment of local melanoma metastasis in an extremity.

INTRODUCTION: The aim is to describe the importance of leakage monitoring in hyperthermic isolated limb perfusion (ILP). It is generally recommended that leakage should not exceed 10% because of risk of systemic toxicity. MATERIAL AND METHODS: Data retrieved by retrospective analysis of 131 perfusions performed in 115 consecutive patients (77 women and 38 men; median age 66 years) with recurrent and/or clinically apparent, cutaneous or subcutaneous melanoma metastases in an extremity. Radionuclide monitoring was performed with continuous, precordial count rate determinations of an intravascular (99m) Tc-labelled tracer infused into the isolated limb circulation. RESULTS: One hundred and sixteen of 131 procedures were completed. In 13%, a leakage of ≥10% was detected; in 6% (n = 8), the cytotoxic drug was never infused because of constant leakage; in 7% (n = 9), leakage ≥10% was measured during the perfusion resulting in two perfusions being terminated before 30 min, 5 perfusions were considered completed though with early termination (after 30 min, before 60 min), and 2 fully completed. No patients had systemic toxicity requiring treatment, whereas considerable or serious local toxicity were observed in 14%. Three of the patients with leakage ≥10% were successfully treated in a repeated procedure. CONCLUSION: Leakage monitoring using a threshold of 10% during ILP saves the patients from systemic toxicity, however, at the expense of early termination or cancellation of ILP treatment in a few patients and repeated ILP procedures in some.

Reliability of estimated glomerular filtration rate in patients treated with platinum containing therapy.

Estimates of glomerular filtration rate (eGFR) are widely used when administering nephrotoxic chemotherapy. No studies performed in oncology patients have shown whether eGFR can safely substitute a measured GFR (mGFR) based on a marker method. We aimed to assess the validity of four major formulas based on PCr (Cockcroft-Gault, MDRD, Wright and CKD-EPI) in comparison to mGFR in an oncology setting. Patients included had disseminated germ cell cancer and received conventional chemotherapy: bleomycin, etoposide and cisplatin. The mGFR of the patients was compared to all estimates with focus on bias (median percentage error), precision (median absolute percentage error) and accuracy (p10 and p30). The precision of carboplatin dosage based on eGFR was calculated. Data on mGFR, eGFR, and PCr were available in 390 patients, with a total of ∼ 1,600 measurements. Median PCr and mGFR synchronically decreased after chemotherapy, yielding high bias and low precision of most estimates. Post-chemotherapy, bias ranged from -0.2% (MDRD after four cycles) to 33.8% (CKD-EPI after five cycles+), precision ranged from 11.6% (MDRD after four cycles) to 33.8% (CKD-EPI after five cycles+) and accuracy (p30) ranged from 37.5% (CKD-EPI after five cycles+) to 86.9% (MDRD after four cycles). Although MDRD appeared acceptable after chemotherapy because of high accuracy, this equation underestimated GFR in all other measurements. Before and years after treatment, Cockcroft-Gault and Wright offered best results. Precision of carboplatin dosage was low. In conclusion, bias, precision and accuracy were unacceptable in all equations due to a synchronous decrease of PCr and mGFR during chemotherapy.

The diagnostic value of adding dynamic scintigraphy to standard delayed planar imaging for sentinel node identification in melanoma patients.

PURPOSE: The aim of this study was to compare early dynamic imaging combined with delayed static imaging and single photon emission computed tomography (SPECT)/CT with delayed, planar, static imaging alone for sentinel node (SN) identification in melanoma patients. METHODS: Three hundred and seven consecutive melanoma patients referred for SN biopsy (SNB) were examined using combined imaging. Secondary interpretation of only the delayed static images was subsequently performed. In 220 patients (72%), complete surgical and pathological information relating to the SNB was available. The number of SNs identified and number of patients with positive SNs were compared between the two interpretations of the imaging studies and, when available, related to pathology data. RESULTS: A slightly higher number of SNs (mean 0.12/patient) was identified when interpreting only delayed static images compared to combined imaging. In a direct patient-to-patient comparison, the number of SN(s) identified on the combined vs static images only showed moderate agreement (kappa value 0.56). In 38 patients (17%), positive SNs were identified by the combined procedure compared to 35 (16%) by static imaging only. Thus by static imaging only, tumour-positive SNs were not identified in 3 of 38 patients (8%). CONCLUSION: For SN identification in melanoma patients, dynamic imaging combined with delayed static imaging and SPECT/CT is superior to delayed static imaging only because the latter is more likely to fail to identify SNs containing metastases.

Axillary sentinel node identification in breast cancer patients: degree of radioactivity present at biopsy is critical.

BACKGROUND: The radioactivity present in the patient (Act(rem) ) at sentinel node (SN) biopsy will depend on injected activity amount as well as on the time interval from tracer injection to biopsy, which both show great variations in the literature. The purpose of this study was to analyse the influence of varying Act(rem) levels on the outcome of axillary SN biopsy in patients with breast cancer (BC). MATERIAL AND METHODS: Eight hundred and fifty-eight patients with BC were consecutively referred to SN biopsy, 21% for a same-day and 79% of the patients for a 2-day procedure. Four hundred and nineteen patients underwent scintigraphy and 439 did not. For same-day procedures, 50 MBq (99m) Tc-nanocolloid (Nanocoll(®) ) was injected, and for 2-day procedures 110 MBq. For the analysis of SN biopsy outcome, the patients were divided into three Act(rem) groups: <10 (56% of the patients), 10-20 (23%), and >20 MBq (21%). During surgery, SNs were located using a hand-held gamma probe supported by image information when available and blue dye injection. Pathology included haematoxylin-eosin staining followed by immunohistochemistry. RESULTS: The number of SNs removed (mean value 1·87 versus 2·14, P = 0·0003) and the probability of finding a malignant SN (P = 0·034) were lower in the <10 MBq group of patients compared with higher Act(rem) >20 MBq. Of the 25 patients with SN non-detection, 20 patients had an Act(rem) <10 MBq. Imaging had no significant influence on the number of patients with a malignant SN (P = 0·48). CONCLUSION: Act(rem) above 10 MBq for nanocolloid tracer appears important for appropriate identification of SNs in patients with BC.

Radiographic absorptiometry for pre-screening of osteoporosis in patients with low energy fractures.

Dual energy X-ray absorptiometry (DEXA) is the most accurate method and thus the method of choice for diagnosing osteoporosis. Due to the limited access to DEXA-scanners, screening of patients with low energy fractures (LEF) for osteoporosis is not routinely performed in Denmark. Pre-screening with a simple, less expensive device might be able to exclude patients with normal bone mineral density (BMD) from further DEXA-scans. We aimed to determine the frequency of osteoporosis in patients with LEF, and evaluate the diagnostic impact of a radiographic absorptiometry (RA) scanner in the casualty department of a major Danish county hospital. In a 5-month period, 136 adult patients with LEF were invited for BMD measurements. In 74 (54%) patients DEXA-scans (spine and femoral neck) and phalangeal RA-scans were performed. A total of 86% of the patients were female and 39% were suffering from osteoporosis (T-scores < or = -2.5) according to the DEXA results. RA-BMD and T-scores differed significantly between the two groups, with and without osteoporosis (p < 0.001). Comparing T-scores from RA with the lowest T-scores from DEXA, a highly significant correlation was found for women (R = 0.7, p < 0.001). Using a RA cut-off value (T-score < -1) for women ensuring 100% sensitivity for identifying women with osteoporosis, the positive predictive value was 46%. Up to 19% of DEXA-scans could be avoided in this setting. In our population the simple RA-BMD-method was cost-effective as a pre-screening tool for osteoporosis in women. However, the final diagnosis still relies on results from DEXA-scans.

Prostacyclin (epoprostenol) induces headache in healthy subjects.

The role of prostanoids in nociception is well established. The headache eliciting effects of prostacyclin (prostaglandin I(2), (PGI(2))) and its possible mechanisms had previously not been systematically studied in man. We hypothesized that infusion of PGI(2) might induce headache and vasodilatation of cranial vessels. A stable analog of PGI(2) epoprostenol (10 ng/kg/min) was infused for 25 min into 12 healthy subjects in a cross-over, double-blind study. Headache intensity was scored on a verbal rating scale from 0 to 10. In addition, we recorded mean flow in the middle cerebral artery (V(mean MCA)) by the transcranial doppler and diameter of the superficial temporal artery (STA) by a high-resolution ultrasonography unit. During the immediate phase (0-30 min) and the post-infusion phase (30-90 min), 11 subjects reported headache on the PGI(2) day and no subjects reported headache on the placebo day (p=0.002). During epoprostenol (0-30 min) and in the post-infusion phase (30-90 min), the area under the curve (AUC) for headache score was significantly larger than during and after placebo (p=0.005). PGI(2) caused headache associated with the dilatation of STA (AUC, p<0.001), but no significant dilatation of the MCA (AUC, p=0.508). These data indicate that PGI(2) induced headache might be due to activation and sensitization of sensory afferents around extracranial arteries.

Source analysis of epileptic discharges using multiple signal classification analysis.

Multiple signal classification is an alternative to the traditional dipole fitting source analysis methods. Our aim was to assess the clinical usefulness of this algorithm and to compare the localization of the epileptiform electroencephalography discharges with the regions of altered cerebral blood flow in 10 patients with complex partial seizures undergoing preoperative investigation. We performed multiple signal classification analysis of ictal and interictal discharges, and registered single-photon emission computed tomography. Localization of the ictal, but not the interictal discharges, as determined by multiple signal classification analysis was consistent with the regions showing perfusion changes on the single-photon emission computed tomography. Multiple signal classification analysis is a promising tool in localizing foci in patients with complex partial seizures and may contribute to the preoperative evaluation.

[Acute multifocal osteomyelitis caused by haemolytic group B streptococci]. / Akut multifokal osteomyelitis forårsaget af haemolytiske streptokokker gruppe B.

Invasive infections due to group B streptococci (Streptococcus agalactiae) usually occur in the peri- and neonatal setting or in adults with chronic underlying diseases. In the presented case a severe infection of haematogenous osteomyelitis caused by group B streptococci in a previously healthy 68-year-old woman is reported. Group B streptococci were isolated in three of three blood culture bottles drawn from the patient at the time of admission to hospital due to fever of unknown cause and pain in the upper and lower extremities as well as the back. A technetium scan showed involvement of the left shoulder, the left sacroilial joint, Th-9, Th-12 and L5. In addition, there was increased activity in the left foot, the right side of the mandibula and probably both hands (insufficiently scanned). The patient was successfully treated with penicillin G and subsequently with oral penicillin V for a total of 12 weeks.

Gamma-camera 18F-FDG PET in diagnosis and staging of patients presenting with suspected lung cancer and comparison with dedicated PET.

UNLABELLED: It is not clear whether high-quality coincidence gamma-PET (gPET) cameras can provide clinical data comparable with data obtained with dedicated PET (dPET) cameras in the primary diagnostic work-up of patients with suspected lung cancer. This study focuses on 2 main issues: direct comparison between foci resolved with the 2 different PET scanners and the diagnostic accuracy compared with final diagnosis determined by the combined information from all other investigations and clinical follow-up. METHODS: Eighty-six patients were recruited to this study through a routine diagnostic program. They all had changes on their chest radiographs, suggesting malignant lung tumor. In addition to the standard diagnostic program, each patient had 2 PET scans that were performed on the same day. After administration of 419 MBq (range = 305-547 MBq) (18)F-FDG, patients were scanned in a dedicated PET scanner about 1 h after FDG administration and in a dual-head coincidence gamma-camera about 3 h after tracer injection. Images from the 2 scans were evaluated in a blinded set-up and compared with the final outcome. RESULTS: Malignant intrathoracic disease was found in 52 patients, and 47 patients had primary lung cancers. dPET detected all patients as having malignancies (sensitivity, 100%; specificity, 50%), whereas gPET missed one patient (sensitivity, 98%; specificity, 56%). For evaluating regional lymph node involvement, sensitivity and specificity rates were 78% and 84% for dPET and 61% and 90% for gPET, respectively. When comparing the 2 PET techniques with clinical tumor stage (TNM), full agreement was obtained in 64% of the patients (Cohen's kappa = 0.56). Comparing categorization of the patients into clinical relevant stages (no malignancy/malignancy suitable for treatment with curative intent/nontreatable malignancy), resulted in full agreement in 81% (Cohen's kappa = 0.71) of patients. CONCLUSION: Comparing results from a recent generation of gPET cameras obtained about 2 h later than those of dPET, there was a fairly good agreement with regard to detecting primary lung tumors but slightly reduced sensitivity in detecting smaller malignant lesions such as lymph nodes. Depending on the population to be investigated, and if dPET is not available, gPET might provide significant diagnostic information in patients in whom lung cancer is suspected.