Histology results of systematic prostate biopsies by in-bore magnetic resonance imaging vs. transrectal ultrasound

IntroductionWe aimed to compare systematic biopsies (SBs) of in-bore magnetic resonance-guided prostate biopsy (MRGpB) with those performed under transrectal ultrasound (TRUS) guidance in the clinical setting.MethodsData on all 161 consecutive patients undergoing prostate biopsy at our institution between November 2017 and July 2019 were retrospectively collected. The patients were referred to biopsy due to elevated prostate-specific antigen (PSA) and/or abnormal digital rectal examination (DRE) and/or at least one Prostate Imaging Reporting and Data System (PI-RADS) lesion score of ≥3 on multiparametric magnetic resonance imaging (mpMRI). We included patients with PSA levels ≤20 ng/ml and those with 8–12 core biopsies. Histology results of SBs performed by in-bore MRGpB were compared to TRUS SBs. Chi-squared, Fischer’s exact, and multivariate Pearson regression tests were used for statistical analysis (SPSS, IBM Corporation).ResultsIn total, 128 patients were eligible for analysis. Their median age was 68 years (interquartile range [IQR] 61.5–72), mean prostate size 55±29 cc, and mean PSA and PSA density levels 7.6±3.5 ng/ml and 0.18±0.13 ng/ml/cc, respectively. Thirty-five patients (27.3%) had suspicious DRE findings. Both biopsy groups were similar for these parameters. Thirty-eight (62.3%) MRGpB patients had a previous biopsy vs. five (7.1%) TRUS-SB patients (p<0.0001). The number of patients diagnosed with clinically significant and non-significant disease was similar for both groups. High-risk disease was more prevalent in the TRUS-SB group (22.4% vs. 4.9%, p<0.01).ConclusionsOur data suggest that in-bore MRGpB is no better than TRUS for guiding SBs for the detection of clinically significant prostate cancer.     

Accurate Molecular Classification of Renal Tumors Using MicroRNA Expression

Subtypes of renal tumors have different genetic backgrounds, prognoses, and responses to surgical and medical treatment, and their differential diagnosis is a frequent challenge for pathologists. New biomarkers can help improve the diagnosis and hence the management of renal cancer patients. We extracted RNA from 71 formalin-fixed paraffin-embedded (FFPE) renal tumor samples and measured expression of more than 900 microRNAs using custom microarrays. Clustering revealed similarity in microRNA expression between oncocytoma and chromophobe subtypes as well as between conventional (clear-cell) and papillary tumors. By basing a classification algorithm on this structure, we followed inherent biological correlations and could achieve accurate classification using few microRNAs markers. We defined a two-step decision-tree classifier that uses expression levels of six microRNAs: the first step uses expression levels of hsa-miR-210 and hsa-miR-221 to distinguish between the two pairs of subtypes; the second step uses either hsa-miR-200c with hsa-miR-139-5p to identify oncocytoma from chromophobe, or hsa-miR-31 with hsa-miR-126 to identify conventional from papillary tumors. The classifier was tested on an independent set of FFPE tumor samples from 54 additional patients, and identified correctly 93% of the cases. Validation on qRT-PCR platform demonstrated high correlation with microarray results and accurate classification. MicroRNA expression profiling is a very effective molecular bioassay for classification of renal tumors and can offer a quantitative standardized complement to current methods of tumor classification.Renal cancers account for more then 3% of adult malignancies and cause more than 13,000 deaths per year in the United States alone.¹ The incidence of renal cancers in the United States rose more than 50% between 1983 and 2002,² and the estimated number of new cases per year in the United States rose from 38,890 in 2006³ to 54,390 in 2008.¹ Despite the trend of increased incidence of relatively small and kidney-confined disease, the rate of mortality has not changed significantly during the last two decades in the United States and Europe.^2,4,5,6,7 In the 1980s, renal tumors were basically regarded as one disease: the higher the stage and the grade, the worse the prognosis. After the 1980s, molecular biologists and pathologists described new entities with different morphological and biological characteristics. Evidence for different long-term prognosis for these subtypes makes the correct pathological diagnosis of a renal cancer critically important for the clinician.^8,9,10,11 Currently, it is well accepted that renal cell carcinoma (RCC) is a family of carcinomas that arise from the epithelium of the renal tubules.¹² The current classification of renal cell carcinoma includes four main types: conventional (clear cell), papillary, chromophobe, and collecting duct carcinoma, as well as unclassified renal cell carcinoma.¹³ Oncocytoma, papillary adenoma, mesonephric adenoma, and angiomyolipoma are the main benign neoplasms in the kidney.These different histological subtypes of RCC vary in their clinical courses and their prognosis, and different clinical strategies have been developed for their management. Patients with conventional RCC have a poorer prognosis, and differences may also exist between the prognosis of patients with papillary or chromophobe RCC.^8,9,10,11 The histological types arise through different constellations of genetic alterations and show expression or mutation in different oncogenic pathways; they therefore offer different molecular candidates for targeted therapy (eg, mTOR, VEGF, KIT).^14,15,16 Initial studies show differences in the responses of RCC subtypes to targeted therapies,^16,17 and future therapies are likely to be individualized for the different types.¹⁵ The correct identification of these subtypes is therefore important for choice of treatment and for the selection of patients for clinical trials.^16,18Conventional RCC is the most frequent subtype of RCC and accounts for 60 to 70% of cases, thus causing the majority of renal cell cancer specific mortality. The term “conventional” is used to replace the name “clear cell,” because some types have eosinophilic cytoplasm, generating a more difficult diagnostic challenge. In tumors of this type, a characteristic vascular network is commonly observed. The conventional carcinoma type is associated with germ line and somatic mutations of the von Hippel–Lindau (VHL) suppressor gene, and such mutations may indicate a more favorable prognosis.^19,20 Papillary RCC typically consists of a central fibrovascular core with epithelial covered papillae. It is subclassified into type 1 and 2 tumors that differ in terms of morphology, genotype, and clinical outcome.²¹ Genetically, this type of tumor is associated with polysomies of chromosomes 7 or 17 and deficiency of Y.²² Chromophobe renal cell carcinoma was included before 1986 in the group of conventional RCC. The typical form exhibits balloon cells with an abundant granular pale cytoplasm or eosinophilic cytoplasm that resemble the cells of oncocytoma.²³ Such features as described above are characteristic of the histological subtypes, but interobserver variations limit the accuracy of histological classification, with some types identified with a sensitivity of 70% or lower.¹⁰ Furthermore, underlying biological mechanisms playing important roles in these tumors are yet to be elucidated.Based on the growing clinical demand for accurate diagnosis of RCC subtypes, recent studies focused on the immunohistochemical profiling of different carcinomas. Allory et al lately described a subset of 12 antibodies as base for classification of renal cell carcinomas. In this report AMACR, CK7, and CD10 had the most powerful classification trees with 78–87% of carcinomas correctly classified.²⁴ Immunohistochemistry provides limited information for distinguishing chromophobe RCC from oncocytoma.^25,26 However, the increasing number of smaller tumors and needle-biopsy procedures places a strain on immunohistochemical methods. In a recent large study of 235 cases, more than 20% of the core needle biopsies were nondiagnostic.²⁷ This emphasized the need for developing additional types of molecular markers for the classification of renal tumors and for their study.MicroRNAs, a family of small noncoding regulatory RNAs,²⁸ show promise as diagnostic biomarkers^29,30 thanks to their distinct expression profiles in tumors of different types and biological origins^31,32 and their chemical stability in clinical samples.³³ Their role in renal cancers and their potential as biomarkers for this family of malignancies are yet to be elucidated. One previous work studied the expression of 248 microRNA clusters in a set of 27 kidney specimens and found no association between microRNA expression and histological type.³⁴ A recent study compared expression of 470 microRNAs in 26 kidney samples and identified microRNAs differentially expressed between conventional and chromophobe renal tumors.³⁵ Another recent study using 20 RCC samples found correlation of microRNA expression to the histological type of the tumor and to prognosis of patients with clear cell RCC.³⁶ These studies included few samples and did not represent all of the major types of renal tumors. Here we report a study of microRNA expression profiles in more than 120 renal tumor samples. We identified microRNA biomarkers that are specifically expressed in the four most common histological subtypes of renal tumors. We designed a microRNA-based classification algorithm that uses expression levels of 6 microRNAs to classify renal tumors. This classifier had an accuracy of 93% in histological classification of an independent test set of renal tumors.     

Histiocytoid neutrophilic dermatoses and panniculitides: variations on a theme

Requena et al, in their article titled "Histiocytoid Sweet syndrome," in 2005, established that the dermal infiltrate in some patients with Sweet's syndrome is composed of histiocyte-like immature myeloid cells, not polymorphonuclear leukocytes as is the norm. With this premise in mind, we report on 6 cases of inflammatory skin disease in which the common denominator was a dermal and/or subcutaneous infiltrate of histiocytoid myeloid cells in patients with new-onset cutaneous eruptions and systemic symptoms. The cases were diverse clinically and microscopically, fell short of the criteria necessary for a diagnosis of classical Sweet's syndrome, and were difficult to categorize at the outset. The systemic manifestations ranged from malaise alone to a combination of fever, chills, night sweats, and polyarthralgia. The clinical morphology of the cutaneous eruptions varied from being papulovesicular in 1 patient to mainly consisting of erythematous plaques and nodules in the remainder. The dermatologists' differential diagnoses included Sweet's syndrome in 3 cases, a drug eruption in 2, and other entities such as erythema nodosum and Well's syndrome. Biopsies in all cases revealed a dermal and/or subcutaneous infiltrate composed predominantly of mononuclear histiocytoid cells of myeloid origin. With the benefit of detailed clinicopathologic correlation, the cases were classified for the purpose of this report as follows: Sweet's-like neutrophilic dermatosis, histiocytoid (3 cases); subcutaneous Sweet's syndrome, histiocytoid (2 cases); histiocytoid neutrophilic dermatosis, unspecified (1 case). In addition, we describe a further instructive case that exhibited overlap with those in the series but proved ultimately to represent leukemia cutis. The spectrum of observations in this report supports and expands the original concept of histiocytoid Sweet's syndrome.     

Circulating leptin levels after cardiopulmonary bypass in children

OBJECTIVE: To characterize the dynamics of circulating leptin in children after cardiac surgery with cardiopulmonary bypass (CPB), which is known to induce a systemic inflammatory response. DESIGN: Investigative study. SETTING: University-affiliated tertiary care hospital. PARTICIPANTS: Eight children (age range, 3 months to 13 years) undergoing CPB to correct congenital heart disease. INTERVENTIONS: The time courses of leptin and cortisol levels were determined. Serial blood samples were collected from the arterial catheter or from the CPB circuit preoperatively; on termination of CPB; and at 2, 4, 8, 12, 18, and 24 hours postoperatively. Plasma was recovered immediately, divided into aliquots, and frozen at -70 degrees C until use. Leptin was measured by a human leptin radioimmunoassay kit. MEASUREMENTS AND MAIN RESULTS: Leptin levels during CPB decreased to 50% of pre-CPB levels (p < 0.01). After termination of CPB, levels increased gradually and peaked at 12 hours postoperatively (10 P.M. to 1 A.M.). Cortisol levels were inversely correlated to leptin levels (p = 0.016). CONCLUSION: CPB is associated with acute changes in circulating leptin levels. These changes parallel those in cortisol, showing an inverse relationship between leptin and cortisol, suggesting a relationship between the neurobiology of these systems that could be important for the neuroendocrine response to CPB. A prognostic role of leptin and its relationship to cortisol after CPB warrant further study.     

Analgesia elicited by OFQ/nociceptin and its fragments from the amygdala in rats

The heptadecapeptide, orphanin FQ/nociceptin (OFQ/N), binds with high affinity to the ORL-1/KOR-3 opioid receptor clone, yet binds poorly with traditional opioid receptors. OFQ/N has a complex functional profile with relation to nociceptive processing, displaying pro-nociceptive properties in some studies, acting as an inhibitor of stress-induced analgesia in others, yet producing both spinal and supraspinal antinociceptive actions in other studies. Among the intracerebral sites at which OFQ/N might produce one or more of these actions is the amygdala which has been intimately implicated in both antinociceptive and stress-related responses. Therefore, the present study assessed whether microinjections into the amygdala of equimolar doses of OFQ/N_1–17 or its shorter-chained active fragments, OFQ/N_1–11 or OFQ/N_1–7, would produce analgesia as measured by either reactivity to high-intensity radiant heat or reactivity to electric shock, and produce hyperalgesia as measured by reactivity to lower-intensity radiant heat. OFQ/N_1–17 in the amygdala produced a dose-dependent and time-dependent increase in high-intensity tail-flick latencies with maximal effects observed at a dose range of 0.75–3 nmol, and lesser effects at lower (0.015–0.15 nmol) and higher (5.5–30 nmol) doses. Both OFQ/N_1–11 and OFQ/N_1–7 in the amygdala displayed lower magnitudes of analgesia than OFQ/N_1–17 on this measure, with OFQ/N_1–11 displaying maximal effects at higher (15–30 nmol) doses and OFQ/N_1–7 displaying maximal effects at lower (0.15–1.5 nmol) doses. In contrast to traditional μ and κ opioids and β-endorphin, none of the OFQ/N fragments in the amygdala exhibited any analgesic responses on the jump test. Finally, using a low-intensity radiant heat assay capable of detecting hyperalgesic responses, each of the OFQ/N fragments in the amygdala increased tail-flick latencies on this measure. Therefore, OFQ/N fragments appear to exert only analgesic responses in the amygdala with quantitative and qualitative differences relative to traditional opioid agonists.     

Fluorodeoxyglucose-positron emission tomography/computed tomography imaging in patients with carcinoma of the larynx: diagnostic accuracy and impact on clinical management

OBJECTIVES: The objectives of this study were to assess the value of F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in patients with carcinoma of the larynx as compared with PET and CT alone and to assess the impact of PET/CT on further clinical management. STUDY DESIGN: This was a prospective, nonrandomized study. MATERIALS AND METHODS: Forty-two patients with laryngeal cancer had 51 PET/CT examinations. There were 34 men and eight women, aged 39 to 80 years. All studies were interpreted prospectively with knowledge of the clinical history and results of previous imaging tests. The performance of different imaging modalities was compared on both a study- and lesion-based analysis for sensitivity, specificity, positive (PPV) and negative predictive value (NPV), and accuracy. Changes in patient care resulting from the PET/CT studies were recorded. RESULTS: The study analysis showed that PET/CT had a sensitivity of 92%, specificity 96%, PPV 96%, NPV 92%, and accuracy of 94% as compared with 92%, 73%, 76%, 91%, and 82% for PET, and 88%, 8%, 48%, 40%, and 51% for CT, respectively. There were 112 suspicious sites evaluated in the 51 studies. PET/CT altered management in 25 patients (59%) by sparing previously planned diagnostic procedures (n=13), by changing the planned therapeutic approach (n=9), and by guiding a biopsy to a metabolically active laryngeal area (n=3). CONCLUSIONS: The performance of PET/CT is better than standalone PET or CT in patients with cancer of the larynx. PET/CT had a major impact on management of 59% of patients.     

Identification of a high-affinity orphanin FQ/nociceptin(1-11) binding site in mouse brain.

The presence of pairs of basic amino acids within the orphanin FQ/Nociceptin (OFQ/N) sequence has raised the possibility that truncated versions of the peptide might be physiologically important. OFQ/N(1-11) is pharmacologically active in mice, despite its poor affinity in binding assays (K(i) > 250 nM) for the OFQ/N receptor. Using an analog of OFQ/N(1-11), [(125)I][Tyr(10)]OFQ/N(1-11), we identified a high-affinity binding site (K(D) 234 pM; B(max) 43 fmol/mg protein) with a selectivity profile distinct from the OFQ/N receptor and all the traditional opioid receptors. This site had very high affinity for OFQ/N and its related peptides. The most striking differences between the new site and the OFQ/N receptor previously observed in brain were seen with traditional opioids. Dynorphin A analogs and alpha-neoendorphin competed with [(125)I][Tyr(10)]OFQ/N(1-11) binding in mouse brain with K(i) values below 10 nM, while naloxone benzoylhydrazone (K(i) 3.9 nM) labeled the [(125)I][Tyr(10)]OFQ/N(1-11) binding site as potently as many traditional opioid receptors. Several other opioids, including fentanyl, (-)cyclazocine, levallorphan, naltrindole, and diprenorphine, also displayed moderate affinities for this site. Finally, the [(125)I][Tyr(10)]OFQ/N(1-11) site had a unique regional distribution consistent with a distinct receptor. Thus, [(125)I][Tyr(10)]OFQ/N(1-11) labels a novel site in brain with a selectivity profile intermediate between that of either opioid or OFQ/N receptors.