Multimodal Biomarkers That Predict the Presence of Gleason Pattern 4: Potential Impact for Active Surveillance.

PURPOSE: Latent grade group ≥2 prostate cancer can impact the performance of active surveillance protocols. To date, molecular biomarkers for active surveillance have relied solely on RNA or protein. We trained and independently validated multimodal (mRNA abundance, DNA methylation, and/or DNA copy number) biomarkers that more accurately separate grade group 1 from grade group ≥2 cancers. MATERIALS AND METHODS: Low- and intermediate-risk prostate cancer patients were assigned to training (n=333) and validation (n=202) cohorts. We profiled the abundance of 342 mRNAs, 100 DNA copy number alteration loci, and 14 hypermethylation sites at 2 locations per tumor. Using the training cohort with cross-validation, we evaluated methods for training classifiers of pathological grade group ≥2 in centrally reviewed radical prostatectomies. We trained 2 distinct classifiers, PRONTO-e and PRONTO-m, and validated them in an independent radical prostatectomy cohort. RESULTS: PRONTO-e comprises 353 mRNA and copy number alteration features. PRONTO-m includes 94 clinical, mRNAs, copy number alterations, and methylation features at 14 and 12 loci, respectively. In independent validation, PRONTO-e and PRONTO-m predicted grade group ≥2 with respective true-positive rates of 0.81 and 0.76, and false-positive rates of 0.43 and 0.26. Both classifiers were resistant to sampling error and identified more upgrading cases than a well-validated presurgical risk calculator, CAPRA (Cancer of the Prostate Risk Assessment; P < .001). CONCLUSIONS: Two grade group classifiers with superior accuracy were developed by incorporating RNA and DNA features and validated in an independent cohort. Upon further validation in biopsy samples, classifiers with these performance characteristics could refine selection of men for active surveillance, extending their treatment-free survival and intervals between surveillance.

Nightlife clusters of coronavirus disease in Tokyo between March and April 2020.

We analysed associations between exposure to nightlife businesses and severe acute respiratory syndrome coronavirus 2 PCR test results at a tertiary hospital in Tokyo between March and April 2020. A nightlife group was defined as those who had worked at or visited the businesses. We included 1517 individuals; 196 (12.9%) were categorised as the nightlife group. After propensity score matching, the proportion of positive PCR tests in the nightlife group was significantly higher than that in the non-nightlife group (nightlife, 63.8%; non-nightlife, 23.0%; P < 0.001). An inclusive approach to mitigate risks related to the businesses needs to be identified.

Pathological role of excessive DNA as a trigger of keratinocyte proliferation in psoriasis.

Psoriasis is characterized by excessive growth and aberrant differentiation of epidermal keratinocytes due to persistent inflammation. However, the underlying mechanism that triggers immune activation in psoriasis is not clear. In this study, we explored excessive DNA as a potential trigger of psoriasis using cultured human keratinocytes and psoriatic skin tissues. We demonstrated that human genomic DNA fragments induced tumour necrosis factor (TNF)-α expression, hyperproliferation and over-expression of heparin-binding epidermal-like growth factor (HB-EGF) and transforming growth factor (TGF)-α, accompanied by defective expression of keratins 1 and 10 in cultured normal human epidermal keratinocytes, which have a similar phenotype to that of keratinocytes in psoriatic skin lesions. In psoriatic lesions, we found high levels of double-stranded (ds)DNA fragments, accompanying keratinocytes expressing Ki-67, HB-EGF and TNF-α. In addition, we showed that 1,25-dihydroxyvitamin D3 inhibited genomic DNA fragment-induced TNFA and interleukin-1ß (IFNB) expression in human keratinocytes, and an intact function of cathelicidin anti-microbial peptide (CAMP) was required for this effect. These results suggest that excessive dsDNA fragments probably act as a risk factor for immune activation in psoriasis, and the active form of vitamin D can prevent genomic DNA-mediated skin inflammation via CAMP.

Phase I/II clinical trial to assess safety and efficacy of intratumoral and subcutaneous injection of HVJ-E in castration-resistant prostate cancer patients.

Inactivated Sendai virus particles (hemagglutinating virus of Japan envelope (HVJ-E)) have a novel antitumor effect: HVJ-E fused to prostate cancer cells via cell surface receptor causes apoptosis of prostate cancer cells in vitro and in vivo. HVJ-E also induces antitumor immunity by activating natural killer (NK) cells and cytotoxic T cells and suppressing regulatory T cells in vivo. We conducted an open-label, single-arm, phase I/II clinical trial in patients with castration-resistant prostate cancer (CRPC) to determine the safety and efficacy of intratumoral and subcutaneous injection of HVJ-E. Patients with CRPC who were docetaxel-resistant or could not receive docetaxel treatment were eligible. HVJ-E was injected directly into the prostate on day 1 and subcutaneously on days 5, 8 and 12 in two 28-day treatment cycles using a 3+3 dose-escalation design. The primary end points were to evaluate safety and tolerability of HVJ-E. The secondary end points were to analyze tumor immunity and antitumor effect. The study is registered at UMIN Clinical Trials Registry, number UMIN000006142. Seven patients were enrolled, and six patients received HVJ-E. Grade 2 or 3 adverse events (Common Terminology Criteria for Adverse Events Ver. 4.0) were urinary retention and lymphopenia from which the patients recovered spontaneously. No Grade 4 adverse events were observed. Radiographically, three patients had stable disease in the low-dose group, and one patient had stable disease and two had progressive disease in the high-dose group. The prostate-specific antigen (PSA) declined from 14 to 1.9 ng ml-1 in one patient in the low-dose group after two cycles of HVJ-E treatment, and the PSA response rate was 16.6%. NK cell activity was elevated from day 12 to day 28 after HVJ-E administration, whereas serum interleukin-6, interferon (IFN)-α, IFN-ß and IFN-γ levels were not affected by HVJ-E treatment. Intratumoral and subcutaneous injections of HVJ-E are feasible and PSA response was observed in a subgroup of CRPC patients.

Prostate cancer: state of the art imaging and focal treatment.

In 2016, it is estimated 180,890 men are newly diagnosed with prostate cancer and 3,306,760 men live with prostate cancer in the United States. The introduction of multiparametric (mp) magnetic resonance imaging (MRI) of the prostate, standardised interpretation guidelines such as Prostate Imaging Reporting and Data System (PI-RADS version 2), and MRI-based targeted biopsy has improved detection of clinically significant prostate cancer. Accurate risk stratification (Gleason grade/score and tumour stage) using imaging and image-guided targeted biopsy has become critical for the management of patients with prostate cancer. Recent advances in MRI-guided minimally invasive ablative treatment (MIAT) utilising cryoablation, laser ablation, high-intensity focused ultrasound ablation, have allowed accurate focal or regional delivery of optimal thermal energy to the biopsy proven, MRI-detected tumour, under real-time or near simultaneous MRI monitoring of the ablation zone. A contemporary review on prostate mpMRI, MRI-based targeted biopsy, and MRI-guided ablation techniques is presented.

Measurement of residual platelet thrombogenicity under arterial shear conditions in cerebrovascular disease patients receiving antiplatelet therapy.

UNLABELLED: Essentials A consensus methodology for assessing the effects of antiplatelet agents has not been established. Measuring platelet thrombus formation (PTF) for evaluating antiplatelet effects was assessed. PTF differentially reflected antiplatelet effects compared to other tests. PTF may be associated with the severity of carotid or intracranial arterial stenosis. Click to hear a presentation on platelet function testing in the clinic by Gresele and colleagues SUMMARY: Background A consensus methodology for assessing the effects of antiplatelet agents has not been established. Objective We investigated the usefulness of directly measuring platelet thrombus formation (PTF) using a microchip-based flow chamber system for evaluating antiplatelet therapy. Patients/Methods Platelet thrombus formation in the whole blood of 94 patients with ischemic cerebrovascular disease treated with clopidogrel and/or aspirin was measured in a flow chamber system at a shear rate of 1500 s(-1) and was compared with the results of assays for agonist-induced platelet aggregability, phosphorylation of vasodilator-stimulated phosphoprotein, platelet p-selectin expression (PS), and platelet-monocyte complexes. Results In all patients tested, area under the flow pressure curve (AUC10), which represents platelet thrombogenicity, showed weak correlation with platelet aggregation induced by either adenosine diphosphate or collagen. In addition, AUC10 was lower in patients treated with dual antiplatelet therapy (median 79.4) compared with patients treated with aspirin or clopidogrel alone (217.7 and 301.0, respectively), whereas the parameters evaluated by the other assays did not reflect the combined treatment efficacy. In clopidogrel monotherapy patients, AUC10 was associated with the severity of arterial stenosis (R(2) = 0.127, ß = 1.25), and AUC10 and PS were higher in patients with severe carotid or intracranial arterial stenosis than in those with mild stenosis. Conclusions Platelet thrombus formation measurement using a flow-chamber system was useful for evaluating the efficacy of treatment with aspirin and clopidogrel, both alone and in combination. The present findings indicate that high residual platelet thrombogenicity in patients treated with clopidogrel may be associated with the severity of carotid or intracranial arterial stenosis.

Effectiveness of epidural anesthesia for external cephalic version (ECV).

OBJECTIVE: The Cochrane review conducted in 2001 re-established the usefulness of external cephalic version (ECV). The success rate for ECV using epidural anesthesia or spinal anesthesia is reported to be 35 to 86%. In this study, we examined the effectiveness of epidural anesthesia for ECV. STUDY DESIGN: A retrospective cohort study was conducted of pregnant women who were at 35 to 36 weeks of gestation between 2001 and June 2009, with a single fetus, non-cephalic presentation and without non-reassuring fetal status. The subjects were ultrasonographically examined for placental location, presence/absence of nuchal cord and amniotic fluid volume. Those with placenta previa, early rupture of membranes, uterine anomaly or severe fetal anomaly and those in whom delivery was initiated were excluded from the study. The study protocol was approved by the institutional ethics committee, and written informed consent was obtained for all procedures described in the protocol. The success rate for ECV was compared between the anesthesia and non-anesthesia groups. Analysis was also performed to identify factors contributing to successful ECV. RESULT: There were 86 women with non-cephalic presentation who underwent ECV during the study period. The non-anesthesia group consisted of 34 women in whom ritodrine hydrochloride, a tocolytic agent, was administered alone, and 52 women in whom a tocolytic agent and epidural anesthesia were used constituted the anesthesia group. There were no significant differences between the two groups in terms of age, parity, body mass index and placental location. The success rate for ECV was 55.9% (19/34 patients) in the non-anesthesia group and 78.8% (41/52 patients) in the anesthesia group, showing a significant difference between the two groups (odds ratio 1.75, 95% confidence interval 1.26 to 2.44). Analysis was also performed to identify factors determining successful ECV other than epidural anesthesia from among age, parity, body mass index, placental location, presence/absence of uterine myoma, nuchal code and previous cesarean delivery; however, none of the factors identified was found to be a significant determinant factor. CONCLUSION: The use of epidural anesthesia significantly increases the success rate for ECV for breech presentation.

Androgen receptor and 5alpha-reductase immunohistochemical profiles in extramammary Paget disease.

BACKGROUND: Extramammary Paget disease is an uncommon skin tumour occurring mostly in the genitoperineal region. Previous reports have shown frequent expression of androgen receptor, suggesting a tumour-proliferative effect of androgens on Paget cells. Androgen-converting enzymes such as 5alpha-reductase, which locally produces a bioactive androgen, have recently gained attention in studies of the intratumoral actions of androgens. OBJECTIVES: We investigated correlations between the androgenic microenvironment and invasiveness in extramammary Paget disease, particularly in terms of sex differences. METHODS: We examined 58 cases of extramammary Paget disease (32 men, 26 women; 42 noninvasive, 16 invasive) using immunohistochemistry for androgen receptor and 5alpha-reductase. RESULTS: In all 58 cases, expression rates were 57% for androgen receptor and 55% for 5alpha-reductase, with 38% double-positivity for androgen receptor and 5alpha-reductase. Only 5alpha-reductase expression rate was significantly higher in invasive cases (81%) than in noninvasive cases (45%; P = 0.042). For invasive cases, numbers of double-positive results for androgen receptor and 5alpha-reductase were significantly higher in men (70%) than in women (17%; P = 0.039). CONCLUSIONS: Double positivity for androgen receptor and 5alpha-reductase in Paget cells suggests autocrine synthesis of androgens in extramammary Paget disease. The different hormonal microenvironments in male and female cases and intratumoral androgen levels affect the invasiveness of extramammary Paget disease.

Tryptophan aspartate-containing coat protein (CORO1A) suppresses Toll-like receptor signalling in Mycobacterium leprae infection.

Mycobacterium leprae is an intracellular pathogen that survives within the phagosome of host macrophages. Several host factors are involved in producing tolerance, while others are responsible for killing the mycobacterium. Tryptophan aspartate-containing coat protein (TACO; also known as CORO1A or coronin-1) inhibits the phagosome maturation that allows intracellular parasitization. In addition, the Toll-like receptor (TLR) activates the innate immune response. Both CORO1A and TLR-2 co-localize on the phagosomal membrane in the dermal lesions of patients with lepromatous leprosy. Therefore, we hypothesized that CORO1A and TLR-2 might interact functionally. This hypothesis was tested by investigating the effect of CORO1A in TLR-2-mediated signalling and, inversely, the effect of TLR-2-mediated signalling on CORO1A expression. We found that CORO1A suppresses TLR-mediated signal activation in human macrophages, and that TLR2-mediated activation of the innate immune response resulted in suppression of CORO1A expression. However, M. leprae infection inhibited the TLR-2-mediated CORO1A suppression and nuclear factor-kappaB activation. These results suggest that the balance between TLR-2-mediated signalling and CORO1A expression will be key in determining the fate of M. leprae following infection.

Dual-energy CT iodine overlay technique for characterization of renal masses as cyst or solid: a phantom feasibility study.

The aim of this study was to assess the ability of dual-energy computed tomography (DECT) to classify phantom renal lesions as cysts or enhancing masses. Six cylinders ranging in diameter from 0.5 to 3.0 cm were filled with distilled water or titrated iodinated contrast solutions with CT attenuation values at 120 kVp of 0 Hounsfield units (HU) for a cyst proxy or 10, 20, or 40 HU to represent enhancing masses. These were placed in a 12-cm-diameter renal phantom containing puréed beef mixed with iodinated contrast medium to simulate enhancing renal parenchyma of 100 and 250 HU and submerged within a 28-cm water bath. These combinations produced 48 individual phantom renal lesions of differing sizes, internal and parenchymal enhancement (12 cysts and 36 enhancing masses). DECT using 80 and 140 kVp was performed on a dual-source CT scanner. Commercial software created a color-encoded overlay indicating the location of iodine within the phantom. The lesions were individually graded as a cyst or enhancing mass by blinded, consensus interpretation of two genitourinary radiologists. Thirty-five of 36 enhancing masses and 10/12 cysts were correctly identified, equating to a sensitivity and specificity of 97% (95% CI 84-100%) and 83% (95% CI 51-97%), respectively. All lesions of 20- and 40-HU enhancement and 92% of 10-HU lesions were identified correctly. In a phantom model, the DECT iodine overlay technique is highly sensitive in detecting enhancing renal masses. Refinement of the technique remains necessary to improve specificity. If validated in patients, this may obviate the need for unenhanced acquisitions for renal mass characterization.

Extravascular application of an intravascular ultrasound (IVUS) catheter during carotid endarterectomy to verify distal ends of stenotic lesions.

BACKGROUND: Intravascular ultrasound (IVUS) has been developed initially for intravascular imaging of coronary arteries to investigate vascular structures. We applied the IVUS catheter extravascularly to the cervical carotid arteries to obtain intra-operative ultrasound images during carotid endarterectomy (CEA). Intra-operative assessments of the distal ends of the stenotic lesions as well as pathological vascular structures are important, not only for exposing the lesions sufficiently but also for placing the shunt system safely. METHOD: An IVUS catheter (3.2 French/30 MHz) was intra-operatively applied close to the outer surface of the cervical carotid arteries during CEA. Ultrasound transection vascular images were obtained in 33 consecutive patients (30 males and 3 females) with a mean age of 66.5 years. FINDINGS: In 32 of 33 cases, extravascular application of IVUS catheter before making arteriotomies correctly depicted the distal ends of the internal carotid artery (ICA) stenotic lesions as a thin layer of vascular wall [0.64 +/- 0.16 mm (mean +/- SD) compared with 1.66 +/- 0.42 mm for carotid plaque] with intravascular blood flow. Based on the IVUS findings, we were able to adequately expose the normal ICA portion distal to the stenotic lesion before making the arteriotomy even in cases with stenotic lesions at very high positions, and to insert shunts safely. Furthermore, the properties of lesions and blood flow were also verified. However, it was difficult to examine the far vascular wall. CONCLUSIONS: Extravascular application of IVUS catheter is efficient for intra-operative evaluation of the distal end of the stenotic lesion especially in cases with stenotic lesions at very high positions and cases in whom pre-operative angiograms did not clearly demonstrate the distal end. The findings also demonstrate the properties of lesions and completeness of CEA.

Caveolin-3 gene mutation in Japanese with rippling muscle disease.

OBJECTIVES: Rippling muscle disease (RMD) is a rare myopathy characterized by percussion-induced rapid muscle contractions, muscle mounding, and rippling. Recently a caveolin-3 gene (CAV3) mutation was identified in patients with autosomal dominant RMD. The objective of this study was to determine whether a similar mutation was present in two Japanese families with this condition. PATIENTS AND METHODS: Clinical examination, mutational analysis, and muscle immunohistochemistry were carried out in six patients from two Japanese RMD pedigrees. RESULTS: Apart from the atrophy of the intrinsic muscles in their hands and a slight muscle weakness in their fingers, the clinical features of our patients were compatible with RMD. Our investigation revealed a CAV3 missense mutation, i.e. Arg26Gln in both families. Immunohistochemistry performed on a muscle biopsy specimen showed reduced caveolin-3 surface expression. CONCLUSIONS: Japanese RMD also appears to result from a CAV3 mutation.

The laryngeal tube compared with the laryngeal mask: insertion, gas leak pressure and gastric insufflation.

BACKGROUND: We have compared the laryngeal tube and laryngeal mask in 22 patients for the success rate of insertion, gas leak pressure and the incidence of gastric insufflation. METHOD: In a randomized, crossover design, the laryngeal tube and laryngeal mask were inserted in turn after induction of anaesthesia and neuromuscular block. The cuffs were inflated until the intracuff pressure reached 60 cm H(2)O. We measured adequacy of ventilation and the minimum airway pressure at which gas leaked around the cuff. The presence or absence of gastric insufflation was studied at an inflation pressure of 20 cm H(2)O. RESULTS: It was possible to ventilate through the laryngeal tube in 21 patients and through the laryngeal mask in 21 patients. The mean leak pressure for the laryngeal tube (26 (SD 5) cm H(2)O) was significantly greater than that for the laryngeal mask (19 (4) cm H(2)O) (P<0.01; 95% confidence intervals for mean difference: 5.3-10.2 cm H(2)O). Gastric insufflation did not occur when the laryngeal tube was used and was noted in three patients when the laryngeal mask was used. CONCLUSION: The laryngeal tube provides a better seal in the oropharynx than the laryngeal mask.

Catheter dysfunction and thrombosis of double-lumen hemodialysis catheters placed in the femoral vein.

OBJECTIVE: Intraluminal thrombosis of the catheter was thought to be a major cause of catheter dysfunction. We evaluated if thrombi appear in the luminal side or outside of the catheters placed in the femoral vein in 21 hemodialysis patients. METHODS: 23 double-lumen catheter (25 cm long and 4 mm diameter polyurethane) strippings were consecutively performed. Mean catheter dwell time was 17.9 +/- 11.2 days (2-45 days). The femoral vein was observed with ultrasound echography, and thrombo-venous ratio (thrombus diameter/vein diameter) was calculated. X-rays were also taken to clearly visualize the thrombi followed by contrast medium injection through the catheter. RESULTS: Tube-shaped thrombi were echographically detected in 22 of 23 catheters (95.7%) when the catheter was stripped. Ten catheters (43.5%) were stripped due to the reduced blood flow, and tube-shaped thrombi were observed in the femoral vein, whereas no thrombus was found in the intraluminal side of the catheter. In 7 of 23 patients (30.4%) with leg edema on the same side of the catheter, the thrombovenous ratio was 78.9 +/- 7.4%, which was higher than that in the patients without leg edema (52.1 +/- 11.1%). CONCLUSION: The tube-shaped thrombi, formed around the double-lumen catheter, may cause catheter dysfunction and reduced venous return of the lower legs. The catheter should be removed as soon as thrombosis is diagnosed, especially when accompanied by leg edema.

Efficacy of catheter needles with safeguard mechanisms.

There has been considerable interest in using safeguarded needles to reduce needlestick injury. In a randomised design, we studied the efficacy and safety of two such needles (the Insyte AutoGuard and the Protective Acuvance), by comparing them with a conventional catheter needle (Insyte), for intravenous cannulation (18 G) in 150 patients and for intra-arterial cannulation in another 150 patients (20 G). For intravenous cannulation, the success rates were similar in the three groups but insertion of the AutoGuard or Acuvance catheter was significantly more difficult than the conventional catheter. For the Acuvance, the back-flow of blood into the chamber was sometimes too slow. For intra-arterial cannulation, insertion of the AutoGuard was significantly more difficult than the other two devices, mainly because the backflow chamber of the AutoGuard was too short so that the chamber often filled with blood before cannulation. Insertion of the Acuvance was significantly more difficult than the conventional catheter. For both intravenous and intra-arterial insertion, handling of the withdrawn needle was judged significantly safer in the AutoGuard group than the other two groups, whereas there was no significant difference in the safety between the Acuvance and conventional groups. In five subjects from the AutoGuard group, blood splashed on retraction of the needle. Blood contamination during needle withdrawal occurred frequently in the control and Acuvance groups, but rarely occurred in the AutoGuard group. Therefore, the AutoGuard needle is more suitable for intravenous cannulation, and the Acuvance is more suitable for intra-arterial cannulation.

Imaging evaluation of posttraumatic renal injuries.

Computed tomography plays an important role for the evaluation of most patients with suspected renal injury after trauma. Intravenous urography is used for gross assessment of renal function in hemodynamically unstable patients. Renal injuries can be classified into four large groups: (1) minor renal contusion, lacerations, subcapsular hematoma, and small cortical infarcts; (2) major renal lacerations extending to the medulla with or without involvement of the collecting system; (3) catastrophic renal injuries including fragmentation of the kidney and renal pedicle vascular injuries; and (4) ureteropelvic junction injuries. Integration of the imaging findings of renal injury with clinical information is important to developing a treatment plan.

Soluble osteopontin and vascular calcification in hemodialysis patients.

BACKGROUND: Vascular calcification often occurs in patients with uremia. As osteopontin (OPN) is not only involved in the physiological but also the pathological calcification of tissues, OPN may be associated with the pathogenesis of aortic calcification in hemodialysis (HD) patients. METHODS: We examined the expression of OPN in atherosclerotic aortas of HD patients. In addition, we performed a prospective longitudinal study by using CT scans to detect aortic calcifications and by measuring the plasma OPN concentration by ELISA in HD patients (20 men, 16 women; mean age 55.2 +/- 21.3 years) and in healthy volunteers (18 men, 17 women; mean age 54.0 +/- 13.2 years). RESULTS: By immunohistochemical staining, OPN was abundantly localized in atherosclerotic plaques of HD patients. The macrophages surrounding the atheromatous plaques were identified as the OPN-expressing cells. We furthermore found that the concentration of soluble plasma OPN was significantly higher in HD patients as compared with the concentrations in age-matched healthy volunteers (837.3 +/- 443.2 vs. 315.1 +/- 117.4 ng/ml, p < 0.01). The OPN concentration was positively correlated with the aortic calcification index in HD patients (r = 0.749, p < 0.01). CONCLUSION: These data suggest that OPN, secreted by macrophages, plays a role in the calcification of atheromatous plaques in HD patients.