Position statement for the diagnosis and management of anogenital warts.

BACKGROUND: Anogenital warts (AGW) can cause economic burden on healthcare systems and are associated with emotional, psychological and physical issues. OBJECTIVE: To provide guidance to physicians on the diagnosis and management of AGW. METHODS: Fourteen global experts on AGW developed guidance on the diagnosis and management of AGW in an effort to unify international recommendations. Guidance was developed based on published international and national AGW guidelines and an evaluation of relevant literature published up to August 2016. Authors provided expert opinion based on their clinical experiences. RESULTS: A checklist for a patient's initial consultation is provided to help physicians when diagnosing AGW to get the relevant information from the patient in order to manage and treat the AGW effectively. A number of frequently asked questions are also provided to aid physicians when communicating with patients about AGW. Treatment of AGW should be individualized and selected based on the number, size, morphology, location, and keratinization of warts, and whether they are new or recurrent. Different techniques can be used to treat AGW including ablation, immunotherapy and other topical therapies. Combinations of these techniques are thought to be more effective at reducing AGW recurrence than monotherapy. A simplified algorithm was created suggesting patients with 1-5 warts should be treated with ablation followed by immunotherapy. Patients with >5 warts should use immunotherapy for 2 months followed by ablation and a second 2-month course of immunotherapy. Guidance for daily practice situations and the subsequent action that can be taken, as well as an algorithm for treatment of large warts, were also created. CONCLUSION: The guidance provided will help physicians with the diagnosis and management of AGW in order to improve the health and quality of life of patients with AGW.

Changes in dermal structure and skin oxidative stress in overweight and obese Japanese males after weight loss: a longitudinal observation study.

BACKGROUND/PURPOSE: Previous studies have reported decreased dermal echogenicity and increased skin oxidative stress in overweight males. However, it is unknown whether these skin parameters of overweight and obese people are similar to those of individuals exhibiting a normal body weight following weight loss. The purpose of this study was to (1) compare the changes in the dermal structure parameters and levels of skin oxidative stress before and after weight loss in overweight and obese people in Japan and (2) to clarify how these aspects changed when body weight would be reduced to normal body weight. METHODS: Male volunteers with a body mass index of ≥25 kg/m2 were recruited. The dermal structure was visualized and dermal echogenicity and thickness were measured using ultrasound scanners. The mRNA expression level of heme oxygenase-1 in the hair follicles was quantitatively analyzed as a marker of skin oxidative stress. RESULTS: When overweight individuals in their 20s to 30s reduced their weight to normal, decreased dermal thickness in the abdominal region was observed in 50% of the subjects; however, no increase in dermal echogenicity was observed. A decrease in dermal thickness and an increase in dermal echogenicity in the thighs was observed in 83.3% of the subjects. No decrease in the level of dermal oxidative stress was observed. CONCLUSION: The dermal structure in the thighs of overweight young individuals can be improved to the level of the structure in those of normal body weight individuals following weight loss.

Fas-resistance in ATL cell lines not associated with HTLV-I or FAP-1 production.

A preventive role for human T-cell leukemia virus type-I (HTLV-I) and Fas-associated phosphatase-1 (FAP-1) in Fas-mediated apoptosis has been reported in HTLV-I-infected cells. In the present study, we examined whether these molecules increased during the acquisition of Fas-resistance in adult T-cell leukemia (ATL) cell lines. SO4, ST1 and KK1 are Fas-sensitive ATL cell lines, and produce small amounts of HTLV-I in vitro. Although their subclones RSO4 and RST1 are completely Fas-resistant, they produced an equivalent amount of HTLV-I to SO4 and ST1. Moreover, FAP-1 mRNA was not detected in these cell lines irrespective of Fas sensitivity. Thus, Fas resistance in ATL cells was not directly associated with the increased production of HTLV-I or FAP-1.

Minimally differentiated acute myeloid leukemia (AML-M0) with extensive erythrophagocytosis and del(20)(q11) chromosome abnormality.

We describe an 84-year-old woman who presented severe pancytopenia and 36.6% of blasts accompanied with erythrophagocytosis in the bone marrow. According to cytochemical and immunological findings, a diagnosis of minimally differentiated acute myeloid leukemia (AML-M0) was established. Cytogenetic analysis revealed del(20)(q11) which were previously reported for one case each of ALL and MDS associated with cytophagocytosis by blasts, leading us to speculate a disease entity. Interestingly, a high expression of mRNA of TNF-alpha was detected by RT-PCR on the bone marrow mononuclear cells.

Successful treatment with a chimeric anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab) for a patient with relapsed mantle cell lymphoma who developed a human anti-chimeric antibody.

Mantle cell lymphoma (MCL) has a poor prognosis without cure; the median overall survival ranges only from 3 to 4 years irrespective of conventional therapeutic regimens. IDEC-C2B8 (rituximab), a chimeric monoclonal antibody against the B-cell-specific antigen CD20, induces an evaluable clinical response in patients with MCL with mild toxicities. However, the single agent rituximab cannot cure MCL. Due to its low immunogenicity, an antibody against IDEC-C2B8 (human antichimeric antibody [HACA]) has rarely been produced in vivo. We report a patient with relapsed MCL who was successfully treated with IDEC-C2B8 for over a year although she developed HACA 6 months after the initial administration of IDEC-C2B8 in the phase II clinical trial conducted by Zenyaku Kogyo Co. Ltd. We followed the pharmacokinetics of IDEC-C2B8, the serum HACA titer, and the number of B lymphocytes in the peripheral blood in relation to clinical response. The HACA became undetectable soon after subsequent administrations of IDEC-C2B8. When the serum level of IDEC-C2B8 was kept elevated, clinical responses were apparently observed and HACA disappeared during this response period. There were no significant clinical toxicities related to the appearance of HACA. The present findings suggested that IDEC-C2B8 is effective and safe even in patients who have developed HACA.

Comparison of energy metabolism in insulin-dependent and non-insulin-dependent diabetes mellitus.

To compare the metabolic consequences of insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM), glycemic control and energy metabolism were evaluated in 18 children displaying IDDM and 19 NIDDM adult patients. With rising concentrations of fasting blood glucose (FBG), hemoglobin A1C and free fatty acid, the percentage of the ratio of resting energy expenditure (REE) to predicted REE expressed as %REE increased and the respiratory quotient (RQ) decreased. The linear regression between RQ and FBG showed the same gradient in IDDM and NIDDM although the RQ in IDDM was always 0.07 lower than that in NIDDM given various FBG concentrations. Those patients whose RQ values were less than 0.7, indicating ketone body production, included 8 (44%) IDDM and 2 (11%) NIDDM patients. These results may explain the relatively greater manifestation of ketoacidosis in IDDM.

Effectiveness of dynamic MRI for diagnosing pericicatricial minimal residual breast cancer following excisional biopsy.

The purpose of this study was to investigate the effectiveness of dynamic MRI for diagnosing pericicatricial minimal residual breast cancer following excisional biopsy. Twenty-six patients who underwent excisional biopsy of a tumor or calcified lesion of the breast underwent gadolinium-enhanced dynamic MRI by the fat-saturated 2D fast spoiled gradient echo (SPGR) sequence (group 1), 24 patients by the spectral IR enhanced 3D fast gradient echo (Efgre3d) sequence (group 2). Pericicatricial residual cancer was confirmed histologically in 29 of the 50 patients. The overall sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of MRI for residual cancer diagnosis was 66, 81, 72, 83 and 63%. A nodular, thick and discontinuous enhanced rim around the scar is indicative of a residual tumor. However, false-positive findings due to granulation or proliferative fibrocystic change remain limitations.

[Trial of combined cytosine arabinoside with granulocyte colony-stimulating factor therapy or refractory acute myeloid leukemia].

Thirteen cases, including 10 relapse cases, of refractory acute myeloid leukemia (AML) (aged 17-70, median 46) by cytosine arabinoside (Ara-C) combined with granulocyte colony-stimulating factor (G-CSF) simultaneously to enhance the sensitivity to Ara-C. Low dose Ara-C (10-40 mg/day) combined with G-CSF was administered in most of them. Complete (CR) and partial remission (PR) were achieved in 5 and 4 patients, respectively, and response (CR + PR) rate was 69.2%. We obtained 5 CRs and 3 PRs in 10 patients with relapsed AML. However, CR and PR duration was short in all cases. None of the 3 patients with MO, AML transformed from myelodysplastic syndrome (MDS), and de novo AML with trilineage myelodysplasia (TMDS) had any response. There was no leukemic colony formation in the culture medium containing G-CSF in the nonresponding patients. The combination therapy caused severe myelosuppression, and most patients experienced prolonged neutropenia, and suffered from infections. In some patients enhanced chemosensitivity of leukemic cells induced by G-CSF was indicated but, the effect of this approach must be determined by large scale controlled studies.

[An approach to prolongation of survival rate in tumor bearing mice using 5-fluorouracil in combination with various kinds of herb medicine].

The effect of 5-fluorouracil (5-FU) in combination with herb medicine on the prolongation of survival rate in tumor bearing mice was studied. 5-FU directly inhibited the growth of cancer cells in vitro. However, the herb medicines used in this experiment showed neither an inhibitory effect on the growth of cancer cells nor prevention of inhibitory effect of 5-FU on the growth of cancer cells. 5-FU in combination with various kinds of herb medicine prolonged the survival time of tumor bearing mice. 5-FU in combination with shosaiko-toh was most effective; its increase of life span (ILS) was by 56%. However, mitomycin C in combination with shosaiko-toh was not associated with the prolongation of the survival rate of tumor bearing mice. The long-term administration of 5-FU to rats resulted in decrease in body weight, food intake, and white blood cell count, and these symptoms were improved when 5-FU was used in combination with shosaiko-toh. However, the increase in A/G ratio due to a decrease in the serum globulin fraction and marked atrophy of the thymus were not improved even when shosaiko-toh was combined with 5-FU.

Effect of saikosaponin derivatives upon the immune response against T-dependent and T-independent antigens in mice.

Effect of water soluble extracts and purified derivatives from the root of the plant Bupletum falcatum L. upon the immune response of BALB/c mice was investigated using heterologous erythrocytes and bacterial lipopolysaccharide. This Chinese Medicine is famous for its reputed anti-inflammatory, anti-tumor and other biological activities, and has been widely used alone or in a complexed form since ancient times in Oriental Countries. The effect on immune responsiveness of this drug was judged by the measurement of antibody secreting cells causing localized hemolysis in agar gel. The purified derivatives, Saikosaponin (SS) a and d, suppressed anti-SRBC plaque-forming cells (PFC), but the other derivatives, b1 and b2 and c, did not. Moreover, derivatives a and d also enhanced anti-LPS PFC. From experiments establishing minimum effective doses for anti-SRBC PFC in mice, one mg/kg was optimum for BALB/c mice. The effect of the drug on antibody formation against heterologous erythrocytes was nonspecific because treated mice had greatly depressed PFC responses against both sheep and rabbit erythrocytes. The phenotypic effect of this drug as judged by PFC against T-dependent or T-independent antigen was not identified. However, it was suggested that the purified derivatives SSa and d stimulated both T- and B-cells. The possible mechanism of effect against immunocompotent cells is discussed.

Breast cancer in dense breast: detection with contrast-enhanced dynamic MR imaging.

The purpose of this study was to identify contrast enhancement patterns of dense breast parenchyma and to investigate the ability of dynamic magnetic resonance imaging (MRI) to detect cancer in the dense breast. Thirty-two patients with breast cancer in dense breast underwent gadolinium-enhanced dynamic MRI. The detectability of cancer by dynamic MRI, mammography, and physical examination was compared. Two parenchymal enhancement patterns could be identified. One was increasingly multiple patchy enhancement found predominantly in the periphery (type A), and the other was faint enhancement without any nodular opacification (type B). Type A was thought to reflect severe proliferative fibrocystic change (PFC). For both patterns, the detection rate of primary cancers by dynamic MRI was found to be superior to that by other modalities. Dynamic MRI also could detect multifocal cancers, which could not be found with other modalities, although the detectability of these small cancers might be reduced in patients with severe PFC.

Contrast-enhanced MR angiography (enhanced 3-D fast gradient echo) for diagnosis of cerebral aneurysms.

We evaluated contrast-enhanced MRA (enhanced 3-D fast gradient echo, EFGRE3D, with spectral IR) for the identification of unruptured cerebral aneurysms. We examined 22 aneurysms from 15 patients. In its ability to identify aneurysms, contrast-enhanced MRA was superior to 3-D-time of flight (3D-TOF) MRA in 4 instances, equal in 17, and inferior in 1. Contrast-enhanced MRA demonstrated thrombus formation more clearly and accurately than did 3D-TOF MRA. Contrast-enhanced MRA was performed in less than 1 min, and was found to be a useful method for the identification of intracranial aneurysms.

Contrast-enhanced MRA for investigation of cerebral arteriovenous malformations.

We evaluated contrast-enhanced MRA (enhanced 3-D fast gradient-echo [efgre3d] with spectral inversion recovery) for identification of 15 intracranial arteriovenous malformations (AVMs) in 14 patients. Demonstration of the feeding arteries was classified as good for 16 examinations on maximum-intensity projections and multiprojection volume reconstruction images. The nidus was seen well in all patients. Definition of the draining veins was good or fair except for one poor result. Therapeutic effects were clearly demonstrated in three follow-up series. Contrast-enhanced MRA using efgre3d is useful for delineation of AVMs and for follow-up after treatment.

Diversity of leukaemic cell morphology in ATL correlates with prognostic factors, aberrant immunophenotype and defective HTLV-1 genotype.

To investigate the diversity of morphology in adult T-cell leukaemia/lymphoma (ATL) and its possible association with the pathophysiology of ATL, we selected 36 acute cases and 14 chronic cases phenotypically confirmed to have >90% ATL cells in peripheral blood mononuclear cells. Prototype ATL cells were observed in all cases, although the percentage of all lymphoid cells varied considerably (48.9 +/- 23.8 in acute type, 29.6 +/- 18.9 in chronic type; P = 0.015). Chronic lymphocytic leukaemia (CLL)-like morphology with round nuclei was more frequent in chronic type than in acute type (52.0 +/- 24.9% v 16.6 +/- 13.1%; P < 0.0001). Unusual morphology (UM; lymphoblastic, vacuolated, granular pleomorphic or large cells) was more frequent in acute type than in chronic type (20.1 +/- 18.7% v 2.7 +/- 3.2%; P < 0.0001). Furthermore, there were significant negative and positive correlations of % CLL-like cells and % UM cells respectively, with serum LDH level, hypercalcaemia, performance status, and total number of involved lesions. Cases with aberrant immunophenotype (n = 6) or defective HTLV-1 integration (n = 22) showed lower % CLL-like cells and higher % UM cells than other cases, respectively. Cases with >50% CLL-like cells (n = 7; all chronic type) were younger (53.1 +/- 12.2 v 66.9 +/- 10.6 years; P = 0.038) and showed longer acute-crisis free survival (mean: 16.7 v 3. 0 years; P = 0.012) than chronic cases with <50% CLL-like cells. These results suggest that diversity in genotype, phenotype, morphology and behaviour of ATL are closely associated, and that CLL-like morphology is a good prognostic factor for chronic type.

Lactacystin activates FLICE (caspase 8) protease and induces apoptosis in Fas-resistant adult T-cell leukemia cell lines.

Lactacystin (LC) is a specific inhibitor of the proteasome, and has recently been shown to induce apoptosis in certain cell lines. In the present study, we established Fas-resistant adult T-cell leukemia (ATL) cell subclones RSO4 and RST1 from their parental Fas-sensitive cell lines SO4 and ST1, and examined whether LC can overcome Fas resistance. LC completely inhibited proteasome function as determined by a peptidyl-MCA substrate (LLVY-MCA and LLE-MCA), and induced apoptosis in these cell lines irrespective of Fas sensitivity at low concentrations (approximately 10 microM). LC induced the activation of caspase 3 (CPP32/Yama) and caspase 6 proteases in an identical manner to Fas-mediated apoptosis. Moreover, LC induced the activation of caspase 8 (FLICE) protease, which is the initiator of the Fas-mediated apoptotic cascade. Synthesized proteasome inhibitory peptide MG-115 (ZLLnV-CHO) also induced apoptosis in these cell lines. These results indicated that proteasome inhibitors overcome Fas-resistance by bypassing the proximal part of the Fas signal. Inhibition of the proteasome function may be a new strategy for the treatment of ATL.