Effects of MAL-PDT, ingenol mebutate and diclofenac plus hyaluronate gel monitored by high-frequency ultrasound and digital dermoscopy in actinic keratosis - a randomized trial.

BACKGROUND: The efficacy for actinic keratosis (AK) clearance of field-directed treatments has been investigated in randomized studies against placebo, but the comparison of results is difficult for several methodological reasons. OBJECTIVES: The present study aims to compare efficacy of MAL-photodynamic therapy (MAL-PDT), ingenol mebutate gel (IMB) and diclofenac plus hyaluronate gel (DHA) on multiple AKs assessing a new performance index of efficacy, the cumulative AK area and evaluating dermoscopical and high-frequency ultrasound (HFUS) changes. METHODS: Patients with ≥5 Olsen II AKs in a 25 cm2 area of the scalp and face were enrolled and randomized to one of the treatment choices. Number of AKs and cumulative area were assessed before and after treatment. Dermoscopy and HFUS were performed on a single AK and surrounding photo-damaged skin in the treatment area. RESULTS: Cumulative AKs area reduced significantly more with PDT compared to other treatment options and with IMB in comparison to DHA. PDT was also the only treatment option that increased at a significant level the dermal density in both target AK and the surrounding skin and decreased significantly the SLEB thickness in the perilesional skin at HFUS. CONCLUSIONS: MAL-PDT is more effective than IMB and DHA for reducing the cumulative AK area which is calculated digitally from 3D pictures and should be the preferred performance index for the evaluation of the efficacy of treatments for AKs, rolling out clinical and dermoscopy evaluation. MAL-PDT improves all HFUS features of chronic photodamages of the dermis of the skin underlying and surrounding the AK spots.

Clinical, histological and high-frequency ultrasonographic evaluation (50 MHz) of morphoea treated with ultraviolet A1 phototherapy.

BACKGROUND: There are few studies in the literature correlating the ultrasonographic findings, clinical scoring systems or histological findings in morphoea after ultraviolet (UV)A1 phototherapy. AIMS: To evaluate the quantitative and morphological aspects of high-frequency ultrasonography in the treatment of plaque morphoea in response to UVA1 phototherapy, and to correlate these with clinical and histological scores. METHODS: In total, 17 patients with morphoea were studied. Initially and at study end, high-frequency ultrasonography (50 MHz) was performed on the edge of a morphoea lesion treated with UVA1 phototherapy. A quantitative and qualitative analysis of dermal features was performed and compared with the features of healthy skin. Skin biopsy specimens were obtained from lesions analysed at the beginning and end of the study, assessing dermal sclerosis and dermal inflammatory infiltrate and their distribution. RESULTS: All affected skin showed a statistically significant increase in dermal thickness and hypoechogenicity, corresponding to a reduction in dermal density by ultrasonography compared with healthy skin. Morphological evaluation identified undulations of the dermis in 11 of 17 lesions (64.7%) and in 5 healthy skin areas (29.4%) (P = 0.08), while 'yoyo' figures were identified in 8 lesions (47%) but only 1 healthy skin area (5.9%) (P = 0.02). Ultrasonographic morphological analysis highlighted an improvement in dermal hyperechogenic bands and disappearance of yoyo figures after UVA1 treatment. Histology revealed a reduction in dermal sclerosis and inflammation, although this was not statistically significant. CONCLUSIONS: Ultrasonographic pattern analysis of morphoea is a suitable technique for monitoring UVA1 phototherapy response.

Cutaneous infiltration of plasmacytoid dendritic cells and T regulatory cells in skin lesions of polymorphic light eruption.

BACKGROUND: Polymorphic light eruption (PLE) is the most common autoimmune photodermatosis. Plasmacytoid dendritic cells (PDCs) are important mediators of innate antimicrobial immunity involved in the pathogenesis of many inflammatory skin diseases. In addition to PDCs, regulatory T cells (Tregs) are involved in controlling inflammation and adaptive immunity in skin by their immunosuppressive capacity. OBJECTIVE: The aim of this study was to investigate the presence of PDCs and Tregs in photoexposed skin from PLE compared to healthy skin. METHODS: Patients with PLE diagnosis and healthy controls were recruited and underwent a photoprovocative test. A 4-mm punch biopsy was taken from the site of positive photoprovocation test reaction, and immunohistochemistry for BDCA2 as marker for PDCs, CD4 and FOXP3 as markers for Tregs was performed. Double immunostain for FOXP3 and CD4 was performed as well. Absolute counts for CD4, BDCA2 and FOXP3 were performed in at least 5 High Power Fields (HPF). Percentage of CD4-, BDCA2- and CD4FOXP3-positive cells over the total inflammatory infiltrate was assessed for each case. RESULTS: We enrolled 23 patients and controls. BDCA2+ cells were present in 91.3% of PLE skin samples and 100% of healthy volunteer. Both in PLE patients and healthy controls, PDCs distribution was mainly dermic (P < 0.05). Compared to healthy controls, both epidermic and dermic BDCA2+ cells count were significantly higher in PLE patients (P < 0.05). Both in PLE patients and healthy controls, Tregs distribution was mainly dermic (P < 0.05). The presence of both CD4+ cells and FOXP3+ cells was significantly higher in the dermis of PLE patients compared to controls (P < 0.05). Relative percentages of cellular infiltrations confirmed these results. CONCLUSIONS: D-PDCS and Tregs may play a significant role in the development of PLE, and dermal distribution of PDCs in PLE skin biopsies seems to confirm a possible overlap with cutaneous lupus erythematosus (CLE).

Cryotherapy is preferable to ablative CO2 laser for the treatment of isolated actinic keratoses of the face and scalp: a randomized clinical trial.

BACKGROUND: Actinic keratosis (AK) may progress to squamous cell carcinoma. In the case of normal or mildly photodamaged skin, lesion-directed treatments are considered valuable options despite poor published evidence of their therapeutic activity. OBJECTIVES: The aim of this single-centre, open-label, prospective, nonsponsored, randomized, controlled clinical trial was to compare CO2 laser ablation with cryotherapy in the treatment of isolated AKs of the face and scalp. PATIENTS AND METHODS: Patients with isolated (≤ 4) AKs of the face and scalp were randomized to receive CO2 laser ablation or cryotherapy. After 90 days, the overall complete remission (CR) rates of patients and lesions were assessed and correlated with thickness grade. RESULTS: Two hundred patients with a total number of 543 AKs were enrolled. The CR rates of lesions after 3 months were 78·2% with cryotherapy and 72·4% with CO2 laser ablation. Thicker lesions were significantly more responsive to cryotherapy (P = 0·034). Seventy-three patients (71·6%) had CR of all lesions 3 months after cryotherapy and 64 (65·3%) after laser ablation. At 12 months after treatment the number of patients with CR was reduced to 53 with cryotherapy and 14 with laser ablation. CONCLUSIONS: The rate of patients and lesions with CR is similar after 3 months, but more patients remain in stable remission for 12 months after cryotherapy. Cryotherapy is more effective for thick lesions. The cosmetic outcome was good or excellent in almost all patients.

A randomized clinical trial of photodynamic therapy with methyl aminolaevulinate vs. diclofenac 3% plus hyaluronic acid gel for the treatment of multiple actinic keratoses of the face and scalp.

BACKGROUND: A gel containing diclofenac and hyaluronic acid (DHA) and photodynamic therapy with methyl aminolaevulinate (MAL-PDT) are widely used treatments for actinic keratoses (AKs). OBJECTIVES: The aim of this single-centre, open-label, prospective, nonsponsored, randomized controlled clinical trial was to compare the treatment results and cost-effectiveness of MAL-PDT and DHA. METHODS: Patients with multiple AKs of the face and scalp were randomized to receive MAL-PDT or DHA. After 90 days, the overall complete remission (CR) rate of patients and the CR rate of lesions according to thickness score were assessed, and patients and an investigator scored the cosmetic outcome. In addition, patients scored their overall satisfaction with the treatment. Patients with CR of all lesions were followed up for 12 months. RESULTS: Two hundred patients with a total of 1674 AKs were enrolled. The lesion CR rates at 3 months were 85·9% with MAL-PDT and 51·8% with DHA (P < 0·0001). AKs of all thicknesses were significantly more responsive to MAL-PDT. The patient CR rates at 3 months were 68% with MAL-PDT and 27% with DHA. At the 12-month examination, the number of patients with CR reduced to 37 with MAL-PDT and seven with DHA. Rating of cosmetic outcome was very good or excellent in the vast majority of patients with both treatments. The analysis of cost-effectiveness showed that the costs per patient with CR at 3 months and at 12 months are €566·7 and €1026·2, respectively, with MAL-PDT and €595·2 and €2295·6, respectively, with DHA. CONCLUSIONS: Efficacy, cosmetic outcome and patients' overall satisfaction with MAL-PDT are superior in comparison with DHA. MAL-PDT is more expensive but it is more cost-effective.

Synergism between narrowband ultraviolet B phototherapy and etanercept for the treatment of plaque-type psoriasis.

BACKGROUND: Previous investigations have demonstrated that a combination of etanercept (ETN) and narrowband ultraviolet B (NB-UVB) phototherapy is more effective than ETN alone. However, it is unclear if this combination is more effective than NB-UVB phototherapy alone. OBJECTIVES: To evaluate whether the combination of NB-UVB phototherapy with ETN improves the efficacy of ETN alone in the treatment of moderate-to-severe psoriasis. METHODS: We enrolled 322 consecutive patients with moderate-to-severe plaque-type psoriasis, who were treated with NB-UVB phototherapy as the first-line treatment option. Patients who did not achieve a 75% improvement in Psoriasis Area and Severity Index (PASI 75) were treated with conventional systemic therapies for psoriasis. If they were ineligible for these, they were treated with ETN 50 mg twice weekly. If they did not achieve PASI 75 within 12 weeks, NB-UVB phototherapy was added. RESULTS: PASI 75 was achieved in 262 patients (81.4%) treated with NB-UVB phototherapy. Sixteen patients (5.0%) dropped out for personal reasons and 24 (7.5%) were treated with at least one of the conventional systemic treatments for psoriasis. Twenty patients (6.2%) were treated with ETN. The combination regimen was needed in eight patients (2.5%) with poor response to both phototherapy and ETN alone. All of these patients achieved PASI 75 and three of them had a complete remission after 14.6 ± 3.3 NB-UVB exposures. The combined treatment was well tolerated without acute adverse events. Unfortunately, all of these patients relapsed, with PASI > 10 within 2.8 ± 1.7 months. CONCLUSIONS: The combined treatment has a synergistic effect for clearing plaque-type psoriasis previously unresponsive to ETN and NB-UVB phototherapy alone. The clearance rate is very high in a very short time without short-term adverse effects. However, concerns regarding potential cocarcinogenicity remain. Therefore the number of patients who require, and could benefit from, the combined treatment is likely to be small.

The main organizational changes in dermatological practice in the Lombardy Region, Italy, from 2001 to 2009.

BACKGROUND: Changes in financing health care delivery, including the adoption of diagnosis-related groups (DRG), has deeply influenced dermatological practice across Europe. OBJECTIVE: To define the current status of dermatological care in the Lombardy Region, Italy, and compare the status of 2009 to that of 2001. METHODS: Data were analysed from the annual reports of the Healthcare General Department of the Lombardy Region; legislative and administrative data were taken into consideration. RESULTS: Beds for inpatients in Dermatologic Wards decreased from 251.7 (2001) to 49.07 (2009). In 2009, a large proportion of inpatients with skin diseases were admitted to non-dermatological departments. Beds for day-hospital activities increased from 55.9 (2001) to 61.0 (2009), and the proportion of admissions for surgical purposes progressively increased. In addition, the complexity and quality of surgical procedures increased, in view of the need to justify a day-hospital admission. The total number of services for outpatients increased from 1,090,052 (2001) to 1,503,692 (2009); in addition, the weighted numbers (an indicator of complexity) increased from 2,117,000 (2001) to 3,644,032 (2009). The number of dermatologists with unlimited contracts decreased, and the number of low paid scholarship recipients and external consultants increased. Three of six medical faculties currently do not have a university department of Dermatology. CONCLUSION: Over the last decade, the number of patients hospitalized in Dermatological Departments has declined; moreover, patients hospitalized with dermatological disorders have been increasingly admitted to wards with a non-dermatologist attending physician.

A randomized split-face clinical trial of conventional vs indoor-daylight photodynamic therapy for the treatment of multiple actinic keratosis of the face and scalp and photoaging.

BACKGROUND: Recently, indoor daylight photodynamic therapy (idl-PDT) has been developed; however, its efficacy and tolerability remain to be assessed. OBJECTIVE: This is a not-inferiority study to compare treatment outcomes of cPDT with a red LED lamp and idlPDT with a polychromatic white LED lamp in adult patients affected by symmetrical AKs of face and/or scalp. METHODS: In this comparative, intra-patient, split-face, randomized clinical trial forty-three adult patients were enrolled. Two contralateral and symmetrical target areas of the face and/or scalp harboring at least 5 AKs were selected and randomized 1:1 to treatment with cPDT and idlPDT. The AKs number and cumulative area were assessed at baseline (T0). Efficacy and cosmetic outcome were assessed 3 months after treatment (T1). RESULTS: Total AKs number and area reduced significantly with both idlPDT (p < .0001) and cPDT (p < .0001) in comparison to baseline. cPDT was more painful (p < .0001) and induced a more severe inflammation (p < .0001). Twenty-nine patients (70.7%) gave their overall preference to idlPDT (p < .001). CONCLUSION: idlPDT may represent an alternative treatment protocol to cPDT for in-office treatment of AKs patients with better tolerability and a not inferior efficacy.

The separate daily application of tacalcitol 4 µg/g ointment and budesonide 0.25 mg/g cream is more effective than the single daily application of a two compound ointment containing calcipotriol 50 µg/g and betamethasone dipropionate 0.5 mg/g.

AIM: This pilot randomized intra-patient side to side trial was designed to assess the antipsoriatic efficacy, safety and tolerability of once daily versus the separate application of a vitamin D3 analogue and a powerful corticosteroid. METHODS: Twenty patients with plaque type psoriasis were enrolled. Two similar symmetrical lesions were randomized to be treated with an application of an ointment containing calcipotriol 50 µg/g plus betamethasone dipropionate 0.5 mg/g once daily or the application of budesonide 0.25 mg/g cream in the morning and tacalcitol 4 µg/g ointment in the evening. RESULTS: Eighteen patients completed the study. Both treatments proved to be effective but budesonide cream and tacalcitol ointment gave a faster improvement of lesions and itching relief at t1 and were better tolerated. CONCLUSION: The separate daily regimen may represent a suitable treatment option for patients who need a faster improvement and a better moisturizing activity. Further studies which compare the efficacy and safety of these regimens need to be developed.

[Malignant fibrous histiocytoma. Case report]. / Istiocitoma fibroso maligno. Caso clinico.

Malignant fibroous histiocytoma (MFH) is an aggressive soft tissue sarcoma, that most frequently occurs in the muscles of the extremities and in abdominal or in retroperitoneal space of young adults. It is seldom confined to the skin and subcutaneous tissue. It is rarely diagnosed before excision and pathological exam, and has an unfavorable prognostic in some cases. This work reports the case of a 94 years old patient with originally cutaneous MFH stressing the importance of the early diagnosis.

[GIST: our experience]. / GIST: nostra esperienza.

Gastrointestinal stromal tumors (GIST) are generally found in the stomach or small intestine and less commonly in the colon and rectum. Complete surgical remove remains the best current therapy. In the treatment of advanced/metastatic GIST is available imatinib, a selective tyrosine kinase inhibitor. In our experience, 12 patients observed between 2000 and 2007 and affected by GIST underwent surgery, in one case associated to treatment with imatinib.

[Colo-anal anastomosis. Our experience]. / Anastomosi coloanale. Casistica clinica.

The aim of study is to report the results of our experience about ultra-low rectum carcinomas treated with anterior resection and colo-anal anastomosis. The surgery still represents the treatment of choice for the cancer of the rectum. The problems concern the conservation of the sphincter functions (anal and urethral), and sexual function and the reduction of the locoregional recurrences. From 2005 to 2007, 33 patients underwent surgery for low and ultralow rectal carcinoma (30 treated with neoadjuvant radio-chemotherapy, and 3 only with surgery). In 16 of these we have performed a colo-anal anastomosis, in 11 an ultralow colorectal anastomosis and in 7 a Miles resection. We report our updated results.

Tomato roots exhibit in vivo glutamate dehydrogenase aminating capacity in response to excess ammonium supply.

In higher plants ammonium (NH4+) assimilation occurs mainly through the glutamine synthetase/glutamate synthase (GS/GOGAT) pathway. Nevertheless, when plants are exposed to stress conditions, such as excess of ammonium, the contribution of alternative routes of ammonium assimilation such as glutamate dehydrogenase (GDH) and asparagine synthetase (AS) activities might serve as detoxification mechanisms. In this work, the in vivo functions of these pathways were studied after supplying an excess of ammonium to tomato (Solanum lycopersicum L. cv. Agora Hybrid F1) roots previously adapted to grow under either nitrate or ammonium nutrition. The short-term incorporation of labelled ammonium (15NH4+) into the main amino acids was determined by GC-MS in the presence or absence of methionine sulphoximine (MSX) and azaserine (AZA), inhibitors of GS and GOGAT activities, respectively. Tomato roots were able to respond rapidly to excess ammonium by enhancing ammonium assimilation regardless of the previous nutritional regime to which the plant was adapted to grow. The assimilation of 15NH4+ could take place through pathways other than GS/GOGAT, since the inhibition of GS and GOGAT did not completely impede the incorporation of the labelled nitrogen into major amino acids. The in vivo formation of Asn by AS was shown to be exclusively Gln-dependent since the root was unable to incorporate 15NH4+ directly into Asn. On the other hand, an in vivo aminating capacity was revealed for GDH, since newly labelled Glu synthesis occurred even when GS and/or GOGAT activities were inhibited. The aminating GDH activity in tomato roots responded to an excess ammonium supply independently of the previous nutritional regime to which the plant had been subjected.

[Downstaging after neoadjuvant therapy for rectal cancer modifies the planned original surgery]. / Il downstaging dopo terapia neoadiuvante del cancro del retto modifica l'intervento originariamente programmato.

Cancer of the rectum has been for more years burdened with a heavy rate of local relapse about 30%. The introduction of total meso-rectum excision has reduced the rate of up to 5-8%. Later more studies proved how the preoperative radiotherapy was able to reduce the rate of local relapse. The Authors introduce studies about downstaging after neoadjuvant chemoradiotherapy for rectal cancer and discuss about their own series from 2005 to 2007.

Limiting dilution analysis of a novel tripeptide anticancer agent Ambamustine (PTT-119): effect on K-562, CCRF-SB and multidrug resistant LoVo-Dk cell lines.

Cell suspensions of normal human bone marrow were mixed with human acute lymphoblastic or myelogenous leukemic cells of the CCRF-SB or K-562 lines. After incubating the cell mixtures in vitro with different dose levels of Ambamustine (PTT-119), a quantity of 10(4) treated cells were dispensed into microculture plates, and graded cell numbers of the lines used to contaminate the normal marrow were added. Limiting dilution analysis (LDA) was used to estimate the frequency of leukemic cells persisting after treatment. Incubation with 50 micrograms/mL of PTT-119 produced a total elimination of K-562 acute myelogenous blasts, whereas nearly 0.17 and 0.27 leukemic cells were still present in the cell mixtures after treatment with 5 and 25 micrograms/mL, respectively. When normal bone marrow was contaminated with CCRF-SB lymphoblastic cells, incubation with either 50 or 25 micrograms/mL of PTT-119 produced a complete clearing of leukemic cells, whereas with 5 micrograms/mL the leukemic cells in each well were 0.18. When PTT-119 was incubated with LoVo-DX, a colon cancer cell line which expresses the pleiotropic drug resistance MDR phenotype, virtually complete inhibition of clonogenic colonies was observed with as little as 5 micrograms/mL. This suggests that PTT-119 could be used in clinical trials as a non-cross-resistant agent in multidrug protocol.

Effect of two cyclophosphamide derivatives on hemopoietic progenitor cells and pluripotential stem cells.

The studies described herein were undertaken to help define the effects of certain cyclophosphamide derivatives that have been used for selective removal of leukemic cells from marrow samples used for autologous transplantation. We have tested the effect of 4-HC and another cyclophosphamide congener, ASTA-Z 7557, on pluripotent stem cells (CFU-S) and committed progenitor cells (CFU-GM) in mice. The CFU-S were evaluated by the spleen colony assay at eight days and 12 days after transplant. The eight-day colonies are transient in nature, rapidly growing, mainly erythroid, and lack pluripotential precursors. The 12-day colonies are believed to provide a measure of hemopoietic stem cells as they slowly grow and do contain primitive precursors. Our data show that at the maximum dose levels tested, both drugs caused a 100% loss of CFU-GM and about 80%-95% inhibition of early transient CFU-S. In contrast, about 70% of the pluripotent 12-day CFU-S were spared. These data appear to explain the hemopoietic recovery seen in man after transplantation with marrow cells treated with 4-HC despite their relative absence of hemopoietic progenitor cells.

NMR determination of isosorbide dinitrate and beta-adrenergic blocking agents in tablets.

An NMR spectroscopic method for the determination of isosorbide dinitrate, alone or together with alprenolol or propranolol, is described. Spectra are determined in dimethyl sulfoxide-d6 containing maleic acid or 1,4-dinitrobenzene as internal standards. Both synthetic mixtures and commercial formulations were assayed, and the results were compared using compendial procedures.