Cutaneous targets in drug-induced reactions.

Skin is the main sufferer of the adverse drug reactions (ADRs), being involved in 30% of all ADRs cases. However, ADRs are generally underestimated because of the difficulty to correlate the event to a particular drug. A careful anamnestic history is crucial to establish the causal link between an ADR and the specific drug. Clinical, developmental and medical history is important to define an ADR but sometimes you need to make histological examination to get additional diagnostic indications. However, the histological findings observed during the ADRs are hardly or not easily distinguishable from other skin diseases. Furthermore, the patient is often administered multiple drugs, so that the evaluation of histological findings is a complex one. In the present work we have reviewed the most frequently reported histological pictures induced by drugs as associated with a specific ADR, following, as criterion, the localization of the damage within the skin. So ADRs are divided into reactions in which the damage is localized in the epidermis, at dermal-epidermal (junction) level, in the dermis, subcutaneous fat and adnexal structures. We then briefly describe the clinical and histological pictures most frequently observed in ADRs.

Mycosis fungoides: disease evolution of the "lion queen" revisited.

Mycosis fungoides (MF), which represents the most common subtype of primary cutaneous T-cell lymphoma (CTCL), is an epidermotropic lymphoma included as an indolent form in the recent WHO/EORTC classification. From a clinical point of view, the classic disease progression usually is slow and takes over years or even decades, and characterized by the evolution from patches to more infiltrated plaques and eventually to tumours or erythroderma. However, the analysis of the MF disease course has been greatly impaired by the rarity of the disease, thus data about the time course of disease progression and pattern of relapse during time are not well known. In this review, a summary of published data on MF large patients cohorts will be presented, together with the results obtained by a retrospective analysis of clinical features and follow-up data of 1,422 MF patients diagnosed and followed-up from 1975 to 2010 in 27 Italian Centres (Italian Study Group for Cutaneous Lymphoma). From a clinical perspective, the amount of data support the relevance of a stage-tailored, differentiated follow-up strategy, in as much as the TNMB staging appears not only to be associated with different progression rates, but also shows as a new finding a relationship with different patterns of disease progression. From a biological point of view, there is the need to understand the molecular basis of the different clinical pathways of disease progression, to be able to potentially identify at an earlier phase of disease evolution, the patients who are more likely to develop erythroderma or tumour-stage progression. In conclusion, if MF is indeed a true "lion queen", as dermatologists we need to be expert and wise tamers to keep it under control.

Anti-tumor necrosis factor treatment in occult hepatitis B virus infection: a retrospective analysis of 62 patients with psoriatic disease.

One of the problems possibly related to the use of biological agents targeting tumor necrosis factor (TNF)-alpha is the increased risk of infections, including the activation of hepatitis B virus (HBV). HBV activation can occur in carriers of hepatitis B surface antigen (HBsAg), but the risk may also involve the HBsAg-negative (anti-HBc ± anti-HBs) occult carriers. Precise data on the safety of anti-TNF and/or other immunosuppressive drugs in HBV occult carriers are not available. We performed a retrospective analysis of 62 psoriatic patients with occult HBV infection treated with anti-TNF biological agents over a period of approximately 4 years: 44 subjects were treated with etanercept, 8 with infliximab and 10 with adalimumab. During the observational treatment period, no signs of HBV activation were observed. Only in one patient the reappearance of HBsAg, without detectable HBV-DNA, was noted before retreatment with etanercept and after 10 months from discontinuation of the previous course. In this patient etanercept was re-administered in association with lamivudine without any adverse event. Our results suggest the overall safety of treatment with anti-TNF drugs in HBV occult carriers, although a careful and constant monitoring of virological markers is required in such patients during treatment with anti-TNF drugs in order to have an early recognition of viral reactivation.

Treatment of psoriasis with different dosage regimens of etanercept: preliminary results from the Tαranta Plastic Study Group.

This pilot open-label study is aimed to assess clinical response in psoriasis patients receiving diverse dose regimens of etanercept, consisting of the same global cumulative dose of etanercept administered over different treatment periods. Eligible patients were assigned sequentially in a 1:1 ratio to receive: etanercept 50 mg once weekly (QW) or 50 mg twice weekly (BIW) for 12 weeks. The final analysis included a total of 72 patients. At week 12 the Psoriasis Area and Severity Index (PASI) and Skindex-29 scores notably improved in both treatment arms, without significant differences between the two groups. The rate of patients attaining a PASI improvement >or= 50% (PASI 50) at week 12 was 92% in the high-dose group. In these patients, etanercept dosage was decreased to 50 mg QW from week 13, with persistence of the PASI 50 response at week 24 in all cases. Thereafter, treatment was discontinued up to week 36 and almost 30 % of patients experienced a gradual relapse of their psoriasis within this period. In the low-dose group, the PASI 50 response was observed in 75% of patients. These responders continued to be treated with etanercept 50 mg QW up to week 36 with persistence of the PASI 50 in 100% of cases at week 24 and 93% at week 36. In the low-dose regimen, 8 patients who did not respond at week 12 underwent dose escalation to 50 mg BIW for a further 12 weeks. At week 24, six of these patients gained the PASI 50 response, 4 of whom maintained the response up to week 36, after treatment discontinuation from week 24. Our results confirm that etanercept is very effective and well-tolerated in psoriasis and that the drug dosages and treatment duration may be modulated and adapted to clinical needs in a flexible way.

Pemphigus vulgaris with circulating anti-desmoglein 3 and anti-BP180 antibodies: a case report and brief review of cases with coexistence of pemphigus vulgaris and bullous pemphigoid.

Pemphigus vulgaris (PV) and bullous pemphigoid (BP) are two autoimmune blistering diseases involving the skin and the mucous membranes characterized by circulating autoantibodies directed against desmosomal cadherins or antigens expressed in the basement membrane zone, respectively. The simultaneous presence of clinical and/or immunopathological features of PV and BP in the same patient has been reported in very few cases in the literature to date. Most of these cases had exclusive cutaneous involvement, while a minority showed concomitant oral lesions. We describe the case of a 59-year-old female patient with a 10-year history of refractory PV lesions limited to mucous membranes (conjunctiva, oral cavity and genital mucosa), which were controlled by the addition of mycophenolate sodium to oral prednisone. Immunofluorescence studies revealed findings consistent with PV, whereas enzyme-linked immunosorbent assay revealed circulating anti-BP180 antibodies in association with anti-desmoglein 3 antibodies. The significance and relevance of this finding are briefly discussed, in light of the literature data.

A multicenter open-label experience on the response of psoriasis to Adalimumab and effect of dose escalation in non-responders: the Aphrodite project.

There is much evidence to show the efficacy of adalimumab, a human monoclonal antibody targeting tumour necrosis factor-alpha, in the treatment of plaque psoriasis. In this open-label experience, 147 high-need patients suffering from plaque psoriasis, with a mean Psoriasis Area and Severity Index (PASI) of 18.8, and concomitant psoriatic arthritis (PsA) received subcutaneous injections of 40 mg of adalimumab every other week (EOW). This was actually the dosage regimen recommended for PsA, as the drug had not then been approved for psoriasis at the time of the patients enrolment. At week 12, an improvement of at least 50 percent of the PASI (PASI-50) was observed in 111 (77 percent) patients. Continuation of treatment in responders with adalimumab 40 mg EOW led to a sustained response, with the PASI-50 achieved by 97 percent of patients in the as-treated analysis at week 24 (PASI-75 in 82 percent and PASI-90 in 45 percent out of 109 patients who received EOW injections up to week 24). Thirty subjects who failed to attain the PASI-50 response at week 12 were treated with adalimumab 40 mg every week for a further 12 weeks. At week 24, 80 percent of these patients obtained a PASI-50 response after dose escalation. Tolerability was good in the majority of patients. Only two patients discontinued treatment because of an adverse event (repeated flu-like episodes and a pleuropericarditis of unknown origin, respectively).

Efalizumab in moderate-to-severe plaque psoriasis: a retrospective case series analysis from clinical practice.

Efalizumab is an anti-CD11a humanized monoclonal antibody which is safe and effective for the treatment of plaque psoriasis. We performed a retrospective analysis on -high-need- patients with moderate-to-severe psoriasis treated with Efalizumab monotherapy for more than 2 years. Chart review of patient records also concerned information about rebound, relapse, and retreatment after temporary interruption, as well as transitioning from Efalizumab to alternative treatments. Of the 52 patients who completed the initial 12 weeks of treatment, 65% attained the PASI-50 response at week 12. A notable improvement of skin lesions on critical sites, such as palmoplantar surfaces or genitals, was also observed. Continuous treatment resulted in a sustained response in the majority of patients, with a PASI-75 response in nearly 88% of those Efalizumab-treated in the long term (week 72 onwards) and a PASI-90 in 77% of patients by weeks 120-132. In general, the treatment was well tolerated, with mild-to-moderate flu-like symptoms as the most frequent adverse events, particularly after the first two doses. Increase of leukocyte and/or lymphocyte counts was the most common laboratory test alteration during treatment, also in the long term. In our case series, Efalizumab was safe and well-tolerated even in patients with relevant comorbidities, including one patient with HBsAg carriage and five patients with latent TB.

Risk factors for sensitization to AnisakiS simplex: a multivariate statistical evaluation.

Anisakis simplex is a nematode belonging to the Anisakidae family. The ingestion of third stage larvae in uncooked or undercooked seafood may cause human diseases known as anisakiasis and anisakidosis. A total of 400 (159 atopic and 241 non-atopic) subjects living in an area of southern Italy (Bari district) were consecutively evaluated to identify the association of some factors (sex, age, atopy, consumption of uncooked seafood and sensitization to dust mites) with the risk of Anisakis simplex sensitization. Patients were investigated on history of atopy and allergic diseases and were skin prick tested with commercial allergen extracts of Anisakis simplex, Acarus siro, Lepidoglyphus destructor, Tyrophagus putrescentiae, Glycyphagus domesticus, Euroglyphus maynei, Dermatophagoides pteronyssinus and Dermatophagoides farinae. Our results suggest that atopic subjects have a lower risk of Anisakis allergy than non-atopic subjects and show the association of Anisakis simplex sensitization with the consumption of uncooked seafood (anchovies and squid), increasing age and sensitization to Glycyphagus domesticus.

Evaluation of goiter using ultrasound criteria: a survey in a middle schoolchildren population of a mountain area in Central Italy.

Iodine deficiency is still an important health care problem in the world. In Italy, as in most European countries, it is responsible for the development of mild to moderate endemic goiter. In 1995 we conducted a goiter survey in the Gubbio township, an area of Umbria region in Italy, close to the Appenine mountain chain. This study demonstrated a high prevalence of goiter in the middle schoolchildren population, indicating the presence of moderate endemic goiter. Soon after, a goiter prevention campaign aimed at implementing the consumption of iodinated salt was started. In 2001, a second survey was conducted in the middle schoolchildren (age 11-14 yr old) of Gubbio and neighbour townships. Eight hundred thirteen subjects were studied. Data obtained in 240 age-matched children, studied in the same area in 1995, were used for comparison to monitor changes 5 yr after the beginning of iodine prophylaxis. Thyroid volume was measured by ultrasonography. Gland volume was expressed in ml. A large population living in a iodine-sufficient area, previously reported by others, was used as control. Urinary iodine excretion was measured randomly in 20% of the children. The overall prevalence of goiter decreased between 1995 and 2001 from 29 to 8%. Goiter odds ratio (OR), corrected for age, was 4.0 (95% CI 2.8-5.9) for 1995 compared to 2001 (p<0.000). Mean thyroid volume in the matched populations was 7.6+/-2.5 ml in 1995 and 5.7+/-2.1 ml in 2001. Median iodine urinary excretion increased from 72.6 to 93.5 mug/l, at the limit of statistical significance. Living in a rural area, no consumption of iodized salt and familiarity for goiter represented independent risk factors for goiter development. This study was the first conducted in Umbria region and confirmed that an implementation campaign for iodized salt consumption is a simple and useful instrument to prevent endemic goiter and related diseases. A new survey to evaluate goiter prevalence in the same area 10 yr after the beginning of iodine prophylaxis is already planned.

A population survival model for breast cancer.

Breast cancer is a major health problem, and disease control depends on an effective healthcare system. A registry-based tool to monitor the quality of breast cancer care could be useful. The aim of this study was to develop a population survival model for breast cancer based on the Nottingham Prognostic Model (NPM). To this end, 1452 cases of breast cancer diagnosed in the Umbria Region, Italy, during the period 1994-1996 were studied. An extensive search for routinely available variants in prognosis and treatment was performed. In about 80% of cases complete information on factors included in the NPM was available. The Cox model was used to assess the prognostic value of study factors. Nodal stage was the most important prognostic factor. In women who did not undergo axillary dissection (17%) the risk of death was twice that in women with no affected nodes, but they received chemotherapy with the same frequency. Radiotherapy was also less frequently used in this group. Grading was a significant prognostic factor only when women over 80 were excluded. Population survival models based on data from cancer registries may provide a tool that can be used to evaluate healthcare systems and the effectiveness of interventions. The inclusion of older women in our models decreased the significance of many established prognostic factors because of the frequency of incomplete evaluation and less aggressive treatment in these patients. Not undergoing surgical axillary dissection was associated with a worse prognosis and with less aggressive treatment.

Incidence, mortality and long-term survival from prostate cancer in Umbria, Italy, 1978-1994.

OBJECTIVES AND METHODS: Incidence, mortality and long-term survival from prostate cancer were examined in the Umbria region of Italy, for the period 1978-1994. Incidence rates were derived from an ad hoc survey carried out over the period 1978-1982 and from 1994 cancer registry records. The mortality over the period derived from data of the official publications and the survival rates, at 15 years, were calculated starting from the ad hoc survey incident cases. RESULTS: In the Umbria region, over the period 1978-1994, crude incidence rates from prostate cancer increased from 31.2 to 81. 9 per 100,000 and mortality rates from 22.7 to 31.9 per 100,000. The rates were from 30.5 to 61.2 for age-adjusted incidence while standardized mortality remained constant (from 22.6 to 22.7 per 100, 000). Survival in Umbria, compared with rates from other European Cancer Registries, is low both at 5- and 10-year follow-up. CONCLUSION: The great incidence increase observed over the study period could depend on a lesser completeness achieved by the 1978-1982 ad hoc survey with respect to the 1994 cancer registry data and/or from the screening campaign carried out in a large part of the region in 1994. Different elements support these hypotheses. However the above hypotheses can be verified over the next years when further incidence and survival data from the cancer registry will be available.

Long term survival of upper aerodigestive tract cancer in male patients in the Umbria region (Italy).

The aim of this work was to make a study of the whole population of a central Italian region, the Umbria region--cancer survival rates for the upper aerodigestive tract, which includes cancers of the head and neck (tongue, oral cavity, pharynx), oesophagus and larynx. In Italy cancer survival rates do not cover entire regions but single municipalities or provinces. Cases of incidence were derived from an 'ad hoc' survey carried out during the period 1978-1982. Starting from the nominative data, we studied up to 15 years 245 head and neck, 87 oesophagus and 321 larynx cases of cancer in males. Data for female cases were not considered because of the small number. Cancer cases were followed up mainly by verification at the Registry Office of several municipalities, the Regional Death Registry and the list of persons under the Regional Health Service. Observed survival rates for head and neck cancer were 0.63, 0.29, 0.17 and 0.12 at 1, 5, 10 and 15 years of follow-up respectively; rates for cancers of the oesophagus and larynx were 0.30, 0.08, 0.06, 0.03 and 0.79, 0.54, 0.41, 0.30 respectively. Relative survival rates were 0.65, 0.34, 0.24, 0.23 for cancer of the head and neck, 0.31, 0.10, 0.09, 0.08 for cancer of the oesophagus, and 0.81, 0.63, 0.59, 0.56 for cancer of the larynx, at 1, 5, 10 and 15 years of follow-up. The worst survival rates were observed for oesophagus and hypopharynx. Overall survival values for Umbrian patients were relatively good, being higher than survival data reported for a similar period by Italian Cancer Registries. They were also strikingly similar to survival rates for England and Scotland.

The effect of sucrose or starch-based diet on short-chain fatty acids and faecal microflora in rats.

An investigation was carried out to determine whether variations of dietary carbohydrates could modify the colonic flora in rats. Sprague-Dawley rats were fed with two equicaloric diets based on the AIN-76 diet (American Institute of Nutrition 1977) but differing from that diet in content of carbohydrates, i.e. high sucrose (64%) of high corn starch (64%). Feeding was continued for 9 months ad libitum and no variation in weight gain was recorded among the different diets. A prevalence of aerobes, and a significant reduction in the ratio anaerobes/aerobes in the faeces of rats on the high starch diet compared with the high sucrose diet, was observed. The anaerobe genera identified included Actinomyces, Bacteroides, Bifidobacterium, Clostridium, Eubacterium, Lactobacillus and Propionibacterium. Bacteroides was the most prevalent genus in both dietary groups (51.2 and 29.5% in the faeces of rats fed the sucrose and starch diets, respectively). In contrast, clostridia were prevalent in the starch-fed group (23.8%) and less so in the sucrose diet (11.5%), as propionibacteria were prevalent in faeces of rats fed the starch diet (15.5%), and low in the sucrose diet (3.9%). The remaining genera were scarce in faeces from rats on either diet. Total short-chain fatty acids (SCFA) were significantly higher in the faeces of animals fed the starch diet compared with those fed the sucrose diet. The relative concentrations of acetic, propionic and butyric acids were not significantly different between the two dietary groups. In conclusion, high starch diet can markedly modify the composition of faecal flora and alter considerably the faecal concentration of SCFAs, compound which might have a health-promoting effect.

Urinary organ cancer survival in the Umbria region (Italy): follow-up at ten years.

OBJECTIVES AND METHODS: Survival of 687 urinary bladder and 217 kidney cancer patients was investigated using incident cases registered in an ad hoc survey in the Umbria region for the period 1978-1982. Death certificate only cases were excluded. The follow-up was carried out through the General Nominative Register of Causes of Death and verified at the Registrar's Offices of the various towns of the Region. RESULTS: At 10 years about one third of all bladder cancer patients were still alive while for kidney cancer the rate was 0.41 for females and 0.26 for males. Observed survival rates, at 1 year time intervals, never differed significantly in the two sexes even if, for kidney cancer, both observed and relative survival rates were somewhat higher in females than in males and, for bladder cancer, higher in males than in females. From survival rates by age groups both observed and relative rates decreased with age in males. In females the trend was unsteady due to the low survival in the first age group (15-44 years) for the two sites and a lower rate for kidney cancers in the 55-64 years age group compared to the next age groups. This trend was also probably due to the small number of cases. CONCLUSIONS: Comparison of survivals in Umbria with those of European registries shows higher rates for bladder cancer in both sexes and for kidney cancer in females in Umbria, while the value for kidney cancer survival in males was intermediate.

Deoxycholic acid and SCFA-induced apoptosis in the human tumor cell-line HT-29 and possible mechanisms.

Short chain fatty acids (propionate and butyrate) and deoxycholic acid (DCA) are able to induce apoptosis in HT-29 colonic tumor cell line, but DCA induces a much higher level of apoptosis than butyrate and propionate. Mixtures of DCA with butyrate or propionate enhance the effect of the single components. Apoptosis is not affected by the PKC, PTK or de novo mRNA and protein synthesis inhibitors, so that the involvement of these enzymes and processes is ruled out. In contrast, DCA-induced apoptosis is directly related to [Ca2+]i concentration as demonstrated by the apoptosis inhibition caused by [Ca2+]i chelator BAPTA/AM.

Possible mechanisms involved in apoptosis of colon tumor cell lines induced by deoxycholic acid, short-chain fatty acids, and their mixtures.

Apoptosis of tumor cells is an important growth-regulating event in tumor masses. In this study we have confirmed that deoxycholic acid (DCA) and the short-chain fatty acids (SCFA) butyrate and propionate induce a time- and concentration-dependent apoptosis in two human colon tumor cell lines: HT-29 and CaCO2. DCA is more potent, inducing effects at low concentration (50 microM) and after 24 hours of incubation, whereas SCFA (4 mM) requires 72-96 hours of treatment. Combining low concentrations of DCA (12.5-25 microM) with butyrate and propionate (4 mM) produces an additive effect on the percentage of apoptotic cells, as demonstrated by flow cytometry and DNA fragmentation. Protein kinase C, protein tyrosine kinase, and gene transcription/translation inhibitors do not significantly modify the rate of apoptosis, whereas the intracellular Ca2+ chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM) completely abolishes the DCA-induced effect without affecting the SCFA-induced apoptosis. Measurement of intracellular Ca2+ by inverted fluorescence microscopy reveals that DCA induces a rapid increase of cytosolic Ca2+ that is abolished when the cells are preincubated with BAPTA-AM, whereas ethyleneglycolbis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid has a minimal effect. In contrast, SCFA does not modify the intracellular Ca2+ concentration. Thus the DCA-induced apoptosis is a Ca(2+)-dependent process, whereas the intracellular signals responsible for the SCFA-induced effect remain unknown. The ionophore activity of DCA could be responsible for the increased intracellular Ca2+, but other mechanisms, such as activation of phospholipase C and phosphoinositide hydrolysis, have to be considered.

Ten-year survival of patients with cancer of the digestive tract in Umbria, Italy.

Survival statistics of 4135 incident cases of digestive system cancers in the Umbria region of Italy are reported. The original data are derived from an ad hoc survey carried out in the period 1978-1982. Observed and relative rates at 1, 5 and 10 years are presented separately by sex and age (< 60 and > or = 60 years). In both sexes there are very short survival rates for liver, bile duct and pancreas cancers, whereas about 50% of colon and rectum cancer patients survived at five years. About 20% stomach cancer patients survived at the same time. In males the survival rate for oesophagus cancer is close to 10%. The rates at ten years confirm the trend. Comparisons between sexes show that there is no significant differences in age at first diagnosis. Survival values are higher in females only for rectum cancers. In both sexes, for stomach, colon and rectum sites younger patients had a significantly longer survival than older ones.

Cancer survival from incident cases of a population-based study in the Umbria region, Italy.

Survival of 12,051 cancer patients was investigated in incident cases registered in an ad hoc survey in the Umbria region for the period 1978-82. Death certificate only cases were excluded. The follow-up was carried out by an automatic link with the RENCAM (nominative register of causes of death) and verified at the Registrar's Offices of the various towns of the region. Both observed and relative survival rates according to sex and selected time periods (1, 5 and 10 years) were calculated. Generally, the relative survival rate for all tumour sites at 5 years was 0.35 in males and 0.53 in females (P < 0.01), and 0.31 and 0.49, respectively, at 10 years. 5-year relative survival rates greater than 0.50 were found for only three tumour sites in men (bladder, larynx, colon), accounting for approximately 21% of all men included in the study, but for six sites in females (breast, uterus, kidney, bladder, rectum, colon), accounting for more than 50% of the female cases. The 5-year age-adjusted relative survival rates in Umbria were higher than in other Italian and European registries for selected sites (stomach, colon, rectum, lung). High survival in Umbria could probably be related to the availability of specialist care and to the easy access to a network of oncological services.

Ten-year survival and age at diagnosis of women with breast cancer from a population-based study in Umbria, Italy.

We analyzed the 10-year survival of 1,512 women with breast cancer in relation to age at diagnosis. The incident cases were from an ad hoc investigation in Umbria, a region of central Italy, for the period 1978-1982. The follow-up was carried out by an automatic link with the RENCAM (Nominative register of causes of death) and verified at the Register's Offices of the various towns of the region. Observed survival at 1 year was 0.89, at 3 years 0.75, at 5 years 0.64 and at 10 years 0.47. Median survival was 9.0 years. Relative survival at 1, 3, 5, 10 years was respectively 0.91, 0.79, 0.71 and 0.59. Women < 35 years of age had a better prognosis both at 5 (0.83) and 10 years (0.69) from diagnosis. Thereafter, survival decreased with increasing age. The exception to this trend was women in the 45-49 and 60-64 year age ranges, for which survival was greater than the previous age range classes by 6% and 13%, respectively, at 5 years from diagnosis and 6% and 14% at 10 years. Comparison of data from Umbria and Italian and European Registries shows that the prognosis for Umbrian women with breast cancer is quite good.