Detection of desmoplastic melanoma with dermoscopy and reflectance confocal microscopy.

BACKGROUND: Desmoplastic melanoma (DM) is frequently misdiagnosed clinically and often associated with melanoma in situ (MIS). OBJECTIVE: To improve the detection of DM using dermoscopy and reflectance confocal microscopy (RCM). METHODS: A descriptive analysis of DM dermoscopy features and a case-control study within a melanoma population for RCM feature evaluation was performed blindly, using data obtained between 2005 and 2015. After retrospectively identifying all DM cases with RCM data over the study period (n = 16), a control group of non-DM melanoma patients with RCM data, in a ratio of at least 3 : 1, was selected. The control group was matched by age and primary tumour site location, divided into non-DM invasive melanomas (n = 27) and MIS (n = 27). Invasive melanomas were selected according to the melanoma subtypes associated with the DM cases. The main outcomes were the frequency of melanoma-specific features on dermoscopy for DM; and the odds ratios of RCM features to distinguish DM from MIS and/or other invasive melanomas; or MIS from the combined invasive melanoma group. RESULTS: At least one of the 14 melanoma-specific features evaluated on dermoscopy was found in 100% of DMs (n = 15 DM with dermoscopy). Known RCM melanoma predictors were commonly found in the DMs, such as pagetoid cells (100%) and cell atypia (100%). The RCM feature of spindle cells in the superficial dermis was more common in DM compared with the entire melanoma control group (OR 3.82, 95% CI 1.01-14.90), and particularly compared to MIS (OR 5.48, 95% CI 1.11-32.36). Nucleated cells in the dermis and the RCM correlate of dermal inflammation were also significant RCM features favouring DM over MIS, as well as invasive melanoma over MIS. CONCLUSION: Dermoscopy and RCM may be useful tools for the identification of DM. Certain RCM features may help distinguish DM from MIS and other invasive melanomas. Larger studies are warranted.

A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma.

We report four previously undescribed families with germline BRCA1-associated protein-1 gene (BAP1) mutations and expand the clinical phenotype of this tumor syndrome. The tumor spectrum in these families is predominantly uveal malignant melanoma (UMM), cutaneous malignant melanoma (CMM) and mesothelioma, as previously reported for germline BAP1 mutations. However, mutation carriers from three new families, and one previously reported family, developed basal cell carcinoma (BCC), thus suggesting inclusion of BCC in the phenotypic spectrum of the BAP1 tumor syndrome. This notion is supported by the finding of loss of BAP1 protein expression by immunochemistry in two BCCs from individuals with germline BAP1 mutations and no loss of BAP1 staining in 53 of sporadic BCCs consistent with somatic mutations and loss of heterozygosity of the gene in the BCCs occurring in mutation carriers. Lastly, we identify the first reported recurrent mutation in BAP1 (p.R60X), which occurred in three families from two different continents. In two of the families, the mutation was inherited from a common founder but it arose independently in the third family.

Self-expandable metal stent placement for treatment of severe sphincterotomy bleeding.

One of the most frequent complications of endoscopic sphincterotomy (ES) is bleeding. When post-ES bleeding does not respond to the use of typical endoscopic therapy, the only alternative is angiography or surgery. A 82-year-old female was admitted for jaundice. A RMN-cholangiography revealed multiple stones in the common bile duct (CBD). She underwent endoscopic retrograde cholangiopancreatography (ERCP). The papilla major was located between two large periampullary diverticula. During the ES, a severe bleeding was observed from the upper part of the biliary cut. Several methods of hemostasis (injection of adrenaline, thermal methods and balloon tamponate) were performed without efficacy. A partially covered metallic stent was placed across the biliary orifice, in order to compress mechanically the bleeding site archiving the hemostasis.

Comprehensive geriatric assessment in female elderly patients with Alzheimer disease and other types of dementia.

The most visible manifestation of dementia is the progressive inability to activities of daily living (ADL) and to instrumental activities of daily living (IADL). The comprehensive geriatric assessment (CGA) is the validated and recommended instrument to a correct evaluation and decision making in elderly patients. To judge if the decline in cognitive functions is associated with a worsening in functional, emotional and clinical status measured by CGA, we also compared CGA in the same patients stratified for mild, moderate and severe dementia. From September 2004 to November 2005 we studied 47 institutionalized female patients with Alzheimer's disease (AD) and other types of dementia. Mean age was 83.70+/-0.88 years (range 70-101). Their multidimensional evaluation was performed by the CGA. We evaluated geriatric syndromes (AGS, 2004), polypharmacy, frailty, hemoglobin (Hb), serum creatinine (CR) and white blood cells (WBC). We stratified the population in 3 groups for the mini mental state examination (MMSE): severe (MMSE 0-9; 5 patients), moderate (MMSE 10-29; 23 patients) and mild dementia group (MMSE 20-30; 19 patients), and searched for statistical differences in the parameters of CGA. MMSE was significantly related to dependence in ADL (mean=x=1.85), IADL (x=0.57), cumulative illness rating scale-geriatrics (CIRS-G) (x=9.55), geriatric depression scale (GDS) (x=8.71), geriatric syndromes (x=2.49), Hb, CR, WBC and number of drugs (x=6.51, range 2-15) (p=0.001). MMSE low score was also correlated with a worse mini nutritional assessment (MNA) (x=19.5; p=0.003). Frail patients were 61.7%. We found a statistically significant difference in the prevalence of geriatric syndromes between mild vs. moderate dementia group (p=0.02). Mild vs. moderate group, and moderate vs severe group were significantly different concerning Hb levels (p=0.009 and 0.002, respectively). Patients with severe cognitive impairment are more likely to be dependent at ADL and IADL; to present a larger number of comorbidity and geriatric syndromes; to have lower !evels of Hb and higher levels of CR; to be in a worse nutritional status and to take a larger number of drugs. Polypharmacy maybe related to high comorbidity but the risk of irrational drug use should be evaluated. We suggest single testing with CGA as an effective tool providing a comprehensive assessment of elderly, and able to detect unaddressed corrigible problems.

Identification of Mycobacterium avium subsp. paratuberculosis in biopsy specimens from patients with Crohn's disease identified by in situ hybridization.

Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract of unknown etiology. We report on the presence of cell wall-deficient Mycobacterium avium subsp. paratuberculosis in 35 of 48 paraffin-embedded tissue specimens from 33 patients with Crohn's disease by in situ hybridization with IS900 as a probe.

Hepatitis C virus genotypes: distribution and clinical significance in patients with cirrhosis type C seen at tertiary referral centres in Europe.

The aim of this study was to evaluate the distribution and clinical significance of hepatitis C virus (HCV) genotypes in European patients with compensated cirrhosis due to hepatitis C (Child class A) seen at tertiary referral centres. HCV genotypes were determined by genotype-specific primer PCR in 255 stored serum samples obtained from cirrhotics followed for a median period of 7 years. Inclusion criteria were biopsy-proven cirrhosis, absence of complications of cirrhosis and exclusion of all other potential causes of chronic liver disease. The proportion of patients with types 1b, 2, 3a, 1a, 4 and 5 were 69%, 19%, 6%, 5%, 0.5% and 0.5%, respectively. Kaplan-Meier 5-year risk of hepatocellular carcinoma (HCC) was 6% and 4% for patients infected by type 1b and non-1b, respectively (P=0.8); the corresponding figures for decompensation were 18% and 7% (P=0.0009) and for event-free survival were 79% and 89% (P=0.09), respectively. After adjustment for baseline clinical and serological features, HCV type 1b did not increase the risk for HCC [adjusted relative risk=1.0 (95% confidence interval=0.47-2.34)], whereas it increased the risk for decompensation by a factor of 3 (1.2-7.4) and decreased event-free survival by a factor of 1.7 (0.9-3.10). In conclusion, type 1b and, to a lesser extent, type 2, are the most common HCV genotypes in European patients with cirrhosis. HCV type 1b is not associated with a greater risk for HCC, but increases the risk for decompensation by threefold in patients with cirrhosis.

Mode of action and application of Scorpion primers to mutation detection.

Scorpion primers can be used to detect PCR products in homogeneous solution. Their structure promotes a unimolecular probing mechanism. We compare their performance with that of the same probe sequence forced to act in a bimolecular manner. The data suggest that Scorpions indeed probe by a unimolecular mechanism which is faster and more efficient than the bimolecular mechanism. This mechanism is not dependent on enzymatic cleavage of the probe. A direct comparison between Scorpions, TaqMan and Molecular Beacons on a Roche LightCycler indicates that Scorpions perform better, particularly under fast cycling conditions. Development of a cystic fibrosis mutation detection assay shows that Scorpion primers are selective enough to detect single base mutations and give good sensitivity in all cases. Simultaneous detection of both normal and mutant alleles in a single reaction is possible by combining two Scorpions in a multiplex reaction. Such favourable properties of Scorpion primers should make the technology ideal in numerous applications.

[Four corner bladder base and bladder neck suspension with intraosseous anchorage in the treatment of moderate cystocele]. / La sospensione della base e del collo vescicale ai quattro angoli con ancoraggio intraosseo per la correzione del cistocele moderato.

During the last 10 years the original Pereyra technique of needle bladder neck suspension has been object of more than 36 modifications with the goal to improve long term results and to enhance feasibility. It represents also a part of the so called four corner bladder and bladder neck suspension (anterior suspending sutures) which is at present a reliable and durable manner to manage mild to moderate cystocele; this procedure reestablishes safely and simply support to bladder base, bladder neck and urethra preventing the onset of a denovo stress urinary incontinence. Complications include post-operative pain which could represent a problem in about 16% of the patients: it has been related to the entrapment of the ileoinguinal nerve between prolene sutures and rectus fascia and may be responsible of a delay in the re-establishment of a normal voiding pattern due to the pain elicited during any rectus muscle contraction. We propose a refinement of this procedure which includes the osseous anchoring of the suspending suture through the Mitek G II anchor system. Reduction in postoperative pain and fast recovery of a normal voiding pattern soon after surgery seems to be the most important result of this modification. Osteitis pubis has not been noted. Any improvement in long term durability of the procedure has not yet been determined due to the short follow-up and limited series of cases and the need for subsequent long term follow-up.

Delayed clearance of serum HBsAg in compensated cirrhosis B: relation to interferon alpha therapy and disease prognosis. European Concerted Action on Viral Hepatitis (EUROHEP)

OBJECTIVE: The aim of this study was to evaluate the incidence, prognostic factors and clinical significance of delayed clearance of serum HBsAg in compensated cirrhosis B. METHODS: This was a retrospective cohort study of 309 consecutive white patients with biopsy-proved compensated cirrhosis type B. RESULTS: During a mean follow-up of 68 months, HBsAg loss occurred in 32 patients, including 16 (8%) of 196 untreated patients (mean annual incidence 0.8%), 8 (10%) of 82 interferon (IFN) alpha-treated patients and eight patients who had been treated with other antivirals or steroids. The 5-yr probability of HBsAg loss was 4% and 16% for untreated and IFN-treated patients, respectively (p = 0.0001). Cox's regression analysis identified hepatitis B e antigen-positivity at entry as the sole independent prognostic factor for HBsAg loss. Of the 32 patients who lost HBsAg, one (3%) subsequently developed hepatocellular carcinoma (HCC) and died, whereas, among the patients who remained HBsAg-positive, 11% developed HCC and 20% had died. The probability of HCC appearance was lower (p = 0.0137) and survival was longer (p = 0.0006) in patients who cleared HBsAg compared with patients with HBsAg persistence. CONCLUSION: The incidence of HBsAg loss is about 0.8% in cirrhosis type B. Prognostic factors for clearance of HBsAg are initial HBeAg positivity and therapy with alpha interferon. Patients with cirrhosis type B, who lose HBsAg, have a low risk for liver cancer or liver-related death.

Effectiveness of interferon alfa on incidence of hepatocellular carcinoma and decompensation in cirrhosis type C. European Concerted Action on Viral Hepatitis (EUROHEP).

BACKGROUND/AIMS: The role of interferon alfa treatment in improving morbidity endpoints in patients with chronic hepatitis C infection is currently under debate. The aim of this study was to evaluate the effectiveness of interferon in preventing hepatocellular carcinoma and decompensation in cirrhosis type C. METHODS: A retrospective cohort study was carried out on 329 consecutive Caucasian patients with cirrhosis followed for a mean period of 5 years at seven tertiary care university hospitals. Inclusion criteria were biopsy-proven cirrhosis, anti-HCV positivity, abnormal serum aminotransferase levels and absence of complications of cirrhosis. RESULTS: The yearly incidence of hepatocellular carcinoma was 2.3% for 136 untreated patients and 1.0% for 193 patients treated with interferon alfa. The yearly incidence of hepatic decompensation was 5.7 for untreated and 1.5 for the treated patients. Fourteen (7%) of 193 treated patients showed sustained aminotransferase normalization and none of them developed complications of cirrhosis. At enrollment, untreated patients were older and had more severe liver disease than patients treated with interferon. After adjustment for clinical and serologic differences at entry between treated and untreated patients, the 5-year estimated probability of the occurrence of hepatocellular carcinoma was 2.1% and 2.7% and of decompensation was 7% and 11% for treated and untreated cases, respectively. CONCLUSIONS: This analysis did not detect any significant benefit of interferon alfa on morbidity in patients with compensated cirrhosis type C, although it suggests a reduction in complications of cirrhosis for those with a sustained response to therapy, and it indicates the need for better therapies.

Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients.

BACKGROUND & AIMS: Few data are available concerning the long-term prognosis of chronic liver disease associated with hepatitis C virus infection. This study examined the morbidity and survival of patients with compensated cirrhosis type C. METHODS: A cohort of 384 European cirrhotic patients was enrolled at seven tertiary referral hospitals and followed up for a mean period of 5 years. Inclusion criteria were biopsy-proven cirrhosis, abnormal serum aminotransferase levels, absence of complications of cirrhosis, and exclusion of hepatitis A and B viruses and of metabolic, toxic, or autoimmune liver diseases. RESULTS: Antibodies against hepatitis C virus were positive in 98% of 361 patients tested. The 5-year risk of hepatocellular carcinoma was 7% and that of decompensation was 18%. Death occurred in 51 patients (13%), with 70% dying of liver disease. Survival probability was 91% and 79% at 5 and 10 years, respectively. Two hundred five patients (53%) were treated with interferon alfa. After adjustment for clinical and serological differences at baseline between patients treated or not treated with interferon, the 5-year estimated survival probability was 96% and 95% for treated and untreated patients, respectively. CONCLUSIONS: In this cohort of patients, life expectancy is relatively long, in agreement with the morbidity data showing a slowly progressive disease.

Targeted antibodies in the treatment of lymphomas.

Monoclonal antibodies coupled to drugs and toxic agents (immunotoxins) or radionuclides (radioimmunoconjugates) represent new tools for immunotherapy of haematological malignancies. Immunotoxins constructed with toxins of either plant or bacterial origin have shown a powerful antitumor activity both in vitro and in mice with severe combined immunodeficiency bearing various kinds of leukaemias and lymphomas. Preliminary clinical trials have shown an activity of these compounds at least in a proportion of patients. However, tumour responses have generally been partial and transient. The main problems with immunotoxin therapy remain the inability of immunotoxins to target tumour cells in the presence of a high burden of disease, the host immune response against both the antibody and the toxin moieties, which precludes repeated administration of immunotoxins, and the vascular leak syndrome. Targeting of tumour cells with specific antibodies armed with radionuclides (usually iodine-131 or yttrium-90) appears to be an even more attractive approach. Preliminary clinical studies have clearly demonstrated the ability of radioimmunoconjugates, especially when administered at high dose followed by bone marrow rescue, to induce durable complete remission in patients with non-Hodgkin's lymphomas refractory to conventional therapies. Radioimmunotherapy also overcomes the antigenic heterogeneity of the tumour cell population, since antigen negative tumour cells will be irradiated by the nearby targeted antigen-positive cells. Efforts should now be focused on defining more precisely the optimal clinical setting for administration of immunotoxin and radioimmunoconjugates (e.g. minimal residual disease), to reduce the immunogenicity of these compounds and solve the problem of vascular leak syndrome.

[Ambulatory phlebectomy with Müller procedure in the treatment of lower limb varices. Indications, technique and long-term results]. / La flebectomia ambulatoriale sec. Müller nel trattamento delle varici degli arti inferiori. Indicazioni, tecnica e risultati a distanza.

The authors report the results of more than five years experience of phlebectomies, according to Müller's method, performed both in general anesthesia during stripping operations and in local practice. The results confirmed the validity of this complementary surgical treatment for its radicality, execution simpleness and best respect for aesthetics.

Is there a role for adjuvant immunochemotherapy after radical nephrectomy in pT2-3N0M0 renal cell carcinoma?

Five-year overall survival after radical surgery in N0M0 renal cell carcinoma varies from 45-80% in pT2 to 35-50% in pT3 categories. In view of the alpha interferon and vinblastine combination which has shown some activity in advanced disease with increasing efficacy in limited metastatic invasion, we decided to explore the theoretical advantage of adjuvant chemo-immunotherapy in radically resected stage II, III renal cell carcinoma. A single-institution phase II study was undertaken to evaluate the efficacy and tolerability of alpha 2a-interferon (alpha 2a-INF) in combination with vinblastine in 30 patients with pT2-T3 N0M0 renal cell carcinoma (RCC). Thirty-two patients who received only radical nephrectomy and extended lymphadenectomy were analyzed and results were compared with the first group. Twenty-three of 30 (76.6%) patients in the first group are alive with no evidence of disease. The median follow-up for the 23 patients still alive was 67 months (range 60 to 72). Metastases were documented in 5 patients (16.6%) with a median interval to progression of 24 months. Four of them (13.6%) died of tumor. In the control group, 16 out of 32 patients (50%) are still alive, with a median follow-up for the patients still alive of 62 months (range 60 to 68). Fifteen patients developed distant metastases and 2 of them had a local recurrence. All of them (46.8%) died of tumor. Median progression interval was 24 months. After stratification by pathological grade, site, laterality and number of nodes found at lymphadenectomy there were no statistical differences in risk of progression or death in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of pre-core hepatitis B virus mutants on the long-term outcome of chronic hepatitis B virus hepatitis. A longitudinal study.

To define the relationship between pre-core hepatitis B virus mutants and the long-term outcome of chronic hepatitis B virus infection, we monitored the type of circulating pre-core hepatitis B virus-DNA by polymerase chain reaction and sequencing in 41 selected chronic HBsAg carriers with extensive follow up. They included 12 HBeAg-positive patients with chronic hepatitis, who seroconverted to anti-HBe during follow up and 29 anti-HBe positive patients, 23 of whom had chronic hepatitis and six acute severe exacerbation occurring spontaneously (three cases) or during antitumor chemotherapy (three cases). In the presence of HBeAg, all showed prevalence of the pre-core wild type along with high levels of viral replication and elevated alanine aminotransferase. Anti-HBe seroconversion was accompanied by a dramatic reduction of hepatitis B virus replication and normalization of alanine aminotransferase in all, except one, and by the emergence of mutated strains with a pre-core stop codon (point mutation G to A at nt 1896) that replaced the wild type in seven of the 12. Of the seven who harboured the pre-core mutant, three continued to show normal alanine aminotransferase during subsequent follow up, three had mild alanine aminotransferase elevation and one had an acute short-lived reactivation after 4.4 years of normal alanine aminotransferase. The five cases who continued to show prevalence of wild type in spite of anti-HBe seroconversion all revealed persistently normal alanine aminotransferase.(ABSTRACT TRUNCATED AT 250 WORDS)

[Neonatal abstinence syndrome and maternal toxicological profile]. / Sindrome d'astinenza neonatale e profilo tossicologico materno.

Neonatal abstinence syndrome (NAS) is one of the most frequent manifestations in the neonates of drug-addicted mothers. It is caused by the abrupt interruption of the transplacentar passage of drugs from the mother to the fetus. The aim of this study was to evaluate the correlation between drugs taken during pregnancy and NAS. Data were examined relating to 223 neonates born during 1975-1992 to drug-addict mothers. Neonates were subdivided into four groups according to the maternal toxicological profile. It was thus possible to observe that there is a greater prevalence of NAS in cases of polypharmacomania and that it gradually diminishes in the children of heroin addicts and those receiving methadone treatment. Moreover, the intensity of the syndrome is correlated to the high doses of methadone and/or heroin. In the group of neonates whose mothers had complied with the methadone treatment protocol, the severity of NAS was proportional to the dose taken by the mother. In conclusion, the management of pregnant drug addicts following a controlled methadone treatment programme is accompanied by improved obstetric help and is the most suitable way of reducing perinatal complications and the prevalence of NAS.

Long-term follow-up of patients with chronic hepatitis C treated with different doses of interferon-alpha 2b.

Eighty patients with chronic hepatitis C who completed a previously reported randomized controlled trial on the efficacy of interferon-alpha 2b were followed up for at least 36 mo after therapy discontinuation. Seventeen patients (21.2%) maintained normal ALT values throughout the follow-up; 63 (78.8%) either did not normalize the levels of ALT or relapsed during the follow-up. A significantly greater proportion of patients treated with 3 million units of interferon three times a week subcutaneously for 48 wk were long-term responders compared with patients treated for 24 wk. Sex, age, hepatitis C virus antibody status, source of infection and pretreatment levels of ALT were not predictive of long-term response. Cirrhosis was found to be an unfavorable predictive factor. After 3 yr of follow-up, clearance of viremia was observed in 58.9% of the 17 long-term responders but in none of the non-responders (p = 0.002). E2-NS1 antibody tested negative in 88.2% of long-term responders and in 14.3% of nonresponders (p = 0.001). Fifty-nine percent of long-term responders tested negative for C100-NS4 antibody compared with 14.3% of nonresponders (p = 0.031). No significant change was observed in other antibodies. Four long-term responders underwent liver biopsy 2 yr after discontinuation of therapy. All four patients had normal liver histology compared with baseline assessment of chronic active hepatitis in three and chronic persistent hepatitis in the other. Three of the four were negative for serum hepatitis C virus RNA.