Predictive genetic markers in neoadjuvant chemoradiotherapy for locally advanced esophageal cancer: a long way to go. Review of the literature.

The role of genetic molecular markers in neoadjuvant treatment for locally advanced esophageal cancer has been reviewed, focusing strictly on concurrent chemoradiation protocols followed by surgery. Eleven studies evaluated the role of mRNA expression profile; the end point was overall survival (OS) in two studies and different definitions of histological response in nine. Genes reported as significant were involved in cell cycle control (30), apoptosis (7), structural molecules (9), cell metabolism (6) and DNA repair (1). Seven studies reported about 15 microRNA (miRNA) molecules associated with OS (2) or histological response (13), however, defined with different classifications. Their target genes were prevalently involved in cell cycle control (4), apoptosis (1), cell adhesion (1), migration (1) and angiogenesis (1). Gene polymorphisms (single-nucleotide polymorphisms (SNPs)) have been evaluated in 8 studies reporting 10 variants associated with survival or pathological response. OS was the end point in six of these studies. SNPs reported as significant were involved in DNA repair system (4), detoxification (2), folate metabolism (6), drug efflux (2) and others (2). In a study, a panel including histology, pathological response and five SNPs discriminated two subsets of patients with 5-year survival rates of 79.3% and 26.3% (hazard ratio 6.25, P<0.0001). In another study, combination of stage, grade and 4 miRNAs improved prediction of pathological response (P=10-30). At present, given the great inconsistency of the data and the variability of the end points, definite conclusions are extremely difficult, if not impossible. More consistent data can derive only from analyses obtained from patients included in prospective randomized trials while panels combining genetic and clinical factors may improve prediction.

Genetic prediction of long-term survival after neoadjuvant chemoradiation in locally advanced esophageal cancer.

Candidate genes involved in DNA repair, 5-fluorouracil metabolism and drug detoxification were genotyped in 124 patients receiving neoadjuvant chemoradiation treatment for locally advanced esophageal cancer and their predictive role for long-term relapse-free survival (RFS) and cancer-specific survival (CSS) were evaluated. A panel including MTHFR 677TT, MDR1 2677GT, GSTP1 114CC, XPC 499CC and XPC 939AC+CC, defined as high-risk genotypes, discriminated subgroups with significantly different outcomes. When the panel was combined with histology, patients split into two subsets with 5-year RFS and CSS rates of 65% vs 27% (hazard ratio (HR) 3.0, P<0.0001) and 69% vs 31% (HR 2.9, P<0.0001), respectively. Combining the 5-single-nucleotide polymorphism (5-SNP) panel with pathological response defined two major informative risk classes with 5-year PFS and CSS rates of 79.4% vs 17.7% (HR 6.71, P<0.0001) and 79.3% vs 26.3% (HR 6.25, P<0.0001), respectively. This classification achieved a sensitivity of 79%, a specificity of 85.4% and an accuracy of 81.8%.

Heat urticaria: a revision of published cases with an update on classification and management.

Heat urticaria (HU) is a rare type of physical inducible urticaria, characterized by itchy erythema and well-demarcated weals appearing soon after heat exposure. Most cases occur in female patients aged 20-45 years. Both localized and generalized forms exist, depending on the limitation of the reaction to the skin area directly exposed to the physical stimulus or the involvement of distant sites, respectively. In most cases, HU is an immediate reaction, but delayed forms (mostly familial) have been described. HU is a long-lasting disease with overall duration at diagnosis of approximately 2 years. In about half of cases it is associated with systemic symptoms such as weakness, wheezing, headache, flushing, nausea, vomiting, diarrhoea, tachycardia, even dyspnoea or syncope. The main differential diagnosis includes cholinergic urticaria, exercise-induced anaphylaxis and solar urticaria. The diagnosis of HU is established by provocation testing, which is also helpful to evaluate the critical temperature threshold. The mean threshold temperature is about 44 °C. A heat desensitization programme can be an effective treatment. Nonsedating H1 antihistamines administered at licensed doses are the mainstay of symptomatic therapy in nearly 60% of patients, but full symptom relief is achieved in only a minority of them. Omalizumab has proven effective in recent case reports.

Preheated autologous serum skin test in localized heat urticaria.

Localized heat urticaria (LHU) is a rare type of physical urticaria, characterized by itching and erythema and well-demarcated weals, appearing within minutes at heat-exposed body sites. Its pathogenesis has not yet been clarified. We report the case of a 46-year-old woman with a generalized form of LHU, which was induced by exposure to warm baths, and consumption of warm food and drinks. Weal reaction was obtained 10 min after application of a metal cylinder heated to 43 °C. Interestingly, only serum previously heated to 56 °C and injected intradermally for autologous serum skin test induced a weal and flare reaction, whereas serum preheated to 45 °C did not induce any reaction. Our patient did not respond to high-dose antihistamines, and refused a heat desensitization programme. Treatment with colchicine 1 mg/day or ciclosporin A 3.5 mg/kg/day for 1 month yielded no improvement. Mild improvement was obtained with intramuscular injection of triamcinolone acetonide 40 mg every 2 weeks for 2 months.

Latent tuberculosis infection in patients with chronic plaque psoriasis who are candidates for biological therapy.

BACKGROUND: Screening for latent tuberculosis infection (LTBI) is mandatory in patients with psoriasis prior to biological therapy. OBJECTIVES: To investigate the prevalence of LTBI in patients with psoriasis who are candidates for biological therapy. METHODS: LTBI was investigated in patients with moderate-to-severe psoriasis (n = 243), Crohn disease (n = 64) or rheumatoid arthritis (RA) (n = 56) and in healthcare workers (n = 1683). LTBI diagnosis was based on positive QuantiFERON-B Gold In-Tube (QFT-GIT) in vitro assay without any clinical, radiological or microbiological evidence of active tuberculosis. RESULTS: LTBI was diagnosed in 8.2% of patients with psoriasis, 7% with Crohn disease and 9% with RA, and in 8.8% of healthcare workers (P = 0.9). Patients with psoriasis who also had LTBI (n = 20) received a 9-month prophylaxis with isoniazid (5 mg kg(-1) daily). None of these patients developed active tuberculosis infection after receiving biological therapy (etanercept, adalimumab, infliximab or ustekinumab) for 37 ± 32 weeks (mean ± SD). All patients with psoriasis were retested for LTBI after 31 ± 1.7 months. Five of the 20 patients with LTBI presented QFT-GIT reversion and two patients out of 243 (0.8%) had QFT-GIT conversion and received antibiotic prophylaxis. CONCLUSIONS: The prevalence of LTBI in patients with psoriasis is similar to that in patients with Crohn disease or RA and in healthcare workers. Prophylaxis with isoniazid is effective in preventing tuberculosis reactivation in patients with LTBI receiving biological therapy.