Background:Programmed death-ligand 1 (PD-L1) may be induced by oncogenic signals or can be upregulated via interferon gamma (IFN-γ). We have explored whether the expression of IFNG, the gene encoding IFN-γ, is associated with clinical response to the immune checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma patients. The role of inflammation-associated transcription factors STAT3, IKBKE, STAT1 and other associated genes has also been examined.Methods:Total RNA from 17 NSCLC and 21 melanoma patients was analyzed by quantitative reverse transcription PCR. STAT3 and Rantes, YAP1 and CXCL5, DNMT1, RIG1 and TET1, EOMES, IFNG, PD-L1 and CTLA4, IKBKE and NFATC1 mRNA were examined. PD-L1 protein expression in tumor and immune cells and stromal infiltration of CD8+ T-cells were also evaluated. Progression-free survival and overall survival were estimated.Results:A total of 17 NSCLC patients received nivolumab and 21 melanoma patients received pembrolizumab. Progression-free survival with nivolumab was significantly longer in NSCLC patients with high versus low IFNG expression (5.1 months versus 2 months, p = 0.0124). Progression-free survival with pembrolizumab was significantly longer in melanoma patients with high versus low IFNG expression (5.0 months versus 1.9 months, p = 0.0099). Significantly longer overall survival was observed for melanoma patients with high versus low IFNG expression (not reached versus 10.2 months p = 0.0183). There was a trend for longer overall survival for NSCLC patients with high versus low IFNG expression.Conclusions:IFN-γ is an important marker for prediction of response to immune checkpoint blockade. Further research is warranted in order to validate whether IFNG is more accurate than PD-L1.

Background: Survival data support the use of first-line osimertinib as the standard of care for epidermal growth factor receptor (EGFR)epositive non-small cell lung cancer (NSCLC). However, it remains unclear whether upfront osimertinib is superior to sequential first-or second-generation tyrosine kinase inhibitors (TKIs) followed by osimertinib for all patients. It is impossible to predict which patients are at high risk of progression, and this constitutes a major limitation of the sequential TKI approach. Patients and methods: A total of 830 plasma samples from 228 patients with stage IV, EGFRpositive NSCLC who were treated with first-line TKIs were analysed by digital polymerase chain reaction (dPCR). Results: The circulating tumour DNA (ctDNA) levels helped to identify patients with significantly improved survival rate, regardless of the treatment. Patients treated with first-or second-generation TKIs (N Z 189) with EGFR mutations in plasma at a mutant allele frequency (MAF) <7% before treatment initiation (low-risk patients) or who were ctDNA negative after 3 or 6 months of treatment and with an MAF <7% at diagnosis (high responders) had two-thirds lower risk of death than patients in the opposite situation (adjusted hazard ratio [HR] Z 0.38; 95% confidence interval [CI]: 0.23e0.64 and HR Z 0.22; 95% CI: 0.12e0.42, respectively). The median overall survival (OS) for low-risk patients and high responders treated with first-or second-generation TKIs was 34.2 months and not reached, respectively, regardless of second-line treatment. There were no significant difference in OS between lowrisk or high-responder patients treated upfront with osimertinib (N Z 39) and those treated under a sequential approach with osimertinib (N Z 60). Median OS was not reached in both cases. Conclusions: Pre-treatment ctDNA levels identify low-risk patients, who may benefit from sequential TKI treatment. Information regarding EGFR mutation clearance can help to improve patient selection.

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Background. For patients with unresectable non‐metastatic squamous cell carcinoma of the esophagus (SCCE), the conventional treatment has been radiation therapy (RT). Because RT alone is unsatisfactory, there has been increasing interest in including chemotherapy (CT) in the management of these patients. Methods. Twenty‐five previously untreated patients with unresectable nonmetastatic SCCE were treated with sequential CT and RT. CT consisted of cisplatin 35 mg/m2/day for 3 days plus bleomycin 15 mg/ day for 3 days as an 18–hour infusion every 3 weeks. After three courses of CT, RT was administered (dose, 200 rads/day with a planned total dose of 50–60 Gy). Results. Nineteen tumors were T3; six were T2 and larger than 7 cm. Fifteen patients (60%) had severe dysphagia that required placement of nasogastric tubes in 14 and gastrostomy in 1. All patients were evaluable for respons. Thirteen patients (52%) had a partial response to CT. After combined treatment, four patients had complete responses (16%), and nine had partial responses (36%; overall response rate, 52%). The median survival was 8 months; 20% were alive at 1 year, and 8% lived more than 4 years. The median survival for responders to CT was 8 months compared with 5 months for nonresponders (P = 0.005). Combined treatment improved dysphagia in 16 patients (64%) with complete resolution in 13. Toxicity was mild. Conclusions. The use of sequential CT (cisplatin and bleomycin) and RT in this group of patients is feasible; there is little additional toxicity, and good palliative effects can be achieved. The patient's response to CT is a good prognostic factor. The development of more effective combinations that induce more durable responses and higher rates of complete response are required.

Dear Sirs, Upshaw-Schulman syndrome (USS) is a rare life-threatening congenital disorder characterised by a thrombotic thrombocytopenic purpura (TTP), associated with an inherited deficiency of the von Willebrand factor-cleaving protease ADAMTS13. Mutations in the ADAMTS13 have been identified in congenital TTP patients (1, 2), most of whom have initial episodes during infancy or in early childhood (< 10 years of age), but may also manifest the condition during adolescence and adulthood (3-5). The exact incidence of congenital TTP has not been established, but is less than 1/1,000,000 persons/year. However, some authors have suggested that its incidence may be greatly underestimated. Indeed, ADAMTS13 mutations have been found in patients who were initially diagnosed with idiopathic thrombocytopenic purpura (ITP), atypical haemolytic uraemic syndrome or Evans syndrome (6-8). Here, we