Surfaceome profiling enables isolation of cancer-specific exosomal cargo in liquid biopsies from pancreatic cancer patients.

Background: Detection of circulating tumor DNA can be limited due to their relative scarcity in circulation, particularly while patients are actively undergoing therapy. Exosomes provide a vehicle through which cancer-specific material can be enriched from the compendium of circulating non-neoplastic tissue-derived nucleic acids. We carried out a comprehensive profiling of the pancreatic ductal adenocarcinoma (PDAC) exosomal 'surfaceome' in order to identify surface proteins that will render liquid biopsies amenable to cancer-derived exosome enrichment for downstream molecular profiling. Patients and methods: Surface exosomal proteins were profiled in 13 human PDAC and 2 non-neoplastic cell lines by liquid chromatography-mass spectrometry. A total of 173 prospectively collected blood samples from 103 PDAC patients underwent exosome isolation. Droplet digital PCR was used on 74 patients (136 total exosome samples) to determine baseline KRAS mutation call rates while patients were on therapy. PDAC-specific exosome capture was then carried out on additional 29 patients (37 samples) using an antibody cocktail directed against selected proteins, followed by droplet digital PCR analysis. Exosomal DNA in a PDAC patient resistant to therapy were profiled using a molecular barcoded, targeted sequencing panel to determine the utility of enriched nucleic acid material for comprehensive molecular analysis. Results: Proteomic analysis of the exosome 'surfaceome' revealed multiple PDAC-specific biomarker candidates: CLDN4, EPCAM, CD151, LGALS3BP, HIST2H2BE, and HIST2H2BF. KRAS mutations in total exosomes were detected in 44.1% of patients undergoing active therapy compared with 73.0% following exosome capture using the selected biomarkers. Enrichment of exosomal cargo was amenable to molecular profiling, elucidating a putative mechanism of resistance to PARP inhibitor therapy in a patient harboring a BRCA2 mutation. Conclusion: Exosomes provide unique opportunities in the context of liquid biopsies for enrichment of tumor-specific material in circulation. We present a comprehensive surfaceome characterization of PDAC exosomes which allows for capture and molecular profiling of tumor-derived DNA.

Consensus: the follow-up of the treated patient.

This is the first consensus document on the follow-up of the treated patient with non-small cell lung cancer that has been written by this group. The document has been drawn up by doctors coming from many different cultures and philosophical backgrounds. It acknowledges that there are published guidelines on the follow-up particularly those in trials, and does not wish to contradict these. There is lack of evidence-based medicine to recommend a strong general policy in this area. For those patients who were treated with curative intent the initial follow-up will depend upon the toxicity that is evident from the treatment given. Thereafter the interval between follow-up visits should be every 3 months for the first two years, then every 6 months for up to five years. Rapid and easy access to the multidisciplinary team should be available. Full examination and chest X-ray should be carried out on each visit but other investigations should be determined by clinical need. For those patients treated with palliative intent the interval between follow-up visits once the acute reactions have settled will depend upon the adequacy of the control of the symptom and the availability of separate palliative care teams. At all times the patient should have rapid access to the multidisciplinary team and in general frequent follow-up, that is at intervals of one to two months, may be appropriate during the first six months. Follow-up constitutes an important part of lung cancer management. Efforts should be made to gain clinical material to give us evidence-based guidelines.

Estudio fenotípico familiar en el déficit de Alfa 1 Antitripsina / Familiar phenotypic study in Alpha 1 antitrypsin deficiency

El déficit de alfa 1 antitripsina (DA1AT), es una enfermedad hereditaria autosómica de expresión condominante, con una provalencia aproximada de 1 caso cada 3000 individuos. Fenotipos anormales de DA1AT particularmente el PiZ se asocian con el riesgo de padecer patología hepática en la infancia y enfisema pulmonar en la edad adulta. Las manifestaciones y el pronóstico en esta enfermedad hepática hereditaria es extremadamente variable. Se presenta un caso de DA1AT con signos de colestasis neonatal

Frequency of upper gastrointestinal lesions in patients with liver cirrhosis.

The frequency of gastroduodenal lesions has been investigated in 142 patients with liver cirrhosis of various degrees of severity and in 63 patients with mild liver disease (controls) in whom liver biopsy excluded nodular regeneration. Cirrhotic patients were subdivided in three groups according to the Pugh modification of the Child-Turcotte criteria. Although the frequency of peptic ulcer was not different, gastroduodenal erosions were observed more frequently in cirrhotics than in controls (29.6% vs 11.1%, P less than 0.01). The occurrence of erosions was related to the severity of the disease: in Child A and B patients their frequency was 21 and 26% respectively, but rose to 48.4 (15 of 31 vs 7 of 63 in controls, P less than 0.001) in the Child C group. Both mild and severe gastroduodenitis occurred more frequently, although not significantly, in patients with liver cirrhosis. All together one or more endoscopic lesions were observed in almost 60% of cirrhotics but only in 25.4% of controls (P less than 0.001). In conclusion, our data do not show an increased prevalence of peptic ulcer in cirrhotic patients; in contrast, liver cirrhosis is significantly associated with the endoscopic finding of gastroduodenal erosions, especially in the more advanced stages of the disease. These findings would suggest a cautious use, in cirrhotic patients, of drugs which may damage the gastroduodenal mucosa; moreover, long-term administration of antacids or of other drugs with a protective effect on gastroduodenal mucosa might be taken into consideration for Child C patients.