Telomerase activation cooperates with inactivation of p16 in early head and neck tumorigenesis

Alteration of the p16/pRb pathway may cooperate with telomerase activation during cellular immortalization and tumour progression. We studied p16 expression status by immunohistochemistry and telomerase activity using the TRAP assay in 21 premalignant lesions of the head and neck epithelium as well as 27 squamous-cell carcinomas. We also examined expression of other components of the pathway (cyclin D1 and pRb) as well as presence of human papillomavirus genomes which can target these molecules. 4 of 9 mild dysplastic lesions (44%), 8 of 12 moderate/severe dysplastic lesions (67%), and 25 of 27 squamous-cell carcinomas (92%) demonstrated high telomerase activity (P = 0.009). There was a parallel increase with severity of lesions for the trend in proportions of cases demonstrating p16 inactivation or cyclin D1 overexpression (P = 0.02 and P = 0.01, respectively). For Ki67, a marker of cell proliferation, this trend was not significant (P = 0.08). Human papillomavirus infection was only found in 4 cases among the 48 samples tested (8.3%). In conclusion, progression of disease is accompanied by a parallel and continuous increase in telomerase activity and alterations in cell cycle regulators (p16, cyclin D1), as proposed by in vitro models. © 2001 Cancer Research Campaign http://www.bjcancer.co

Increased frequency of anti-Ma2 encephalitis associated with immune checkpoint inhibitors

Objective To report the induction of anti-Ma2 antibody-associated paraneoplastic neurologic syndrome (Ma2-PNS) in 6 patients after treatment with immune checkpoint inhibitors (ICIs). We also analyzed (1) patient clinical features compared with a cohort of 44 patients who developed Ma2-PNS without receiving ICI treatment and (2) the frequency of neuronal antibody detection before and after ICI implementation. Methods Retrospective nationwide study of all patients with Ma2-PNS developed during ICI treatment between 2017 and 2018. Results Our series of patients included 5 men and 1 woman (median age, 63 years). The patients were receiving nivolumab (n = 3), pembrolizumab (n = 2), or a combination of nivolumab and ipilimumab (n = 1) for treatment of neoplasms that included lung (n = 4) and kidney (n = 1) cancers and pleural mesothelioma (n = 1). Clinical syndromes comprised a combination of limbic encephalitis and diencephalitis (n = 3), isolated limbic encephalitis (n = 2), and a syndrome characterized by ophthalmoplegia and head drop (n = 1). No significant clinical difference was observed between our 6 patients and the overall cohort of Ma2-PNS cases. Post-ICI Ma2-PNS accounted for 35% of the total 17 Ma2-PNS diagnosed in our center over the 2017-2018 biennium. Eight cases had been detected in the preceding biennium 2015-2016, corresponding to a 112% increase of Ma2-PNS frequency since the implementation of ICIs in France. Despite ICI withdrawal and immunotherapy, 4/6 patients died, and the remaining 2 showed a moderate to severe disability. Conclusions We show a clear association between ICI use and increased diagnosis of Ma2-PNS. Physicians need to be aware that ICIs can trigger Ma2-PNS because clinical presentation can be challenging

Quantitative methylation analyses of resection margins predict local recurrences and disease-specific deaths in patients with head and neck squamous cell carcinomas

This study sought to determine whether the presence of hypermethylated genes in the surgical margins can predict local recurrences in head and neck squamous cell carcinomas (HNSCCs). We prospectively collected tumour and surgical margin specimens from patients with HNSCCs who had undergone surgical resections. Quantitative methylation-specific PCR (QMSP) of CDKN2A, CCNA1 and DCC were performed in these specimens and correlated with clinical data. Of the 42 patients eligible for the study, 27 were hypermethylation informative for the above three genes. This latter group was associated with longer disease-free survivals (P=0.007) and longer time to disease-specific deaths (P=0.004). Multivariate analyses confirmed hypermethylation non-informative tumours as an independent prognosticating factor for disease-specific deaths (risk ratio 3.8, P=0.026). Quantitative MSP of the margins of 24 hypermethylation informative tumours revealed that 11 patients had molecularly positive margins, of which, five developed disease-specific events (DSEs, three local recurrences and two metastases), compared to none in patients with molecularly negative margins, after a median follow-up of 48 months. Log-rank analyses showed that molecularly positive margins were associated with shorter time to local recurrences and disease-specific deaths (P=0.03 and 0.01, respectively). This study demonstrated that QMSP of hypermethylated promoters in surgical margins predicted all the local recurrences in our series of HNSCC patients. We have also identified hypermethylation non-informative tumours as an independent predictor for the development of DSEs

Characteristics of Acacia mangium shoot apical meristems in natural and in vitro conditions in relation to heteroblasty

PDF version of the authors can be published in January 2013International audienceMorphological and histocytological characteristics of Acacia mangium shoot apical meristems (SAMs) were assessed in natural and in vitro conditions in relation to heteroblasty. In the natural environment, SAMs with a mature-phyllode morphology were much bigger, contained more cells with larger vacuolated area, or vacuome, and lower nucleoplasmic ratios than those from the juvenile type (Juv). In these latter, nuclei appeared more voluminous, evenly and lightly stained, with clearly distinguishable nucleolei and less abundant chromocenters. In vitro, where reversions from mature to juvenile morphological traits do occur unpredictably, heteroblasty was less obvious in the SAM characteristics examined. In vitro SAMs corresponding to the juvenile and mature types showed similarities with outdoor Juv SAMs, but could be distinguished from these latter by a much larger vacuome that might be induced by the culture conditions. These findings encourage pursuing the investigations at the chromatin and nucleolus level in SAM zones where heteroblasty-related differences have been detected

Multimodality Imaging of Cardiac Transthyretin Amyloidosis 16 Years After a Domino Liver Transplantation

International audienceWe report the case of a 62-year-old man hospitalized in May 2015 for symptomatic heart failure. His medical history included two liver transplantations. The first liver transplantation was performed in 1999 for a mixed alcoholic and hepatitis C-related cirrhosis and the patient received the liver of another patient with Val30Met transthyretin amyloidosis using the domino technique. In 2008, he complained of neuropathic pains and an iatrogenic-acquired transthyretin amyloidosis was diagnosed. On cardiac evaluation, amyloidosis was suspected. In March 2010, a second liver transplantation was performed with a deceased donor without complication. In May 2015, a first episode of symptomatic heart failure occurred and cardiac amyloidosis was investigated by a multimodality evaluation. Electrocardiogram, cardiac biomarkers, echocardiography, and cardiac MRI were in favor of the diagnosis of amyloidosis, whereas 99m Tc-dicarboxypropane diphosphonate scintigraphy was not. Endomyocardial biopsy finally confirmed the positive diagnosis of iatrogenic-acquired cardiac amyloidosis. This case is, to the best of our knowledge, the first to report biopsy-proven cardiac amyloidosis induced by domino liver transplantation and progressing heart failure in spite of retransplantation. The diagnostic modalities are discussed. This case should alert physicians to the cardiac risk in domino liver transplanted patients