Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults.

New neurons continue to be generated in the subgranular zone of the dentate gyrus of the adult mammalian hippocampus. This process has been linked to learning and memory, stress and exercise, and is thought to be altered in neurological disease. In humans, some studies have suggested that hundreds of new neurons are added to the adult dentate gyrus every day, whereas other studies find many fewer putative new neurons. Despite these discrepancies, it is generally believed that the adult human hippocampus continues to generate new neurons. Here we show that a defined population of progenitor cells does not coalesce in the subgranular zone during human fetal or postnatal development. We also find that the number of proliferating progenitors and young neurons in the dentate gyrus declines sharply during the first year of life and only a few isolated young neurons are observed by 7 and 13 years of age. In adult patients with epilepsy and healthy adults (18-77 years; n = 17 post-mortem samples from controls; n = 12 surgical resection samples from patients with epilepsy), young neurons were not detected in the dentate gyrus. In the monkey (Macaca mulatta) hippocampus, proliferation of neurons in the subgranular zone was found in early postnatal life, but this diminished during juvenile development as neurogenesis decreased. We conclude that recruitment of young neurons to the primate hippocampus decreases rapidly during the first years of life, and that neurogenesis in the dentate gyrus does not continue, or is extremely rare, in adult humans. The early decline in hippocampal neurogenesis raises questions about how the function of the dentate gyrus differs between humans and other species in which adult hippocampal neurogenesis is preserved.

PD-1 blockade induces responses by inhibiting adaptive immune resistance.

Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types. One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8(+) T cells (termed adaptive immune resistance). Here we show that pre-existing CD8(+) T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analysed samples from 46 patients with metastatic melanoma obtained before and during anti-PD-1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next-generation sequencing for T-cell antigen receptors (TCRs). In serially sampled tumours, patients responding to treatment showed proliferation of intratumoral CD8(+) T cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8-, PD-1- and PD-L1-expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. Our findings indicate that tumour regression after therapeutic PD-1 blockade requires pre-existing CD8(+) T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance.

Genetic epidemiology, demographic, and clinical characteristics of Charcot-Marie-tooth disease in the island of Gran Canaria (Spain).

Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuromuscular disorder. This study involves the entire known CMT patient registry in Gran Canaria, represented by 256 patients belonging to 79 unrelated families, who were clinically and genetically characterized, along with physical and neurophysiological evaluation on 181 and 165 patients, respectively. Complete genotyping showed an estimated prevalence of CMT disease of 30.08/100 000 (95% confidence interval [CI] = 26.5;33.9), corresponding mainly (78.5%) to CMT1A (23.6/100 000) and hereditary neuropathy with liability to pressure palsies [HNPP] 17.5%; 5.29/100 000). Most patients (198) with CMT1A carried the 17p11.2 duplication including the PMP22 gene, 45 patients with HNPP were all affected by deletion of the 17p11.2 locus, and 10 patients presented with axonal phenotypes: CMT2A (MFN2), CMT2N (AARS), and CMT1X (GJB1). Despite showing a classical CMT1A phenotype, we found a much earlier age of onset in our CMT1A patients, along with increased frequency of appearance of postural hand tremor. Bilateral tongue atrophy was an additional phenotype observed. Being this CMT1A group, one of the largest cohorts known to date, this study provided a unique opportunity to further define the clinical phenotype of CMT1A patients carrying the 17p11.2 duplication in a homogeneous ethnic group.

Non-small cell lung cancer clinical trials requiring biopsies with biomarker-specific results for enrollment provide unique challenges.

BACKGROUND: Clinical trials in lung cancer increasingly require patients to provide fresh tumor tissue as a prerequisite to enrollment. The effects of this requirement on enrollment rates, enrollment durations, and patient selection have not been fully elucidated. METHODS: The authors retrospectively reviewed data generated by patients who consented to 1 or more interventional lung cancer clinical trials at the University of California-Los Angeles Jonsson Comprehensive Cancer Center between January 2013 and December 2014. Trials were considered to require a biopsy when enrollment was conditional on the procurement of tissue without intervening therapy between procurement and enrollment. RESULTS: In total, 311 patients underwent 368 screening incidents for 1 or more of 19 trials. Trials that required a new biopsy had a longer median screening duration (34 vs 14 days) than trials that did not require a biopsy (P < .001). Trials that required a biopsy had a greater screen failure rate (49.1% vs 26.5%; P < .001), which was largely driven by patients who did not undergo the required biopsy or lacked the required biomarker. Worsening performance status led to the majority of screen failures (56.5%) among biomarker-eligible patients. CONCLUSIONS: Although the scientific benefits of obtaining a new biopsy and requiring specific results for trial enrollment are clear, these requirements lead to a lengthening of the screening period, which, in some patients, is associated with clinical decline before enrollment. Implications for the interpretation of data from studies of this design should be explored. Cancer 2017;123:4800-7. © 2017 American Cancer Society.

Radiofrequency ablation of lung tumors: imaging features of the postablation zone.

Radiofrequency ablation (RFA) is used to treat pulmonary malignancies. Although preliminary results are suggestive of a survival benefit, local progression rates are appreciable. Because a patient can undergo repeat treatment if recurrence is detected early, reliable post-RFA imaging follow-up is critical. The purpose of this article is to describe (a) an algorithm for post-RFA imaging surveillance; (b) the computed tomographic (CT) appearance, size, enhancement, and positron emission tomographic (PET) metabolic activity of the ablation zone; and (c) CT, PET, and dual-modality imaging with PET and CT (PET/CT) features suggestive of partial ablation or tumor recurrence and progression. CT is routinely used for post-RFA follow-up. PET and PET/CT have emerged as auxiliary follow-up techniques. CT with nodule densitometry may be used to supplement standard CT. Post-RFA follow-up was divided into three phases: early (immediately after to 1 week after RFA), intermediate (>1 week to 2 months), and late (>2 months). CT and PET imaging features suggestive of residual or recurrent disease include (a) increasing contrast material uptake in the ablation zone (>180 seconds on dynamic images), nodular enhancement measuring more than 10 mm, any central enhancement greater than 15 HU, and enhancement greater than baseline anytime after ablation; (b) growth of the RFA zone after 3 months (compared with baseline) and definitely after 6 months, peripheral nodular growth and change from ground-glass opacity to solid opacity, regional or distant lymph node enlargement, and new intrathoracic or extrathoracic disease; and (c) increased metabolic activity beyond 2 months, residual activity centrally or at the ablated tumor, and development of nodular activity.

ACR Appropriateness Criteria® pulmonary hypertension.

Pulmonary hypertension (PH) may be idiopathic or related to a variety of diseases. The diagnosis, accurate assessment of etiology and severity, prognosis, treatment response, and follow-up of PH can be achieved using a diverse set of diagnostic examinations. In this review, the role of imaging in the evaluation of PH as suggested by the American College of Radiology Appropriateness Criteria Expert Panel on Thoracic Imaging has been discussed. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The development and review of the guidelines include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Impact of PACS and voice-recognition reporting on the education of radiology residents.

RATIONALE AND OBJECTIVES: The introduction of picture archiving and communication system (PACS) has decreased the time needed to interpret radiology examinations resulting in an increased workflow. Because of concerns that the increase in exam throughput and the use of voice recognition may have a negative impact upon radiology resident education, a survey was conducted to assess the impact of PACS and voice recognition. MATERIALS AND METHODS: Residents at four diagnostic radiology training programs were surveyed. Survey topics included resident demographics, didactic and technical issues, and areas for improvement. RESULTS: One hundred thirty-four residents were polled with 42 respondents (42/134, 31.3%). The majority have been using PACS for more than 1 year (29/41, 70.7%) to interpret 75-100% of cases (33/39, 84.6%). A majority believed PACS is a superior teaching tool to printed film (28/38, 73.7%). However, only a minority (9/40, 22.5%) indicated that PACS was always used to contain teaching files and to conduct departmental conferences (5/40, 12.5%). The majority of respondents believed PACS have decreased the time needed to interpret diagnostic examinations (33/41, 80.5%). A majority (80.6%, 25/31) indicated that voice recognition takes more time than the traditional dictation and transcription process, where 51.3% (20/39, 51.3%) felt that voice recognition works well less than 50% of the time. CONCLUSIONS: Residents believe that PACS has positively affected their learning experience but indicate that it can be better utilized for resident education. Residents believe that voice recognition is less reliable and more time consuming than the traditional dictation system.