Evaluation of yield and experiences of age-related molecular investigation for heritable and nonheritable causes of mismatch repair deficient colorectal cancer to identify Lynch syndrome

Universal mismatch repair deficiency (dMMR) testing of colorectal cancer (CRC) is promoted as routine diagnostics to prescreen for Lynch syndrome. We evaluated the yield and experience of age-related molecular investigation for heritable and nonheritable causes of dMMR in CRC below age 70 to identify Lynch Syndrome. In a prospective cohort of 3602 newly diagnosed CRCs below age 70 from 19 hospitals, dMMR, MLH1 promoter hypermethylation, germline MMR gene and somatic MMR gene testing was assessed in daily practice. Yield was evaluated using data from the Dutch Pathology Registry (PALGA) and two regional genetic centers. Experiences of clinicians were evaluated through questionnaires. Participating clinicians were overwhelmingly positive about the clinical workflow. Pathologists routinely applied dMMR-testing in 84% CRCs and determined 10% was dMMR, largely due to somatic MLH1 hypermethylation (66%). Of those, 69% with dMMR CRC below age 70 without hypermethylation were referred for genetic testing, of which 55% was due to Lynch syndrome (hereditary) and 43% to somatic biallelic pathogenic MMR (nonhereditary). The prevalence of Lynch syndrome was 18% in CRC < 40, 1.7% in CRC age 40-64 and 0.7% in CRC age 65-69. Age 65-69 represents most cases with dMMR, in which dMMR due to somatic causes (13%) is 20 times more prevalent than Lynch syndrome. In conclusion, up to age 65 routine diagnostics of (non-)heritable causes of dMMR CRCs effectively identifies Lynch syndrome and reduces Lynch-like diagnoses. Above age 64, the effort to detect one Lynch syndrome patient in dMMR CRC is high and germline testing rarely needed.     

Mitochondrial encephalomyopathy showing prominent microvacuolation and necrosis of intestinal smooth muscle cells: a case diagnosed by rectal biopsy

A 40-year-old woman who developed intestinal dysmobility was found, at rectal biopsy, to have marked microvacuolation of mucosal muscle layer cells, which corresponded to increased accumulation of abnormal mitochondria. Skeletal muscle biopsy specimens showed ragged-red fibers, vessels strongly reactive for succinic dehydrogenase, and focal deficiency of cytochrome c oxidase. Autopsy performed at the age of 50 revealed prominent accumulation of abnormal mitochondria in the intestinal smooth muscle cells with a mottled distribution of focal necrosis, multiple small cerebral infarcts with diffuse neuronal loss, and rarefaction of the perivascular white matter. Mitochondrial DNA analysis showed a point mutation at position 3243. This case, showing features of both mitochondrial neurogastrointestinal encephalomyopathy and mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), indicates that routine intestinal biopsy can detect mitochondrial encephalomyopathy with gastrointestinal involvement. The main intestinal changes were extensive accumulation of abnormal mitochondria in the leiomyocytes and scattered focal necrosis. Received: 13 July 1997 / Revised, accepted: 1 December 1997     

An autopsy case of drug‐induced diffuse cerebral axonopathic leukoencephalopathy: The pathogenesis in relation to reversible posterior leukoencephalopathy syndrome

An autopsy case of diffuse axonopathic leukoencephalopathy induced by drug treatment is reported. A 70‐year‐old woman with multiple myeloma developed encephalopathy several days after completing a course of intravenous human immunoglobulin (IVIg) and granulocyte‐colony stimulating factor (G‐CSF), and died within I month. T2‐weighted MRI demonstrated multifocal high‐signal areas in the bilateral cerebral white matter, especially in the right frontal lobe. Neuropathologically, multifocal hydropic axonal swelling with a poor glial reaction was recognized diffusely in the bilateral deep cerebral white matter, being especially marked in the frontal lobe. The cortex, subcortical U‐fibers, corpus callosum, and anterior commissure were spared. The cerebellar white matter also showed similar changes, albeit less marked, but the brainstem was spared. Microscopically, the myeloma involvement of the CNS was limited to the dura, and the cerebral arteries showed slight atherosclerosis, but neither thrombi nor angitis. This case, although ultimately fatal, neurologically and neuroradiologically resembled reversible posterior leukoencephalopathy syndrome (RPLS) induced by IVIg and/or G‐CSF, and the nature and selective distribution of the neuropathological changes suggested that the pathogenesis involved vasospasm of the bilateral internal carotid artery and the main trunks of the cerebral arteries, due to unknown cause, inducing ischemia in the deep white matter, which is supplied by long nutrient arteries.     

Sleep modulates cortical connectivity and excitability in humans: Direct evidence from neural activity induced by single‐pulse electrical stimulation

Sleep‐induced changes in human brain connectivity/excitability and their physiologic basis remain unclear, especially in the frontal lobe. We investigated sleep‐induced connectivity and excitability changes in 11 patients who underwent chronic implantation of subdural electrodes for epilepsy surgery. Single‐pulse electrical stimuli were directly injected to a part of the cortices, and cortico‐cortical evoked potentials (CCEPs) and CCEP‐related high‐gamma activities (HGA: 100–200 Hz) were recorded from adjacent and remote cortices as proxies of effective connectivity and induced neuronal activity, respectively. HGA power during the initial CCEP component (N1) correlated with the N1 size itself across all states investigated. The degree of cortical connectivity and excitability changed during sleep depending on sleep stage, approximately showing dichotomy of awake vs. non‐rapid eye movement (REM) [NREM] sleep. On the other hand, REM sleep partly had properties of both awake and NREM sleep, placing itself in the intermediate state between them. Compared with the awake state, single‐pulse stimulation especially during NREM sleep induced increased connectivity (N1 size) and neuronal excitability (HGA increase at N1), which was immediately followed by intense inhibition (HGA decrease). The HGA decrease was temporally followed by the N2 peak (the second CCEP component), and then by HGA re‐increase during sleep across all lobes. This HGA rebound or re‐increase of neuronal synchrony was largest in the frontal lobe compared with the other lobes. These properties of sleep‐induced changes of the cortex may be related to unconsciousness during sleep and frequent nocturnal seizures in frontal lobe epilepsy. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc .     

New Approach for Exploring Cerebral Functional Connectivity: Review of Cortico-cortical Evoked Potential

There has been a paradigm shift in the understanding of brain function. The intrinsic architecture of neuronal connections forms a key component of the cortical organization in our brain. Many imaging studies, such as noninvasive magnetic resonance imaging (MRI) studies, have now enabled visualization of the white matter fiber tracts interconnecting the functional cortical areas in the living brain. Although such a structural connectome is essential for understanding of cortical function, the anatomical information alone is not sufficient. Practically, few techniques allow the investigation of the excitatory and inhibitory mechanisms of the cortex in vivo in humans. Several attempts have been made to track neuronal connectivity by applying direct electrical stimuli to the brain in order to stimulate subdural and/or depth electrodes and record responses from the functionally connected cortex. In vivo single-pulse electrical stimulation (SPES) and/or cortico-cortical evoked potential (CCEP) were recently introduced to track various brain networks. This article reviews the concepts, significance, methods, mechanisms, limitations, and clinical applications of CCEP in the analysis of these dynamic connections.     

Auditory and visual information in speech perception: A developmental perspective

This study investigates the development of audiovisual speech perception from age 4 to 80, analysing the contribution of modality, context and special features of specific language being tested. Data of 77 participants in five age groups is presented in the study. Speech stimuli were introduced via auditory, visual and audiovisual modalities. Monosyllabic meaningful and nonsense words were included in a signal-to-noise ratio of 0 dB. Speech perception accuracy in audiovisual and auditory modalities by age resulted in an inverse U-shape, with lowest performance at ages 4–5 and 65–80. In the visual modality, a clear difference was shown between performance of children (ages 4–5 and 8–9) and adults (age 20 and above). The findings of the current study have important implications for strategic planning in rehabilitation programmes for child and adult speakers of different languages with hearing difficulties.     

Effects of Low-Intensity Cycle Training with Restricted Leg Blood Flow on Thigh Muscle Volume and VO2MAX in Young Men

Concurrent improvements in aerobic capacity and muscle hypertrophy in response to a single mode of training have not been reported. We examined the effects of low-intensity cycle exercise training with and without blood flow restriction (BFR) on muscle size and maximum oxygen uptake (VO₂max). A group of 19 young men (mean age ± SD: 23.0 ± 1.7 years) were allocated randomly into either a BFR-training group (n=9, BFR-training) or a non-BFR control training group (n=10, CON-training), both of which trained 3 days/wk for 8 wk. Training intensity and duration were 40% of VO₂max and 15 min for the BFR-training group and 40% of VO₂max and 45 min for the CON-training group. MRI-measured thigh and quadriceps muscle cross-sectional area and muscle volume increased by 3.4-5.1% (P < 0.01) and isometric knee extension strength tended to increase by 7.7% (p < 0.10) in the BFR-training group. There was no change in muscle size (~0.6%) and strength (~1.4%) in the CON-training group. Significant improvements in VO₂max (6.4%) and exercise time until exhaustion (15.4%) were observed in the BFR-training group (p < 0.05) but not in the CON-training group (-0.1 and 3. 9%, respectively). The results suggest that low-intensity, short-duration cycling exercise combined with BFR improves both muscle hypertrophy and aerobic capacity concurrently in young men.

Key points

• Concurrent improvements in aerobic capacity and muscle hypertrophy in response to a single mode of training have not been reported.
• In the present study, low-intensity (40% of VO2max) cycle training with BFR can elicit concurrent improvement in muscle hypertrophy and aerobic capacity.

Key words: Muscle hypertrophy, Aerobic exercise, Occlusion, Muscle strength     

Can endoscopic submucosal dissection be safely performed in a smaller specialized clinic?

AIM:To investigate whether endoscopic submucosal dissection(ESD) can be safely performed at small clinics,such as the Shirakawa Clinic.METHODS:One thousand forty-seven ESDs to treat gastrointestinal tumors were performed at the Shirakawa Clinic from April 2006 to March 2011.The efficacy,technical feasibility and associated complications of the procedures were assessed.The ESD procedures were performed by five endoscopists.Sedation was induced with propofol for esophagogastorduodenal ESD.RESULTS:One thousand forty-seven ESDs were performed to treat 64 patients with esophageal cancer(E),850 patients with gastric tumors(G:764 patients with cancer,82 patients with adenomas and four others),four patients with duodenal cancer(D) and 129 patients with colorectal tumors(C:94 patients with cancer,21 patients with adenomas and 14 others).The en bloc resection rate was 94.3%(E:96.9%,G:95.8%,D:100%,C:79.8%).The median operation time was 46 min(range:4-360 min) and the mean size of the resected specimens was 18 mm(range:2-150 mm).No mortal complications were observed in association with the ESD procedures.Perforation occurred in 12 cases(1.1%,E:1 case,G:9 cases,D:1 case,C:1 case) and postoperative bleeding occurred in 53 cases(5.1%,G:51 cases,D:1 case,C:1 case);however,no case required either emergency surgery or blood transfusion.All of the perforations and postperative bleedings were resolved by endoscopic clipping or hemostasis.The other problematic complication observed was pneumonia,which was treated with conservative therapy.CONCLUSION:ESD can be safely performed in a clinic with established therapeutic methods and medical services to address potential complications.     

Successful perioperative management for a breast cancer patient with Bernard–Soulier syndrome

We herein report the first case of a Bernard–Soulier syndrome (BSS) patient undergoing a surgical procedure for breast cancer. BSS is a rare hereditary thrombocytopathy associated with defects of the platelet glycoprotein complex glycoprotein Ib/V/IX and characterized by large platelets, thrombocytopenia, and severe bleeding symptoms. Because of the rarity of BSS, there are as yet no defined protocols for the perioperative management, which can be very complex and challenging in patients with coagulopathies, in particular BSS. In this case we successfully performed both an interventional examination as well as mastectomy with axillary lymph node dissection, under the preventive and intermittent transfusion of platelets. No intra- or postoperative bleeding complications occurred. Unfortunately, the patient was diagnosed as having metastatic disease involving liver, lungs, and bones 10 months after the surgery. She had received 1st, 2nd, and 3rd line chemotherapy without severe adverse events. However, gastrointestinal bleeding appeared after she was treated with 4th line chemotherapy. Finally, she succumbed 22 months after the breast surgery.