Stephan Hollerbach

Feasibility and Diagnostic Utility of Video Capsule Endoscopy for the Detection of Small Bowel Polyps in Patients with Hereditary Polyposis Syndromes

OBJECTIVES:At present, surveillance of premalignant small bowel polyps in hereditary polyposis syndromes has a number of limitations. Capsule endoscopy (CE) is a promising new method to endoscopically assess the entire length of the small bowel.METHODS:We prospectively examined 40 patients with hereditary polyposis syndromes (29 familial adenomatous polyposis (FAP), 11 Peutz-Jeghers syndrome (PJS)). Results were compared with push-enteroscopy (PE) results in FAP and with esophagogastroduodenoscopy, PE, (MR)-enteroclysis, and surgical specimen in PJS patients.RESULTS:A total of 76% of the patients with FAP with duodenal adenomas (n = 21) had additional adenomas in the proximal jejunum that could be detected by CE and PE. Moreover, 24% of these FAP patients had further polyps in the distal jejunum or ileum that could only be detected by CE. In contrast, in FAP patients without duodenal polyps (n = 8), jejunal or ileal polyps occurred rarely (12%). CE detected polyps in 10 of 11 patients with PJS, a rate superior to all other reference procedures employed. Importantly, the findings of CE had immediate impact on further clinical management in all PJS patients.CONCLUSIONS:Our results suggest that CE may be of clinical value in selected patients with FAP, whereas in PJS, CE could be used as first line surveillance procedure.

The Accuracy of Abdominal Ultrasound in the Assessment of Bowel Disorders

BACKGROUND Little is known about the sensitivity, specificity, and predictive values of transabdominal ultrasonographic (US) findings in a teaching hospital setting. METHODS We carried out a prospective study including 227 patients with symptoms suggestive of inflammatory bowel disorder. The Picker 9200 CS equipment (5-mHz curved-array probe) was used to obtain bowel images. Gastrointestinal endoscopy, enteroclysis, bowel enema, computed tomography scan, or bowel surgery was used as reference. RESULTS Of 227 patients, 168 had pathologic findings of the bowel as final diagnosis. The overall sensitivity of US was 76%, whereas the positive predictive value was 98%. Overall specificity was 95%. The negative predictive value for bowel disorders was only 58%, since US missed pathologic findings in 48 patients. Subgroup analysis showed a sensitivity of 84% for Crohns disease, 66% for ulcerative colitis, 46% for bowel tumors, and 60% for diverticulitis. Topographic comparisons showed that US detected inflammatory bowel-wall alterations preferentially in the terminal ileum and colon, whereas abnormalities in the duodenum, jejunum, and rectum were frequently missed (sensitivity, 10%-20%). CONCLUSIONS Positive US findings are useful for the diagnosis of bowel processes. US is highly predictive albeit not disease-specific. Negative US examinations, however, do not exclude pathologic bowel processes. A topographic location of pathologic US findings is mostly confined to the colon.

The feasibility of triple-drug chemotherapy combination in older adult patients with oesophagogastric cancer: A randomised trial of the Arbeitsgemeinschaft Internistische Onkologie (FLOT65+)

BACKGROUND We evaluated the feasibility and tolerability of triple- versus double-drug chemotherapy in elderly patients with oesophagogastric cancer. METHODS Patients aged 65 years or older with locally advanced or metastatic oesophagogastric cancer were stratified and randomised to infusional 5-FU, leucovorin and oxaliplatin without (FLO) or with docetaxel 50 mg/m(2) (FLOT) every 2 weeks. The study is registered at ClinicalTrials.gov, identifier NCT00737373. FINDINGS One hundred and forty three (FLO, 71; FLOT, 72) patients with a median age of 70 years were enrolled. The triple combination was associated with more treatment-related National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3/4 adverse events (FLOT, 81.9%; FLO, 38.6%; P<.001) and more patients experiencing a ≥10-points deterioration of European Organization for Research and Treatment of Cancer Quality of Life (EORTC QoL) global health status scores (FLOT, 47.5%; FLO 20.5%; p=.011). The triple combination was associated with more alopecia (P<.001), neutropenia (P<.001), leukopenia (P<.001), diarrhoea (P=.006) and nausea (P=.029).). No differences were observed in treatment duration and discontinuation due to toxicity, cumulative doses or toxic deaths between arms. The triple combination improved response rates and progression-free survival in the locally advanced subgroup and in the subgroup of patients aged between 65 and 70 years but not in the metastatic group or in patients aged 70 years and older. INTERPRETATION The triple-drug chemotherapy was feasible in elderly patients with oesophagogastric cancer. However, toxicity was significantly increased and QoL deteriorated in a relevant proportion of patients. FUNDING The study was partially funded by Sanofi-Aventis.

Brain electrical activity mapping of EEG for the diagnosis of (sub)clinical hepatic encephalopathy in chronic liver disease.

We studied the role of brain electrical activity mapping (BEAM) in the assessment of neuropsychiatric disturbances in 48 cirrhotic patients without clinical evidence of hepatic encephalopathy (no HE, n = 19), with subclinical HE (grade 0, denoting pathological psychometric tests, n = 13) and mild-to-moderate HE (grade I, n = 6; grade II, n = 10). Results were compared with 23 healthy controls. BEAM variables quantified were: (i) the peak frequency (PF); (ii) the amplitude of PF; and (iii) the topographic localization of the maximum peak amplitude digitized for quantification by using a co-ordinate system. Mean amplitudes and their topographic localization in the following frequency-bands were analysed: delta (1.0–3.5 Hz), theta (4.0–7.5 Hz), alpha 1 (8.0–9.5 Hz), alpha 2 (10.0–11.5 Hz), beta 1 (12.0–15.5 Hz), beta 2 (16.0–19.5 Hz), and beta 3 (20.0–23.5 Hz). The PF was significantly slower in all HE patients than in healthy controls (8.5 ± 2.0 Hz v. 10.1 ± 1.0 Hz, P < 0.001). Even in no HE, the PF was significantly slower than in controls (8.6 ± 1.5 Hz v. 10.1 ± 1.0 Hz, P < 0.01). No relevant topographic differences of PF were observed. The mean amplitudes of the following bands differed significantly between controls and patients: theta (increased in HE, P < 0.05), alpha 2 (decreased in HE, P < 0.05), and beta 2 and beta 3 (increased in HE, P < 0.05). In HE patients, the topographic localization of all beta bands showed a significant shift from parieto-occipital areas to central areas of the cortex. We conclude that BEAM is a sensitive tool for detecting neuropsychiatric disturbances in cirrhotics with no HE and with subclinical HE. The combination of PF in the theta band, increased mean amplitude in the beta 2 band, and the localization of the latter band in the frontocentral area of the cortex is an objective and sensitive tool for identifying neuropsychiatric disturbances in 85% of cirrhotic patients with no HE. Further studies are required to determine the clinical implications of these abnormal findings in the absence of overt clinical symptoms.

Neurocardiac and cerebral responses evoked by esophageal vago-afferent stimulation in humans: effect of varying intensities.

OBJECTIVE This study was designed to determine whether esophageal vago-afferent electrostimulation, over a wide range of stimulus intensities, can sustain a cardiac vago-efferent effect by way of central nervous system processing. METHODS Studies were performed in ten healthy male subjects (23.9 +/- 6.3 years). Esophageal electrostimulation was carried out using a stimulating electrode placed in the distal esophagus. Stimulation of esophageal vago-afferent fibres was employed using electrical impulses (200 microseconds at 0.2 Hz x 128 s) varying from 2.7 to 20 mA. Respiratory frequencies, beat-to-beat heart rate autospectra and cerebral evoked potentials were recorded at baseline and at each stimulus intensity in random order. RESULTS With esophageal electrical stimulation, we observed a small non-significant decrease in heart rate. There was a dramatic shift of the instantaneous heart rate power spectra towards enhanced cardiac vagal modulation with intensities as low as 5 mA. This effect was sustained throughout all intensities with no further change in either the low frequency or high frequency power. Conversely, there was a linear dose response relationship between cerebral evoked potential amplitude and stimulus intensity mainly occurring above perception threshold (10 mA). Esophageal stimulation had no significant effect on heart rate or respiratory frequency at any stimulus intensity. CONCLUSIONS These results indicate that electrical stimulation of the distal esophagus across a wide range of current intensities elicits a reproducible shift in the heart rate power spectrum towards enhanced vagal modulation. The data suggest a closed loop afferent/efferent circuitry wherein tonic visceral afferent impulses appear to elicit a phasic or modulatory vago-efferent cardiac response in healthy subjects.

The magnitude of the central response to esophageal electrical stimulation is intensity dependent.

BACKGROUND & AIMS Cerebral evoked potential (EP) responses to visceral stimulation represent a powerful method to assess visceral afferent pathways. The aim of this study was to establish basic stimulation parameters (dose-response relationship in EP amplitude and topographic brain organization) during electrical esophageal stimulation. METHODS Electrical esophageal stimulation was performed in repeated series of 24 stimuli in 15 healthy subjects (25 years) by steps of 5 mA, ranging from 0.5 mA (sham) to 25 mA. EPs were obtained using scalp electrodes positioned according to the 10/20 International electroencephalographic system. Topographic EP maps were created using interpolation techniques. RESULTS No cerebral responses were recorded with sham stimulation. A significant intensity-dependent increase of the major EP peaks (N1-P2) was observed between 5 and 25 mA (P < 0.05). A significant shortening of the mean peak latency of the first peak (N1) occurred with increasing stimulus intensity (P < 0.0001). Topographic brain maps localized the early EP peaks centrally, whereas later peaks were spread symmetrically over the centroparietal region. CONCLUSIONS The clear dose-response relationship in the brain response with increasing stimulus intensities probably reflects increased recruitment of afferent fibers. Early peaks originate from deep central brain structures, whereas later peaks are localized exclusively in cortical regions.

The cerebral response to electrical stimuli in the oesophagus is altered by increasing stimulus frequencies.

Recording of cerebral evoked responses (EP) allows the assessment of visceral afferent pathways and gut–brain communication, but the optimal stimulation parameters remain to be established. The present study determined the optimal stimulation frequency of electrical stimulation of the oesophagus to elicit EP responses. In 13 healthy male volunteers (24.1 ± 5.9 years), a 5 mm stainless‐steel electrode was placed in the distal oesophagus for electrical stimulation (ES). EP were recorded from 21 scalp electrodes placed according to the 10/20 International system. ES (15 mA, 200 μs) were delivered in repeated series of 24 stimuli. Stimulus frequency was randomly altered in different series using a pseudologarithmic range (0.1, 0.2, 0.3, 0.5, and 1 Hz). Two series of stimuli were applied using each stimulation frequency. Two‐dimensional topographic brain maps were created using interpolation techniques at each stimulation frequency. With increasing stimulus frequency, a significant and progressive decrease of EP amplitudes was observed between frequencies of 0.1 Hz and 1.0 Hz (P1/N2: 7.6 ± 1.2 vs 1.4 ± 0.3* μV, N2/P2: 17.2 ± 1.7 vs 4.6 ± 0.4* μV, P2/N3: 6.9 ± 0.7 vs 4.2 ± 0.5* μV; * = P < 0.05). In addition, there was a significant shortening of the mean peak latency of the intercalated P2 peak (P < 0.0005), with a similar trend for the P3 peak (P < 0.06), with increasing stimulus frequency from 0.1–1.0 Hz. Topographic brain maps localized the maximal early peaks (N1,P1,N2) in the paracentral cortical region (C3, Cz, C4), whereas the later peaks (P2 to P3) were symmetrically spread over the centro‐parietal and temporal regions (Cz, Pz, T5, T4). There was no difference in the cortical location of maximal EP amplitudes with increasing stimulus frequency. In conclusion, there is a clear relationship between stimulus frequency and amplitude of EP, suggesting rapid attenuation of the cerebral autonomic neural responses with increased electrical stimulation frequency. The effect of increased frequency on peak latencies suggests an alteration of stimulus processing in the thalamocortical region due to an altered perception of stimuli. Early EP peaks originate from basal structures of primarily the dominant hemisphere, while later peaks are localized in centroparietal cortical regions.

Multicenter randomized controlled trial comparing the performance of 22 gauge versus 25 gauge EUS–FNA needles in solid masses

Abstract Background and aims. Few randomized studies have assessed the clinical performance of 25-gauge (25G) needles compared with 22-gauge (22G) needles during endoscopic ultrasound-guided fine needle aspiration (EUS–FNA) biopsy of intra-abdominal lesions. We aimed to compare the diagnostic yield, as well as performance characteristics of 22G versus 25G EUS biopsy needles by determining their diagnostic capabilities, the number of needle passes as well as cellularity of aspirated tissue specimen. Methods. The study is a prospective, randomized, multicenter study. Patients were referred between January 2009 and January 2010 for diagnostic EUS including EUS-guided FNA of different lesions adjacent to the upper GI tract. All patients were randomized to EUS–FNA performed with either a 22G or 25G aspiration needle. Results. EUS–FNA was performed in 135 patients (62 patients with a 22G needle). Sensitivity and specificity of the 22G needle was 94.1% and 95.8%, respectively, and for the 25G needle 94.1% and 100%, respectively. Investigators reported better visualization and performance for the 22G needle compared to the 25G (p < 0.0001). The number of tissue slides obtained was higher for the 22G needle during the second and third needle passes (p < 0.05). We did not observe significant differences between the number and preservation status of obtained cells (p > 0.05). Conclusions. A significant difference was found between the two types of needles in terms of reduced visualization of the 25G needle and suboptimal performance rating. However, this did not impact on overall results since both needles were equally successful in terms of a high diagnostic yield and overall accuracy.

Cortical Evoked Responses Following Esophageal Balloon Distension and Electrical Stimulation in Healthy Volunteers

Recording of evoked potential responsesrepresents an objective and quantifiable method to studyvisceral afferent sensory pathways in humans. Weexamined the evoked responses to mechanical distension(balloon) and electrical stimulation of the proximal anddistal esophagus. A standard manometric catheter with alatex balloon and an additional electrode attached toits body was placed in the lower esophagus in 15 healthy young volunteers. Repeatednonpainful balloon distension stimuli above theindividual sensation threshold (0.17 Hz, 12-20 ml) orshort electrical impulses (0.2 Hz, 12-16 mA) weredelivered in an alternate fashion at 23 and 33 cm from thenares. Evoked potential responses (EP) were recordedthrough 22 scalp surface electrodes using the standard10/20 International EEG system of electrode placement. Balloon distension produced a reproducibletriphasic response at both sites. Peak latencies ofthree negative EP peaks were 92 ± 17, 229± 40, and 339 ± 36 msec with proximalstimulation versus 154 ± 24, 275 ± 24, and384 ± 30 msec obtained with distal stimulation (P< 0.001). Electrical stimulation produced a triphasicresponse with significantly shorter peak latencies atboth sites when compared to mechanical stimulation (P <0.001). Peak latencies were 74 ± 12, 137 ±11, and 245 ± 27 msec proximal versus 83 ±12, 148 ± 32, and 247 ± 51 msec withdistal stimulation (P < 0.01). The calculated conduction velocities forboth modes of stimulation (balloon: 1.73 ± 0.9m/sec vs electrical: 10.1 ± 3.4 m/sec) arecompatible with conduction through C fibers and Adeltafibers, respectively. Both modes of stimulation producecharacteristic brain responses that are conveyed throughdifferent types of afferent fibers. The respectivecontributions of both types of fibers to esophageal function and symptomatology can be specificallyaddressed using this approach in both normal andpathologic conditions.

Treatment with bevacizumab and FOLFOXIRI in patients with advanced colorectal cancer: presentation of two novel trials (CHARTA and PERIMAX) and review of the literature.

BackgroundMore than half of patients with colorectal cancer will develop metastatic disease either evident at the time of initial diagnosis or during their course of disease. Besides multidisciplinary management further treatment intensification is warranted to improve the still limited prognosis.Methods/designIn these two multi-centre, randomized phase II trials, conducted in Germany, 380 patients with R0-resectable colorectal liver metastases (PERIMAX) and with unresectable, metastatic colorectal cancer (CHARTA) will be recruited. Patients previously untreated for metastatic disease with either synchronous or metachronous metastases are randomly assigned in a 1:1 ratio to resection of colorectal liver metastases followed by postoperative FOLFOX for 6 months or perioperative FOLFOXIRI and bevacizumab for 3 months pre- and postoperative and resection (PERIMAX), or to induction chemotherapy with FOLFOX and bevacizumab +/− irinotecan for a maximum of 6 months followed by maintenance treatment with fluoropyrimidine and bevacizumab. The primary objective of these trials is to evaluate the feasibility and efficacy of FOLFOXIRI and bevacizumab in metastatic colorectal cancer. Primary endpoint is failure free survival rate at 18 months in the PERIMAX trial and progression free survival rate at 9 months in CHARTA. Secondary objectives include efficacy, safety and tolerability.DiscussionThe CHARTA and PERIMAX trials are designed to evaluate the benefits and limitations of a highly active four-drug regimen in distinct treatment situations of metastatic CRC. Eligible patients are classified into resectable liver metastases to be randomized to perioperative treatment with FOLFOXIRI and bevacizumab or postoperative FOLFOX in the PERIMAX, or unresectable metastatic CRC to be randomized between FOLFOX and bevacizumab with or without irinotecan, stratified for clinical groups according to disease and patients’ characteristics in the CHARTA trial.Trial registrationClinical trial identifier CHARTA: NCT01321957, PERIMAX: NCT01540435