Treatment of a broncho-esophageal fistula complicated by severe ARDS.

INTRODUCTION: Broncho-esophageal fistula formation is a rare complication of tuberculosis, most often seen in immunocompromised patients. METHODS AND RESULTS: In this paper, we report the case of a young non-immunocompromised refugee from Somalia diagnosed with open pulmonary tuberculosis complicated by extensive osseous involvement and a broncho-esophageal fistula with consecutive aspiration of gastric contents. The patient rapidly developed a severe acute respiratory distress syndrome (ARDS) requiring venovenous extracorporeal membrane oxygenation (ECMO) therapy for nearly 2 months. The fistula was initially treated by standard antituberculous combination therapy and implantation of an esophageal and a bronchial stent. Long-term antibiotic treatment was instituted for pneumonia and mediastinitis. 7 months later, discontinuity resection of the esophagus was performed and the bronchial fistula covered by an intercostal muscle flap. DISCUSSION: This case illustrates that tuberculosis should always be suspected in patients from high-incidence countries in case of lung involvement and that an interdisciplinary approach including long-term intensive care management can enable successful treatment of tuberculosis with severe, near-fatal complications.

[Surgical strategy in multimodal treatment of gastric and esophageal cancer]. / Chirurgische Strategie in der multimodalen Behandlung des Magen- und Ösophaguskarzinoms.

The majority of curatively treatable esophageal and gastric carcinomas are currently diagnosed in a locally advanced stage in Western Europe. The vast majority of patients in Western Europe and the USA are now treated in multimodal treatment protocols. These protocols consist of neoadjuvant chemoradiation or perioperative chemotherapy plus radical surgical resection including lymphadenectomy. Radical esophagectomy and gastrectomy are still the main curative therapeutic step in these  multimodal protocols. The current surgical recommendations and guidelines were, however, based on experience and studies from almost exclusively unimodal treatment of patient groups. The validity for the patients, particularly those who undergo multimodal treatment, therefore urgently needs to be reviewed. In particular, there are results and indirect indications from recent studies that show a difference between unimodal surgical therapy and multimodal therapy in the efficacy of radical lymphadenectomy on the oncological results. Against the background of these studies, the question arises whether it is possible to adapt surgical resection to the multimodal overall concept under the influence of the additional therapeutic modalities. Future prospective randomized surgical trials should have a tailor-made adaptation to the multimodal therapy concepts concerning primary tumor and locoregional tumor compartments. The different histological tumor entities of the upper gastrointestinal tract must also be included.

Perioperative platin-based chemotherapy for locally advanced esophagogastric adenocarcinoma: Postoperative chemotherapy has a substantial impact on outcome.

BACKGROUND: A combination of platin-based perioperative chemotherapy (PBPC) plus surgical resection has become the standard of care in Europe for locally advanced esophagogastric adenocarcinoma (EGAC). In contrast to preoperative chemotherapy, the postoperative administration of chemotherapy is omitted in a high percentage of patients. We conducted this database study to analyse the impact of postoperative completion of perioperative chemotherapy on patient outcome. METHODS: Patients with EGAC (cT3-4 and/or cN+) were treated with preoperative PBPC plus curative surgical resection. Patient demographics, postoperative tumour stages, histopathological regression (HPR) and administration of postoperative chemotherapy were correlated with overall survival. RESULTS: Of one-hundred-thirty-four patients, 76 received preoperative docetaxel, folinic acid, fluorouracil, oxaliplatin (FLOT), 53 patients epirubicin, cisplatin, folinic acid (ECF) and 5 epirubicin, oxaliplatin, capecitabine (EOX) chemotherapy. The 5-year-survival for the whole collective was 58%. Designated postoperative chemotherapy was omitted in 36% of the patients. 5-year-survival was 75.8% in patients who received pre- and post-operative chemotherapy and 40.3% in patients with only preoperative chemotherapy (p < 0.001). Histopathological regression, postoperative nodal status and administration of postoperative chemotherapy were identified as independent prognostic factors. Analysis of subgroups revealed a pronounced survival benefit after administration of postoperative chemotherapy in patients with ypN+ stages (5-year-survival 64.5% vs 9.7%, p = 0.002) and poor HPR (5-year-survival 55.5% vs 19.3%, p = 0.015). CONCLUSION: Our study provides further evidence that administration of postoperative chemotherapy may contribute to the achieved survival benefit of PBPC in patients with EGAC and implies a beneficial effect especially in presence of lymphonodular tumour involvement and limited HPR.

[Surgical treatment of esophageal cancer : Evolution of management and prognosis over the last 3 decades]. / Chirurgische Therapie des Ösophaguskarzinoms : Entwicklung von Management und Prognose über die letzten drei Jahrzehnte.

BACKGROUND: An increasing incidence of adenocarcinoma, a modified surgical strategy and the increasing use of multimodal therapeutic protocols have had a major impact on the surgical treatment of esophageal cancer during the last 3 decades. OBJECTIVES: This study analyzed the development of these factors and their impact on the short and long-term prognosis of esophageal cancer over the last 25 years. PATIENTS AND METHODS: The study included 366 patients with esophageal cancer treated by esophagectomy at the University Hospital in Freiburg from 1988 to 2012. The study period was split into four time periods for further comparisons, i.e. 1988-1994, 1995-2001, 2001-2006 and 2007-2012. RESULTS: Within the time periods analyzed a marked increase in adenocarcinoma was found (time periods1988-1994, 1995-2001, 2001-2006 and 2007-2012: 21%, 37%, 61% and 64%, respectively, p<0.001). The initially commonly used transhiatal approach and reconstruction with cervical anastomosis was gradually replaced by the thoracoabdominal procedure with intrathoracic reconstruction (i.e. Ivor Lewis esophagectomy, 2007-2012: 98 %). During the study period increasingly more patients received multimodal therapy (13%, 85%, 72% and 84%, p<0.001), the overall rate of perioperative complications (70%, 88%, 73% and 56%, p<0.001) and perioperative mortality (16%, 18%, 8% and 2.5%, p<0.001) were significantly reduced, while the overall 5-year survival (12%, 34%, 41% and 62%, p<0.001) improved. An early tumor stage (p=0.002), N0 status (p<0.001) and histological type of adenocarcinoma (p=0.011) were identified as independent predictors of improved survival. CONCLUSION: During the period from 1988 to 2012 a significant improvement of long-term survival as well as a marked reduction of perioperative mortality after esophagectomy were observed. The improved outcome was associated with an increased use of multimodal therapeutic protocols, the preferred use of thoracoabdominal esophagectomy and epidemiological changes in histology over the study period.

Cancer cell invasion and EMT marker expression: a three-dimensional study of the human cancer-host interface.

Cancer cell invasion takes place at the cancer-host interface and is a prerequisite for distant metastasis. The relationships between current biological and clinical concepts such as cell migration modes, tumour budding and epithelial-mesenchymal transition (EMT) remains unclear in several aspects, especially for the 'real' situation in human cancer. We developed a novel method that provides exact three-dimensional (3D) information on both microscopic morphology and gene expression, over a virtually unlimited spatial range, by reconstruction from serial immunostained tissue slices. Quantitative 3D assessment of tumour budding at the cancer-host interface in human pancreatic, colorectal, lung and breast adenocarcinoma suggests collective cell migration as the mechanism of cancer cell invasion, while single cancer cell migration seems to be virtually absent. Budding tumour cells display a shift towards spindle-like as well as a rounded morphology. This is associated with decreased E-cadherin staining intensity and a shift from membranous to cytoplasmic staining, as well as increased nuclear ZEB1 expression.

[Hybrid laparoscopic thoracotomic esophagectomy with intrathoracic esophagogastric anastomosis]. / Laparoskopisch-thorakotomische Ösophagusresektion mit intrathorakaler Ösophagogastrostomie als Hybridverfahren.

INTRODUCTION: In the past decades various techniques of esophagectomy for the curative treatment of esophageal cancer have been described. Especially minimally invasive techniques of esophagectomy have been used increasingly in the last decade. Technical issues and results of hybrid laparoscopic-thoracotomic en bloc esophagectomy with intrathoracic esophagogastric anastomosis (HMIE) are presented and discussed in the article. PATIENTS AND METHODS: Between May 2013 and April 2014 a total of 23 patients underwent esophagectomy for esophageal cancer at the University of Freiburg Medical Center. Of these patients 10 were treated by HMIE and the other 13 patients had open esophagectomy (OE). RESULTS: A detailed description of the operative technique of HMIE is given in a step-by-step fashion. Margin negative resection was achieved in all patients after HMIE and OE and the median lymph node yield of lymphadenectomy in HMIE and OE (29 vs. 27) was nearly the same. The medium duration of the operation (347 min vs. 412 min) and median length of stay on the intensive care unit (6 days vs. 9 days) and hospital (13 days vs. 17 days) were decreased in HMIE patients compared to OE, respectively. Overall postoperative morbidity (40 % vs. 69 %) and especially pulmonary morbidity (10 % vs. 46 %) were also favorable in HMIE. No anastomotic leakage and postoperative in-hospital mortality occurred after HMIE. CONCLUSION: The HMIE procedure combines the advantages of minimally invasive operative approaches on especially postoperative pulmonary morbidity after esophagectomy with the high safety of anastomosis and reconstruction achieved in OE. Further advantages are shorter duration of operation and shorter length of hospital stay in HMIE.

[Laparoscopic total gastrectomy with extended lymphadenectomy and intracorporal circular stapled esophagojejunostomy]. / Die total-laparoskopische Gastrektomie mit D2-Lymphadenektomie und intrakorporaler Ösophagojejunostomie in zirkulärer Staplertechnik.

Laparoscopic total gastrectomy for early and advanced gastric cancer is an exacting procedure which is increasingly performed in specialised institutions. Not only gastric resection and extended lymphadenectomy but especially the reconstruction by oesophagojejunostomy is a technically demanding and vulnerable operative step. In this article we present our laparoscopic technique of total gastrectomy with extended lymphadenectomy and complete intracorporal reconstruction by end-to-side circular stapled oesophagojejunostomy. The operative technique of the gastric resection, the extended lymphadenectomy and the reconstruction are described in detail in a step-by-step approach and demonstrated in a supplemental video.

Postpancreatectomy hemorrhage--incidence, treatment, and risk factors in over 1,000 pancreatic resections.

BACKGROUND: Postpancreatectomy hemorrhage is a rare but often severe complication after pancreatic resection. The aim of this retrospective study was to define incidence and risk factors of postpancreatectomy hemorrhage and to evaluate treatment options and outcome. PATIENTS AND METHODS: Clinical data was extracted from a prospectively maintained database. Descriptive statistics, univariate and multivariate risk factor analysis by binary logistic regression were performed with SPSS software at a significance level of p = 0.05. RESULTS: N = 1,082 patients with pancreatic resections between 1994 and 2012 were included. Interventional angiography was successful in about half of extraluminal bleeding. A total of 78 patients (7.2 %) had postpancreatectomy hemorrhage (PPH), and 29 (2.7 %) were grade C PPH. Multivariate modeling disclosed a learning effect, age, BMI, male sex, intraoperative transfusion, portal venous and multivisceral resection, pancreatic fistula and preoperative biliary drainage as independent predictors of severe postpancreatectomy hemorrhage. High-risk histopathology, age, transfusion, pancreatic fistula, postpancreatectomy hemorrhage and pancreatojejunostomy in pancreatoduodenectomies were independent predictors of mortality. CONCLUSIONS: Our study identifies clinically relevant risk factors for postpancreatectomy hemorrhage and mortality. Interventional treatment of extraluminal hemorrhage is successful in about half of the cases and if unsuccessful constitutes a valuable adjunct to operative hemostasis. Based on our observations, we propose a treatment scheme for PPH. Risk factor analysis suggests appropriate patient selection especially for extended resections and pancreatogastrostomy for reconstruction in pancreatoduodenectomy.

Pitfalls and technical aspects during the research of intestinal anastomotic healing in rats.

BACKGROUND: Fundamental experimental research into intestinal anastomotic healing in rodent models will gain increasing interest in the future. METHODS: The aim of this study was to describe our 5-year experience with a standardized experimental setup of small and large bowel anastomoses in a rodent model and present a basic set of assessment tools investigating anastomotic healing. Anastomotic technique, perioperative complications such as anastomotic insufficiency (AI) and obstructive ileus were in the focus. RESULTS: During different studies with varying study patterns, 167 rat small bowel anastomoses and 120 colonic anastomoses were performed. Overall mortality was 3.6% in small bowel and 2.5% in colonic anastomoses, AI occurred in 2.9 and 4%, respectively. A postoperative obstructive ileus was seen in 3/167 small bowel anastomoses and none in the colonic group. CONCLUSION: When performing experimental intestinal anastomoses in a standardized operative setting and critically considering special perioperative issues, the incidence of relevant complications can be maintained at an adequately low level.

Reinforcement of colonic anastomoses with a collagenous double-layer matrix extracted from porcine dermis.

BACKGROUND: Anastomotic leakage is a major factor for morbidity in colorectal surgery. Anastomotic reinforcement with biological or synthetic materials has been claimed to be useful in preventing anastomotic leakage. METHODS: We evaluated a non-cross-linked collagenous matrix Bio-Gide (BG) for sealing colonic anastomoses in a rodent model. The animals were investigated for 4, 30 and 90 days. Macroscopic examination, histological examination and measurement of bursting pressure were performed. The anastomotic stricture rate was evaluated by radiographic contrast enema. RESULTS: Microscopically anastomoses sealed by BG showed impaired anastomotic healing. Blood vessel ingrowth and collagen deposition were decreased without reaching significance after 4 days. The anastomotic bursting pressure was significantly decreased (p = 0.0454) in the early phase of healing. Anastomotic neovascularization was significantly decreased compared to the control group after 30 (p = 0.0058) and 90 days (p = 0.0275). Although no difference in anastomotic stricture rate was evident, the rate of intra-abdominal adhesions was significantly increased after 30 (p = 0.0124) and 90 days (p = 0.0281). CONCLUSION: BG failed to improve colonic anastomotic healing. Early anastomotic healing was impaired if anastomoses were reinforced with BG. BG did not affect the anastomotic stricture rate for up to 3 months; nevertheless, intra-abdominal adhesions were increased.

Modulation of motorcortical excitability by methylphenidate in adult voluntary test persons performing a go/nogo task.

This study investigated the interaction between motorcortical excitability (short interval cortical inhibition, intracortical facilitation and long interval cortical inhibition), different requirement conditions [choice reaction test (CRT), attention/go/nogo], and their pharmacological modulation by methylphenidate (MPH) in normal healthy adults (n = 31) using a transcranial magnetic stimulation paradigm. MPH was administered in a dosage of 1 mg/kg body weight, maximum 60 mg. Additionally, serum level and clearance of MPH were controlled. The statistical analysis of variance revealed a significant three-way interaction of 2 (MPH) x 3 (CRT) x 6 (ISI) predicting motor evoked potential amplitudes (P = 0.032, MPH none and full dose, n = 31). In order to compare effects of dosage an additional between-subjects factor (half vs. full MPH dose) was introduced. None of the interactions involving this between-subject factor reached statistical significance. Exploring interactions with MPH only, a 3 (MPH none, half and full dose) x 3 (CRT) x 6 (ISI) analysis of variance revealed significant two-way interactions for MPH x ISI (P = 0.040) and condition x ISI (P < 0.001, n = 18). Effects observed for MPH were strongest on facilitatory processes, weaker for intracortical inhibition. In sum, MPH seems to interact via striato-thalamo-cortical pathways with original motorcortical processes (ISI), to a lesser extent with task-dependent or behavioral parameters (CRT).

Modulation of transcallosally mediated motor inhibition in children with attention deficit hyperactivity disorder (ADHD) by medication with methylphenidate (MPH).

Motor hyperactivity is one of the most outstanding symptoms of attention deficit hyperactivity disorder (ADHD) which might be caused by a disturbed inhibitory motor control. Using focal transcranial magnetic stimulation (TMS) we tested the cortico-callosal inhibition (duration and latency of the ipsilateral Silent Period, iSP) in 23 children with ADHD (mean age 11+/-2.6 years) before and on treatment with methylphenidate (MPH). iSP latency was age correlated, whereas iSP duration as well as Conners scores were age independent. Analyses of mean differences revealed a significant prolongation of iSP duration (p=0.001), shortening of iSP latency (p=0.027) and reduction of Conners score (p=0.001) under medication. Increase of iSP duration and reduction of Conners score under medication were significantly correlated (t=-9.87, p=0.016). Reduced iSP duration and prolonged iSP latency in ADHD children could be the result of a disturbed transcallosally mediated inhibition, most probable due to a combination of maturation deficits of callosal fiber tracts as well as neuronal synaptical transmission within the neuronal network between ipsilaterally stimulated cortex layer III--the origin of transcallosal motor-cortical fibers--and contralateral layer V, the origin of the pyramidal tract. MPH may indirectly improve the dysbalance between excitatory and inhibitory interneuronal activities of this neuronal network via dopaminergic modulatory effects of the striato-thalamo-cortical loop.

Language outcome following multiple subpial transection for Landau-Kleffner syndrome.

Landau-Kleffner syndrome is an acquired epileptic aphasia occurring in normal children who lose previously acquired speech and language abilities. Although some children recover some of these abilities, many children with Landau-Kleffner syndrome have significant language impairments that persist. Multiple subpial transection is a surgical technique that has been proposed as an appropriate treatment for Landau-Kleffner syndrome in that it is designed to eliminate the capacity of cortical tissue to generate seizures or subclinical epileptiform activity, while preserving the cortical functions subserved by that tissue. We report on the speech and language outcome of 14 children who underwent multiple subpial transection for treatment of Landau-Kleffner syndrome. Eleven children demonstrated significant postoperative improvement on measures of receptive or expressive vocabulary. Results indicate that early diagnosis and treatment optimize outcome, and that gains in language function are most likely to be seen years, rather than months, after surgery. Since an appropriate control group was not available, and that the best predictor of postoperative improvements in language function was that of length of time since surgery, these data might best be used as a benchmark against other Landau-Kleffner syndrome outcome studies. We conclude that multiple subpial transection may be useful in allowing for a restoration of speech and language abilities in children diagnosed with Landau-Kleffner syndrome.

Task-dependent modulation of inhibitory actions within the primary motor cortex.

In 11 healthy subjects motor-evoked potentials (MEPs) and silent periods (SPs) were measured in the right first dorsal interosseus (FDI) and abductor pollicis brevis muscles (APB): (1) when transcranial magnetic cortex stimulation (TMS) was applied at tonic isometric contraction of 20% of maximum force, (2) when TMS was applied during tactile exploration of a small object in the hand, (3) when TMS was applied during visually guided goal-directed isometric ramp and hold finger flexion movements, and (4) when at tonic isometric contraction peripheral electrical stimulation (PES) of the median nerve was delivered at various intervals between PES and TMS. Of the natural motor tasks, duration of SPs of small hand muscles was longest during tactile exploration (APB 205+/-42 ms; FDI 213+/-47 ms). SP duration at tonic isometric contraction amounted to 172+/-35 ms in APB and 178+/-31 ms in FDI, respectively. SP duration in FDI was shortest when elicited during visually guided isometric finger movements (159+/-15 ms). At tonic isometric contraction, SP was shortened when PES was applied at latencies -30 to +70 ms in conjunction with TMS. The latter effect was most pronounced when PES was applied 20 ms before TMS. PES-induced effects increased with increasing stimulation strength up to a saturation level which appeared at the transition to painful stimulation strengths. Both isolated stimulation of muscle afferents and of low-threshold cutaneous afferents shortened SP duration. However, PES of the contralateral median nerve had no effect on SPs. Amplitudes of MEPs did not change significantly in any condition. Inhibitory control of motor output circuitries seems to be distinctly modulated by peripheral somatosensory and visual afferent information. We conclude that somatosensory information has privileged access to inhibitory interneuronal circuits within the primary motor cortex.

Evaluating medication response in ADHD: cognitive, behavioral, and single-subject methodology.

Although evidence supports the use of double-blind placebo medication trials to evaluate methylphenidate (MPH) effects on the core behavioral symptoms of attention-deficit/hyperactivity disorder (ADHD), few studies have demonstrated their utility in examining MPH effects on the cognitive deficits associated with ADHD. This article presents a technique for evaluating behavioral and cognitive dose-response relationships at the single-subject level of analysis. Case study results and multivariate analyses suggest that systematic evaluation of behavioral and cognitive MPH dose-response relationships could lead to more accurate MPH titration and greater long-term multimodal treatment efficacy.

Developmental changes of parental-reported sleep disturbance symptoms in children with attention deficit disorder.

The primary goal of this retrospective study was to assess parental report of current sleep disorders in school-aged attention deficit disorder (ADD) children, as well as recalled sleep problems from when the children were infants (0-12 months) and toddlers (1-3 years). Results of a sleep questionnaire completed by mothers of 48 ADD children and a comparison group of 30 patients with school problems indicate that ADD children were perceived to have significantly more sleep problems and that these problems had onset in infancy. Specific items in the questionnaire which were increased included latency to sleep onset of more than 30 min at least 3 nights per week, fatigue upon awakening, and recall of nightmares. Pediatric clinicians should be alert to possible sleep disorders in children suspected of attention disorders and should consider "sleep hygiene" measures as a component of treatment.

Mismatch negativity in the neurophysiologic/behavioral evaluation of auditory processing deficits: a case study.

The subject of this case report is an 18-year-old woman with grossly abnormal auditory brain stem response (ABR), normal peripheral hearing, and specific behavioral auditory processing deficits. Auditory middle latency responses (MLRs) and cortical potentials N1, P2, and P300 were intact. The mismatch negativity (MMN) was normal in response to certain synthesized speech stimuli and impaired to others--consistent with her behavioral discrimination of these stimuli. Behavioral tests of auditory processing were consistent with auditory brain stem dysfunction. A neuropsychological evaluation revealed normal intellectual and academic performance. The subject was in her first year of college at the time of the evaluation. This case study is important because: (1) Although there have been several reports of absent/abnormal ABR with preserved peripheral hearing and deficits in auditory processing, little is known about the specific nature of the auditory deficits experienced by these individuals. Such information may be valuable to the clinical management of patients with this constellation of findings. (2) Of interest is the information that the mismatch negativity (MMN) cortical event-related potential can bring to the evaluation of patients with auditory processing deficits. The MMN reflects central auditory processing of small acoustic differences and may provide an objective measure of auditory discrimination. (3) From a theorectical standpoint, a patient with neural deficits affecting specific components of the auditory pathway provides insight into the relationship between evoked potentials and physiological mechanisms of auditory processing. How do various components of the auditory pathway contribute to speech discrimination? How might evoked potentials reflect the processes underlying the neural coding of specific features of speech stimuli such as timing and spectral cues?

The go-no go test in attention deficit disorder is sensitive to methylphenidate.

The go-no go test requires a subject to emit a simple motor response to one cue while inhibiting the response in the presence of another cue. This test has been effective in demonstrating impulsivity (elevated commission error rate) in children with attention deficit disorder (ADD). In this study, we examined the effects on go-no go test performance of two doses of methylphenidate (0.15 mg/kg and 0.3 mg/kg) administered in double-blind placebo-controlled fashion to children with ADD. Our results indicate that even modest doses of methylphenidate improve the go-no go performance of these children by decreasing their tendency to make impulsive commission errors. Thus the test is sensitive to the effects of methylphenidate and can be used to monitor a response to therapy.

Pitfalls in the use of a continuous performance test as a diagnostic tool in attention deficit disorder.

Although automated continuous performance tests (CPT) are gaining popularity as aids to the diagnosis of attention deficit disorder (ADD), little is known of their validity in this context. Our preliminary experience with a commercially available visual CPT indicated that as many as a third of children meeting the DMS-III criteria for ADD may score well enough on this measure to escape detection. We therefore analyzed the results of neuropsychological testing as well as CPT performance in 14 ADD children and six non-ADD children in an effort to determine whether CPT performance might reflect higher level cognitive variables other than attention and/or impulsivity. We found that those ADD children classified as "abnormal" on the basis of the CPT scored significantly below those classified as "normal" on measures of abstract reasoning and logical problem solving, simple verbal reasoning, nonverbal problem solving, and simple arithmetic skills. The non-ADD group contained a high proportion (83%) of subjects with CPT performance outside of the normal range. These data suggest that CPT may yield both false negative and false positive results when used as screening tools for ADD, and we recommend therefore that caution be used in their interpretation.