Impact of encorafenib on survival of patients with BRAFV600E-mutant metastatic colorectal cancer in a real-world setting.

PURPOSE: Patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC) have a dismal prognosis. The best strategies in these patients remain elusive. Against this background, we report the clinical course of patients with BRAFV600E-mutant mCRC to retrieve the best treatment strategy. PATIENTS AND METHODS: Clinico-pathological data were extracted from the electronic health records. Kaplan-Meier method was used to estimate overall (OS) and progression-free survival (PFS). Objective response rate (ORR) was assessed according to RECIST 1.1. RESULTS: In total, 51 patients were enrolled. FOLFOXIRI was administered to 12 patients; 29 patients received FOLFOX or FOLFIRI as first-line treatment. Median OS was 17.6 months. Median PFS with FOLFOXIRI (13.0 months) was significantly prolonged (HR 0.325) as compared to FOLFOX/FOLFIRI (4.3 months). However, this failed to translate into an OS benefit (p = 0.433). Interestingly, addition of a monoclonal antibody to chemotherapy associated with superior OS (HR 0.523). A total of 64.7% patients received further-line therapy, which included a BRAF inhibitor in 17 patients. Targeted therapy associated with very favourable OS (25.1 months). CONCLUSION: Patients with BRAFV600E-mutated mCRC benefit from the addition of an antibody to first-line chemotherapy. Further-line treatment including a BRAF inhibitor has a dramatic impact on survival.

Smaller panel, similar results: genomic profiling and molecularly informed therapy in pancreatic cancer.

BACKGROUND: Pancreatic cancer has a dismal prognosis. One reason is resistance to cytotoxic drugs. Molecularly matched therapies might overcome this resistance but the best approach to identify those patients who may benefit is unknown. Therefore, we sought to evaluate a molecularly guided treatment approach. MATERIALS AND METHODS: We retrospectively analyzed the clinical outcome and mutational status of patients with pancreatic cancer who received molecular profiling at the West German Cancer Center Essen from 2016 to 2021. We carried out a 47-gene DNA next-generation sequencing (NGS) panel. Furthermore, we assessed microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) status and, sequentially and only in case of KRAS wild-type, gene fusions via RNA-based NGS. Patient data and treatment were retrieved from the electronic medical records. RESULTS: Of 190 included patients, 171 had pancreatic ductal adenocarcinoma (90%). One hundred and three patients had stage IV pancreatic cancer at diagnosis (54%). MMR analysis in 94 patients (94/190, 49.5%) identified 3 patients with dMMR (3/94, 3.2%). Notably, we identified 32 patients with KRAS wild-type status (16.8%). To identify driver alterations in these patients, we conducted an RNA-based fusion assay on 13 assessable samples and identified 5 potentially actionable fusions (5/13, 38.5%). Overall, we identified 34 patients with potentially actionable alterations (34/190, 17.9%). Of these 34 patients, 10 patients (10/34, 29.4%) finally received at least one molecularly targeted treatment and 4 patients had an exceptional response (>9 months on treatment). CONCLUSIONS: Here, we show that a small-sized gene panel can suffice to identify relevant therapeutic options for pancreatic cancer patients. Informally comparing with previous large-scale studies, this approach yields a similar detection rate of actionable targets. We propose molecular sequencing of pancreatic cancer as standard of care to identify KRAS wild-type and rare molecular subsets for targeted treatment strategies.

Open retropubic radical prostatectomy: Still a well-established surgical technique for prostate cancer management.

INTRODUCTION: The surgical treatment options for prostate cancer have changed rapidly, given the expansion of robotics. However, open retropubic radical prostatectomy (ORP) will continue to be performed in areas with financial limitations or with limited access to robotics. The purpose of this study was to determine the long-term oncological outcomes, to categorize complication rates and to examine the early continence rates in patients treated with ORP. METHODS: We identified all patients who underwent ORP at our institution between 2000 and 2020. A standardized pad test was used to determine the early continence rates upon catheter removal, the late continence around a year after surgery was determined by the number of pads per day. The Clavien-Dindo classification was used to report the complication rates. The biochemical recurrence (BCR)-free survival and overall survival (OS) rates were defined using the Kaplan-Meier method and log-rank analysis. Multivariable Cox-regression models were used to test the effect of different factors on biochemical recurrence. RESULTS: We analyzed 1095 patients. The median follow-up was 93.4 months. An overall 10-year BCR-free survival and OS of 73% and 82% respectively was found. A complication rate for Clavien Dindo≥3 was seen in 4.8% of patients. The early continence rate was 81.4% and the late continence 89,1%. Preoperative PSA level, Gleason score sum, pT stage, lymph node status, and surgical margin status were independent predictors of BCR (p<0.001, 95% CI). Limitations include retrospective and single center study design. CONCLUSIONS: ORP is a surgical procedure that provides excellent oncological- and early continence-rates.

A prognostic systemic inflammation score (SIS) in patients with advanced intrahepatic cholangiocarcinoma.

PURPOSE: Systemic-inflammatory response parameters (SIR) are known prognostic markers in different tumour entities, but have not been evaluated in patients with iCCA treated with systemic chemotherapy. Therefore, we evaluated the impact of different SIR markers on the clinical course of patients with advanced iCCA treated at our center. METHODS: SIR markers were retrospectively evaluated in 219 patients with iCCA at the West-German-Cancer-Center Essen from 2014 to 2019. Markers included neutrophil/lymphocyte ratio (NLR), lymphocyte/monocyte ratio (LMR), CRP, and the modified Glasgow-Prognostic-Score (mGPS), which were correlated with clinico-pathological findings, response to chemotherapy (ORR), progression-free (PFS) and overall survival (OS) using Kaplan-Meier analyses, and Cox proportional models. RESULTS: Median overall survival (OS) of the entire cohort was 14.8 months (95% CI 11.2-24.4). Median disease-free survival (DFS) in 81 patients undergoing resection was 12.3 months (95% CI 9.7-23.1). The median OS from start of palliative CTX (OSpall) was 10.9 months (95% 9.4-14.6). A combined Systemic Inflammatory Score (SIS) comprising all evaluated SIR markers correlated significantly with ORR, PFS, and OSpall. Patients with a high SIS (≥ 2) vs. SIS 0 had a significantly inferior OSpall (HR 8.7 95% CI 3.71-20.38, p < 0.001). Multivariate analysis including known prognostic markers (ECOG, CA19-9, LDH, and N- and M-status) identified the SIS as an independent prognostic factor. CONCLUSIONS: Inflammatory markers associate with inferior survival outcomes in patients with iCCA. A simple SIS may guide treatment decisions in patients treated with systemic chemotherapy.

Multimodal survival prediction in advanced pancreatic cancer using machine learning.

BACKGROUND: Existing risk scores appear insufficient to assess the individual survival risk of patients with advanced pancreatic ductal adenocarcinoma (PDAC) and do not take advantage of the variety of parameters that are collected during clinical care. METHODS: In this retrospective study, we built a random survival forest model from clinical data of 203 patients with advanced PDAC. The parameters were assessed before initiation of systemic treatment and included age, CA19-9, C-reactive protein, metastatic status, neutrophil-to-lymphocyte ratio and total serum protein level. Separate models including imaging and molecular parameters were built for subgroups. RESULTS: Over the entire cohort, a model based on clinical parameters achieved a c-index of 0.71. Our approach outperformed the American Joint Committee on Cancer (AJCC) staging system and the modified Glasgow Prognostic Score (mGPS) in the identification of high- and low-risk subgroups. Inclusion of the KRAS p.G12D mutational status could further improve the prediction, whereas radiomics data of the primary tumor only showed little benefit. In an external validation cohort of PDAC patients with liver metastases, our model achieved a c-index of 0.67 (mGPS: 0.59). CONCLUSIONS: The combination of multimodal data and machine-learning algorithms holds potential for personalized prognostication in advanced PDAC already at diagnosis.

Combined systemic inflammation score (SIS) correlates with prognosis in patients with advanced pancreatic cancer receiving palliative chemotherapy.

PURPOSE: The prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) remains dismal. New cytotoxic agents such as nab-paclitaxel and liposomal irinotecan (nal-Iri) have extended the armamentarium of therapeutic options in the last years. Nowadays, sequential therapeutic strategies with moderately toxic chemotherapeutic protocols can be administered to the patients. However, prognostic and predictive biomarkers are still missing to identify those patients, which profit most from a "continuum of care" concept rather than receiving intensive first-line protocols such as FOLFIRINOX. To this end, we retrospectively evaluated the impact of the systemic inflammation as one essential hallmark of cancer in patients with advanced PDAC treated with sequential systemic. METHODS: A cohort of 193 PDAC patients treated at our center from January 2005 to August 2011 were retrospectively evaluated for the following systemic inflammatory response (SIR) markers: neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR) C-reactive protein (CRP), and the modified Glasgow Prognostic Score (mGPS). SIR markers were correlated with clinico-pathological findings, response to chemotherapy and overall survival (OS) using Kaplan-Meier curves and Cox proportional models. RESULTS: All evaluated SIR markers were significantly associated with OS in patients with metastatic disease but not in patients with locally advanced PDAC. Interestingly, all SIR markers were only prognostic in patients not receiving antibiotics as surrogate marker for systemic bacterial infections. Based on the evaluated SIR markers, we propose a new Systemic Inflammation Score (SIS), which significantly correlated with reduced OS (HR: 3.418 (1.802-6.488, p < 0.001)) and the likelihood of receiving further-line systemic therapies (p = 0.028). CONCLUSION: Routinely assessed SIR biomarkers have potential to support therapeutic decision making in patients with metastatic PDAC.

Interdisciplinary consensus on indications for transfemoral transcatheter aortic valve implantation (TF-TAVI) : Joint Consensus Document of the Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte e.V. (ALKK) and cooperating Cardiac Surgery Departments.

Indications for TF-TAVI (transfemoral transcatheter aortic valve implantation) are rapidly changing according to increasing evidence from randomized controlled trials. Present trials document the non-inferiority or even superiority of TF-TAVI in intermediate-risk patients (STS-Score 4-8%) as well as in low-risk patients (STS-Score < 4%). However, risk scores exhibit limitations and, as a single criterion, are unable to establish an appropriate indication of TF-TAVI vs transapical TAVI vs SAVR (surgical aortic valve replacement). The ESC (European Society of Cardiology)/EACTS (European Association for Cardio-Thoracic Surgery) guidelines 2017 and the German DGK (Deutsche Gesellschaft für Kardiologie)/DGTHG (Deutsche Gesellschaft für Thorax-, Herz- und Gefäßchirurgie) commentary 2018 offer a framework for the selection of the best therapeutic method, but the individual decision is left to the discretion of the heart teams. An interdisciplinary TAVI consensus group of interventional cardiologists of the ALKK (Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte e.V.) and cardiac surgeons has developed a detailed consensus on the indications for TF-TAVI to provide an up-to-date, evidence-based, comprehensive decision matrix for daily practice. The matrix of indication criteria includes age, risk scores, contraindications against SAVR (e.g., porcelain aorta), cardiovascular criteria pro TAVI, additional criteria pro TAVI (e.g., frailty, comorbidities, organ dysfunction), contraindications against TAVI (e.g., endocarditis) and cardiovascular criteria pro SAVR (e.g., bicuspid valve anatomy). This interdisciplinary consensus may provide orientation to heart teams for individual TAVI-indication decisions. Future adaptations according to evolving medical evidence are to be expected. Interdisciplinary consensus on indications for transfemoral transcatheter aortic valve implantation (TF-TAVI).

The German CPU registry: Comparison of smokers and nonsmokers.

BACKGROUND: Chest pain is a major reason for admission to an internal emergency department, and smoking is a well-known risk factor for coronary artery disease (CAD) and acute coronary syndrome (ACS). The aim of this analysis is to illustrate the differences between smokers and nonsmokers presenting to German chest pain units (CPU) in regard to patient characteristics, CAD manifestation, treatment strategy, and prognosis. METHODS: From December 2008 to March 2014, 13,902 patients who had a complete 3­month follow-up were enrolled in the German CPU registry. The analysis comprised 5796 patients with ACS and documented smoking status. RESULTS: Of all the patients in the CPU registry, 35.2% were smokers. Compared with nonsmokers, they were 13.5 years younger (58.2 vs. 71.7 years, p < 0.001), predominantly men (77.1% vs. 65.2%, p < 0.001), and were more frequently diagnosed with single-vessel disease (32.1% vs. 25.2%) as well as ST-elevation myocardial infarction (STEMI; 23.8% vs. 15.5%, p < 0.001). Although the Global Registry of Acute Coronary Events (GRACE) Risk Score for hospital mortality was lower in the group of smokers (106.1 vs. 123.3, p < 0.001), we did not observe any differences in CPU death (0.4% vs. 0.4%, p = 0.69) and CPU major adverse cardiac event (MACE) rates (3.8% vs 2.9%, p = 0.073) between the groups. In the 3­month follow-up, we documented higher mortality rates in the nonsmoker group (1.9% vs. 2.9%, p = 0.035) in correlation with the GRACE Risk Score (80.3 vs. 105.2, p < 0.001). MACE rates were similar during the follow-up (3.1% vs. 4.1%, p = 0.065). CONCLUSION: Observations from the German CPU registry demonstrate that smoking is a strong predictor of acute CAD manifestation early in life, especially STEMI. In spite of a lower GRACE Risk Score and fewer comorbidities, smokers had a rate of hospital mortality similar to the older group of nonsmokers.

Long-term outcome of patients with advanced pancreatic cancer treated with sequential chemotherapies before the era of modern combination therapy protocols.

INTRODUCTION: Patients (pts) with locally advanced (LAPC) or metastatic pancreatic ductal adenocarcinoma (mPDAC) have a dismal prognosis. Recently, new combination chemotherapies such as FOLFIRINOX and nab-paclitaxel/gemcitabine have demonstrated superiority over gemcitabine monotherapy. However, a substantial proportion of pts cannot tolerate these intensive front-line protocols. Moreover, the long-term superiority of multiagent protocols over less intensive strategies remains to be shown. To provide a benchmark for future studies, we analyzed the outcome of patients with LAPC or mPDAC treated at the West German Cancer Center before the FOLFIRINOX/nab-paclitaxel + gemcitabine era. METHODS: This retrospective analysis included 201 consecutive pts with LAPC and mPDAC treated between 2007 and 2011. Efficacy parameters were correlated with type of chemotherapy, number of treatment lines and clinicopathological parameters. RESULTS: Gemcitabine monotherapy was given as first-line therapy in 51.1%, whereas 48.9% received combination chemotherapies such as gemcitabine/oxaliplatin or FOLFOX. Patients received a median of two lines of treatment, with 54.8% receiving second-line and 37.9% receiving third- and further-line therapies. There was no significant difference between gemcitabine monotherapy and combination therapies. Despite moderate activity of first-line treatment, median overall survival for LAPC was 11.3 months and 8.7 months for mPDAC. Multivariate analysis identified age and number of treatment lines as prognostic markers. CONCLUSION: The long-term outcome of unselected pts with LAPC and mPDAC treated before the introduction of aggressive multiagent chemotherapy protocols compares favorably with the results of contemporary benchmark trials. This suggests a multifactorial benefit from interdisciplinary care provided over sequential treatment lines at high volume expert centers.

UV light-blocking contact lenses protect against short-term UVB-induced limbal stem cell niche damage and inflammation.

UVB irradiation has been linked to pathogenesis of pterygium, a conjunctival tumor growing onto transparent cornea, the windscreen of the eye. Due to corneal anatomy, ambient UVB irradiation is amplified at the stem cell-containing nasal limbus. The aim of this study was to analyse the effect of a UV-blocking contact lens (UVBCL, senofilcon A, Class 1 UV blocker) on limbal epithelial cells and fibroblasts under UVB irradiation compared to a non-UVB-blocking contact lens. UVBCL prevented UVB-induced DNA damage (as assessed by cyclobutane pyrimidine dimer immunostaining) as well as a decrease in proliferation and scratch wound closure rate of both limbal epithelial and fibroblast cells. Similarly, UVBCL protected limbal epithelial cells from UVB-induced loss of their phenotype in terms of colony forming efficiency and stem cell marker expression (ABCB5, P63α, integrin ß1) compared to controls. Moreover, with UVBCL pro-inflammatory cytokines such as TNFα and MCP1 remained unchanged. These data demonstrate the significance of UV-protection in preserving the limbal niche in response to at least short-term UVB. Our data support the use of UVBCL in protecting limbal niche cells, especially after limbal stem cell transplantation and in patients after pterygium surgery, to help prevent recurrences.

Modeling of live-birth rates and cost-effectiveness of oocyte cryopreservation for cancer patients prior to high- and low-risk gonadotoxic chemotherapy.

STUDY QUESTION: What is the live-birth rate (LBR) and cost-effectiveness of fertility preservation with oocyte cryopreservation (FP-OC) compared to expectant management in cancer patients age 25-40 based on estimated gonadotoxicity of treatments 5 years after cancer diagnosis? SUMMARY ANSWER: Oocyte cryopreservation prior to cancer treatment is more costly, yet more effective (producing more live births), than not undergoing oocyte cryopreservation but it is most beneficial for patients undergoing high-risk chemotherapy (HRC). WHAT IS KNOWN ALREADY: The decision to undergo FP prior to treatment is multifactorial and can be costly and delay treatment. Not all treatments carry the same gonadotoxicity and patients may choose to undergo FP-OC based on the probability of premature ovarian insufficiency, predicted outcomes and cost. A comprehensive model that incorporates age at diagnosis and toxicity of treatment to help guide patients in the decision to undergo FP-OC does not yet exist. STUDY DESIGN, SIZE DURATION: This study used a Decision Analysis Model to estimate effectiveness and cost of FP for cancer patients. PARTICIPANTS/MATERIALS, SETTING, METHODS: Age-based estimates of LBR and cost per live birth were calculated for ages 25-40 years based on gonadotoxicity of treatment. A decision analysis model was constructed using Treeage Pro 2015 with case base probabilities derived from national registries, practice guidelines and medical records from a national network of infertility practices (IntegraMed). MAIN RESULTS AND THE ROLE OF CHANCE: Compared to no FP-OC, FP-OC improved LBRs for women of all ages undergoing either low-risk chemotherapy (LRC) or HRC; however, it was most cost effective for women undergoing LRC at older ages or HRC at younger ages. Although FP-OC results in higher LBRs, it was always more costly. Using donor oocyte IVF can be a successful alternative to autologous FP-OC. LIMITATIONS REASONS FOR CAUTION: Decision tree results reflect probabilities of certain events and are compiled from multiple reputable sources but are not directly derived from a recruited cohort of patients. Outcomes are based on United States estimates and should be interpreted in the broader context of individual patient diagnoses, treatment care plans and country of origin. WIDER IMPLICATIONS OF THE FINDINGS: The development of this analytic model will help guide practitioners in their counseling of women from age 25 to 40 years, who are considering FP-OC at the time of cancer diagnosis. It provides a realistic pathway from diagnosis to LB and accounts for the majority of costs and outcome possibilities. STUDY FUNDING/COMPETING INTEREST(s): This study was partially funded by a grant from National Institute of Health (NIH)/National Institute of Child Health and Human Development (NICHD) (R01 HD67683) to A.Z.S. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Targeting transcription-coupled nucleotide excision repair overcomes resistance in chronic lymphocytic leukemia.

Treatment resistance becomes a challenge at some point in the course of most patients with chronic lymphocytic leukemia (CLL). This applies to fludarabine-based regimens, and is also an increasing concern in the era of more targeted therapies. As cells with low-replicative activity rely on repair that triggers checkpoint-independent noncanonical pathways, we reasoned that targeting the nucleotide excision repair (NER) reaction addresses a vulnerability of CLL and might even synergize with fludarabine, which blocks the NER gap-filling step. We interrogated here especially the replication-independent transcription-coupled-NER ((TC)-NER) in prospective trial patients, primary CLL cultures, cell lines and mice. We screen selected (TC)-NER-targeting compounds as experimental (illudins) or clinically approved (trabectedin) drugs. They inflict transcription-stalling DNA lesions requiring TC-NER either for their removal (illudins) or for generation of lethal strand breaks (trabectedin). Genetically defined systems of NER deficiency confirmed their specificity. They selectively and efficiently induced cell death in CLL, irrespective of high-risk cytogenetics, IGHV status or clinical treatment history, including resistance. The substances induced ATM/p53-independent apoptosis and showed marked synergisms with fludarabine. Trabectedin additionally perturbed stromal-cell protection and showed encouraging antileukemic profiles even in aggressive and transforming murine CLL. This proof-of-principle study established (TC)-NER as a mechanism to be further exploited to resensitize CLL cells.

Endoscopic therapy for infected pancreatic necrosis using fully covered self-expandable metal stents: combination of transluminal necrosectomy, transluminal and percutaneous drainage.

BACKGROUND/AIMS: Endoscopic transluminal therapy has become the standard of care as a less invasive alternative to surgery. In a retrospective case series of two tertiary referral centers we report on an individualized concept combining EUS-guided drainage with self-expanding metal stents, direct transluminal debridement und percutaneous drainage. METHODS: We treated 13 patients with infected pancreatic necrosis. Initially in all patients an EUS-guided drainage with plastic stents was performed under antibiotic protection (transduodenal: 2, transgastral: 11). After clinical consolidation (after 9.6 ±â€Š9.4 days) a covered self-expanding metal stent (Niti-S, Taewoong medical Co., Seoul, Korea) was inserted by performing direct endoscopic necrosectomy in 2.9 ±â€Š1.7 sessions through the stent. In cases of disrupted duct syndromes a pancreatic plastic stent was inserted (5 of 13 patients). In 5 of 13 cases additional percutaneous drainage was applied because of extended necrosis. In one patient percutaneous endoscopic drainage using the percutaneous access was needed. RESULTS: A sustained clinical success was achieved in 12 of 13 cases (CRP before therapy 23.5 ±â€Š14.4 mg/L, after 3.1 ±â€Š2.6 mg/lL). Discharge occurred after 2.5 ±â€Š22.4 days. The self-expanding metal stent was extracted after 82.5 ±â€Š56.6 days. Mean follow up was 8.5 ±â€Š5.9 months. CONCLUSION: Our concept of combining transluminal drainage, direct endoscopic necrosectomy and percutaneuos drainage offers a safe and reliable alternative to surgery, even in case of extended necrosis.

Efficacy and safety of a novel submucosal lifting gel used for endoscopic submucosal dissection: a study in a porcine model.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) is technically demanding. A viscous gel for submucosal lifting might induce mechanical submucosal dissection facilitating easier and safer ESD. METHODS: In 12 female pigs (median 64 kg), ESDs of simulated lesions were performed at the posterior wall and greater curvature in the gastric body (one ESD per location) with randomly assigned injection fluids: gel or control fluid (0.9% saline with hydroxypropyl methylcellulose 3 mg/ml [7:1] and indigo carmine droplets). Additionally, 10 cc gel was injected into the submucosa at the anterior wall without ESD to assess effects of inappropriate injection. Pigs were euthanized at day 0, 3 or 28. In four additional pigs (euthanized day 3 or 28) 10 cc gel was injected into the muscularis propria (MP) after four endoscopic mucosal resections in the gastric body. RESULTS: Both fluid groups showed equal ESD-procedure times (28 [gel] vs. 26 min [control]) and complications. Gel-ESDs required less accessory interchanges (3.5 vs. 5.5; p = 0.01). Mechanical dissection after circumferential incision was achieved in 25% of gel-ESDs; none in control-ESDs. The severity of inflammation and fibrosis was equal in both fluid groups. Normal architecture and vital mucosa were found after inappropriate submucosal injection. MP-injections resulted in one transmural hematoma (day 3), and intramuscular encapsulation in 25% of the sites (day 28). LIMITATIONS: A pig's stomach differs from the human stomach. CONCLUSIONS: The mechanical dissection properties of the gel may reduce the need for submucosal dissection during ESD. The gel is safe when advertently injected in the submucosa and MP. The porcine model appeared suboptimal to evaluate the true mechanical dissection properties of the gel.

[The role of peroral endoscopic myotomy (POEM) in achalasia]. / Die Rolle der peroralen endoskopischen Myotomie (POEM) bei der ösophagealen Achalasie.

Achalasia is a rare motility disorder of the oesophagus. Classic achalasia is characterised by a lack of propulsive peristalsis of the distal oesophagus and incomplete relaxation of the lower oesophageal sphincter (LES). Traditionally achalasia is treated either endoscopically by pneumatic balloon dilatation or laparoscopically by Heller's myotomy. Both therapeutic procedures show a comparable effectiveness. Recently, peroral endoscopic myotomy was introduced as a new definitive treatment option. So far, this minimally invasive therapy was evaluated in a few clinical studies only. In this survey, peroral endoscopic myotomy is presented and compared to the well established surgical treatment. The diagnosis of achalasia is based on the patient's medical history and analysis of symptoms and particularly on oesophageal manometry. In addition, a barium swallow (oesophagram) and upper endoscopy are performed to rule out other reasons causing dysphagia. The patient's complaints should be recorded by use of a symptoms score. The POEM procedure starts with an incision of the mucosa at the level of the mid-oesophagus. Then, a submucosal tunnel is created distally passing approximately 2 cm over the oesophagogastric junction. After this step, myotomy of (at least) the circular muscle bundle of the distal oesophagus is performed and should be extended to a distance of 2 cm over the cardiac. Finally the mucosal entry site at the level of the mid-oesophagus is closed with endoscopic clips. First results of this technique are very promising with significant symptom relief and reduction of the mean LES pressure. In conclusion, POEM is a new, minimally invasive therapeutic option for the treatment of oesophageal achalasia. First results are very promising; long-term results and results of comparative clinical trials with established treatment methods must be awaited.

Propofol sedation for colonoscopy with a new ultrathin or a standard endoscope: a prospective randomized controlled study.

BACKGROUND AND STUDY AIMS: The majority of colonoscopies in Germany are performed under conscious sedation. Previous studies reported that pediatric colonoscopes reduce the demand for sedative drugs and may improve cecal intubation. The aim of this study was to compare a new ultrathin and a standard colonoscope in terms of propofol demand during colonoscopy. PATIENTS AND METHODS: A total of 203 patients were prospectively randomized to undergo colonoscopy with either a 9.5-mm ultrathin (UTC) colonoscope or a standard colonoscope of variable stiffness. Initially, 40 or 60 mg of propofol were administered according to body weight, followed by bolus injections of 20 mg as deemed necessary. Propofol was administered by a separate physician who was blinded to the endoscope used. Sedation levels were defined according to guidelines; pain and complaints were recorded on a numeric rating scale. RESULTS: Significantly less propofol was required to reach the cecum with the UTC (adjusted mean 94.9 mg [95 % confidence interval (CI) 85.7 - 105.0] vs. 115.3 mg [95 %CI 105.8 - 124.7]; P = 0.003). The level of sedation and pain score were lower with the UTC (sedation level 1 76 % vs. 61 %; P = 0.003; pain score adjusted mean 2.0 [95 %CI 1.7 - 2.4] vs. 2.8 [95 %CI 2.5 - 3.1]; P = 0.001). The rate of ileal and cecal intubation, time to reach the cecum, number of external compressions, withdrawal time, polyp and adenoma detection rate, and patient satisfaction were not different between the two colonoscopes. The time to intubate the ileum was longer with the UTC (1.73 minutes [95 %CI 1.42 - 2.04] vs. 1.22 minutes [95 %CI 0.91 - 1.52]; P = 0.020). CONCLUSIONS: Use of a new ultrathin colonoscope was associated with reduced propofol consumption, lower patient sedation levels, and less pain than the standard colonoscope, but ileal intubation time was longer.

Endoscopic submucosal dissection plus radiofrequency ablation of neoplastic Barrett's esophagus.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) of early gastrointestinal tumors has been shown to achieve complete resection rates superior to endoscopic mucosal resection (EMR), but at the cost of higher risk. The aim of this study was to prospectively assess the feasibility and oncological results of ESD in patients with neoplastic Barrett's esophagus in conjunction with subsequent radiofrequency ablation (RFA). METHODS: Patients with Barrett's esophagus who had visible lesions containing high grade intraepithelial neoplasia (HGIN) or mucosal adenocarcinoma (MAC) up to 3 cm in diameter were included in the study. ESD was performed using a new waterjet-assisted system (WESD) with a HybridKnife (Erbe Elektromedizin GmbH, Tübingen, Germany). Primary outcome was the rate of complete tumor resection. RFA of residual intestinal metaplasia was offered to all patients with at least two negative follow-up endoscopies. RESULTS: Of 30 patients (m:f = 21:9; median age 60 years) with biopsy-proven MAC (n = 24) or HGIN (n = 6) with a median diameter of 2 cm, complete resection of the targeted area was achieved in 29 patients (96.7 %; 95 % confidence interval [CI] 82 % - 99 %); en bloc resection was achieved in 27 of these patients (90.0 %; 95 %CI 74 % - 97 %). Minor delayed bleedings occurred in two patients. One patient died due to a sudden cardiac death 7 days after an uneventful WESD. Specimen histology (n = 29) revealed no neoplasia in 3 patients, HGIN in 2, MAC in 21, and submucosal cancer in 3; complete resection was histologically confirmed in only 10 of the 26 patients with HGIN or adenocarcinoma (38.5 %; 95 %CI 22 % - 57 %). However, endoscopic follow-up (median 17 months) showed complete remission of neoplasia in 27 /28 (96.4 %; 95 %CI 81 % - 99 %) patients who underwent successful WESD and were alive at 30 days. One patient underwent EMR of residual tumor. All Barrett's tissue was eradicated by ESD alone in 15 cases and by additional RFA in 8 /10 cases (not done in three patients). CONCLUSIONS: ESD of Barrett's neoplasia is feasible and safe, but does not achieve sufficient R0 resection rates to warrant its recommended use over piecemeal EMR. In combination with RFA it can achieve complete eradication of neoplastic and non-neoplastic Barrett's epithelium. The discrepancy between insufficient oncological resection and good medium-term results needs to be studied further.

[Radiofrequency ablation using the HALO system in the treatment of Barrett's oesophagus]. / Radiofrequenzablation mit dem HALO-System in der Behandlung des Barrett-Ösophagus.

In recent years radiofrequency ablation using the HALO system in the treatment of Barrett's oesophagus has become established. The HALO system consists of a circumferential ablation using a balloon-based electrode and a focal ablation using an endoscope-mounted bipolar electrode on an articulated platform. In combination with prior endoscopic resection radiofrequency ablation is a valuable therapeutic technique in selected patients with early Barrett's neoplasia. Clinical trials demonstrate that radiofrequency ablation is highly effective and durable, has low complication rates, preserves the functional integrity of the oesophagus, is easy to apply and the regenerating neosquamous epithelium is free of pre-existing oncogenetic alterations.

[Hypoxemia 4 month after right-sided pneumonectomy]. / Hypoxämie 4 Monate nach rechtsseitiger Pneumektomie.

A 64-year-old male reported worsening dyspnea four months after right-sided pneumonectomy, due to lung cancer. Platypneu-or-thodeoxie syndrome was suspected due to a decrease in oxygen-saturation while the patient was in upright position. The shift of the right hemidiaphragm and liver caused compression of the right atrium and a shunt over a persistent foramen ovale. The right-to-left shunt was proven during right heart catheter. Interventional closure of the shunt resulted in immediate improvement of arterial oxygenation and a decrease in dyspnea.

A new partially covered nitinol stent for palliative treatment of malignant bile duct obstruction: a multicenter single-arm prospective study.

BACKGROUND AND STUDY AIMS: Covered self-expanding metal stents (SEMSs) have proven effective for managing malignant bile duct strictures and may reduce risk of tumor ingrowth. A new nitinol partially covered biliary SEMS was prospectively evaluated. PATIENTS AND METHODS: 70 patients with inoperable extrahepatic biliary obstructions were enrolled in a prospective multicenter trial, and followed up to 6 months or death, whichever came first. Primary endpoint was adequate palliation defined as absence of recurrent biliary obstruction from partly covered SEMS placement to end of follow-up. RESULTS: Mean age of the patients was 69 years and 52 % were men. Pancreatic carcinoma was present in 68 %. One stent was placed in 67 patients, two patients received two, and in one patient a guide wire could not traverse the stricture. In 55 % of patients the SEMS was inserted de novo and in 45 % for exchange with a plastic stent. Technical success was 97 %. At 6 months, 62 % of patients were free of obstructive symptoms; compared with baseline the mean number of symptoms per patient was significantly reduced (3.1 at baseline, 0.6 at 6 months; P < 0.0001) and total bilirubin levels dropped by 73 %. There were four cases of recurrent biliary obstruction, due to stent migration (2), tumor overgrowth (1), and sludge formation (1). Device-related complications included cholecystitis (3), right upper quadrant pain (1), and moderate pancreatitis (1). No tumor ingrowth was reported. CONCLUSIONS: This new partially covered nitinol SEMS is easily inserted, and safe and effective in the palliation of biliary obstruction secondary to malignant bile duct strictures.