Impact of sex on the efficacy and safety of panitumumab plus fluorouracil and folinic acid versus fluorouracil and folinic acid alone as maintenance therapy in RAS WT metastatic colorectal cancer (mCRC). Subgroup analysis of the PanaMa-study (AIO-KRK-0212).

BACKGROUND: Clinical trials in metastatic colorectal cancer (mCRC) are usually conducted irrespective of sex. Sex-associated differences relating to safety and efficacy in the treatment of mCRC, however, are gaining interest. METHODS: PanaMa investigated the efficacy of panitumumab (Pmab) plus fluorouracil and folinic acid (FU/FA) versus FU/FA alone after induction therapy with six cycles of FU/FA and oxaliplatin plus Pmab in patients with RAS wild-type mCRC. In this post hoc analysis, the study population was stratified for sex. Evaluated efficacy endpoints during maintenance treatment were progression-free survival (PFS, primary endpoint of the trial), overall survival (OS) and objective response rate during maintenance therapy. Safety endpoints were rates of any grade and grade 3/4 adverse events during maintenance therapy. RESULTS: In total, 165 male and 83 female patients were randomized and treated. Male and female patients showed numerically better objective response rates with Pmab, without reaching statistical significance. Male patients derived a significant benefit from the addition of Pmab to maintenance treatment with regard to PFS [hazard ratio (HR) 0.63; 95% confidence interval (CI) 0.45-0.88; P = 0.006] that was not observed in female patients (HR 0.85; 95% CI 0.53-1.35; P = 0.491). The better PFS for male patients treated with Pmab did not translate into improved OS (HR 0.85; 95% CI 0.55-1.30; P = 0.452). Female patients showed numerically improved OS when treated with Pmab. There was no difference in the total of grade ≥3 adverse events during maintenance regarding sex (P = 0.791). Female patients, however, had a higher rate of any grade nausea, diarrhea and stomatitis. CONCLUSIONS: In the PanaMa trial, the addition of Pmab to maintenance treatment of RAS wild-type mCRC with FU/FA improved the outcome in terms of the primary endpoint (PFS) particularly in male patients. Female patients did not show the same benefit while experiencing higher rates of adverse events. Our results support the development of sex-specific protocols.

[Endoscopic diagnosis, treatment, and follow-up of polyps of the upper gastrointestinal tract]. / Endoskopische Diagnostik, Therapie und Nachsorge von Polypen des oberen Gastrointestinaltrakts.

Polyps occur significantly less frequently in the upper gastrointestinal tract compared to the lower gastrointestinal tract. They are usually incidental findings at esophagogastroduodenoscopy. A distinction is made between epithelial lesions and subepithelial tumors. Endoscopic screening is not recommended in Germany (exception: hereditary risk groups). Polyps are sometimes symptomatic, generally in the case of advanced tumor size. In this case, or in the case of potential for malignant transformation, resection is necessary and can usually be performed endoscopically. Surgical resections are rarely necessary. Epithelial lesions are removed by means of endoscopic mucosal resection (EMR). For subepithelial tumors, advanced procedures such as endoscopic submucosal dissection (ESD), submucosal tunneling endoscopic resection (STER), or endoscopic full-thickness resection are available. These procedures should primarily be performed at centers with appropriate expertise. Endoscopic follow-up is primarily determined by the tumor entity and the resection status.

Efficacy of gemcitabine plus erlotinib in rash-positive patients with metastatic pancreatic cancer selected according to eligibility for FOLFIRINOX: A prospective phase II study of the 'Arbeitsgemeinschaft Internistische Onkologie'.

INTRODUCTION: In metastatic pancreatic ductal adenocarcinoma (mPDAC) treatment, erlotinib is known to be more effective in patients developing skin rash. Treatment with the FOLFIRINOX regimen is only performed in fit patients following defined inclusion criteria. The present study investigates the efficacy of gemcitabine plus erlotinib (gem/erlotinib) in rash-positive patients fit for FOLFIRINOX. PATIENTS AND METHODS: For this prospective phase II study, 150 patients were recruited in 20 centres. All patients received gem/erlotinib for 4 weeks (run-in phase); the subsequent treatment was determined by the development of skin rash: patients with rash grades 1-4 continued with gem/erlotinib, rash-negative patients were switched to FOLFIRINOX. Primary study end-point was to achieve a 1-year survival rate in rash-positive patients ≥40%. RESULTS: Ninety patients were deemed positive for skin rash by the end of the run-in phase, showing a 1-year survival rate of 40.0% (95% confidence interval [CI] 29.8-50.9). Median overall survival (OS) was 10.1 months, progression-free survival (PFS) was 3.8 months and overall response rate (ORR) was 23.3%. Patients switched to FOLFIRINOX (n = 27) had a 1-year survival rate of 48.1% (95% CI 28.7-68.1), a median OS of 10.9 months, a median PFS of 6.6 months and an ORR of 33.3%. Rash-negative patients had a lower quality of life at baseline but seemed to experience an improved control of pain during FOLFIRINOX. CONCLUSIONS: First-line treatment with gem/erlotinib was effective in fit, rash-positive mPDAC patients achieving a 1-year survival rate comparable to previous reports for FOLFIRINOX. The study was registered at clinicaltrials.gov (NCT0172948) and Eudra-CT (2011-005471-17).

[Acute right-sided upper abdominal pain in a 46-year-old woman]. / Akute rechtsseitige Oberbauchschmerzen bei einer 46-Jährigen.

A 46-year-old woman presented with acute abdominal pain in the right upper quadrant. Esophagogastroduodenoscopy revealed a duodenal stenosis within the horizontal part of the duodenum. Based on the findings of abdominal computed tomography (CT), endosonography, Doppler duplex sonography and angiography, the diagnosis of an aneurysm of a branch of the inferior pancreaticoduodenal artery was established. This arterial branch was part of a collateral circulation between the superior mesenteric artery and the proper hepatic artery caused by obturation of the celiac artery. The symptomatic duodenal stenosis was the result of a local hematoma due to prior rupture of an aneurysm. After successful coiling of the afferent vessels to the aneurysm follow-up examinations showed progredient resorption of the hematoma and the patient was free of complaints.

[Endoscopic full-thickness resection]. / Die endoskopische Vollwandresektion.

Conventional endoscopic resection techniques such as endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) are powerful tools for the treatment of gastrointestinal (GI) neoplasms. However, those techniques are limited to the superficial layers of the GI wall (mucosa and submucosa). Lesions without lifting sign (usually arising from deeper layers) or lesions in difficult anatomic positions (appendix, diverticulum) are difficult - if not impossible - to resect using conventional techniques, due to the increased risk of complications. For larger lesions (>2 cm), ESD appears to be superior to the conventional techniques because of the en bloc resection, but the procedure is technically challenging, time consuming, and associated with complications even in experienced hands. Since the development of the over-the-scope clips (OTSC), complications like bleeding or perforation can be endoscopically better managed. In recent years, different endoscopic full-thickness resection techniques came to the focus of interventional endoscopy. Since September 2014, the full-thickness resection device (FTRD) has the CE marking in Europe for full-thickness resection in the lower GI tract. Technically the device is based on the OTSC system and combines OTSC application and snare polypectomy in one step. This study shows all full-thickness resection techniques currently available, but clearly focuses on the experience with the FTRD in the lower GI tract.

[Rituximab therapy for relapsing IgG4-autoimmune pancreatitis and cholangitis - a case report]. / Rituximab als Therapieoption bei rezidivierender IgG4-Autoimmunpankreatitis und -cholangitis - ein Fallbericht.

We report a patient with autoimmune pancreatitis and cholangitis. During a period of 3 years and despite therapy with steroids and immunmodulatory drugs such as azathioprine and mycophenolate mofetil he suffered from multiple relapse episodes including bile duct stenoses requiring endoscopic interventions. After initiation of therapy with the monoclonal CD20 antibody Rituximab, steroids could be stopped completely and the patient remains in remission. Rituximab should be considered in therapy of relapsing autoimmune pancreatitis and cholangitis.

Manifestation of an abdominal immune reconstitution inflammatory syndrome associated with a nontuberculous mycobacterial infection - a case report.

Immune reconstitution inflammatory syndrome (IRIS) is an inflammatory reaction in HIV-infected patients after initiation of antiretroviral therapy. It results from restored immunity to specific infectious or non-infectious antigens. We describe the case of a 47-year-old female patient who presented with an unspecific painful pressure in the abdomen and weight loss that was diagnosed as intra-abdominal (unmasking) IRIS due to nontuberculous mycobacterial infection (Mycobacterium avium complex). Antiretroviral therapy had been initiated six months earlier when pneumocystis pneumonia led to the diagnosis of HIV infection with a viral load of 123 000 copies/ml and a CD 4 cell count of 6/µl. Although IRIS is a known complication after initiation of antiretroviral therapy in HIV-infected patients this case with a rare site of manifestation and symptoms that are common in all day gastroenterological clinic highlights a differential diagnosis that requires a high index of suspicion and the need for the careful use of diagnostic tools.

A randomised multicentre phase II study with cisplatin/docetaxel vs oxaliplatin/docetaxel as first-line therapy in patients with advanced or metastatic non-small cell lung cancer.

BACKGROUND: This study was designed to compare cisplatin/docetaxel with oxaliplatin/docetaxel in patients with advanced and metastatic non-small lung cancer as a first-line treatment. METHODS: Patients were randomly assigned to receive either cisplatin 75 mg m(-2) and docetaxel 75 mg m(-2) every 3 weeks or oxaliplatin 85 mg m(-2) and docetaxel 50 mg m(-2) every 2 weeks. The primary end point was response rate, and secondary end points were toxicity, time to progression and overall survival. RESULTS: A total of 88 patients (median age: 65 (39-86) years; stage IV: 93%) were randomly assigned. Response rate (complete and partial response) was 47% (95% CI: 33-61%) in the cisplatin/docetaxel arm and 28% (95% CI: 17-43%) in the oxaliplatin/docetaxel arm (P=0.118). There was no significant difference in time to progression (6.3 vs 4.9 months, P=0.111) and median overall survival (11.6 vs 7.0 months, P=0.102) with cisplatin/docetaxel vs oxaliplatin/docetaxel, although slight trends favouring cisplatin were seen. Oxaliplatin/docetaxel was associated with significantly less (any grade) renal toxicity (56% vs 11%), any grade fatigue (81% vs 59%), complete alopecia (76% vs 27%), any grade leukopenia (84% vs 61%) and grade 3/4 leukopenia (44% vs 14%) and neutropenia (56% vs 27%). CONCLUSION: Oxaliplatin/docetaxel has activity in metastatic non-small cell lung cancer, but it seems to be inferior to cisplatin/docetaxel.

Standard diagnostic laparoscopy is superior to NOTES approaches: results of a blinded, randomized controlled porcine study.

BACKGROUND AND STUDY AIM: The use of transluminal endoscopic access via the stomach or colon for flexible diagnostic peritoneoscopy has been proposed, although the diagnostic value of the technique has not yet been fully clarified. In this animal trial, the two main natural orifice transluminal endoscopic surgery (NOTES) approaches - transgastric (TG) and transcolonic (TC) - were compared with standard transabdominal access using both rigid (TAR) and flexible instruments (TAF) for diagnostic laparoscopy. METHODS: A total of 48 peritoneoscopies were performed using two randomly assigned approaches in 24 anesthetized pigs. The ability of the examinations to detect 576 electrocautery markings simulating intraperitoneal metastases, to achieve complete organ visualization, and to simulate organ biopsies was analyzed. RESULTS: Sensitivities for the detection of lesions were 78.5 %, 59.7 %, 48.6 %, and 38.9 % for TAR, TAF, TC, and TG, respectively; standard laparoscopy was superior to all other approaches (P < 0.01). Among the NOTES approaches, TC was superior for examining the upper abdomen (P = 0.03). Complete organ visualization was better with the transabdominal approach (visual analogue scale TAR 7.15, TAF 6.71) than with the NOTES access routes (TC 5.07, TG 4.35); standard rigid laparoscopy was superior to both NOTES approaches (P < 0.01). Organ biopsy simulation was possible in 87 %, 85 %, 72 %, and 65 % of cases with TAR, TAF, TC, and TG, respectively. Standard rigid laparoscopy was again superior to both NOTES approaches (TAR vs. TC, P = 0.03; TAR vs. TG, P < 0.01). CONCLUSIONS: In this experimental trial, rigid standard laparoscopy provided better organ visualization, better lesion detection, and better biopsy capability than the transgastric and transcolonic NOTES approaches. In its current form, NOTES appears to be unsuitable for diagnostic laparoscopy.

A German multicenter, randomized phase III trial comparing irinotecan-carboplatin with etoposide-carboplatin as first-line therapy for extensive-disease small-cell lung cancer.

BACKGROUND: This trial was designed to prove superiority of irinotecan over etoposide combined with carboplatin in extensive-disease small-cell lung cancer. PATIENTS AND METHODS: Patients were randomly assigned to receive carboplatin area under the curve 5 mg x min/ml either in combination with irinotecan 50 mg/m2 on days 1, 8, and 15 (IP) or etoposide 140 mg/m2 on days 1-3 (EP). Primary end point was progression-free survival (PFS) at 6 months. Secondary end points were overall survival (OS), response rate, and toxicity. RESULTS: Of 226 patients, 216 were eligible. Median PFS was 6.0 months [95% confidence interval (CI) 5.0-7.0] in the IP arm and 6.0 months (95% CI 5.2-6.8) in EP arm (P = 0.07). Median survival was 10.0 months (95% CI 8.4-11.6) and 9.0 months (95% CI 7.6-10.4) in the IP and EP arm (P = 0.06), respectively. Hazard ratios for disease progression and OS were 1.29 (95% CI 0.96-1.73, P = 0.095) and 1.34 (95% CI 0.97-1.85, P = 0.072), respectively. No difference in response rates was observed. Grade 3 and 4 hematologic toxicity favored the IP arm, whereas diarrhea was significantly more frequent in the IP arm. CONCLUSION: This trial failed to show superiority of irinotecan over etoposide in combination with carboplatin.

Effectivity of current sterility methods for transgastric NOTES procedures: results of a randomized porcine study.

BACKGROUND AND AIM: Natural-orifice transluminal endoscopic surgery (NOTES) is an emerging transluminal technique in which interventions are carried out by entering the abdominal cavity via a natural orifice such as the stomach. Infection is a potential risk of the procedure, and the potential pathogens are different from those encountered with skin incisions. Currently, available data regarding prophylactic anti-infective treatment are limited. We compared the effectiveness of topical antimicrobial lavage of mouth and stomach and proton pump inhibitor therapy with gastric cleansing with sterile saline solution in preventing NOTES-related contamination and infection. METHODS: A randomized survival swine study was performed. Eight pigs underwent preparation with intravenously administered proton pump inhibitors, mouth and gastric lavage (chlorhexidine), and gastric irrigation (diluted neomycin), plus single-shot intravenous antibiotics. Control group (n = 8) underwent gastric cleansing with sterile saline solution. Peritoneal biopsy, multiple smears, and dilutions for cultures were taken and incubated. The swine were sacrificed after 14 days. Bacterial load was expressed in colony-forming units (CFU). RESULTS: One pig died due to gallbladder perforation after 3 days, 2/15 swine presented minor clinical signs of infection in the 14-day follow-up (all 3 pigs were in the control group). Mean C-reactive protein levels were 5.7 +/- 2.4 g/dL (therapy group) and 12.2 +/- 3.8 g/dL (control) ( P = 0.17). Bacterial growth was seen in 1/8 swine (therapy group) and 6/8 swine (control group) ( P = 0.002). Bacterial load was 282 CFU/mL (therapy) vs. 3.2 x 10 (5) CFU/mL (control) ( P = 0.023) in the follow-up. CONCLUSION: The use of intravenous antibiotics in addition to topical antimicrobial lavage of mouth and stomach and treatment with proton pump inhibitors decreased the peritoneal bacterial load to almost zero and this was associated with a significantly lower peritoneal infection rate compared with saline-only lavage.

Endoscopic mucosal resection using a grasp-and-snare technique.

BACKGROUND AND STUDY AIM: Endoscopic mucosal resection (EMR) is a minimally invasive method for en bloc removal of superficial gastrointestinal lesions. The aim of this study was to evaluate the feasibility of a novel grasp-and-snare EMR technique. METHODS: In 10 domestic pigs, gastric lesions of approximately 3 cm were marked using electrocautery. EMR was performed using a double-channel endoscope. A novel tissue anchor was used through one channel, and a monofilament snare through the other. After submucosal injection, a circumferential mucosal incision was created. The tissue-anchoring device was then advanced through the open snare and anchored into the submucosal layer. The tissue-anchoring device was partly retracted into the endoscope and the snare was positioned into the circular incision. The snare was subsequently closed and the specimen resected by applying high-frequency electrocautery. RESULTS: Mean time to perform EMR was 32.4 minutes (range 22-41 minutes, SD 6.3). EMR yielded specimens that ranged in area from 2.7 cm (minor axis) by 2.8 cm (major axis) to 4.0 cm by 4.2 cm (mean area 9.36 cm(2); range 5.94-13.19 cm(2); SD +/- 2.50). Complete en bloc resection including all electrocautery markings was achieved in 9/10 cases. In one case, resection was achieved in two steps. One gastric wall perforation occurred. No other adverse events were observed. CONCLUSIONS: Grasp-and-snare EMR is feasible in an animal model. The technique can be performed efficiently compared with standard methods. To avoid perforation, caution is needed to ensure that tissue anchor needles are placed within and not deeper than the submucosal layer prior to tissue retraction.

Endoscopic closure of large colonic perforations using an over-the-scope clip: a randomized controlled porcine study.

BACKGROUND AND STUDY AIMS: Perforation of the colon is considered to be one of the most serious complications of flexible endoscopy. The over-the-scope clip system (OTSC) has previously been shown to close small colonic perforations effectively. The aim of this randomized controlled porcine study was to compare acute closure strengths between the novel 11-mm over-the-scope-clip and surgical closure for large colonic perforations. MATERIAL AND METHODS: In 24 anesthetized domestic pigs, an 18-mm sigmoid perforation was created endoscopically using a needle knife and dilating balloon. The animals were randomly assigned to undergo either open surgical repair (n = 12) or endoscopic closure using the OTSC system (n = 12). Pressurized leak tests were performed during necropsy. RESULTS: Mean time to perform the incision in the sigmoid colon and obtain peritoneal access was 5.5 minutes (range 3-12; SD +/- 2.5). Mean time for endoscopic closure was 6.8 minutes (range 3-14; SD +/- 3). At necropsy, all OTSC and surgical closures demonstrated complete sealing of colotomy sites. In one case peritoneum and in a second case adjacent small intestine were found incorporated into the OTSC closure. No other complications occurred. Pressurized leak tests revealed a mean burst pressure of 62.8 mmHg (range 18-112; SD 35.7) for OTSC closures and 67.4 mmHg (range 30-90; SD 19) for sutured closure. No significant differences in burst pressures were noted between the OTSC closures and surgical repair. CONCLUSION: Closure of acute perforations using the OTSC system is comparable to surgical closure in a nonsurvival porcine model.

Endoscopic full-thickness plication for the treatment of gastroesophageal reflux disease using multiple Plicator implants: 12-month multicenter study results.

BACKGROUND: The full-thickness Plicator (Ethicon Endosurgery, Sommerville, NJ, USA) was developed for endoscopic treatment of gastroesophageal reflux disease (GERD). The goal is to restructure the antireflux barrier by delivering transmural pledgeted sutures through the gastric cardia. To date, studies using this device have involved the placement of a single suture to create the plication. The purpose of this study was to evaluate the 12-month safety and efficacy of this procedure using multiple implants to restructure the gastroesophageal (GE) junction. METHODS: A multicenter, prospective, open-label trial was conducted at four tertiary centers. Eligibility criteria included symptomatic GERD [GERD Health-Related Quality-of-Life (GERD-HRQL) questionnaire, off of medication], and pathologic reflux (abnormal 24-h pH) requiring daily proton pump inhibitor therapy. Patients with Barrett's epithelium, esophageal dysmotility, hiatal hernia > 3 cm, and esophagitis (grade III or greater) were excluded. All patients underwent endoscopic full-thickness plication with linear placement of at least two transmural pledgeted sutures in the anterior gastric cardia. RESULTS: Forty-one patients were treated. Twelve months post treatment, 74% of patients demonstrated improvement in GERD-HRQL scores by > or = 50%, with mean decrease of 17.6 points compared with baseline (7.8 vs. 25.4, p < 0.001). Using an intention-to-treat model, 63% of patients had symptomatic improvements of > or = 50%, with mean GERD-HRQL decrease of 15.0 (11.0 vs. 26.0, p < 0.001). The need for daily proton pump inhibitor (PPI) therapy was eliminated in 69% of patients at 12 months on a per-protocol basis, and 59% on an intention-to-treat basis. Adverse events included postprocedure abdominal pain (44%), shoulder pain (24%), and chest pain (17%). No long-term adverse events occurred. CONCLUSIONS: Endoscopic full-thickness plication using multiple Plicator implants can be used safely and effectively to improve GERD symptoms and reduce medication use.

[Gastrointestinal oncology - therapy update 2008 / 2009]. / Gastrointestinale Onkologie - Therapieupdate 2008 / 2009.

As a consequence of recent studies the treatment of gastrointestinal cancers has become challenging and is undergoing constant changes on the basis of the results of new trials. The steering committee of the working group on gastrointestinal cancers of the Deutsche Gesellschaft für Verdauungs- und Stoffwechselkrankheiten has decided to summarise and present recent updates of the current treatment guidelines and recommendations for the most relevant gastrointestinal malignancies. In this review we have included recent findings from large trials on esophageal, gastric, pancreatic, cholangiocellular and liver cancers, as well as colorectal cancers, neuroendocrine tumours and lymphomas. This includes an update on the combination with novel targeted agents and the introduction of potential predictive biomarkers in the selection of the appropriate treatment strategy.

Endoscopic closure of the natural orifice transluminal endoscopic surgery (NOTES) access site to the peritoneal cavity by means of transmural resorbable sutures: an animal survival study.

BACKGROUND AND STUDY AIMS: Endoscopic closure of the transgastric access site is still a critical area of active research and development into natural orifice transluminal surgery (NOTES). To date, no endoscopic technique has utilized resorbable transmural sutures for closure of the NOTES gastrostomy. MATERIAL AND METHODS: Endoscopic gastrostomy closure by means of resorbable sutures was performed in ten female domestic pigs in an animal survival study. Peritoneal cavity access was gained through the anterior gastric wall using the percutaneous endoscopic gastrostomy (PEG) technique and an 18-mm balloon dilator. NOTES exploration of the gallbladder and tubal ligation were performed prior to endoscopic gastrostomy closure. Necropsy was performed 3 weeks post procedure. RESULTS: Mean suturing time was 26 minutes (range 14 - 35 minutes). In total 90 % (9/10) of gastrostomy closures were performed by means of two transmural resorbable sutures. One gastrostomy was closed using a single resorbable suture. One case of gallbladder perforation occurred during peritoneoscopy and the pig was sacrificed due to subsequent peritonitis 2 days after the procedure. All other pigs (9/10) were found to be healthy 3 weeks after the NOTES procedure and were sacrificed as planned per protocol. Of all the 17 sutures that were applied in the remaining nine pigs, 16 (94 %) had been absorbed, releasing the pledgets intraluminally. During laparotomy no signs of injury to adjacent organs were found in any of these nine animals. In 8/10 pigs (80 %) the gastrostomy site did not burst with pressures exceeding 100 mmHg. Two suturing sites did burst at pressures of 57 and 62 mmHg, respectively. CONCLUSIONS: Endoscopic transmural suturing enables rapid and easy placement of leak-proof resorbable sutures and is suitable for closure of the NOTES transgastric access.