Analysis of 72,469 UK Biobank exomes links rare variants to male-pattern hair loss.

Male-pattern hair loss (MPHL) is common and highly heritable. While genome-wide association studies (GWAS) have generated insights into the contribution of common variants to MPHL etiology, the relevance of rare variants remains unclear. To determine the contribution of rare variants to MPHL etiology, we perform gene-based and single-variant analyses in exome-sequencing data from 72,469 male UK Biobank participants. While our population-level risk prediction suggests that rare variants make only a minor contribution to general MPHL risk, our rare variant collapsing tests identified a total of five significant gene associations. These findings provide additional evidence for previously implicated genes (EDA2R, WNT10A) and highlight novel risk genes at and beyond GWAS loci (HEPH, CEPT1, EIF3F). Furthermore, MPHL-associated genes are enriched for genes considered causal for monogenic trichoses. Together, our findings broaden the MPHL-associated allelic spectrum and provide insights into MPHL pathobiology and a shared basis with monogenic hair loss disorders.

FDG-PET/CT for lymph node staging prior to radical cystectomy.

BACKGROUND: 18F-Fluorodeoxyglucose positron emission combined with computed tomography (FDG-PET/CT) has been proposed to improve preoperative staging in patients with bladder cancer subjected to radical cystectomy (RC). OBJECTIVE: Our aim was to assess the accuracy of FDG-PET/CT for lymph node staging ascertained at the multidisciplinary tumour board compared to lymph node status in the surgical lymphadenectomy specimen obtained at RC, and to explore potential factors associated with false-positive FDG-PET/CT results. DESIGN, SETTING AND PARTICIPANTS: Consecutive patients with bladder cancer undergoing RC with extended lymph node dissection between 2011 and 2019 without preoperative chemotherapy in a tertial referral cystectomy unit were included in the study. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Sensitivity, specificity, positive and negative predictive values and likelihood ratios were calculated. Potential factors investigated for association with false-positive FDG-PET/CT were; bacteriuria within four weeks prior to FDG-PET/CT, Bacillus Calmette-Guerin (BCG) treatment within 12 months prior to FDG-PET/CT and transurethral resection of bladder tumour (TURB) within four weeks prior to FDG-PET/CT. RESULTS: Among 157 patients included for analysis, 44 (28%) were clinically node positive according to FDG-PET/CT. The sensitivity and specificity for detection of lymph node metastasis were 50% and 84%, respectively, and the corresponding positive predictive and negative predictive values were 61% and 76%. Positive and negative likelihood ratios were 3.0 and 0.6, respectively. No association was found between bacteriuria, previous BCG treatment or TURB within 28 days and false-positive FDG-PET/CT results. CONCLUSIONS: Preoperative FDG-PET/CT prior to RC had a clinically meaningful high specificity (84%) but lower sensitivity (50%) for detection of lymph node metastases compared to lymph node status in an extended pelvic lymphadenectomy template. We could not identify any factors associated with false-positive FDG-PET/CT outcomes.

Pre-clinical evaluation of APrevent® VOIS for unilateral vocal fold paralysis medialization.

Objective: To evaluate the concept and efficacy of an adjustable implant (Prototype SH30: porcine implant and APrevent® VOIS: human concept) for treatment of unilateral vocal fold paralysis (UVFP) via in vivo mini-pig studies, human computed tomographic (CT) and magnetic resonance (MR) image analysis, ex-vivo aerodynamic and acoustic analysis. Methods: Feasibility testing and prototype implantation were performed using in-vivo UVFP porcine model (n = 8), followed by a dimensional finding study using CT and MR scans of larynges (n = 75) for modification of the implant prototypes. Acoustic and aerodynamic measurements were recorded on excised canine (n = 7) larynges with simulated UVFP before and after medialization with VOIS-Implant. Results: The prototype showed in the in-vivo UVFP porcine model an improved glottic closure from grade 6 incomplete closure to complete closure (n = 5), to grade 2 incomplete closure (n = 2) and grade 3 incomplete closure (n = 1). On human CT/MR scans the identification of the correct size was successful in 97.3% using the thyroid cartilage alar "distance S" as the only parameter, which is an important step towards procedure standardization and implant design. Results were confirmed with implantation in human laryngeal cadavers (n = 44). Measurements of the acoustic and aerodynamic effects after implantation showed a significant decreased phonation threshold pressure (p = .0187), phonation threshold flow (p = .0001) and phonation threshold power (p = .0046) on excised canine larynges with simulated UVFP. Percent jitter and percent shimmer decreased (p = .2976; p = .1771) but not significant. Conclusions: Based on the preclinical results four sizes, differing in medial length, implant width and expansion direction of silicone cushions, seem to be enough to satisfy laryngeal size variations. This concept is significantly effective in medializing UVFP and improving the aerodynamic and acoustic qualities of phonation as reported in a preliminary clinical outcome study with long-term implantation. Level of Evidence: N/A.

Preemptive endoluminal vacuum therapy with the VACStent-A pilot study to reduce anastomotic leakage after Ivor Lewis hybrid esophagectomy.

Introduction: Endoscopic treatment by vacuum therapy (EVT) or covered stents has emerged as an improved treatment option for upper gastrointestinal wall defects and is regarded as an improved treatment option for anastomotic leakage (AL) after esophagectomy. However, endoluminal EVT devices may lead to obstruction of the GI tract; and a high rate of migration and missing functional drainage has been shown for covered stents. The recently developed VACStent, a combination of a fully covered stent within a polyurethane sponge cylinder may overcome these issues allowing EVT while stent passage is still open. Initial clinical applications have demonstrated efficacy, practicability and safety in the treatment of esophageal leaks (AL). Methods: In this pilot study, 9 patients with high-risk anastomosis after neoadjuvant therapy undergoing hybrid esophagectomy received the VACStent in a preemptive setting for the assessment of the reduction of the AL rate, postoperative morbidity and mortality. Results: Technical success of the application of the VACStent® was achieved in all interventions. One patient experienced anastomotic leakage 10 days after esophagectomy and was successfully treated with two consecutive VACStents and a VAC Sponge. In summary, mortality in-hospital was 0% and anastomotic healing was uneventful without septic episodes. No severe device-related adverse events (SADE) nor significant local bleeding or erosion could be observed. Oral intake of liquids or food was documented in all patients. The device handling was regarded uncomplicated. Discussion: The preemptive application of the VACStent offers a promising new option for improved clinical treatment avoiding of critical situations in hybrid esophagectomy, which should be validated in a large clinical study.

Metabolic parameters of [18F]FDG PET-CT before and after radiotherapy may predict survival and recurrence in cervical cancer.

BACKGROUND: Cervical cancer is the fourth most common female malignancy. [18F]-fluorodeoxyglucose (FDG) positron emission tomography with computed tomography (PET-CT) is routinely performed in patients with locally advanced cervical cancer for staging and treatment response evaluation. With this retrospective, observational cohort study, we wanted to investigate the prognostic value of the maximum standardised uptake value (SUVmax) and the volumetric parameters of metabolic tumour volume (MTV) and total lesion glycolysis (TLG) before and after treatment in women with cervical cancer, with overall survival (OS) and recurrence as outcome measures. METHODS: Women with cervical cancer referred for curative radiotherapy and who underwent two PET-CT scans (before treatment and approximately 7 months post-treatment) were included. SUVmax, MTV and TLG were measured at baseline and post-treatment on the primary tumour, pelvic and distant lymph node metastases, distant organ metastases, and on total tumour burden. The PET parameters were associated with OS by Cox regression and recurrence by multivariable logistic regression. Kaplan-Meier curves and C-index were used to visualise the prognostic potential of the different measures. RESULTS: A total of 133 patients were included. At the primary tumour level and on total tumour burden, age- and clinical-stage adjusted analyses showed a significant association between PET parameters and OS and recurrence when measured post-treatment. At baseline (pre-treatment), MTV and TLG were associated with OS and recurrence, whereas SUVmax was not. C-index from adjusted Cox models on total tumour burden showed higher values for the post-treatment PET compared to baseline. Kaplan-Meier curves demonstrated a greater prognostic potential for MTV and TLG compared to SUVmax, both at baseline and post-treatment. CONCLUSIONS: The FDG PET-CT-derived parameters SUVmax, MTV, and TLG measured post-treatment can predict OS and recurrence in cervical cancer. Parameters measured before treatment had overall lower prognostic potential, and only MTV and TLG showed significant association to OS and recurrence.

VACStent: Combining the benefits of endoscopic vacuum therapy and covered stents for upper gastrointestinal tract leakage.

Background and study aims Endoscopic treatment has markedly improved the high morbidity and mortality in patients with upper gastrointestinal tract leakage. Most procedures employ either covered self-expanding metal stents (SEMS) or endoscopic vacuum therapy (EVT), both with good clinical success but also with concomitant significant shortcomings inherent in each technique. A newly developed device, the VACStent, combines the fully covered SEMS with a polyurethane sponge cylinder anchored on the outside. This allows endoluminal EVT while keeping the intestinal lumen patent. The benefit is prevention of stent migration because the suction force of the sponge-cylinder immobilizes the VACStent on the intestinal wall, while at the same time, the attached external vacuum pump suctions off any secretions and improves healing with negative-pressure wound treatment (NPWT). Patients and methods In this pilot study, the first patients to receive the VACStent were assessed. Outcomes included the applicability and stability of the VACStent system together with the clinical course. Results Three patients with different clinical courses were managed with the VACStent. The first patient suffered anastomotic leakage following subtotal esophagectomy and was successfully treated with two postoperative VACStents for 12 days. The second patient received a covered SEMS for 14 days for acute Boerhaave syndrome. Due to persistent leakage, management was converted to EVT. Seven days, later a VACStent was inserted to allow oral nutrition while the leak finally closed. In the third patient, a LINX Reflux Management System had to be removed for erosion, leaving the gastroesophageal junction (GEJ) with a full-thickness gap. After VACstent insertion, successful closure was achieved within 4 days. Conclusions These clinical cases demonstrate the applicability and efficacy of the VACstent in management of esophageal and anastomotic leakage. With its vacuum sponge, the stent fosters wound healing while the covered SEMS keeps the passage patent for nutrition.

The influence of regression models on genome-wide association studies of alcohol dependence: a comparison of binary and quantitative analyses.

INTRODUCTION: Genome-wide association studies (GWAS) of alcohol dependence syndrome (ADS) offer a platform to detect genetic risk loci. However, the majority of the ADS GWAS undertaken, to date, have utilized a case-control design and have failed to identify consistently replicable loci with the exception of protective variants within the alcohol metabolizing genes, notably ADH1B. The ADS phenotype shows considerable variability which means that the use of quantitative variables as a proxy for the severity of ADS has the potential to facilitate identification of risk loci by increasing statistical power. The current study aims to examine the influences of using binary and adjusted quantitative measures of ADS on GWAS outcomes and on calculated polygenic risk scores (PRS). METHODS: A GWAS was performed in 1251 healthy controls with no history of excess alcohol use and 739 patients with ADS classified using binary DMS-IV criteria. Two additional GWAS were undertaken using a quantitative score based on DSM-IV criteria, which were applied assuming both normal and non-normal distributions of the phenotypic variables. PRS analyses were performed utilizing the data from the binary and the quantitative trait analyses. RESULTS: No associations were identified at genome-wide significance in any of the individual GWAS; results were comparable in all three. The top associated single nucleotide polymorphism was located on the alcohol dehydrogenase gene cluster on chromosome 4, consistent with previous ADS GWAS. The quantitative trait analysis adjusted for the distribution of the criterion score and the associated PRS had the smallest standard errors and thus the greatest precision. CONCLUSION: Further exploitation of the use of qualitative trait analysis in GWAS in ADS is warranted.

Seeing is believing? When scanning electron microscopy (SEM) meets clinical dentistry: The replica technique.

In restorative dentistry, the in situ replication of intra-oral situations, is based on a non-invasive and non-destructive scanning electron microscopy (SEM) evaluation method. The technique is suitable for investigation restorative materials and dental hard- and soft-tissues, and its interfaces. Surface characteristics, integrity of interfaces (margins), or fracture analysis (chipping, cracks, etc.) with reliable resolution and under high magnification (from ×50 to ×5,000). Overall the current study aims to share detailed and reproducible information about the replica technique. Specific goals are: (a) to describe detailed each step involved in producing a replica of an intra-oral situation, (b) to validate an integrated workflow based on a rational sequence from visual examination, to macrophotography and SEM analysis using the replica technique; (c) to present three clinical cases documented using the technique. A compilation of three clinical situations/cases were analyzed here by means the replica technique showing a wide range of possibilities that can be reached and explored with the described technique. This guidance document will contribute to a more accurate use of the replica technique and help researchers and clinicians to understand and identify issues related to restorative procedures under high magnification.

The current status of immunotherapy in peritoneal carcinomatosis.

INTRODUCTION: Peritoneal carcinomatosis (PC) is a cancer disease with an urgent need for effective treatment. Conventional chemotherapy failed to show acceptable results. Cytoreductive surgery and hyperthermic chemoperfusion (HIPEC) are only beneficial in few patients with resectable peritoneal metastasis. Immunotherapy could be attractive against PC, as all requirements for immunotherapy are available in the peritoneal cavity. AREAS COVERED: This review analyzes the present literature for immunotherapy of PC. Advances from immune stimulators, radionucleotide-conjugated- and bispecific antibodies to future developments like adoptive engineered T-cells with chimeric receptors are discussed. The clinical development of catumaxomab, which was the first intraperitoneal immunotherapy to be approved for clinical treatment, is discussed. The requirements for future developments are illustrated. Expert commentary: Immunotherapy of peritoneal carcinomatosis is manageable, showing striking cancer cell killing. Improved profiles of adverse events by therapy-induced cytokine release, enhanced specific killing and optimal treatment schedules within multimodal treatment will be key factors.

Transvaginal/transumbilical hybrid--NOTES--versus 3-trocar needlescopic cholecystectomy: short-term results of a randomized clinical trial.

OBJECTIVE: For cholecystectomy, both the needlescopic cholecystectomy (NC) 3-trocar technique using 2 to 3 mm trocars and the umbilical-assisted transvaginal cholecystectomy (TVC) technique have found their way into clinical routine. This study compares these 2 techniques in female patients who are in need of an elective cholecystectomy. BACKGROUND: Natural orifice transluminal endoscopic surgery (NOTES) is a surgical concept permitting scarless intra-abdominal operations through natural orifices, such as the vagina. Because of the lack of an adequately powered trial, we designed this first randomized controlled study for the comparison of TVC and NC. METHODS: This prospective, randomized, nonblinded, single-center trial evaluates the safety and effectiveness of TVC (intervention), compared with NC (control) in female patients with symptomatic cholecystolithiasis. The primary endpoint was intensity of pain until the morning of postoperative day (POD) 2. Secondary outcomes were among others intra- and postoperative complications, procedural time, amount of analgesics used, pain intensity until POD 10, duration of hospital stay, satisfaction with the aesthetic result, and quality of life on POD 10 as quantified with the Eypasch Gastrointestinal Quality of Life Index (GIQLI). RESULTS: Between February 2010 and June 2012, 40 patients were randomly assigned to the interventional or control group. All patients completed follow-up. Procedural time, length of postoperative hospital stay, and the rate of intra- and postoperative complications were similar in the 2 groups. However, significant advantages were found for the transvaginal access regarding pain until POD 2, but also until POD 10 (P = 0.043 vs P = 0.010) despite significantly less use of peripheral analgesics (P = 0.019). In the TVC group, patients were significantly more satisfied with the aesthetic result (P < 0.001) and had a significantly better GIQLI (P = 0.028). CONCLUSIONS: Although comparable in terms of safety, TVC caused less pain, increased satisfaction with the aesthetic result, and improved postoperative quality of life in the short term.

Transvaginal hybrid NOTES cholecystectomy--results of a randomized clinical trial after 6 months.

INTRODUCTION: For cholecystectomy (CHE), both the needlescopic three-trocar technique with 2-3-mm instruments (needlescopic cholecystectomy (NC)) and the umbilically assisted transvaginal technique with rigid instruments (transvaginal cholecystectomy (TVC)) have been established for further reduction of the trauma remaining from laparoscopy. METHODS: To compare the further outcome of both techniques for elective CHE in female patients, we analyzed the secondary end points of a prospective randomized single-center trial (needlescopic versus transvaginal cholecystectomy (NATCH) trial; ClinicalTrials.gov Identifier: NCT0168577), in particular, satisfaction with aesthetics, overall satisfaction, abdominal pain, and incidence of trocar hernias postoperatively at both 3 and 6 months. After 3 months, the domains "satisfaction" and "pain" of the German version of the Female Sexual Function Index (FSFI-d) were additionally evaluated to detect respective complications. A gynecological control examination was conducted in all TVC patients after 6 months. RESULTS: Forty patients were equally randomized into the therapy and the control groups between February 2010 and June 2012. No significant differences were found for overall satisfaction with the surgical result, abdominal pain, sexual function, and the rate of trocar hernias. However, aesthetics were rated significantly better by TVC patients both after 3 and after 6 months (P = 0.004 and P < 0.001). There were no postoperative pathological gynecological findings. CONCLUSIONS: Following TVC, there is a significantly better aesthetic result as compared to NC, even at 3 and 6 months after the procedure. No difference was found for sexual function.

Transvaginal hybrid-NOTES appendectomy in routine clinical use: prospective analysis of 13 cases and description of the procedure.

BACKGROUND: Access-related abdominal wall injury is part of the operative trauma in laparoscopic appendectomy and accounts for complications. Minimizing this trauma by entering the abdominal cavity by means of natural orifice transluminal surgery (NOTES) may be achieved by a hybrid-appendectomy procedure using the transvaginal route plus a single transumbilical trocar. METHODS: Thirteen patients were prospectively analyzed following transvaginal-hybrid NOTES appendectomy. For the procedure, rigid instruments are used with the patient in lithotomy position. The procedure is performed with two transvaginal and one transumbilical access-points. The specimen is retrieved transvaginally. RESULTS: All procedures were performed without additional trocars. No conversions to standard laparoscopy or open surgery were necessary. All procedures were performed in acceptable time (mean 52 min). No intraoperative complications and two (15%) postoperative complications, an infected hematoma and an abscess, occurred. They were smoothly treated with standard techniques including one laparoscopic reoperation (8%). Drain placement or resection of a Meckel's diverticulum was easily managed without conversion. Gynecological short-term follow-up revealed one complication, which was vaginal fungal infection. It occurred after a 7-day course of antibiotics. CONCLUSION: This method is found to be feasible intraoperatively and early postoperatively in terms of possibility to manage a variety of intraoperative findings that may occur during planned appendectomy, low intraoperative complications, and management of postoperative complications using established concepts. We, therefore, consider the procedure safe and continue to offer hybrid-NOTES appendectomy to suitable patients.

Relative lymphocyte count is a prognostic parameter in cancer patients with catumaxomab immunotherapy.

BACKGROUND: Catumaxomab (anti-EpCAM × anti-CD3) treatment in peritoneal carcinomatosis (PC) of EpCAM-positive cancers was effective in phase I and II studies. Recently, it was approved in the EU for treatment of peritoneal carcinomatosis and malignant ascites. Aim of this hypothesis-generating study was to identify predictive or prognostic biomarkers with relevance for overall survival. METHODS: 34 patients with PC in phase I/II studies with catumaxomab treatment were assessed for age, Karnofsky Index (KI), relative (RLC) and absolute lymphocyte count, relative and absolute granulocyte count, T-cell subsets, NK cells, and monocytes before catumaxomab therapy. Disease control (responder) was defined by stable disease, partial response or complete response (RECIST v1.0) >3 months or survival >6 months. Correlation analysis, Kaplan-Meier curves, ROC calculation, and multivariate regression were used for statistical analysis. RESULTS: Mean RC values significantly differed between the non-responder (14.0%) and the responder group (23.9%; p=0.001). RLC was correlated with overall survival (p=0.03). RLC of >12% defined by ROC calculation was associated with prolonged survival (p=0.035; hazard ratio of 2.775 for patients with RLC <12%). Patients with RLC >12% showed a mean survival of 15.6 versus 5.6 months in patients with RLC ≥ 12% (p=0.001). Multivariate analysis found the individual RLC before therapy (p=0.039) and the KI performance status (p=0.002) to be independent prognostic parameters. Increasing KI by 1% resulted in a risk decrease of 10.1%. Increasing RLC by 1% resulted in a risk decrease of 4.6%. Age and the extent of PC did not significantly influence survival. CONCLUSIONS: RLC and KI were identified as potential prognostic parameters for superior disease control and overall survival after catumaxomab treatment. RLC may be used as a biomarker to indicate a suitable immune status for catumaxomab therapy. The predictive impact has to be confirmed in further studies.

Less pain after transvaginal/transumbilical cholecystectomy than after the classical laparoscopic technique: short-term results of a matched-cohort study.

BACKGROUND: Natural orifice surgery (NOS) is gaining acceptance as an alternative to the traditional laparoscopic technique, especially for cholecystectomy through the transvaginal route. However, NOS remains controversial concerning expected advantages in terms of short- and long-term outcomes and potential side effects. This study was designed to compare short-term outcomes between transvaginal/transumbilical and classical laparoscopic cholecystectomy (LC). METHODS: A prospective matched-cohort study compared the authors' first 50 transvaginal/transumbilical cholecystectomies (TVC) with a group of 50 classical LCs from the corresponding period matched in terms of age, body mass index, and American Society of Anesthesiology classification. In both groups, elective surgery was performed for symptomatic cholecystolithiasis. In the NOS group, a hybrid procedure was performed with one transumbilical rigid instrument and two transvaginal rigid instruments. A numeric rating scale was used for daily pain assessment, initiated postoperatively in the recovery room. Both groups were compared with regard to length of surgery, intra- and postoperative complications, length of hospital stay, postoperative pain, and consumption of analgesics. RESULTS: The length of surgery and the rate of complications were similar in the two groups. But significant advantages were found for the transvaginal access in terms of pain using Numeric Rating Scale (NRS) on the day of surgery (NRS, 1.5/10 vs 3.1/10; p = 0.003) as well as in the morning (NRS, 1.9/10 vs 2.8/10; p = 0.047) and in the evening (NRS, 1.1/10 vs 1.8/10; p = 0.025) of postoperative day 1, and with regard to the length of the postoperative hospital stay (2.7 vs 3.4 days; p = 0.035). CONCLUSIONS: The findings show that TVC is a safe procedure for female patients. It has a risk comparable with that of classic LC, causes significantly less pain in the early postoperative period, and leads to a significantly shorter hospital stay. Prospective randomized trials are necessary to confirm these results.

Appendectomy in Germany-an analysis of a nationwide survey 2011/2012.

INTRODUCTION: Although appendectomies are frequently performed and new procedural techniques have emerged, no nationwide analysis exists after the cessation of the German quality control in 2004. METHODS: One thousand eight hundred seventy surgical hospitals in Germany were asked to answer questions anonymously concerning the size of the department, applied procedural techniques, various technical details, as well as the approach to the intraoperative finding of an inconspicuous appendix. RESULTS: We received 643 questionnaires (34.4 %) for evaluation. Almost all hospitals (95.5 %) offer laparoscopic appendectomy (LA), 15.4 % offer single-port (SPA), and 2.2 % (hybrid-) NOTES technique (NA). LA is the standard procedure in 85.2 % of male and in 89.1 % for female patients. In an open procedure (OA), the appendix and mesoappendix are mostly ligated (93.8 and 91.5 %). A Veress needle and open access are employed equally for LA. In 66.6 % of LA, the appendix is divided using an Endo-GIA, the mesoappendix in 45.5 % with bipolar coagulation. Almost half of the hospitals routinely flush the site in OA and LA. In open surgery with an inconspicuous appendix but a pathological finding elsewhere in the abdomen, it is resected "en principe" in 64.7 % and in the absence of any pathological finding in 91.2 %. For laparoscopic procedures, the numbers are 54.8 and 88.4 %. CONCLUSIONS: Most German hospitals perform appendectomies laparoscopically regardless of patients' gender. Usage of an Endo-GIA is widely established. SPA has not gained much acceptance, nor is NA widely used yet. In the absence of any pathological findings in particular, the macroscopically inconspicuous appendix results in an appendectomy "en principe" in most German hospitals.

Restorative restproctectomy as single-port surgery through the ostomy site in a three-stage procedure.

PURPOSE: Single-port laparoscopic surgery as an alternative to traditional laparoscopic technique is anticipated to be beneficial in the early postoperative course. We describe restorative restproctectomy as single-port surgery through the ostomy site in a three-stage procedure for refractory ulcerative colitis 12 weeks after laparoscopic subtotal colectomy. SURGICAL TECHNIQUE: After release of the terminal ileostomy, creating the ileal J pouch extra-abdominally, a single-port device was placed. Through this, the rectal stump was mobilized and extracorporeally closed. The ileal pouch anal anastomosis was created using circular double-stapling technique. The single-port device was removed, and the loop ileostomy was placed at the same site. RESULTS: We employed this technique in a 54 year-old patient who had suffered from ulcerative colitis. No postoperative complications were observed. CONCLUSIONS: Restorative restproctectomy as single-port surgery through the ostomy site is safe and feasible. No additional incision is necessary. The trauma of conventional laparoscopic access can be further reduced.

Pharmacokinetics, immunogenicity and bioactivity of the therapeutic antibody catumaxomab intraperitoneally administered to cancer patients.

AIMS: Catumaxomab is the first EMEA approved trifunctional anti-EpCAMxanti-CD3 antibody for the treatment of cancer patients with malignant ascites. A phase II pharmacokinetic study was conducted to determine local and systemic antibody concentrations and anti-drug antibody (ADA) development. METHODS: Thirteen cancer patients with symptomatic malignant ascites were treated with four ascending doses of 10, 20, 50, and 150 microg catumaxomab intraperitoneally (i.p.) infused on days 0, 3, 6 or 7 and 10. The pharmacokinetics of catumaxomab were studied by implementation of supportive data from a non clinical mouse tumour model. Additionally, ADA development was monitored. RESULTS: Ten out of 13 patients were evaluable for pharmacokinetic analysis. Catumaxomab became increasingly concentrated in ascites during the course of treatment, attaining effective concentrations in the ng ml(-1) range. Catumaxomab remained immunologically active even after several days in the circulation. The observed systemic catumaxomab exposure was low (<1%), with a maximal median plasma concentration (C(max)) of 403 pg ml(-1). The mean elimination half-life in the plasma was 2.13 days. All patients developed ADA, but not before the last infusion. High observed inter-individual variability and low systemic exposure may be explained by the inverse correlation between tumour burden, effector cell numbers and systemic antibody bioavailability as demonstrated in a defined mouse tumour model. CONCLUSIONS: Based on the high and effective local concentrations, low systemic exposure and acceptable safety profile, we confirmed that the i.p. application scheme of catumaxomab for the treatment of malignant ascites is appropriate.

Effective relief of malignant ascites in patients with advanced ovarian cancer by a trifunctional anti-EpCAM x anti-CD3 antibody: a phase I/II study.

PURPOSE: Malignant ascites in ovarian carcinoma patients is associated with poor prognosis and reduced quality of life. The trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3) enhances the antitumor activity by redirecting T cells and Fcgamma receptor I/III--positive accessory cells to the tumor. This multicenter phase I/II dose-escalating study investigated tolerability and efficacy of i.p. catumaxomab application in ovarian cancer patients with malignant ascites containing epithelial cell adhesion molecule (EpCAM)--positive tumor cells. EXPERIMENTAL DESIGN: Twenty-three women with recurrent ascites due to pretreated refractory ovarian cancer were treated with four to five i.p. infusions of catumaxomab in doses of 5 to 200 microg within 9 to 13 days. RESULTS: The maximum tolerated dose was defined at 10, 20, 50, 200, and 200 microg for the first through fifth doses. Side effects included transient fever (83%), nausea (61%), and vomiting (57%), mostly CTCAE (Common Terminology Criteria for Adverse Events) grade 1 or 2. A total of 39 grade 3 and 2 grade 4 treatment-related adverse events (AE), 9 of them after the highest dose level (200 microg), were observed in 16 patients. Most AEs were reversible without sequelae. Treatment with catumaxomab resulted in significant and sustained reduction of ascites flow rate. A total of 22/23 patients did not require paracentesis between the last infusion and the end of study at day 37. Tumor cell monitoring revealed a reduction of EpCAM-positive malignant cells in ascites by up to 5 log. CONCLUSION: I.p. immunotherapy with catumaxomab prevented the accumulation of ascites and efficiently eliminated tumor cells with an acceptable safety profile. This suggests that catumaxomab is a promising treatment option in ovarian cancer patients with malignant ascites.

Urokinase system expression in gastric carcinoma: prognostic impact in an independent patient series and first evidence of predictive value in preoperative biopsy and intestinal metaplasia specimens.

BACKGROUND: The prognostic relevance of urokinase-type plasminogen activator (u-PA), u-PA receptor (u-PAR), and plasminogen activator inhibitor 1 (PAI-1) in gastric carcinoma was demonstrated in an independent patient series. To the authors' knowledge,the roles of these activators as predictors of aggressive phenotypes in preoperative biopsies, Helicobacter pylori infection, and intestinal metaplasia have to date not been investigated simultaneously in resected tumors. The objectives of the current study were 1) to demonstrate the prognostic relevance of u-PA, u-PAR, and PAI-1 in an independent series; 2) to evaluate u-PA system expression in preoperative biopsy specimens compared with resected tumors; and 3) to evaluate u-PA system expression in intestinal metaplasias and samples with H. pylori infection. METHODS: In 104 patients with gastric carcinoma (median follow-up, 68 mos), u-PA, u-PAR, and PAI-1 in tumors and metaplasias were evaluated immunohistochemically. Preoperative biopsies were evaluated in a subset of patients. Patients were screened for H. pylori (urease) and tumor cells in bone marrow (u-PAR/CK18). RESULTS: u-PA and PAI-1 were confirmed as independent prognostic parameters, and u-PAR was associated with a trend toward a poor prognosis. u-PA system tumor expression was found to be correlated significantly with u-PAR in disseminated tumor cells and H. pylori-infected tumors, implicating a role of H. pylori in protease induction. There was a significant correlation noted between u-PA system staining between preoperative biopsies and the results in resected tumors. The expression of u-PAR and PAI-1 in intestinal metaplasias was found to be associated significantly with advanced tumor stage (depth of invasion; pathologic tumor status) and lymph node involvement (pathologic lymph node status) and was correlated significantly with u-PA system expression in tumors. CONCLUSIONS: To the author's know the current study is the first to date to demonstrate that u-PA system expression may serve as a predictor of risk in intestinal metaplasias and preoperative biopsies, implicating consequences for neoadjuvant therapy. The independent impact on recurrence and survival and a correlation with u-PAR-expression of minimal residual disease were identified in this independent series.