Markus Maria Heiss

Laparoscopic extraperitoneal rectal cancer surgery: the clinical practice guidelines of the European Association for Endoscopic Surgery (EAES)

BackgroundThe laparoscopic approach is increasingly applied in colorectal surgery. Although laparoscopic surgery in colon cancer has been proved to be safe and feasible with equivalent long-term oncological outcome compared to open surgery, safety and long-term oncological outcome of laparoscopic surgery for rectal cancer remain controversial. Laparoscopic rectal cancer surgery might be efficacious, but indications and limitations are not clearly defined. Therefore, the European Association for Endoscopic Surgery (EAES) has developed this clinical practice guideline.MethodsAn international expert panel was invited to appraise the current literature and to develop evidence-based recommendations. The expert panel constituted for a consensus development conference in May 2010. Thereafter, the recommendations were presented at the annual congress of the EAES in Geneva in June 2010 in a plenary session. A second consensus process (Delphi process) of the recommendations with the explanatory text was necessary due to the changes after the consensus conference.ResultsLaparoscopic surgery for extraperitoneal (mid- and low-) rectal cancer is feasible and widely accepted. The laparoscopic approach must offer the same quality of surgical specimen as in open surgery. Short-term outcomes such as bowel function, surgical-site infections, pain and hospital stay are slightly improved with the laparoscopic approach. Laparoscopic resection of rectal cancer is not inferior to the open in terms of disease-free survival, overall survival or local recurrence. Laparoscopic pelvic dissection may impair genitourinary and sexual function after rectal resection, like in open surgery.ConclusionsLaparoscopic surgery for mid- and low-rectal cancer can be recommended under optimal conditions. Still, most level 1 evidence is for colon cancer surgery rather than rectal cancer. Upcoming results from large randomised trials are awaited to strengthen the evidence for improved short-term results and equal long-term results in comparison with the open approach.

Clinical efficacy of cytoreductive surgery and hyperthermic chemotherapy in peritoneal carcinomatosis from gastric cancer.

Evaluation of: Yang XJ, Huang CQ, Suo T et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves survival of patients with peritoneal carcinomatosis from gastric cancer: final results of a Phase III randomized clinical trial. Ann. Surg. Oncol. 18(6), 1575–15781 (2011). Peritoneal carcinomatosis (PC) is the most common pattern of metastasis and recurrence in patients with gastric cancer and is associated with poor clinical outcome and survival. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) was recently established as a new treatment option for PC of gastrointestinal cancer. However, the role of cytoreductive surgery in gastric cancer and the intrinsic role of HIPEC remains unclear. The evaluated article presented a single center Phase III study, randomizing 68 patients with PC from gastric cancer to surgical cytoreduction only (CRS; n = 34) versus cytoreduction plus HIPEC with cisplatin and mitomycin (CRS+HIPEC; n = 34). Median overall was 6.5 months in the CRS group and 11.0 months in the CRS+HIPEC group (p = 0.046). Serious adverse events were acceptable in both groups. Multivariate analysis found CRS+HIPEC, synchronous PC, complete cytoreduction, systemic chemotherapy >6 cycles and no incidence of severe adverse events independent predictive factors for survival. This was the first study to show the positive effects of HIPEC in addition to CRS in PC independently of the tumor entity. In patients with gastric cancer, multimodal treatment concepts combining surgical cytoreduction and HIPEC may provide a new option in carefully selected 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.

The current status of immunotherapy in peritoneal carcinomatosis

ABSTRACT 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.

Erratum to: Transvaginal hybrid NOTES cholecystectomy—results of a randomized clinical trial after 6 months

1 Department of Abdominal, Vascular and Transplant Surgery, Cologne-Merheim Medical Center, Witten/Herdecke University, Ostmerheimer Strasse 200, 51109 Cologne, Germany 2 Department of General, Visceral, Vascular and Thoracic Surgery, Clinic of Kempten, Robert-Weixler-Strasse 50, 87439 Kempten, Germany 3 Department for Obstetrics and Gynecology, Holweide Hospital, Neufelder Strasse 32, 51067 Cologne, Germany Langenbecks Arch Surg DOI 10.1007/s00423-016-1472-6 (2019) 404 (Suppl 1):S25

Erratum to: Appendectomy in Germany—an analysis of a nationwide survey 2011/2012

Stapling device/endo-GIA 3.6 66.6 Endoloop only n.a. 24.2 Endoloop with purse string/Z-suture n.a. 2.6 Resorbable clips 2.2 3.8 Nonresorbable clips 0.3 1.2 Mesoappendix Ligation 91.5 n.a. Bipolar coagulation 6.1 45.5 Stapling device 1.2 12.5 Resorbable clips 0.9 15.1 Nonresorbable clips 0.3 9.2 Monopolar coagulation n.a. 6.4 Lavage routinely Yes 48.1 49.9 No 51.9 50.1 Abdominal drain Always/mostly 9.5 8.3 Rarely/never 21.4 34.5 Depending on intraoperative finding 69.1 57.2 Subcutaneous Redon drain Always/mostly 4.5 n.a. Rarely/never 75.6 n.a. Depending on intraoperative finding 19.9 n.a. Subcutaneous suture Always/mostly 42.6 n.a. Rarely/never 42.4 n.a. Depending on intraoperative finding 15 n.a. Skin closing Intracutaneous and resorbable 36.5 48.3 Interrupted sutures 35.2 44.8 Staples 14.1 3.1 Intracutaneous and non resorbable 10.3 3.8

Effektivität der intraperitonealen Immuntherapie mit dem trifunktionalen Antikörper Catumaxomab (anti-EpCAM x anti-CD3) bei Patienten mit gastrointestinalen Karzinomen: Ergebnisse einer matched-pair Analyse

Background: Peritoneal carcinomatosis (PC) of gastrointestinal cancer is an advanced tumor stage with limited prognosis. Presently, there is no standard therapy available. The trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3) represents a novel class of antibodies, which is able to activate T lymphocytes against tumor cells. Simultaneously, they are able to stimulate FcγRI/III+ antigen presenting cells (APC) and to induce cellular anti-tumor immunity. The clinical efficacy of intraperitoneal catumaxomab treatment was evaluated in patients with PC in a prospective phase I/II trial by a matched pair analysis. Methods: 22 Patients (8 gastric-ca, 10 colon-ca, 3 pancreatic-ca, 1 CUP) with EpCAM positive peritoneal carcinomatosis were included. Treatment consisted of 4 i. p. applications (10-20-50-200 μg) within 10 days. Abdominal lavages were analysed by immunohistochemical staining. A clinical follow-up was done every 6 weeks, CT-scans were evaluated by RECIST criteria. A matched pair analysis regarding sex, age, surgery, chemotherapy and PC stage. Patients with ileus or ascites were excluded. Results: Analysis of abdominal lavages showed a significant tumor cell destruction (p = 0.04, chi-square). RECIST evaluation was done in 15 patients, which showed complete or partial response in 3/15 patients and stable disease in 8/15 patients. Matched pair analysis showed a mean survival of 15.5 months after diagnosis of PC in the catumaxomab group vs. 9.7 months in patients with any other therapy (p = 0.005, logrank). Conclusion: Intraperitoneal Immunotherapy with the trifunctional antibody catumaxomab is a promising option for treatment of peritoneal carcinomatosis in patients with gastrointestinal cancer, which will be evaluated in further phase II/III trials.

Intraperitoneale Applikation trifunktioneller Antikörper: Ein neuartiges Konzept zur Behandlung der Peritonealkarzinose solider Tumoren

Introduction: Peritoneal carcinomatosis of solid tumor is a fatal tumor diagnosis without standard treatment. In a pilot study, a new therapy concept using trifunctional antibodies (trAb) was evaluated, which are able to redirect CD3+ T-lymphocytes to tumor cells and to induce anti-tumor immunity by activation of Fcγ-receptor type I and III accessory cells by their intact Fc fragment. Material and methods: In 9 patients (group A) with peritoneal carcinomatosis of solid tumors, intraperitoneal application of trAb was performed after tumor resection and/or ineffective chemotherapy. Additionally, 8 patients with malignant ascites due to peritoneal carcinomatosis (group B) were treated intraperitoneally. Treatment consisted of 2–6 applications of the trAbs anti-EpCAM × anti-CD3 or anti-HER2/neu × anti-CD3 (30–940) µg within 9–23 days. In group A, restimulation by trAb + PBMC + irradiated autologous tumor cells was performed after 30 days. After another 10 days, specific tumor reactive T-lymphocytes were detected by FACS analysis. In group B, monitoring of tumor cells in ascites was done by immunofluorescence staining, FACS and PCR analysis. Results: i. p. treatment was tolerated without severe side effects. In group A, 5/9 patients had tumor reactive T-lymphocytes after therapy and restimulation. 5/9 patients showed a clinical response (stable disease, partial remission) with time to progression of 3.6 months. In group B, ascites accumulation was diminished in 8/8 patients, which was correlated to a total elimination of tumor cells in ascites (p = 0.04). Conclusion: Intraperitoneal application of trifunctional antibodies showed convincing immunological effects, as induction of active anti-tumor immunity and clinical efficacy was seen in patients with peritoneal carcinomatosis. The novel concept is actually evaluated in clinical phase II/III trials.