Publications by authors named "Philipp Horvath"

30 Publications

  • Page 1 of 1

Retrospective analysis of different therapeutic approaches for retroperitoneal duodenal perforations.

Sci Rep 2022 Jun 17;12(1):10243. Epub 2022 Jun 17.

Department of General, Visceral and Transplant Surgery, University Hospital of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.

Surgical therapy of duodenal perforation into the retroperitoneum entails high morbidity. Conservative treatment and endoscopic negative pressure therapy have been suggested as promising therapeutic alternatives. We aimed to retrospectively assess outcomes of patients treated for duodenal perforation to the retroperitoneum at our department. A retrospective analysis of all patients that were treated for duodenal perforation to the retroperitoneum at our institution between 2010 and 2021 was conducted. Different therapeutic approaches with associated complications within 30 days, length of in-hospital stay, number of readmissions and necessity of parenteral nutrition were assessed. We included thirteen patients in our final analysis. Six patients underwent surgery, five patients were treated conservatively and two patients received interventional treatment by endoscopic negative pressure therapy. Length of stay was shorter in patients treated conservatively. One patient following conservative and surgical treatment each was readmitted to hospital within 30 days after initial therapy whereas no readmissions after interventional treatment occurred. There was no failure of therapy in patients treated without surgery whereas four (66.7%) of six patients required revision surgery following primary surgical therapy. Conservative and interventional treatment were associated with fewer complications than surgical therapy which involves high morbidity. Conservative and interventional treatment using endoscopic negative pressure therapy in selected patients might constitute appropriate therapeutic alternatives for duodenal perforations to the retroperitoneum.
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http://dx.doi.org/10.1038/s41598-022-14278-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9205956PMC
June 2022

Current Medical Care Situation of Patients in Germany Undergoing Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC).

Cancers (Basel) 2022 Mar 11;14(6). Epub 2022 Mar 11.

Department of General, Visceral and Thoracic Surgery, Academic Teaching Hospital Feldkirch, Carinagasse 47, 6807 Feldkirch, Austria.

Objective: Tailored approaches in gastrointestinal oncology have been more frequently introduced in past years and for patients with peritoneal metastases. This article attempts to overview the current strategies in surgical gastrointestinal oncology, with a focus on gastrointestinal peritoneal metastases.

Methods: In 2019, all patients undergoing PIPAC therapy in Germany were retrospectively analyzed regarding morbidity and in-hospital mortality rates. Furthermore, patients with chemotherapy-refractory peritoneal metastases from gastric cancer undergoing PIPAC-therapy at our institution were analyzed.

Results: In 2019, 534 patients received PIPAC treatment in german hospitals. The in-hospital mortality rate was 0%. In total, 36 patients suffered from postoperative complications (8%). From April 2016 to September 2021, a total of 44 patients underwent 93 PIPAC applications at our institution. The non-access-rate was 0%. The median PRGS was two (range, 1-4). Eleven patients (44%) showed histologically stable disease, whereas six patients (24%) showed histological regression. Median survival, calculated from the date of the first PIPAC application, was 181 days (range, 43-636 days).

Conclusions: PIPAC is a safe and feasible procedure with a low in-hospital morbidity and mortality. Furthermore, PIPAC in the palliative and chemorefractory setting and is an appealing approach for patient management in the future.
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http://dx.doi.org/10.3390/cancers14061443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8946267PMC
March 2022

Limitations of laparoscopy to assess the peritoneal cancer index and eligibility for cytoreductive surgery with HIPEC in peritoneal metastasis.

Langenbecks Arch Surg 2022 Jun 2;407(4):1667-1675. Epub 2022 Feb 2.

Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.

Purpose: We aimed to determine the value of laparoscopy to assess the intra-abdominal tumor extent and predict complete cytoreduction.

Methods: All patients at our department in the period from 2017 to 2021 that underwent laparoscopy to assess peritoneal metastasis and subsequent open exploration with the intention to perform cytoreductive surgery (CRS) with HIPEC were retrospectively identified in a continuously maintained database.

Results: Forty-three patients were analyzed. Peritoneal cancer index (PCI) determination by laparoscopy compared to open surgery was overestimated in five patients (11.6%), identical in eleven patients (25.6%), and underestimated in 27 patients (62.8%). PCI differences were independent of surgeons, tumor entities, and prior chemotherapy. Thirty-four patients (79.1%) were determined eligible for CRS with HIPEC during open exploration, whereas nine patients (20.9%) underwent a non-therapeutic laparotomy. Complete or almost complete cytoreduction was achieved in 33 patients (76.7%). In one patient, completeness of cytoreduction was not documented.

Conclusions: We demonstrate a moderate agreement according to weighted Cohen's kappa analysis of PCI values calculated during laparoscopy and subsequent open exploration for CRS with HIPEC. Uncertainty of PCI assessment should therefore be kept in mind when performing laparoscopy in patients with peritoneal metastasis.
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http://dx.doi.org/10.1007/s00423-022-02455-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8809494PMC
June 2022

The ISSPP PIPAC database: design, process, access, and first interim analysis.

Pleura Peritoneum 2021 Sep 22;6(3):91-97. Epub 2021 Apr 22.

Department of Surgery, Odense University Hospital, Odense, Denmark.

Objectives: Several trials have documented the favorable safety profile, and promising clinical results of pressurized intraperitoneal aerosol chemotherapy (PIPAC) directed treatment in different types of peritoneal malignancies. However, until the results of randomized trials are available, the quality of documentation and acceptance by the users may be improved through a worldwide registry. The International Society for the Study of Pleura and Peritoneum (www.ISSPP.org) facilitated this process by creating a dedicated focus group and providing the funding needed for the creation and implementation of an international database. This article describes the design and the journey of establishing this international database and the first, preliminary results from the ISSPP PIPAC online database.

Methods: In 2019 the ISSPP PIPAC Registry Group started to create a database with a minimal dataset relevant to many diseases and applicable in different framework conditions. The task was divided into three phases including design, testing, implementation, protocol, handbook, legal requirements, as well as registry rules and bylaws for the registry group.

Results: The ISSPP PIPAC online database has six key elements (patient, consent, treatment, complications, response evaluation and follow-up). Following design, testing and implementation the database was successfully launched in June 2020. Ten institutions reported on 459 PIPAC procedures in 181 patients during the first 6 months, and the recorded data were comparable to the present literature.

Conclusions: A new international multicenter PIPAC database has been developed, tested and implemented under the auspices of ISSPP. The database is accessible through the ISSPP website (www.ISSPP.org), and PIPAC institutions worldwide are highly encouraged to participate.
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http://dx.doi.org/10.1515/pp-2021-0108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482445PMC
September 2021

Cost-effectiveness analysis of pressurized intraperitoneal aerosol chemotherapy (PIPAC) in patients with gastric cancer and peritoneal metastasis.

Eur J Surg Oncol 2022 Jan 28;48(1):188-196. Epub 2021 Aug 28.

Mercer University, College of Pharmacy, Atlanta, GA, United States. Electronic address:

Objective: The aim of this study was to assess the cost-effectiveness of pressurized intraperitoneal aerosol chemotherapy with low-dose cisplatin and doxorubicin (PIPAC C/D) for the treatment of advanced gastric cancer.

Methods: A Partitioned Survival Model followed by state transition Markov model was developed to estimate the costs and effectiveness of the use of PIPAC C/D versus palliative chemotherapy in the UK. The intervention was assessed at two different levels of care, including upfront therapy (PIPAC C/D plus Oxaliplatin in combination with Capecitabine (XELOX) chemotherapy versus first-line chemotherapy alone) and second-line therapy (PIPAC C/D alone versus second-line chemotherapy (ramucirumab monotherapy)). Data from multiple sources, including published literature and UK-based databases, were used to inform the economic model.

Results: For the upfront therapy analysis, the estimated total costs in the intervention and comparator arms were £32,606 (SD: £3877) and £17,844 (SD: £920), respectively. PIPAC C/D plus XELOX led to an increase of 0.46 in quality-adjusted life-years (QALYs) gained. The incremental cost per QALY gained was £31,868. For the second-line therapy analysis, the use of PIPAC C/D led to an increase of 0.19 in QALYs and a £21,474 reduction in costs, meaning the intervention was a dominant strategy.

Conclusions: The cost-effectiveness results for the upfront therapy analysis indicate that PIPAC C/D plus chemotherapy is a cost-effective strategy. Additionally, PIPAC C/D alone as a second-line therapy has the potential to reduce costs and improve clinical outcomes for patients with advanced gastric cancer with peritoneal metastasis.
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http://dx.doi.org/10.1016/j.ejso.2021.08.024DOI Listing
January 2022

A Prospective, Phase I/II, Open-Label Pilot Trial to Assess the Safety of Hyperthermic Intraperitoneal Chemotherapy After Oncological Resection of Pancreatic Adenocarcinoma.

Ann Surg Oncol 2021 Dec 15;28(13):9086-9095. Epub 2021 Jun 15.

Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a common fatal disease with unfavorable prognosis, even after oncological resection. To improve survival, adding hyperthermic intraperitoneal chemotherapy (HIPEC) has been suggested. Whether HIPEC entails disproportional short-term mortality is unknown and a prospectively determined adverse events profile is lacking. Since both pancreatic resection and HIPEC may relevantly influence morbidity and mortality, this uncontrolled single-arm, open-label, phase I/II pilot trial was designed to assess the 30-day mortality rate, treatment feasibility, and adverse events connected with HIPEC after oncological pancreatic surgery.

Methods: This trial recruited patients scheduled for PDAC resection. A sample size of 16 patients receiving study interventions was estimated to establish a predefined margin of treatment-associated short-term mortality with a power of > 80%. Patients achieving complete macroscopic resection received HIPEC with gemcitabine administered at 1000 mg/m body surface area heated to 42 °C for 1 hour.

Results: Within 30 days after intervention, no patient died or experienced any adverse events higher than grade 3 that were related to HIPEC. Furthermore, treatment-related adverse events were prospectively documented and categorized as expected or unexpected. This trial supports that the actual mortality rate after PDAC resection and HIPEC is below 10%. HIPEC treatment proved feasible in 89% of patients allocated to intervention. Pancreatic fistulas, as key complications after pancreas surgery, occurred in 3/13 patients under risk.

Conclusion: Combined pancreas resection and gemcitabine HIPEC proved feasible and safe, with acceptable morbidity and mortality. Based on these results, further clinical evaluation can be justified.

Registration Number: NCT02863471 ( http://www.clinicaltrials.gov ).
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http://dx.doi.org/10.1245/s10434-021-10187-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205203PMC
December 2021

Twelve-Year Single Center Experience Shows Safe Implementation of Developed Peritoneal Surface Malignancy Treatment Protocols for Gastrointestinal and Gynecological Primary Tumors.

Cancers (Basel) 2021 May 19;13(10). Epub 2021 May 19.

Comprehensive Cancer Center, Department of General, Visceral and Transplant Surgery, University of Tübingen, 72076 Tübingen, Germany.

(1) : Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy provide survival benefits to selected patients. We aimed to report our experience and the evolution of our peritoneal surface malignancy program. (2) : From June 2005 to June 2017, 399 patients who underwent cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy at the Tübingen University Hospital were analyzed from a prospectively collected database. (3) : Peritoneal metastasis from colorectal cancer was the leading indication (group 1: 28%; group 2: 32%). The median PCI was 15.5 (range, 1-39) in group 1 and 11 (range, 1-39) in group 2 ( = 0.002). Regarding the completeness of cytoreduction (CC), a score of 0 was achieved in 63% vs. 69% for group 1 and 2, respectively ( = 0.010). Median overall survival rates for patients in group 1 and 2 for colon cancer, ovarian cancer, gastric cancer and appendix cancer were 34 and 25 months; 45 months and not reached; 30 and 16 months; 39 months and not reached, respectively. The occurrence of grade-III and -IV complications slightly differed between groups (14.5% vs. 15.6%). No 30-day mortality occurred. (4) : Specialized centers are able to provide low-morbidity cytoreductive surgery and hyperthermic intraperitoneal chemotherapy without mortality. Strict patient selection during the time period significantly improved CC scores.
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http://dx.doi.org/10.3390/cancers13102471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159136PMC
May 2021

Reply to: "Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Definitively Does Not Deserve Its Bad Reputation".

Ann Surg Oncol 2021 09 26;28(9):5450-5451. Epub 2021 Feb 26.

Department of General, Visceral and Transplant Surgery, Comprehensive Cancer Center, University of Tübingen, Tübingen, Germany.

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http://dx.doi.org/10.1245/s10434-021-09743-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349317PMC
September 2021

In-Hospital Mortality and Complication Rates According to Health Insurance Data in Patients Undergoing Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Surface Malignancies in Germany.

Ann Surg Oncol 2021 Jul 9;28(7):3823-3830. Epub 2020 Nov 9.

Department of General, Visceral and Transplant Surgery, Comprehensive Cancer Center, University of Tübingen, Tübingen, Germany.

Background: Morbidity and in-hospital mortality rates of patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in Germany are not known.

Methods: From 2009 to 2018 all patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in Germany were retrospectively analyzed regarding morbidity and in-hospital mortality rates according to nationwide hospital billing data based on diagnosis-related groups (DRG). The "failure to rescue" (FTR) index, characterizing patients who died after severe but potentially manageable complications, was calculated.

Results: In total, 8463 patients were included and analyzed. Female sex predominated (1.5:1). Colonic origin of peritoneal metastasis was highest throughout all years, reaching its highest level in 2017 (55%; n = 563) and its lowest level in 2012 (40%; n = 349). Median length of hospital stay reached its maximum in 2017 at 23.9 days and its minimum in 2010 at 22.0 days. Analysis of the total FTR index showed a noticeable improvement over the years, reaching its lowest values in 2017 (9.8%) and 2018 (8.8%). The FTR index for sepsis, peritonitis, and pulmonary complications significantly improved over time. Of the 8463 included patients, 290 died during hospital stay, reflecting an in-hospital mortality rate of 3.4%.

Conclusion: In-hospital mortality after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is reasonably low compared with other surgical procedures. The improvement in the FTR index reflects efforts to centralize treatment at specialized high-volume centers.
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http://dx.doi.org/10.1245/s10434-020-09301-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184558PMC
July 2021

Standardizing training for Pressurized Intraperitoneal Aerosol Chemotherapy.

Eur J Surg Oncol 2020 12 30;46(12):2270-2275. Epub 2020 May 30.

Department of Visceral Surgery, Lausanne University Hospital CHUV, University of Lausanne (UNIL), Switzerland.

Background: PIPAC is a novel mode of intraperitoneal drug delivery for patients with peritoneal cancer (PC). PIPAC is a safe treatment with promising oncological results. Therefore, a structured training program is needed to maintain high standards and to guarantee safe implementation.

Methods: An international panel of PIPAC experts created by means of a consensus meeting a structured 2-day training course including essential theoretical content and practical exercises. For every module, learning objectives were defined and structured presentations were elaborated. This structured PIPAC training program was then tested in five courses.

Results: The panel consisted of 12 experts from 11 different centres totalling a cumulative experience of 23 PIPAC courses and 1880 PIPAC procedures. The final program was approved by all members of the panel and includes 12 theoretical units (45 min each) and 6 practical units including dry-lab and live surgeries. The panel finalized and approved 21 structured presentations including the latest evidence on PIPAC and covering all mandatory topics. These were organized in 8 modules with clear learning objectives to be tested by 12 multiple-choice questions. Lastly, a structured quantifiable (Likert scale 1-5) course evaluation was created. The new course was successfully tested in five courses with 85 participants. Mean overall satisfaction with the content was rated at 4.79 (±0.5) with at 4.71 (±0.5) and at 4.61 (±0.7), respectively for course length and the balance between theory and practice.

Conclusions: The proposed PIPAC training program contains essential theoretical background and practical training enabling the participants to safely implement PIPAC.
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http://dx.doi.org/10.1016/j.ejso.2020.05.007DOI Listing
December 2020

Overcoming Drug Resistance by Taking Advantage of Physical Principles: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC).

Cancers (Basel) 2019 Dec 20;12(1). Epub 2019 Dec 20.

National Center for Pleura and Peritoneum, University of Tübingen, 72076 Tübingen, Germany.

Theoretical considerations as well as comprehensive preclinical and clinical data suggest that optimizing physical parameters of intraperitoneal drug delivery might help to circumvent initial or acquired resistance of peritoneal metastasis (PM) to chemotherapy. Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is a novel minimally invasive drug delivery system systematically addressing the current limitations of intraperitoneal chemotherapy. The rationale behind PIPAC is: 1) optimizing homogeneity of drug distribution by applying an aerosol rather than a liquid solution; 2) applying increased intraperitoneal hydrostatic pressure to counteract elevated intratumoral interstitial fluid pressure; 3) limiting blood outflow during drug application; 4) steering environmental parameters (temperature, pH, electrostatic charge etc.) in the peritoneal cavity for best tissue target effect. In addition, PIPAC allows repeated application and objective assessment of tumor response by comparing biopsies between chemotherapy cycles. Although incompletely understood, the reasons that allow PIPAC to overcome established chemoresistance are probably linked to local dose intensification. All pharmacological data published so far show a superior therapeutic ratio (tissue concentration/dose applied) of PIPAC vs. systemic administration, of PIPAC vs. intraperitoneal liquid chemotherapy, of PIPAC vs. Hyperthermic Intraperitoneal Chemotherapy (HIPEC) or PIPAC vs. laparoscopic HIPEC. In the initial introduction phase, PIPAC has been used in patients who were quite ill and had already failed multiple treatment regimes, but it may not be limited to that group of patients in the future. Rapid diffusion of PIPAC in clinical practice worldwide supports its potential to become a game changer in the treatment of chemoresistant isolated PM of various origins.
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http://dx.doi.org/10.3390/cancers12010034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016575PMC
December 2019

Pressurized intraperitoneal aerosol chemotherapy with low-dose cisplatin and doxorubicin (PIPAC C/D) in patients with gastric cancer and peritoneal metastasis: a phase II study.

Ther Adv Med Oncol 2019 13;11:1758835919846402. Epub 2019 May 13.

Department of General and Transplant Surgery, University Hospital Tübingen, Germany National Center for Pleura and Peritoneum, University Hospital, Tübingen, Germany.

Background: Efficacy of second-line systemic chemotherapy in recurrent gastric cancer with peritoneal metastasis (RGCPM) is limited. We assessed the feasibility, safety and possible efficacy of pressurized intraperitoneal aerosol chemotherapy (PIPAC) in patients with RGCPM after ⩾1 line of palliative intravenous chemotherapy.

Methods: In this open-label, single-arm, monocentric phase II ICH-GCP clinical trial, patients were scheduled for three courses of PIPAC with cisplatin 7.5 mg/m and doxorubicin 1.5 mg/m (PIPAC C/D) every 6 weeks. Patients with bowel obstruction or extraperitoneal metastasis were ineligible. The primary endpoint was clinical benefit rate (CBR) by Response Evaluation Criteria in Solid Tumors based on clinical records. Secondary endpoints included overall survival (OS), median time to progression (TTP), peritoneal carcinomatosis index (PCI), histological regression and ascites volume. Safety and tolerability were assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4, quality of life (QoL) by EORTC-QLQ30 questionnaire.

Results: A total of 25 patients were enrolled and available for the analysis of the primary endpoint. Of those 25 patients, 10 (40%) had a radiological complete, partial response or stable disease. Median OS [intention to treat (ITT)] was 6.7 months, median TTP was 2.7 months. Complete or major regression on histology were observed in 9/25 patients (36%, ITT) or 6/6 [100%, per protocol (PP)] patients. There were no suspected unexpected serious adverse reactions, no treatment-related deaths, no CTCAE grade 4 toxicity and three (12%) grade 3 toxicities. Changes in the QLQ-C30 scores during PIPAC C/D therapy were small and not significant.

Conclusions: PIPAC C/D was well tolerated and active in patients with RGCPM. Survival was encouraging. Randomized controlled trials should now be designed in this indication.
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http://dx.doi.org/10.1177/1758835919846402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535725PMC
May 2019

Staging laparoscopy and Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) for peritoneal metastasis: safe access to the abdomen.

Pleura Peritoneum 2019 Mar 21;4(1):20190004. Epub 2019 Mar 21.

Department of General and Transplant Surgery and National Center for Pleura and Peritoneum, University of Tübingen, Tübingen, Germany.

Background: Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) is an innovative drug delivery technique. Most common indication is palliative therapy of peritoneal metastasis of gastrointestinal and gynecological origin in the salvage situation. Access to the abdomen is the critical step of the procedure, since most patients had previous surgery. Potential pitfalls include non-access because of adhesions, bowel access lesions and postoperative subcutaneous toxic emphysema.

Methods: We propose a technique, the "finger-access technique" that might prevent largely these pitfalls. A minilaparotomy of 3 cm is performed in the midline, a finger introduced into the abdomen and a 5-mm double-balloon trocar (no Hasson trocar) is placed under finger protection at some distance of the first incision. The fascia of the minilaparotomy, not the skin, is then closed. The abdomen is insufflated with CO and tightness is controlled with saline solution in the minilaparotomy. A second 10-12 mm trocar is then introduced under videoscopic control. The first trocar is then visualized through the second one to exclude a bowel lesion during first access.

Results And Conclusions: In our hands, this access technique has shown to be safe and effective.
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http://dx.doi.org/10.1515/pp-2019-0004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545875PMC
March 2019

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) for Peritoneal Metastases in Solid Organ Graft Recipients: First Experience.

Ann Transplant 2019 Jan 15;24:30-35. Epub 2019 Jan 15.

Department of General, Visceral and Transplant Surgery, University of Tübingen, Tübingen, Germany.

BACKGROUND Therapy of peritoneal metastases (PM) in solid organ transplant recipients is challenging. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) might constitute a new therapeutic opportunity for these patients. MATERIAL AND METHODS This was a single-center, retrospective analysis of prospective registry data (NCT03210298) in a tertiary care center between 1.7.2016 and 31.12.2017. Intraperitoneal administration of oxaliplatin 92 mg/m² body surface or a combination of cisplatin 7.5 mg/m² and doxorubicin 1.5 mg/m², repeated every 6 weeks. Objective tumor response was documented via histology (Peritoneal Regression Grading Score, PRGS), adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) 4.0. RESULTS Out of 71 consecutive patients treated with PIPAC, 2 patients (2.8%) were solid organ transplant recipients. The first patient had metachronous PM of colonic cancer origin after liver transplantation. The second patient had synchronous PM of pancreatic cancer origin after combined kidney-pancreas transplantation. After repeated combined systemic and PIPAC chemotherapy, objective histological response was documented in both patients. No adverse events >CTCAE 2 were recorded. There was no measurable liver or renal toxicity. PIPAC procedures could be repeated (2, resp. 3 cycles) without any interruption of immunosuppressive medication or impairment of respective plasmatic drug levels. The first patient passed away 7 months after the first PIPAC, the second patient was still alive after 8 months. CONCLUSIONS PIPAC can induce objective regression of PM in solid organ transplant recipients without inducing organ toxicity or interfering with immunosuppressive therapy.
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http://dx.doi.org/10.12659/AOT.911905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346813PMC
January 2019

Cellularity in low-grade Pseudomyxoma peritonei impacts recurrence-free survival following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Langenbecks Arch Surg 2018 Dec 1;403(8):985-990. Epub 2018 Dec 1.

Department of General, Visceral and Transplant Surgery, University of Tübingen, Comprehensive Cancer Center, Hoppe-Seyler-Strasse 3, 72076, Tübingen, Germany.

Purpose: Documentation of cellularity in Pseudomyxoma peritonei (PMP) is not performed on a regular basis in everyday clinical practice, but is recommended by the PSOGI (Peritoneal Surface Oncology Group International). We investigated the impact of cellularity in PMP following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) on recurrence-free survival.

Methods: Data from 25 patients with low-grade (American Joint Committee on Cancer grade G1) PMP were retrospectively evaluated. Cellularity was categorized as acellular mucin, scant (< 2% cellularity), moderate (2-19% cellularity), or high cellularity (> 20% cellularity). Impact of cellularity, PCI, CC-score, and HIPEC regimen on recurrence-free and overall survival was primarily assessed.

Results: Assessment of cellularity showed acellular mucin in ten patients (40%), scant cellularity in 11 (44%) patients, moderate cellularity in one (4%) patient, and high cellularity in three (12%) patients. Median PCI was 15 (range, 1-39). A CC-0 score was achieved in 13 (52%) patients and a CC-1 score was achieved in 12 (48%) patients. After a median follow-up of 25 (range, 2-74) months, all patients were still alive. Overall, four (16%) patients suffered from recurrent disease after a median of 38 (range, 36-60) months. PCI above 17 (p = 0.03) and moderate and high cellularity (p = 0.007) were statistically significantly associated with recurrent disease. CC-score and HIPEC compound used did not impact on recurrence-free survival.

Conclusions: Recurrent disease occurs more often in patients with PCI values above 17 and with moderate and high cellularity in low-grade PMP. Pathological assessment of cellularity is crucial for identification of patients at risk for recurrence.
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http://dx.doi.org/10.1007/s00423-018-1735-5DOI Listing
December 2018

Feasibility, Safety, and Efficacy of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) for Peritoneal Metastasis: A Registry Study.

Gastroenterol Res Pract 2018 24;2018:2743985. Epub 2018 Oct 24.

Dept. of General Surgery, Karls-Eberhard University Tübingen, Germany.

Introduction: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel drug delivery system with superior pharmacological properties for treating peritoneal metastasis (PM). Safety and efficacy results of PIPAC with cisplatin/doxorubicin or oxaliplatin from a registry cohort are presented.

Methods: IRB-approved registry study. Retrospective analysis. No predefined inclusion criteria, individual therapeutic recommendation by the interdisciplinary tumor board. Safety assessment with CTCAE 4.0. Histological assessment of tumor response by an independent pathologist using the 4-tied peritoneal regression grading system (PRGS). Mean PRGS and ascites volume were assessed at each PIPAC.

Results: A total of 142 PIPAC procedures were scheduled in 71 consecutive patients with PM from gastric ( = 26), colorectal ( = 17), hepatobiliary/pancreatic ( = 9), ovarian ( = 6), appendiceal ( = 5) origin, pseudomyxoma peritonei ( = 4), and other tumors ( = 3). Mean age was 58 ± 13 years. Patients were heavily pretreated. Mean PCI was 19 ± 13. Laparoscopic nonaccess rate was 11/142 procedures (7.7%). Mean number of PIPAC/patient was 2. All patients were eligible for safety analysis. There was no procedure-related mortality. There were 2.8% intraoperative and 4.9% postoperative complications. 39 patients underwent more than one PIPAC and were eligible for efficacy analysis, and PRGS could be assessed in 36 of them. In 24 patients (67%), PRGS improved or remained unchanged at PIPAC#2, reflecting tumor regression or stable disease. Ascites was present in 24 patients and diminished significantly under therapy. Median survival was 11.8 months (95% CI: 7.45-16.2 months) from PIPAC#1.

Conclusion: PIPAC is feasible, safe, and well-tolerated and can induce histological regression in a significant proportion of pretreated PM patients. This trial is registered with NCT03210298.
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http://dx.doi.org/10.1155/2018/2743985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220392PMC
October 2018

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) for peritoneal metastases of pancreas and biliary tract cancer.

Clin Exp Metastasis 2018 10 30;35(7):635-640. Epub 2018 Jul 30.

Department of General, Visceral and Transplant Surgery, Comprehensive Cancer Center, University of Tübingen, Hoppe-Seyler-Strasse 3, 72076, Tübingen, Germany.

Data on the effectivness of PIPAC in patients with peritoneal metastases of pancreaticobiliary origin is scarce. We here present further proof of treatment efficacy in this subset of patients. Repetitive PIPAC treatment with low-dose cisplatin 7.5 mg/m and doxorubicin 1.5 mg/m body surface area every 6 weeks and prospective data collection. Documentation included microscopic histological regression, median overall survival and treatment-related adverse events. Twelve patients with a median age of 57 years (range 43-78 years) were included. Six patients suffered from pertioneal metastases of pancreatic adenocarcinoma (PDAC) and six patients from cholangiocarcinoma (CC). In total 23 cycles of PIPAC were adminstered with the median number of PIPAC cycles being two (range 1-4). Complete tumor regression was found in four patients and major regression in one patient. Median overall survival after the first PIPAC cycle was 12.7 months for PDAC patients and 15.1 months for CC patients. 11 of the 12 patients are still alive after a median follow-up of 438 days. There were no CTCAE Grade 3 or 4 complications. PIPAC is an innovative and attractive treatment option in the salvage situation for patients with peritoneal metastases of pancreaticobiliary tumors after failure of systemic chemotherapy. In 40% of the patients histological regression can be induced. Further studies are warranted to further elucidate treatment efficacy.
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http://dx.doi.org/10.1007/s10585-018-9925-7DOI Listing
October 2018

Multimodal Treatment Strategies for Esophageal Perforation.

Surg Laparosc Endosc Percutan Tech 2018 Aug;28(4):232-238

Departments of General, Visceral, and Transplant Surgery.

Purpose: Esophageal perforation constitutes a potentially life-threatening condition, and this study aimed to evaluate the indications and outcome for the different treatment modalities.

Patients And Methods: In total, 43 patients with esophageal perforation were considered for this retrospective analysis. Age, sex, length of hospital stay and intensive care treatment, in-hospital mortality, localization of perforation and etiology, treatment modality, and 90-day morbidity were analyzed.

Results: Most patients suffered from Boerhaave syndrome and from iatrogenic esophageal perforation. In total, 63% of patients (26/41) received successful nonoperative treatment, whereas 36% required additional surgery. Two patients (5%) underwent primary surgery. In all cases no esophagectomy was necessary. In-hospital mortality was 7%. During the 90-day follow-up 1 patient with stenosis required repetitive dilatations.

Conclusions: Initial endoscopic treatment, either by stent or by endosponge, alone or combined with an additional operative treatment, seems feasible in patients suffering from esophageal perforation. In all patients, there was no need for esophagectomy.
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http://dx.doi.org/10.1097/SLE.0000000000000549DOI Listing
August 2018

Peritoneal innervation: embryology and functional anatomy.

Pleura Peritoneum 2017 Dec;2(4):153-161

Department of General and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.

The parietal peritoneum (PP) is innervated by somatic and visceral afferent nerves. PP receives sensitive branches from the lower intercostal nerves and from the upper lumbar nerves. Microscopically, a dense network of unmyelinated and myelinated nerve fibers can be found all over the PP. The unmyelinated fibers are thin and are ending just underneath the PP. The myelinated fibers can penetrate the PP to reach the peritoneal cavity, where they lose their myelin sheath and are exposed to somatic and nociceptive stimuli. PP is sensitive to pain, pressure, touch, friction, cutting and temperature. Noxious stimuli are perceived as a localized, sharp pain. The visceral peritoneum (VP) itself is not innervated, but the sub-mesothelial tissue is innervated by the autonomous nerve system. In contrast to the PP, the visceral submesothelium also receives fibers from the vagal nerve, in addition to the spinal nerves. VP responds primarily to traction and pressure; not to cutting, burning or electrostimulation. Painful stimuli of the VP are poorly localized and dull. Pain in a foregut structure (stomach, duodenum or biliary tract) is referred to the epigastric region, pain in a midgut structure (appendix, jejunum, or ileum) to the periumbilical area and pain from a hindgut source (distal colon or rectum) is referred to the lower abdomen or suprapubic region. Peritoneal adhesions can contain nerve endings. Neurotransmitters are acetylcholine, VIP, serotonin, NO, encephalins, CGRP and substance P. Chronic peritoneal pain can be exacerbated by neurogenic inflammation, e.g. by endometriosis.
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http://dx.doi.org/10.1515/pp-2017-0024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328075PMC
December 2017

Pharmacodynamics of Oxaliplatin-Derived Platinum Compounds During Hyperthermic Intraperitoneal Chemotherapy (HIPEC): An Emerging Aspect Supporting the Rational Design of Treatment Protocols.

Ann Surg Oncol 2017 Jun 3;24(6):1650-1657. Epub 2017 Feb 3.

Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) is used to treat peritoneal surface malignancies with application of cytostatic drugs such as oxaliplatin (OX) after cytoreductive surgery. Despite its increased use, evidence for optimal drug dosage, and notably duration of HIPEC, is scarce.

Methods: In this study, OX distribution was comprehensively assessed in nine patients during HIPEC (300 mg OX/m body surface area in Physioneal solution for 30 min). Oxaliplatin and its derivatives were measured in peritoneal perfusates over time by liquid chromatography coupled with mass spectrometry (LC-MS), and the resulting total platinum concentration in tissue was analyzed by atomic absorption spectrometry. Additionally, a novel impedance-based real-time cytotoxicity assay was used to evaluate the bioactivity of perfusates ex vivo.

Results: Compared with amounts of OX expected in peritoneal perfusates by calculation, only 10-15% of the parent drug could be detected by LC-MS during HIPEC. Notably, the study additionally detected platinum compounds consistent with OX transformation, accounting for a further fraction of the applied drug. The cytotoxic properties of perfusates remained unchanged during HIPEC, with only a slight but significant attenuation evidenced after 30 min.

Conclusions: The bioactivity of peritoneal perfusates ex vivo is a useful parameter for evaluating the actual cytotoxic potential of OX and its derivatives used in HIPEC over time, overcoming important limitations and disadvantages associated with respective drug monitoring only. Ex vivo cytotoxicity assays may be a promising tool to aid guiding future standardization and harmonization of HIPEC protocols based on drug-mediated effects.
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http://dx.doi.org/10.1245/s10434-017-5790-xDOI Listing
June 2017

Morphology of the peritoneal cavity and pathophysiological consequences.

Pleura Peritoneum 2016 Dec 10;1(4):193-201. Epub 2017 Jan 10.

Department of General and Transplant Surgery, Experimental Surgery, University of Tübingen, Hoppe-Seyler Str. 3, 72076 Tübingen, Germany.

The peritoneal cavity (cavum peritonei) is incompletely divided into spaces and recessus (or fossae), which are playing an important role in health and disease. Peritoneal subspaces are determined by the parietal attachments of the abdominal organs, the ligaments and mesenteries. These include the splenorenal, the falciform, the triangular, the gastrosplenic, the phrenicocolic and the gastrocolic ligaments; the greater omentum and the lesser omentum (formed by the gastrohepatic and hepatoduodenal ligaments); the small bowel mesenterium and the mesocolon. These ligaments and mesenteries divide the peritoneal cavity into several distinct anatomic and functional regions. The supramesocolic compartment is divided into a bilateral subphrenic space and a subhepatic space continuing into the lesser sac (bursa omentalis). The inframesolic compartment is divided into a left and right region by the mesentery. The right paracolic gutter communicates with the pelvis and with the right suphrenic space. The left paracolic gutter is separated from the left subphrenic space by the phrenocolic ligament. The peritoneal space is virtual, is completely occupied by the intraabdominal organs and can only be visualized by radiological means in the presence of air (organ perforation), liquid (ascites, pus, bile, gastrointestinal fluids) or tumor invasion. Peritoneal morphology has numerous pathophysiological implications: it impacts on the propagation of intraabdominal infections, determines the spreading of peritoneal metastasis and can cause bowel volvulus. Internal hernias can arise at the junction between intraperitoneal and extraperitoneal bowel segments, in particular into the left paraduodenal recessus. Knowledge of peritoneal morphology is a precondition for developing locoregional therapeutic strategies in peritoneal disease and for effective peritoneal dialysis.
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http://dx.doi.org/10.1515/pp-2016-0023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328071PMC
December 2016

Incidence of leukopenia after intraperitoneal vs combined intravenous/intraperitoneal chemotherapy in pseudomyxoma peritonei.

World J Gastrointest Pharmacol Ther 2016 Aug;7(3):434-9

Philipp Horvath, Stefan Beckert, Florian Struller, Alfred Königsrainer, Ingmar Königsrainer, Department of General, Visceral and Transplant Surgery, University of Tübingen, Comprehensive Cancer Center, 72076 Tübingen, Germany.

Aim: To investigate the clinical impact of post-hyperthermic intraperitoneal chemotherapy (HIPEC) leukopenia, intraperitoneal and combined intravenous/intraperitoneal drug administrations were compared.

Methods: Two patient cohorts were retrospectively analyzed regarding the incidence of postoperative leukopenia. The first cohort (n = 32) received Mitomycin C (MMC)-based HIPEC intraperitoneally (35 mg/m² for 90 min) and the second cohort (n = 10) received a bi-directional therapy consisting of oxaliplatin (OX) (300 mg/m(2) for 30 min) intraperitoneally and 5-fluorouracil (5-FU) 400 mg/m² plus folinic acid 20 mg/m² intravenously. The following data were collected retrospectively: Age, sex, length of operation, length of hospital stay, amount of resection including extent of peritonectomy, peritoneal cancer index, CC (completeness of cytoreduction)-status and leukocyte-count before cytoreductive surgery (CRS) and HIPEC, on days 3, 7 and 14 after CRS and HIPEC. HIPEC leukopenia was defined as < 4000 cells/m³.

Results: Leukopenia occurred statistically more often in the MMC than in the OX/5-FU-group (10/32 vs 0/10; P = 0.042). Leukopenia set-on was on day 7 after CRS and MMC-HIPEC and lasted for two to three days. Three patients (33%) required medical treatment. Patients affected by leukopenia were predominantly female (7/10 patients) and older than 50 years (8/10 patients). The length of hospital stay tended to be higher in the MMC-group without reaching statistical significance (22.5 ± 11 vs 16.5 ± 3.5 d). Length of operation (08:54 ± 01:44 vs 09:48 ± 02:28 h) were comparable between patients with and without postoperative leukopenia. Prior history of systemic chemotherapy did not trigger post-HIPEC leukopenia. Occurrence of leucopenia did not trigger surgical site infections, intraabdominal abscess formations, hospital-acquired pneumonia or anastomotic insufficiencies.

Conclusion: Surgeons must be aware that there is a higher incidence of postoperative leukopenia in MMC-based HIPEC protocols primarily affecting females and older patients.
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http://dx.doi.org/10.4292/wjgpt.v7.i3.434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4986400PMC
August 2016

Functional vascular anatomy of the peritoneum in health and disease.

Pleura Peritoneum 2016 Sep 4;1(3):145-158. Epub 2016 Oct 4.

Department of General, Visceral and Transplant Surgery, Eberhard-Karls-Universitat Tubingen Medizinische Fakultat, Tuebingen, Germany.

The peritoneum consists of a layer of mesothelial cells on a connective tissue base which is perfused with circulatory and lymphatic vessels. Total effective blood flow to the human peritoneum is estimated between 60 and 100 mL/min, representing 1-2 % of the cardiac outflow. The parietal peritoneum accounts for about 30 % of the peritoneal surface (anterior abdominal wall 4 %) and is vascularized from the circumflex, iliac, lumbar, intercostal, and epigastric arteries, giving rise to a quadrangular network of large, parallel blood vessels and their perpendicular offshoots. Parietal vessels drain into the inferior vena cava. The visceral peritoneum accounts for 70 % of the peritoneal surface and derives its blood supply from the three major arteries that supply the splanchnic organs, celiac and superior and inferior mesenteric. These vessels give rise to smaller arteries that anastomose extensively. The visceral peritoneum drains into the portal vein. Drugs absorbed are subject to first-pass hepatic metabolism. Peritoneal inflammation and cancer invasion induce neoangiogenesis, leading to the development of an important microvascular network. Anatomy of neovessels is abnormal and characterized by large size, varying diameter, convolution and blood extravasation. Neovessels have a defective ultrastructure: formation of large "mother vessels" requires degradation of venular and capillary basement membranes. Mother vessels give birth to numerous "daughter vessels". Diffuse neoangiogenesis can be observed before appearance of macroscopic peritoneal metastasis. Multiplication of the peritoneal capillary surface by neoangiogenesis surface increases the part of cardiac outflow directed to the peritoneum.
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http://dx.doi.org/10.1515/pp-2016-0015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328070PMC
September 2016

Overall morbidity but not mortality is increased in elderly patients following cytoreductive surgery and HIPEC.

Langenbecks Arch Surg 2015 Aug 6;400(6):693-8. Epub 2015 Aug 6.

Comprehensive Cancer Center with the Department of General, Visceral and Transplant Surgery, University of Tübingen, Hoppe-Seyler-Strasse 3, 72076, Tübingen, Germany.

Background: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) prolongs survival in selected patients with peritoneal metastases. Since this procedure is likely to be associated with increased morbidity and mortality, it remains controversial whether it is also suitable for patients older than 70 years.

Methods: Consecutive patients with radiographic evidence of peritoneal metastases (PM) were scheduled for CRS and HIPEC at the Comprehensive Cancer Center, University Hospital Tübingen, Germany. Clinical data were retrospectively analyzed categorizing patients with respect to age into elderly (age ≥ 70) and non-elderly patients (age < 70).

Results: Between June 2005 and March 2014, 381 patients with a median age of 55 [14-77] years could be enrolled with 29 patients (8 %) being at least 70 years old. Both groups were comparable for tumor-related parameters including PCI, CC-status, time in operating room, and visceral resections. However, there was a difference in patient-related factors such as cardio-pulmonary comorbidities and ASA score. We found no difference in overall and recurrence-free survival between the two groups. Surgery-related mortality was 0.9 % in patients younger than 70 years whereas no patient died in the elderly group. Overall morbidity was 47 % in the younger and 76 % in the elderly group (p = 0.048). There was no difference in Clavien-Dindo grade III-IV morbidity. Logistic regression analysis proved age as an independent risk factor for increased overall morbidity in elderly patients.

Conclusion: In elderly patients, CRS and HIPEC are associated with increased overall morbidity but neither Dindo III-IV morbidity nor surgery-related mortality.
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http://dx.doi.org/10.1007/s00423-015-1325-8DOI Listing
August 2015

Initial clinical experience with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in signet-ring cell gastric cancer with peritoneal metastases.

J Gastric Cancer 2014 Jun 30;14(2):117-22. Epub 2014 Jun 30.

Department of General, Visceral and Transplant Surgery, University of Tübingen, Comprehensive Cancer Center, Tübingen, Germany.

Purpose: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been shown to improve survival in select patients with gastric cancer and peritoneal metastases. It remains unclear, however, whether this multimodal treatment protocol is also beneficial for signet-ring cell gastric cancer (SRC) patients with peritoneal metastases.

Materials And Methods: Clinical data of patients scheduled for upfront systemic chemotherapy consisting of 5-FU (2,600 mg/m(2)), folinic acid (200 mg/m(2)), docetaxel (50 mg/m(2)), and oxaliplatin (85 mg/m(2)) followed by CRS and HIPEC using cisplatin (50 mg/m(2)) at the Comprehensive Cancer Center, University Hospital Tübingen, Germany were retrospectively analyzed.

Results: Eighteen consecutive patients for whom irresectability has been ruled out by a computed tomography scan were enrolled. However, complete cytoreduction could only be achieved in 72% of patients. When categorizing patients with respect to the completeness of cytoreduction, we found no difference between both groups considering tumor- or patient-related factors. The overall complication rate following complete cytoreduction and HIPEC was 46%. Within a median follow-up of 6.6 (0.5~31) months, the median survival for CRS and HIPEC patients was 8.9 months as opposed to 1.1 months for patients where complete cytoreduction could not be achieved. Following complete cytoreduction and HIPEC, progression-free survival was 6.2 months.

Conclusions: In SRC with peritoneal metastases, the prognosis appears to remain poor irrespective of complete CRS and HIPEC. Moreover, complete cytoreduction could not be achieved in a considerable percentage of patients. In SRC, CRS and HIPEC should be restricted to highly selective patients in order to avoid exploratory laparotomy.
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http://dx.doi.org/10.5230/jgc.2014.14.2.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105376PMC
June 2014

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in recurrent epithelial ovarian cancer with peritoneal metastases: a single centre experience.

Langenbecks Arch Surg 2014 Jun 11;399(5):589-94. Epub 2014 May 11.

Department of General, Visceral and Transplant Surgery, University of Tübingen, Comprehensive Cancer Center, Hoppe-Seyler-Strasse 3, 72076, Tübingen, Germany,

Background: This investigation aims to assess morbidity, mortality and postoperative outcomes of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in recurrent epithelial ovarian cancer (REOC) with peritoneal metastases (PM).

Methods: Consecutive patients with radiographic evidence of REOC with PM were scheduled for CRS and HIPEC at the Comprehensive Cancer Center, University Hospital Tübingen, Germany. Clinical data were retrospectively analyzed.

Results: In total, 90 patients were analyzed. Complete cytoreduction and HIPEC could be performed in 69 % of patients. When categorizing patients with respect to the completeness of cytoreduction (CC-0/1 vs CC-2/3), there was no difference considering baseline demographic characteristics. Cumulative morbidity was 42 %. Morbidity rates did not statistically differ between CC-0/1 patients with HIPEC and CC-2/3 patients without HIPEC. No surgery-related and 90-day postoperative mortality was observed. In CC-0/1 patients, median overall survival was 35 months as opposed to 14 months in CC-2/3 patients. There was no difference in survival with respect to the peritoneal carcinomatosis index (PCI) as long as complete cytoreduction could be achieved.

Conclusions: CRS and HIPEC can be performed with acceptable morbidity and low mortality in specialized centres. Our data do not suggest that HIPEC necessarily increases the risk of postoperative adverse events.
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http://dx.doi.org/10.1007/s00423-014-1207-5DOI Listing
June 2014

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis in a liver graft recipient: a case report.

Ann Transplant 2013 Apr 22;18:182-6. Epub 2013 Apr 22.

Department of General, Visceral and Transplant Surgery, Comprehensive Cancer Center, University of Tübingen, Tübingen, Germany.

Background: Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy is a potentially curative approach for peritoneal carcinomatosis of colonic origin. So far experience concerning the use of this treatment option in transplant recipients is lacking.

Case Report: We herein present the case of a 31-year-old man who had previously been liver transplanted for primary sclerosing cholangitis. Approximately 10 years after transplantation colon carcinoma with co-existing peritoneal carcinomatosis was diagnosed. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy were conducted. Operative management under tacrolimus medication did not trigger infections, wound healing disorders or graft function impairment. At one year follow-up no tumor recurrence was detected.

Conclusions: Recent literature suggests that proctocolectomy for colorectal cancer is considered feasible in liver graft recipients. Virtually all patients suffering from primary sclerosing cholangitis exhibit co-existing ulcerative colitis, rendering this subset of patient at risk for developing colonic malignancies. Furthermore chronic immunosuppression may facilitate malignant growth. The most feared complication in colorectal carcinomas is the occurence of peritoneal carcinomatosis, for which cytoreduction plus hyperthermic intraperitoneal chemotherapy may be a curative option. This, so far unique, case report suggests that even in this patient subset this treatment is feasible and for further cases this dual-approach for the management of PC in transplant recipients should be taken into account.
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http://dx.doi.org/10.12659/AOT.883893DOI Listing
April 2013

Risk factors for recurrence following complete cytoreductive surgery and HIPEC in colorectal cancer-derived peritoneal surface malignancies.

Langenbecks Arch Surg 2013 Jun 1;398(5):745-9. Epub 2013 Mar 1.

Department of General, Visceral and Transplant Surgery, Comprehensive Cancer Center, University of Tübingen, Hoppe-Seyler-Strasse 3, 72076, Tübingen, Germany.

Purpose: Recurrent disease following complete cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a relevant clinical scenario. We aimed to determine risk factors for recurrence.

Methods: Prospectively collected data of patients enrolled in the Peritoneal Surface Malignancy Program at the University of Tübingen between 2005 and 2011 were retrospectively analyzed. All patients were treated by standardized CRS and HIPEC. Recurrence was defined either radiographically by CT, PET-CT scan, or reoperation.

Results: Fifty-two patients received complete CRS (CC-0/CC-1) and HIPEC. Median time to recurrence was 229 days (103-1,028). Overall recurrence rate within follow-up was 48 %. Of patients with recurrent disease, 44 % experienced extraperitoneal systemic tumor spread. In multivariate analysis, grading of ≥ 3 was shown as an independent risk factor for recurrent disease, while a trend was observed for maximal tumor load in the upper abdominal region. Clinical parameters did not show an impact on recurrence.

Conclusions: Primary tumor grading seems to be an independent risk factor for recurrence following complete CRS and HIPEC in colorectal cancer-derived peritoneal surface malignancies.
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http://dx.doi.org/10.1007/s00423-013-1065-6DOI Listing
June 2013

Impact of endotoxin exposure after exhausting exercise on the immune system in solid organ transplant recipients.

Exerc Immunol Rev 2012 ;18:177-83

Department of General Visceral and Transplant Surgery, University of Tuebingen, D-72076 Tuebingen, Germany.

Subsequent to prolonged exhausting exercise a transient immunosuppression is often observed in athletes. This so-called "open window" results in a reduced resistance of the athletes to viral and bacterial infections after an exhaustive exercise bout. Concerning the effect of bacterial endotoxin contact after exhausting exercise in transplant recipients, who are innately immunosuppressed by their medication, no data exists at present. After performing 81 km cycling, including ascending more than 1800 m in altitude, peripheral blood from 10 male kidney transplant recipients and from 10 healthy controls matched for age and gender was obtained. Simulating contact of the athletes with a pathogen post-exercise, the blood samples were incubated with Lipopolysaccharides (LPS). Thereafter microarray analysis was performed. Microarray analysis revealed a markedly oppositional pattern of gene expression in transplant recipients compared with their controls after LPS incubation. Especially immune response genes were significantly over-represented in controls immediately after the exhaustive exercise bout with LPS stimulation, whereas numerous apoptotic genes were over-represented in transplant recipients. Merging our previous data with these recent findings it should be discussed if transplant recipients need to reduce their immunosuppressive medication before performing exhaustive exercise.
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August 2012
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