Philipp Horvath

Initial Clinical Experience with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy in Signet-Ring Cell Gastric Cancer with Peritoneal Metastases

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/m2), folinic acid (200 mg/m2), docetaxel (50 mg/m2), and oxaliplatin (85 mg/m2) followed by CRS and HIPEC using cisplatin (50 mg/m2) 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.

Functional vascular anatomy of the peritoneum in health and disease

Abstract 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.

Morphology of the peritoneal cavity and pathophysiological consequences

Abstract 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.

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

BackgroundHyperthermic 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.MethodsIn this study, OX distribution was comprehensively assessed in nine patients during HIPEC (300 mg OX/m2 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.ResultsCompared 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.ConclusionsThe 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.

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

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.

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

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 (n = 26), colorectal (n = 17), hepatobiliary/pancreatic (n = 9), ovarian (n = 6), appendiceal (n = 5) origin, pseudomyxoma peritonei (n = 4), and other tumors (n = 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.

Peritoneal innervation: embryology and functional anatomy

Abstract 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.

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

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.

Divertikelkrankheit des Kolons – Die laparoskopische Sigmaresektion

Die laparoskopische Sigmaresektion bei Sigmadivertikulitis hat sich als sicheres Verfahren etabliert: Aufgrund des minimalinvasiven Zugangs ist die Morbiditat geringer und der Krankenhausaufenthalt kurzer 1 2 . Dieser Beitrag zeigt die operative Vorgehensweise mit Fokus auf Sondersituationen wie die perforierte Sigmadivertikulitis und die Sigma-Blasen-Fistel.

Divertikelkrankheit des Kolons – Diagnostik und Therapie

Die Divertikelkrankheit des Kolons gehort zu den haufigsten Erkrankungen des Gastrointestinaltrakts. Eine kurzlich erschienene konsensbasierte Leitlinie setzt neue Akzente bei der Behandlung der Erkrankung. So hat der Stellenwert interventioneller Verfahren zugenommen, auch das Paradigma einer generellen Indikation zur Resektion nach dem zweiten Entzundungsschub wurde verlassen. Der folgende Artikel fasst Diagnostik und Therapie unter Berucksichtigung der aktuellen Leitlinie zusammen.