Chemosensitivity of various peritoneal cancer cell lines to HIPEC and PIPAC: comparison of an experimental duplex drug to standard drug regimens in vitro.

We performed an in-vitro study testing the chemosensitivity of peritoneal cancer cell lines (SW620, HCT116, MKN45, 23,132/87, OAW42) to various cytostatic drug regimens. A duplex drug, characterized by reversible linking of the antimetabolites 2'-deoxy-5-fluorouridine (5-FdU) and 3'-C-ethynylcytidine (ECyd), was compared to oxaliplatin or to cisplatin plus doxorubicin. The experiments were designed to reflect the conditions of intraperitoneal chemotherapy. CASY® (Cell Analysis System) technology was used to compare the impact of incubation temperature/duration and drug concentration on the viability of the cancer cell lines versus normal human dermal fibroblasts. Two incubation scenarios were explored: (i) hyperthermic intraperitoneal chemotherapy (HIPEC) with 1 h of incubation at 42 °C, and (ii) pressurized intraperitoneal aerosol chemotherapy (PIPAC) with several successive incubations at 37 °C. Under HIPEC conditions, oxaliplatin induced a potent temperature-dependent growth inhibition of colon cancer cells not seen with the duplex drug. Under PIPAC conditions, the duplex drug achieved the same growth inhibition at a fraction of the dose level required with oxaliplatin. Gastric and ovarian cancer cells were more sensitive to cisplatin plus doxorubicin than to the duplex drug under PIPAC conditions. The duplex drug suggests itself, notably in cases of platinum resistance, as an alternative or addition to intraperitoneal chemotherapies when platinum-based PIPAC technology is used. Using it with HIPEC technology is not recommended. Higher doses of the duplex drug will enhance growth inhibition, albeit at the cost of a severely reduced difference in chemosensitivity between tumor and normal cells. Our findings provide orientation for PIPAC-based personalized intraperitoneal chemotherapy.

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

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.

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

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.

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

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.

Sensitivity of gastric adenocarcinoma and normal cell lines against combined or conjugated antimetabolites.

The in-vitro growth inhibition of cancer and normal cell lines caused by mixed or covalently linked antimetabolites should clarify whether the conjugation of antimetabolites influences cell sensitivity and growth inhibition in a manner that differs from an equimolar mixture of the same antimetabolites or not. Growth inhibition of the human gastric adenocarcinoma cell lines 23132/87 and MKN-45 in comparison with normal gastric intestinal CCL-241 and the dermal fibroblast cell line NHDF was evaluated using CASY technology. The cell lines were incubated with an equimolar mixture of 5-fluoro-2'-deoxyuridine (5FdU)+3'-C-ethynylcytidine (ECyd) or the covalently linked duplex drug 5FdU(5'→5')ECyd. The drug and metabolites of the assays and medium were determined semiquantitatively using high-performance liquid chromatography. The sensitivity of cancer and nonmalignant cell lines was clearly different against the duplex drug. A measure of 0.65 µmol/l 5FdU(5'→5')ECyd, for example, reduced the growth of MKN-45 or 23132/87 gastric cancer cells from 100% on day 0 to about 50 or 20% on day 10, respectively. However, under the same conditions, the growth of the nonmalignant NHDF and CCL-241 cell lines was not markedly inhibited. The cytostatic activity of the duplex drug is based on the active metabolites in and outside the cell formed by the degradation of 5FdU(5'→5')ECyd. The sensitivity of cell lines against the duplex drug depended on its ability to metabolize the duplex drug. 5FdU(5'→5')ECyd should be more advantageous for specific and efficient polychemotherapy of gastric cancer than the corresponding equimolar mixture of 5FdU+ECyd or a standard combination regime of single drugs.

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

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.

A survey among physicians in surgery and anesthesiology departments after the first surge of SARS-CoV-2 infections in Germany : Preparing for further challenges ahead.

BACKGROUND: The SARS-CoV­2 pandemic has extensively challenged healthcare systems all over the world. Many elective operations were postponed or cancelled, changing priorities and workflows in surgery departments. AIMS: The primary aim of this cross-sectional study was to assess the workload and psychosocial burden of surgeons and anesthesiologists, working in German hospitals during the first wave of SARS-CoV­2 infections in 2020. METHODS: Quantitative online survey on the workplace situation including psychosocial and work-related stress factors among resident and board-certified surgeons and anesthesiologists. Physicians in German hospitals across all levels of healthcare were contacted via departments, professional associations and social media posts. RESULTS: Among 154 total study participants, 54% of respondents stated a lack of personal protective equipment in their own wards and 56% reported increased staff shortages since the onset of the pandemic. While routine practice was reported as fully resumed in 71% of surgery departments at the time of the survey, work-related dissatisfaction among responding surgeons and anesthesiologists increased from 24% before the pandemic to 36% after the first wave of infections. As a countermeasure, 94% of participants deemed the establishment of action plans to increase pandemic preparedness and strengthening German public health systems a useful measure to respond to current challenges. CONCLUSION: The aftermath of the first wave of SARS-CoV­2 infections in Germany has left the surgical staff strained, despite temporarily decreased workloads. Overall, a critical review of the altered conditions is indispensable to identify and promote effective solutions and prudent action plans required to address imminent challenges.

Proposal of a Standardized Questionnaire to Structure Clinical Peer Reviews of Mortality and Failure of Rescue in Pancreatic Surgery.

Background: Quality management tools such as clinical peer reviews facilitate root cause analysis and may, ultimately, help to reduce surgery-related morbidity and mortality. This study aimed to evaluate the reliability of a standardized questionnaire for clinical peer reviews in pancreatic surgery. Methods: All cases of in-hospital-mortality following pancreatic surgery at two high-volume centers (n = 86) were reviewed by two pancreatic surgeons. A standardized mortality review questionnaire was developed and applied to all cases. In a second step, 20 cases were randomly assigned to an online re-review that was completed by seven pancreatic surgeons. The overall consistency of the results between the peer review and online re-review was determined by Cohen's kappa (κ). The inter-rater reliability of the online re-review was assessed by Fleiss' kappa (κ). Results: The clinical peer review showed that 80% of the patient mortality was related to surgery. Post-operative pancreatic fistula (POPF) (36%) followed by post-pancreatectomy hemorrhage (PPH) (22%) were the most common surgical underlying (index) complications leading to in-hospital mortality. Most of the index complications yielded in abdominal sepsis (62%); 60% of the cases exhibited potential of improvement, especially through timely diagnosis and therapy (42%). There was a moderate to substantial strength of agreement between the peer review and the online re-review in regard to the category of death (surgical vs. non-surgical; κ = 0.886), type of surgical index complication (κ = 0.714) as well as surgical and non-surgical index complications (κ = 0.492 and κ = 0.793). Fleiss' kappa showed a moderate to substantial inter-rater agreement of the online re-review in terms of category of death (κ = 0.724), category of common surgical index complications (κ = 0.455) and surgical index complication (κ = 0.424). Conclusion: The proposed questionnaire to structure clinical peer reviews is a reliable tool for root cause analyses of in-hospital mortality and may help to identify specific options to improve outcomes in pancreatic surgery. However, the reliability of the peer feedback decreases with an increasing specificity of the review questions.

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

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.

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.

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/m2 and doxorubicin 1.5 mg/m2 (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.

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

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/m2 and doxorubicin 1.5 mg/m2 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.

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.

Primary squamous cell carcinoma of the thyroid: Case report and systematic review of the literature.

BACKGROUND: Primary squamous cell cancer (PSCC) of thyroid is a rare malignancy with poor prognosis. It is mandatory to exclude secondary involvement of the thyroid by panendoscopy, CT-scan and immunohistochemical analysis. As treatment surgery, radiation and rarely chemotherapy is employed. METHODS: A systematic review of the literature was conducted searching medline and embase database using the medical subject headings "primary squamous cell carcinoma of thyroid" and "primary squamous cell cancer of thyroid", for articles published until April 2016 (n=1733). Of interest were the used treatment modalities and survival outcomes. RESULTS: A total of 35 publications reporting on 50 cases including ours were finally analyzed. A curative treatment approach was described in 24 patients (48%). Additional radiotherapy, chemotherapy or radiochemotherapy was applied in 17, 7 and 7 patients respectively. Median overall survival was 6 months [range 0-48] for 47 patients. Disease free survival was only achieved in 8 patients with disease limited to the thyroid gland, complete surgical resection and additional radiotherapy or radiochemotherapy [reported median 20 months; range 12-48]. CONCLUSION: Reported disease free survival of PSCC of the thyroid was only achieved in patients with complete surgical resection in combination with adjuvant radio- and/or chemotherapy. However long term survival has not been reported in the literature yet.

Peritoneal innervation: embryology and functional anatomy.

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.

Functional vascular anatomy of the peritoneum in health and disease.

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.

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.

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/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.