Technology development of hyperthermic pressurized intraperitoneal aerosol chemotherapy (hPIPAC).

BACKGROUND: Optimized drug delivery systems are needed for intraperitoneal chemotherapy. The aim of this study was to develop a technology for applying pressurized intraperitoneal aerosol chemotherapy (PIPAC) under hyperthermic conditions (hPIPAC). METHODS: This is an ex-vivo study in an inverted bovine urinary bladder (IBUB). Hyperthermia was established using a modified industry-standard device (Humigard). Two entry and one exit ports were placed. Warm-humid CO2 was insufflated in the IBUB placed in a normothermic bath to simulate body thermal inertia. The temperature of the aerosol, tissue, and water bath was measured in real-time. RESULTS: Therapeutic hyperthermia (target tissue temperature 41-43 °C) could be established and maintained over 30 min. In the first phase (insufflation phase), tissue hyperthermia was created by insufflating continuously warm-humid CO2. In the second phase (aerosolization phase), chemotherapeutic drugs were heated up and aerosolized into the IBUB. In a third phase (application phase), hyperthermia was maintained within the therapeutic range using an endoscopic infrared heating device. In a fourth phase, the toxic aerosol was discarded using a closed aerosol waste system (CAWS). DISCUSSION: We introduce a simple and effective technology for hPIPAC. hPIPAC is feasible in an ex-vivo model by using a combination of industry-standard medical devices after modification. Potential pharmacological and biological advantages of hPIPAC over PIPAC should now be evaluated.

COVID-19: impact on colorectal surgery.

AIM: The rapid spread of the COVID-19 pandemic has created unprecedented challenges for the medical and surgical healthcare systems. With the ongoing need for urgent and emergency colorectal surgery, including surgery for colorectal cancer, several questions pertaining to operating room (OR) utilization and techniques needed to be rapidly addressed. METHOD: This manuscript discusses knowledge related to the critical considerations of patient and caregiver safety relating to personal protective equipment (PPE) and the operating room environment. RESULTS: During the COVID-19 pandemic, additional personal protective equipment (PPE) may be required contingent upon local availability of COVID-19 testing and the incidence of known COVID-19 infection in the respective community. In addition to standard COVID-19 PPE precautions, a negative-pressure environment, including an OR, has been recommended, especially for the performance of aerosol-generating procedures (AGPs). Hospital spaces ranging from patient wards to ORs to endoscopy rooms have been successfully converted from standard positive-pressure to negative-pressure spaces. Another important consideration is the method of surgical access; specifically, minimally invasive surgery with pneumoperitoneum is an AGP and thus must be carefully considered. Current debate centres around whether it should be avoided in patients known to be infected with SARS-CoV-2 or whether it can be performed under precautions with safety measures in place to minimize exposure to aerosolized virus particles. Several important lessons learned from pressurized intraperitoneal aerosolized chemotherapy procedures are demonstrated to help improve our understanding and management. CONCLUSION: This paper evaluates the issues surrounding these challenges including the OR environment and AGPs which are germane to surgical practices around the world. Although there is no single universally agreed upon set of answers, we have presented what we think is a balanced cogent description of logical safe approaches to colorectal surgery during the COVID-19 pandemic.

Pressurized intraperitoneal aerosol chemotherapy with oxaliplatin in colorectal peritoneal metastasis.

AIM: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is an experimental drug delivery method that applies chemotherapy into the abdominal cavity as an aerosol under pressure. We present the first results obtained with PIPAC in colorectal peritoneal metastasis (CPM). METHOD: This is a retrospective analysis. PIPAC was applied in 17 consecutive patients with pretreated CPM. All patients had previously undergone surgery, and 16 had undergone previous lines of systemic chemotherapy (median, two lines). The mean peritoneal metastasis index (peritoneal cancer index) was 16 ± 10. Forty-eight applications of PIPAC with oxaliplatin (92 mg/m2 ) were given every 6 weeks at 37 °C and 12 mmHg for 30 min. The outcome criteria were microscopic pathological response, survival and adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. RESULTS: Forty-eight PIPAC administrations were performed with no intra-operative complications. The mean number of PIPAC administrations per patient was 2.8 (minimum one, maximum six). Postoperative adverse events (CTCAE level 3) were observed in four patients (23%), no CTCAE level-4 adverse events were reported. The hospital mortality was zero. Objective tumour responses were observed in 12/17 patients (71%), and the overall responses were as follows: complete pathological response (seven patients), major response (four patients), partial response (one patient), no response (two patients) and not eligible (three patients). The mean survival after first PIPAC was 15.7 months. CONCLUSION: Repeated PIPAC with oxaliplatin can induce the regression of pretreated CPM. The toxicity appears to be low. These preliminary results are encouraging and justify prospective clinical studies.

Quality of life of patients with end-stage peritoneal metastasis treated with Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC).

BACKGROUND: Quality of Life (QoL) plays an important role in patients with peritoneal metastasis and is deteriorating continuously until death. Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is an innovative palliative treatment of peritoneal metastasis. We present the first QoL results under PIPAC therapy. METHODS: Retrospective analysis of QLQ30 questionnaire results during repeated courses of PIPAC applications in palliative patients with pretreated peritoneal metastasis. RESULTS: 91 patients (M:F = 40:51, median age 64 (34-77) years) with 158 PIPAC applications were analyzed. 86% patients had previously received systemic chemotherapy. Peritoneal metastasis was advanced (Peritoneal Carcinomatosis Index I = 16 ± 10). At admission, only moderate impairment of functioning (62-83%) and symptom scores (17-47%) was observed. 48 patients received at least 2 PIPAC every 6 weeks. After PIPAC # 1, the global physical score deteriorated slightly (from 82% to 75%), but improved after PIPAC # 2 (up to 89%). Gastrointestinal symptoms (nausea/vomiting, constipation, diarrhoea, anorexia) remained stable under PIPAC therapy. CONCLUSIONS: Quality of life was relatively high in this group of patients with advanced, pretreated peritoneal metastasis, explaining their wish for further therapy. Functioning scores and disease-related symptoms were not altered for at least 3 months in the patients able to receive repeated PIPAC. Except for a transient moderate increase of pain scores, PIPAC did not cause therapy-related QoL deterioration, especially no gastrointestinal symptoms.

[Value of surgery in the palliative therapy for rectal cancer]. / Stellenwert der Chirurgie in der palliativen Behandlung des Rektumkarzinoms.

The treatment of advanced rectal cancer is a complicated task that can only poorly be reduced to the simple question "to operate or not to operate?" Instead the following factors must be taken into consideration: symptomatic versus non-symptomatic patients, emergency surgery versus elective surgery, proximal versus distal rectal cancer, local advanced versus metastatic disease, primary tumour versus recurrence, unresectable versus potentially resectable metastases, resection versus diversionary surgical procedures, etc. Also within the conservative group one must decide between interventional therapy (combined chemotherapy, stent placement, radiotherapy, etc.) and purely palliative therapy. Results from studies are not sufficient for the formulation of general recommendations. However, there are only few arguments against a surgical procedure in a symptomatic situation when the primary tumour dominates. In cases of metastasizing colorectal cancer modern chemotherapeutic procedures and new antibody therapies can markedly prolong survival. These results cannot be achieved by surgery alone. In this situation, it should be considered whether the longer life expectancy will be accompanied by the later occurrence of symptoms, which again justifies a surgical indication within the framework of multimodality therapy. The widely differing starting situations lead to different therapeutic approaches so that an individual indication can be made in the course of a tumour board discussion.

Key genes in lung cancer translational research: a meta-analysis.

In lung cancer, integrating translational data from various histologies obtained in different patients under different conditions can increase their robustness. This is a meta-analysis of cDNA array data obtained in 688 tumor patients (541 non-small cell lung cancer, 33 small cell lung cancer and 114 others) and 205 controls. 1,206 genes were found to be dysregulated in one of the 12 transcriptomics studies available. 748 results (62%) were obtained only once and might be questioned. 38% of observations could be reproduced twice or more. 346 genes were reported twice, 80 three times, 27 four and 5 five times. A common set of genes dysregulated in lung cancer was obtained, including BPA1, DUSP6, ASCL1, RNAS1 and S100P. p63 and CK 5/6 p63 are useful for differentiating adenocarcinoma and small cell lung cancer from squamous cell carcinoma. TFF-3 and MUC1 are over-expressed in adenocarcinoma. INSM1, SGNE1 and H2AFZ are typical for small cell lung cancer. Using a meta-analysis approach, it was possible to detect a robust set of genes differentially expressed in lung cancer and to determine a limited number of key genes linked to subtypes in lung cancer molecular pathology.

Proteomics in cancer.

Proteomic studies have generated numerous datasets of potential diagnostic, prognostic, and therapeutic significance in human cancer. Two key technologies underpinning these studies in cancer tissue are two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and mass spectrometry (MS). Although surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF)-MS is the mainstay for serum or plasma analysis, other methods including isotope-coded affinity tag technology, reverse-phase protein arrays, and antibody microarrays are emerging as alternative proteomic technologies. Because there is little overlap between studies conducted with these approaches, confirmation of these advanced technologies remains an elusive goal. This problem is further exacerbated by lack of uniform patient inclusion and exclusion criteria, low patient numbers, poor supporting clinical data, absence of standardized sample preparation, and limited analytical reproducibility (in particular of 2D-PAGE). Despite these problems, there is little doubt that the proteomic approach has the potential to identify novel diagnostic biomarkers in cancer. In therapeutic proteomics, the challenge is significant due to the complexity systems under investigation (i.e., cells generate over 10(5) different polypeptides). However, the most significant contribution of therapeutic proteomics research is expected to derive not from single experiments, but from the synthesis and comparison of large datasets obtained under different conditions (e.g., normal, inflammation, cancer) and in different tissues and organs. Thus, standardized processes for storing and retrieving data obtained with different technologies by different research groups will have to be developed. Shifting the emphasis of cancer proteomics from technology development and data generation to careful study design, data organization, formatting, and mining is crucial to answer clinical questions in cancer research.

[Options for quality improvement in the treatment of rectum carcinoma]. / Möglichkeiten der Qualitätsverbesserung bei der Therapie des Rektumkarzinoms.

By means of a prospective multi centre study, 13 419 cases of surgically treated patients with rectum carcinomas were registered between 1.1.2000 and 31.12.2003 and assessed in regard to possible problems concerning indications and operative procedures. Beside a high rate of non-local resective procedures in T1-low risk carcinomas, unnecessary extirpations in cases of tumour localisation over 8 cm from the anal verge were found. Tumours of the lower two-thirds of the rectum were treated by incomplete TME in 20 % of the patients. In addition, there seems to be too low a rate of neo-adjuvant therapy procedures. Protective stomata were frequently foregone after low anterior resection. Endoscopic interventional methods were still used reluctantly in inoperable situations.

Proteomic prediction of disease outcome in cancer : clinical framework and current status.

Better than gene sequencing or quantitative amplification, proteomics tools allow the study of tumor phenotype. Indeed, most current prognostic tests in cancer (carcinoembryonary antigen [CEA], prostate-specific antigen [PSA], CA 19-1, CA 125, alpha-fetoprotein [AFP], etc.) are based on the detection and quantification of single proteins in body fluids. However, a common characteristic of these tests is their relatively low predictive value, so that they are usually complemented with other procedures such as biopsy and/or endoscopy. Recently, improved analytical and bioinformatics tools have driven the attention on pattern recognition approaches rather then single-marker tests for prognostic forecasting. It is expected that predicting metastasization on the basis of tumoral protein patterns will soon be a reality. However, currently available technologies either limit the number of proteins that can be analyzed simultaneously or they are expensive, difficult, and time-consuming. Moreover, the tools adapted for expression proteomics might not be the same as those for prognostic studies that require investigation of protein function over time. We believe that clinical proteomics research designed within a precise clinical and pathology framework should be strongly supported, since many prognostic factors are determined not by the tumor itself, but by the patient, the treatment and the environment.

Angiogenesis and dendritic cell density are not correlated with metachronous distant metastasis in curatively operated rectal cancer.

BACKGROUND AND AIMS: Apart from surgery, treatment of rectal cancer increasingly involves the use of (neo-)adjuvant strategies. To optimize the selection process for these therapy regimens, especially in the field of cellular and molecular biology, new prognostic factors additional to the established TNM system are being investigated. PATIENTS AND METHODS: Two groups of patients ( n=2x85) with rectal carcinoma curatively treated by surgery alone were studied retrospectively (median follow-up 6.1 years). To exclude the effect of the surgeon only patients free of locally recurrent disease were selected. Patient groups were matched for age, gender, UICC stage, and year of operation (1982-1991) and differed only in subsequent metachronous distant metastatic spread, i.e., the criterion to be studied. The factors investigated in uni- and multivariate analysis were angiogenesis, density of dendritic cells, grading, venous invasion, and lymphatic invasion. RESULTS: Grading invariably proved to be the only significant prognostic factor. In univariate analysis the absence of venous invasion was also correlated significantly with increased disease-free survival. CONCLUSION: Angiogenesis and dendritic cell density are not prognostic factors for metachronous distant metastasis in rectal cancer and therefore cannot serve as selection parameters for adjuvant therapy.

Oncologic implications of laparoscopic and open surgery.

Although instrumental manipulation and mechanical tumor cell spillage seem to play the major role in port-site metastases from laparoscopic cancer surgery, minimally invasive procedures are used more and more in the resection of malignancies. However, port-site metastases also have been reported after resection of colon cancer in International Union Against Cancer (UICC) stage I [2, 14]. Therefore, changes in the peritoneal environment during laparoscopy also might influence intra- and extraperitoneal tumor growth during laparoscopy and pneumoperitoneum. Different results of experimental studies presented at the Third International Conference for Laparoscopic Surgery are analyzed and discussed.

The role of proteomics in the diagnosis and outcome prediction in colorectal cancer.

Colorectal cancer is the second most frequent cancer in Western countries. Exogenous factors play a major role in the aetiology of sporadic colorectal cancer representing about 90% of all cases, hereditary cancers accounting for about 10% of patients. Thus, in the large majority of cases, cell dysfunction in CRC results from multiple rather than single, gene interactions. Numerous cellular events and environmental influences modify gene expression or post-translational protein modifications. Changes like glycosylation of proteins and lipids which are a common feature in colorectal cancer and influence cancer cell behaviour, cannot be directly detected by genetic studies. Better than genomics studies, functional proteomics studies allow the investigation of environmental factors over time, allowing the monitoring of metabolic responses to various stimuli. However, proteomics studies also have several drawbacks: a) current tools only allow narrow-range analyses, b) identification of proteins of interest remains cumbersome, c) protein studies address multiple compounds of high complexity, d) large amount of proteins are necessary to allow analysis, e) protein research require specific tools, e.g. tagged antibodies, that first have to be developed. Some protein tests are already in application for CRC: a classical prognostic test in colorectal cancer is based on the detection and quantification of a single protein (CEA) in body fluids. Recently, a screening assay based on APC protein truncation test has also been proposed. However, studies linking large protein expression patterns with clinical outcome in colorectal cancer are still in their infancy. To be able to predict occurrence of disease, and treatment outcome, more studies on genotype-phenotype correlations are needed both in sporadic and in hereditary colorectal cancer.

Ethical, legal and economic issues raised by the use of human tissue in postgenomic research.

Ethical, legal and economic framework issues concerning human samples, genetic data and bioresources are rapidly evolving. In most cases, international standards have not been defined. National legislations on the use and exploitation of human sample collections differ widely. Legislations relating to intellectual property rights, access to database information for public or private bodies, of national or foreign origin, are similarly diverse. Importation and exportation rules, concerning in particular data protection, biosafety and protection of individual rights, have not always been defined. This article makes a short assessment of the legal, ethical and economic framework in selected EC countries (Germany, France and UK), and compares them with the conditions in the USA. On the basis of the information collected, it is obvious that the use of human cells, tissues and organs in medical research has to be considered as a global, worldwide question. Such use has profound ethical, cultural and economic consequences not only in the country of origin, but also globally. Biotechnology and pharmaceutical companies conducting research with human samples are facing different framework conditions in the area of data protection, policy measures, economic support, exportation, etc., that already influence trade activities and investments of such firms at the international level. Over the 3 last years, a trend towards harmonization can be recognized: the World Health Organization has recognized the problems of postgenomic medical research as a priority. The OECD has created a taskforce on centers for biological resources. Biobanks are a common theme of the French and the German National Ethic Councils. A lack of international harmonization and consistency might not only present a challenge to biotechnology and pharmaceutical companies, but can also endanger the goals the laws and regulations seek to achieve.

[Angiogenesis and density of dendritic cells do not correlate with metachronous distant metastases after curative surgery of rectal carcinoma]. / Angiogenese und Dichte dendritischer Zellen korrelieren nicht mit der metachronen Fernmetastasierung beim kurativ operierten Rectumcarcinom.

INTRODUCTION: Besides surgery, treatment of rectal cancer increasingly comprises (neo-)adjuvant strategies. To optimise the selection process for these therapy regimens especially in the field of cellular and molecular biology, new prognostic factors besides the established TNM system are being investigated. METHODS: Retrospectively, two groups of patients (n = 2 x 85) with rectal carcinoma curatively treated by surgery alone were studied (median follow-up: 6.1 years). The patients were selected to be free of local disease, in order to exclude surgical influence. Patient groups were matched for age, gender, UICC stage and year of operation (1982-1991) and differed only in subsequent metachronous distant metastatic spread, the criterion to be studied. The factors to be investigated in uni- and multivariate analysis were angiogenesis, density of dendritic cells, grading, venous and lymphatic invasion. RESULTS: Grading always proved to be the only significant prognostic factor (P < 0.0001). In univariate analysis, absent venous invasion also correlated significantly with increased disease-free survival (P = 0.0170). CONCLUSIONS: Angiogenesis and density of dendritic cells in rectal cancer are not prognostic factors for metachronous distant metastasis and, therefore, cannot serve as selection parameters for adjuvant therapy.

Real-time assessment of intraperitoneal tumor growth in a rat model using CEA immunoscintigraphy.

BACKGROUND: In most preclinical models, assessment of intraperitoneal tumor location and size require killing the animal. The dynamics of postoperative intraperitoneal tumor implantation and growth remain unclear. A noninvasive method allowing reliable in vivo, real-time assessment of tumor growth is desirable. METHODS: An intraperitoneal tumor homograft using cultured CC531 colorectal cells was created by laparotomy in 24 Wistar Albino Glaxo rats. Eight additional rats were used as controls. Then, 10 MBq technetium 99m-labeled anticarcinoembryonic antigen (anti-CEA) monoclonal antibodies were administrated intravenously and radioactivity uptake was measured by using extracorporeal gamma counting at various time points. Subsequently, the animals were killed for tumor weighting. In 2 more groups of 8 animals, real-time, repeated measures were performed. RESULTS: Correlation between gamma counting and tumor weight was highly significant (P <.001). The regression equation obtained by using the least squares method was: tumor weight (g) = 2.422 + 0.267 x counts. It was possible to obtain real-time tumor growth curves when repeated measurements of radioactivity were performed. At day 25, the predicted tumor weight was 8.49 +/- 0.76 g, the measured weight was 8.16 +/- 0.99 g. CONCLUSIONS: Immunoscintigraphic measurements with technetium 99m anti-CEA antibodies are highly correlated with tumor weight in this model. As opposed to other tumor graft models based on autopsy findings, real-time monitoring is possible. This will allow dynamic studies of intraperitoneal tumor implantation and growth and will reduce the number of animals used in further studies.