Background
Two significant limitations of intraperitoneal drug therapy are limited drug distribution and poor penetration into peritoneal nodules. A possible solution is the application of the ...so-called “therapeutic pneumoperitoneum,” taking advantage of the gaseous nature and the pressure of capnoperitoneum during laparoscopy. Our objective was to develop a device able to apply such therapeutic pneumoperitoneum.
Methods
The technology presented here is a spraying device and can be introduced through a trocar. It is driven by mechanical pressure and consists of an injector, a line, and a nozzle. An in vivo experimental study was performed in five pigs. A transvaginal cholecystectomy was performed. At the end of the procedure, a standard dose of methylene blue was sprayed/infused into the abdominal cavity for 30 min (4 test animals w/therapeutic pneumoperitoneum (12 mmHg CO
2
) and 1 control animal w/conventional lavage (2 l intra-abdominal volume with extracorporeal circulation)). At the end of the procedure, all animals were autopsied and the peritoneum was analyzed. Outcome criteria were: (1) drug distribution (as assessed by the stained peritoneal surface at autopsy), and (2) diffusion into the peritoneum (presence or not of macroscopic staining of the outer aspect of the peritoneum immediately after surgery).
Results
Stained peritoneal surface was larger after aerosol application compared with peritoneal lavage, and staining more intense. Hidden peritoneal surfaces and the anterior abdominal wall were stained only in the aerosol group. In contrast to peritoneal lavage, the outer aspect of peritoneal membrane was immediately stained after pressurized spraying.
Conclusions
This device and the related approach significantly improve both distribution and penetration of a test substance into the peritoneal cavity in a large animal model. This might be a significant progress in treating intraperitoneal disease, in particular peritoneal carcinomatosis.
The diagnosis of most cancers is made by a board-certified pathologist based on a tissue biopsy under the microscope. Recent research reveals a high discordance between individual pathologists. For ...melanoma, the literature reports on 25–26% of discordance for classifying a benign nevus versus malignant melanoma. A recent study indicated the potential of deep learning to lower these discordances. However, the performance of deep learning in classifying histopathologic melanoma images was never compared directly to human experts. The aim of this study is to perform such a first direct comparison.
A total of 695 lesions were classified by an expert histopathologist in accordance with current guidelines (350 nevi/345 melanoma). Only the haematoxylin & eosin (H&E) slides of these lesions were digitalised via a slide scanner and then randomly cropped. A total of 595 of the resulting images were used to train a convolutional neural network (CNN). The additional 100 H&E image sections were used to test the results of the CNN in comparison to 11 histopathologists. Three combined McNemar tests comparing the results of the CNNs test runs in terms of sensitivity, specificity and accuracy were predefined to test for significance (p < 0.05).
The CNN achieved a mean sensitivity/specificity/accuracy of 76%/60%/68% over 11 test runs. In comparison, the 11 pathologists achieved a mean sensitivity/specificity/accuracy of 51.8%/66.5%/59.2%. Thus, the CNN was significantly (p = 0.016) superior in classifying the cropped images.
With limited image information available, a CNN was able to outperform 11 histopathologists in the classification of histopathological melanoma images and thus shows promise to assist human melanoma diagnoses.
•A convolutional neural network (CNN) was trained with 595 histopathologic images of melanoma and nevi.•In a direct comparison, the CNN and 11 histopathologists classified a test set of 100 additional histopathologic images (1:1 melanoma/nevi).•The CNN systematically outperformed the 11 histopathologists in terms of overall accuracy, sensitivity and specificity (p = 0.016).
Background
Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel approach for treating peritoneal carcinomatosis. First encouraging results have been obtained in human patients. ...However, delivering chemotherapy as an aerosol might result in an increased risk of exposure to health care workers, as compared with other administration routes.
Methods
PIPAC was applied in two human patients using chemotherapeutic drugs (doxorubicin and cisplatin), and air contamination levels were measured under real clinical conditions. Air was collected on a cellulose nitrate filter with a flow of 22.5 m
3
/h. To exclude any risk for health care workers, both procedures were remote controlled. Toxicological research of cisplatin was performed according to NIOSH 7300 protocol. Sampling and analysis were performed by an independent certification organization.
Results
The following safety measures were implemented: closed abdomen, laminar airflow, controlled aerosol waste, and protection curtain. No cisplatin was detected in the air (detection limit < 0.000009 mg/m
3
) at the working positions of the surgeon and the anesthesiologist under real PIPAC conditions.
Conclusions
For the drugs tested, PIPAC is in compliance with European Community working safety law and regulations. Workplace contamination remains below the tolerance margin. The safety measures and conditions as defined above are sufficient. Further protecting devices, such as particulate (air purifying) masks, are not necessary. PIPAC can be used safely in the clinical setting if the conditions specified above are met. However, a toxicological workplace analysis must be performed to confirm that the procedure as implemented complies with local regulations.
Background
Peritoneal carcinomatosis (PC) is an unmet medical need. Despite recent improvements, systemic chemotherapy has limited efficacy. We report the first application of intraperitoneal ...chemotherapy as a pressurized aerosol in human patients.
Methods
Three end-stage patients with advanced PC from gastric, appendiceal, and ovarian origin were treated as a compassionate therapy. All patients had received previous systemic chemotherapy. A pressurized aerosol of CO
2
loaded with doxorubicin 1.5 mg/m
2
and cisplatin 7.5 mg/m
2
(pressurized intraperitoneal aerosol chemotherapy, PIPAC) was applied into the abdomen for 30 min at a pressure of 12 mmHg and a temperature of 37 °C.
Results
No side-effects >2 CTCAE were observed, and the procedures were well tolerated. Early hospital discharge was possible (days 2–5). Nuclear presence of doxorubicin was documented throughout the peritoneum, reaching high local concentration (≤4.1 μmol/g) and plasma concentration was low (4.0–6.2 ng/ml). PIPAC created no significant adhesions, could be repeated, and was applied 6×, 4×, and 2×. Two patients showed a complete and one a partial histological remission. Mean survival after the first PIPAC was 288 days. One patient is alive after 567 days.
Conclusions
PIPAC shows superior pharmacological properties with high local concentration and low systemic exposure. PIPAC can induce regression of PC in chemoresistant tumors, using 10 % of a usual systemic dose.
Background
Intraperitoneal chemotherapy is limited by tissue penetration. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) has been shown to improve drug uptake by utilizing the physical ...properties of gas and pressure. This study investigated the effect of adding electrostatic precipitation to further enhance the pharmacologic properties of this technique.
Methods
A comparative study was performed using an in vivo porcine model. There were 3 cases in each group, PIPAC and electrostatic precipitation pressurized intraperitoneal aerosol chemotherapy (ePIPAC), plus 1 negative control comparing intraperitoneal distribution and tissue uptake of 2 tracer substances (toluidine blue and DT01). Tracer uptake was determined by measuring DT01 in tissue and peritoneal fluid at the end of each procedure.
Results
Electrostatic precipitation of the aerosol was technically feasible in all ePIPAC animals. The aerosol was cleared completely from the visual field within 15 s in the ePIPAC group versus 30 min in the PIPAC group. The peritoneal surface was homogeneously stained in both groups. After 30 min, 1.5 % remaining DT01 was measured in samples of ePIPAC-treated peritoneal fluid versus 15 % in PIPAC animals (
p
= 0.01). Tissue concentration was increased after ePIPAC versus PIPAC (
p
= 0.06).
Conclusions
ePIPAC is technically feasible and improves tissue uptake of 2 tracer substances compared to PIPAC by up to tenfold. Intraperitoneal distribution was homogeneous in both groups. ePIPAC has the potential to allow more efficient drug uptake, further dose reduction, a significant shortening of the time required for PIPAC application, and improved health and safety measures.
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.
Patients with peritoneal metastasis (PM) of gastrointestinal and gynecological origin present with a nutritional deficit characterized by increased resting energy expenditure (REE), loss of muscle ...mass, and protein catabolism. Progression of peritoneal metastasis, as with other advanced malignancies, is associated with cancer cachexia anorexia syndrome (CAS), involving poor appetite (anorexia), involuntary weight loss, and chronic inflammation. Eventual causes of mortality include dysfunctional metabolism and energy store exhaustion. Etiology of CAS in PM patients is multifactorial including tumor growth, host response, cytokine release, systemic inflammation, proteolysis, lipolysis, malignant small bowel obstruction, ascites, and gastrointestinal side effects of drug therapy (chemotherapy, opioids). Metabolic changes of CAS in PM relate more to a systemic inflammatory response than an adaptation to starvation. Metabolic reprogramming is required for cancer cells shed into the peritoneal cavity to resist anoikis (i.e., programmed cell death). Profound changes in hexokinase metabolism are needed to compensate ineffective oxidative phosphorylation in mitochondria. During the development of PM, hypoxia inducible factor-1α (HIF-1α) plays a key role in activating both aerobic and anaerobic glycolysis, increasing the uptake of glucose, lipid, and glutamine into cancer cells. HIF-1α upregulates hexokinase II, phosphoglycerate kinase 1 (PGK1), pyruvate dehydrogenase kinase (PDK), pyruvate kinase muscle isoenzyme 2 (PKM2), lactate dehydrogenase (LDH) and glucose transporters (GLUT) and promotes cytoplasmic glycolysis. HIF-1α also stimulates the utilization of glutamine and fatty acids as alternative energy substrates. Cancer cells in the peritoneal cavity interact with cancer-associated fibroblasts and adipocytes to meet metabolic demands and incorporate autophagy products for growth. Therapy of CAS in PM is challenging. Optimal nutritional intake alone including total parenteral nutrition is unable to reverse CAS. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) stabilized nutritional status in a significant proportion of PM patients. Agents targeting the mechanisms of CAS are under development.
PDF
