Restricted access to innovative surgical technique related to a specific training, is it ethical? Example of the PIPAC procedure. A systematic review and an experts survey.

OBJECTIVE: Using the example of Pressurized Intra Peritoneal Aerosol Chemotherapy (PIPAC), we analyse the development model of this procedure and provide an ethical analysis of the involvement of the industry in a new development. SUMMARY BACKGROUND DATA: In the case of breakthrough innovation, medical training is essential for safe use of the new procedure. In some cases, pharmaceutical companies decide to organise this training. But when it becomes the only training opportunity to use the device, scientists and clinicians could be exposed to a conflict of interest? METHODS: We performed a literature review of PIPAC publications using the STROBE criteria. Then, we conducted interviews with an expert panel to analyse the ethical impact of involvement of the industry in the development of the PIPAC procedure. RESULTS: The number of publications has increased every year since the first publication in Germany, where the technology was developed in 2013. The scientific production was of good quality, with a mean STROBE score of 18.2 ± 2.4 out of 22 points. Ten of the 33 included studies declared a conflict of interest. From the interviews, the main axe concerning the implication of the industry was the training model. The company had decided that only trained and approval surgeon could perform the PIPAC procedure. All four interviewed practitioners agreed that it was initially a good way to implement the procedure safely, but later they felt uncomfortable about the control and validation by the industry. CONCLUSION: Based on the growing number of published papers from a growing number of international centres, the controlled training model is not limiting. However, the different levels of conflict of interest complicate transparency, and we postulated that this development model is limited to the beginning of the procedure diffusion. CLINICALTRIAL. GOV REGISTRATION: NCT04341337.

Utilization of virtual low-keV monoenergetic images generated using dual-layer spectral detector computed tomography for the assessment of peritoneal seeding from ovarian cancer.

This study aimed to compare the quality of virtual low-keV monoenergetic images vs conventional images reconstructed from dual-layer spectral detector computed tomography (SDCT) for the detection of peritoneal implants of ovarian cancer.Fifty ovarian cancer patients who underwent abdominopelvic SDCT scans were included in this retrospective study. Virtual monoenergetic images at 40 (VMI40) and 50 keV (VMI50), and two conventional images were reconstructed using filtered back projection (FBP) and iterative model reconstruction (IMR) protocols. The mean attenuation of the peritoneal implant, signal-to-noise ratio (SNR), contrast-to-noise ratio relative to ascites (CNRA) and adjacent reference tissues (e.g., bowel wall, hepatic, or splenic parenchyma [CNRB]) were calculated and compared using paired t tests. Qualitative image analysis regarding overall image quality, image noise, image blurring, lesion conspicuity, was performed by two radiologists. A subgroup analysis according to the peritoneal implant region was also conducted.VMI40 yielded significantly higher mean attenuation (183.35) of SNR and CNR values (SNR 11.69, CNRA 7.39, CNRB 2.68), compared to VMI50, IR, and FBP images (P < .001). The mean attenuation (129.65), SNR and CNR values (SNR 9.37, CNRA 5.72, CNRB 2.02) of VMI50 were also significantly higher than those of IR and FBP images (P < .001). In the subgroup analysis, all values were significantly higher on VMI40 regardless of the peritoneal implant region (P < .05). In both readers, overall image quality and image blurring showed highest score in VMI50, while image noise and lesion conspicuity showed best score in IMR and VMI40 respectively. Inter-reader agreements are moderate to almost perfect in every parameter.The low-keV VMIs improved both quantitative assessment and lesion conspicuity of peritoneal implants from ovarian cancer compared to conventional images.

Assessment of the aerosol distribution pattern of a single-port device for intraperitoneal administration of therapeutic substances.

BACKGROUND: In the last 20 years, intraperitoneal chemotherapy (IPC) has been explored as a modality for the management of peritoneal metastases of gynecologic, gastrointestinal, and primary peritoneal tumors. Direct delivery of chemotherapeutic agents to the peritoneal cavity space has proved superior to systemic chemotherapy when evaluating characteristics such as drug concentration reached in the peritoneal space, penetration into peritoneal metastases, and chemotherapy-related toxicity. Traditionally, IPC is delivered by peritoneal lavage with a liquid solution. This form of delivery has limitations, including inhomogeneous intraperitoneal distribution and limited ability to penetrate tissues and metastatic nodules. An alternative mode of delivery is so-called pressurized intraperitoneal aerosol chemotherapy (PIPAC). Within this context, the present study sought to identify the pattern of spatial distribution of therapeutic solutions aerosolized into the peritoneal space using a single-port PIPAC device and ascertain whether the aerosolized method is superior to the traditional (liquid) mode of IPC delivery. METHODS: Analysis of the rate of intra-abdominal staining with aerosolized 2% silver nitrate in five porcine models. RESULTS: Assessment of differences in stain impregnation between the upper, middle, and lower abdomen did not reveal significant differences (p = 0.42). The median sum scores were 1 for the upper abdomen and 3 for the middle and lower abdomen. CONCLUSIONS: Aerosolization does not reach all regions of the abdomen homogeneously. However, adequate exposure of the upper abdomen, mid-abdomen, and lower abdomen to chemotherapeutic agents can be achieved with PIPAC.

Is there such a thing as biocompatible peritoneal dialysis fluid?

Introduction of the so-called biocompatible peritoneal dialysis (PD) fluids was based on a large body of experimental evidence and various clinical trials suggesting important clinical benefits. Of these, until now, only preservation of residual renal function-likely due to lower glucose degradation product load and, in case of icodextrin, improved fluid and blood pressure control-have consistently been proven, whereas the impact on important clinical endpoints such as infectious complications, preservation of PD membrane transport function, and patient outcome, are still debated. In view of the high morbidity and mortality rates of PD patients, novel approaches are warranted and comprise the search for alternative osmotic agents and enrichment of PD fluids with specific pharmacologic agents, such as alanyl-glutamine, potentially counteracting local but also systemic sequelae of uremia and PD.

A comparison of the results from intra-pleural and intra-peritoneal studies with those from inhalation and intratracheal tests for the assessment of pulmonary responses to inhalable dusts and fibres.

The aim of this paper is to compare results from inhalation studies with those from intraperitoneal and intrapleural tests, where available, for a number of fibrous and particulate test materials. The objective is to determine how well intraperitoneal/intrapleural studies predict the pathological responses observed in more standard in vivo studies of pulmonary toxicity, with a particular focus on carcinogenicity. Published toxicity data was obtained for a number of materials including asbestos, wollastonite, MMVFs (including glass fibres, stone wools and RCF), silicon carbide whiskers, potassium octatitanate, quartz, kevlar, polypropylene and titanium dioxide. For some of the fibrous material reviewed, there is conformity between the results of intraperitoneal and inhalation tests such that they are either consistently positive or consistently negative. For the remaining fibrous materials reviewed, intraperitoneal and inhalation tests give different results, with positive results in the intraperitoneal test not being reflected by positive inhalation results. It is suggested that the intraperitoneal test can be used to exonerate a dust or fibre (because if negative in the intraperitoneal test it is extremely unlikely to be positive in either inhalation or intratracheal tests) but should not be used to positively determine that a dust or fibre is carcinogenic by inhalation. We would argue against the use of intraperitoneal tests for human health risk assessment except perhaps for the purpose of exoneration of a material from classification as a carcinogen.

[Feasibility, morbidity and survival of surgery combined with HIPEC in the management of recurrent ovarian cancer]. / Faisabilité, morbidité et survie de la chirurgie avec CHIP dans la prise en charge des récidives du cancer de l'ovaire.

OBJECTIVE: The management of recurrent ovarian cancer is based on intravenous chemotherapy with or without debulking surgery. The hyperthermic intraperitoneal chemotherapy (HIPEC) is sometimes proposed as a complement to complete surgery. The purpose of this study was to evaluate the feasibility, morbidity and survival of HIPEC associated with complete surgical cytoreduction in the management of patients with a first recurrence of ovarian cancer. PATIENTS AND METHODS: Between 2005 and 2010, 27 patients underwent surgery for a recurrence of ovarian cancer. Among them, 17 patients (63%) have received HIPEC. RESULTS: Sixteen patients (94%) were completely resected after surgery. No patient died postoperatively. Two patients had intraoperative complications: a bladder injury and a section of the ureter. Eight patients had postoperative complications including 3 grade 3 or higher (two organ failure and one reoperation). Fifteen patients had a recurrence with a median DFS of 11.9 months (95% CI [5.4-32.9]) from the HIPEC. The median overall survival from diagnosis was 107.8 months. DISCUSSION AND CONCLUSION: These results showed that the association of HIPEC with a complete cytoreduction for recurrent ovarian cancer presents acceptable morbidity and survival. The results of the ongoing French multicenter study (CHIPOR) are expected to generalize this support.

A bioengineered 3D ovarian cancer model for the assessment of peptidase-mediated enhancement of spheroid growth and intraperitoneal spread.

Cancer-associated proteases promote peritoneal dissemination and chemoresistance in malignant progression. In this study, kallikrein-related peptidases 4, 5, 6, and 7 (KLK4-7)-cotransfected OV-MZ-6 ovarian cancer cells were embedded in a bioengineered three-dimensional (3D) microenvironment that contains RGD motifs for integrin engagement to analyze their spheroid growth and survival after chemotreatment. KLK4-7-cotransfected cells formed larger spheroids and proliferated more than controls in 3D, particularly within RGD-functionalized matrices, which was reduced upon integrin inhibition. In contrast, KLK4-7-expressing cell monolayers proliferated less than controls, emphasizing the relevance of the 3D microenvironment and integrin engagement. In a spheroid-based animal model, KLK4-7-overexpression induced tumor growth after 4 weeks and intraperitoneal spread after 8 weeks. Upon paclitaxel administration, KLK4-7-expressing tumors declined in size by 91% (controls: 87%) and showed 90% less metastatic outgrowth (controls: 33%, P < 0.001). KLK4-7-expressing spheroids showed 53% survival upon paclitaxel treatment (controls: 51%), accompanied by enhanced chemoresistance-related factors, and their survival was further reduced by combination treatment of paclitaxel with KLK4/5/7 (22%, P = 0.007) or MAPK (6%, P = 0.006) inhibition. The concomitant presence of KLK4-7 in ovarian cancer cells together with integrin activation drives spheroid formation and proliferation. Combinatorial approaches of paclitaxel and KLK/MAPK inhibition may be more efficient for late-stage disease than chemotherapeutics alone as these inhibitory regimens reduced cancer spheroid growth to a greater extent than paclitaxel alone.

Natural orifice transluminal endoscopic surgery (NOTES): assessment of peritoneal bacterial load after intraperitoneal antimicrobial wash and evaluation of hemodynamic changes in a porcine model.

AIMS: Natural orifice transluminal endoscopic surgery (NOTES) is a promising newly developed procedure; however, it is associated with many complications. The main aim of our study is to assess whether peritoneal wash with antibiotics decreases the bacterial load contamination related to the transgastric approach. METHODS: Ten female farm pigs underwent transgastric peritoneoscopy with fallopian tubal ligation. Five pigs were randomized to antibiotic wash of the peritoneal cavity and five to placebo. All animals were given one intravenous dose of antibiotic before the procedure. Hemodynamic variables were continuously monitored throughout the procedure. The next day, peritoneal cultures were taken. The fallopian tubes were inspected to determine the success of ligation and the gastric incision sites were assessed for leakage. RESULTS: No significant difference was noted between the antibiotic peritoneal wash group and the placebo group in terms of peritoneal bacterial load with respective median colony-forming units per ml (CFU/ml) of 0 [0; 1] vs. 0 [0; 4], p = 0.637. No clinically significant hemodynamic changes were noted during the procedure. CONCLUSIONS: The results of our study indicate that NOTES carries minimal risk of peritoneal bacterial contamination, regardless of the use of intraperitoneal antibiotics, and is not associated with hemodynamic compromise.

The beneficial effects of preperitoneal catheter analgesia following colon and rectal resections: a prospective, randomized, double-blind, placebo-controlled study.

BACKGROUND: Preperitoneal catheter analgesia following abdominal surgery has attracted interest in the last decade. We conducted this study to evaluate the benefits of preperitoneal catheter analgesia in managing pain after abdominal colon and rectal resections. METHODS: A total of 50 patients undergoing colon and rectal resections for benign and malignant diseases received analgesic medicines via an epidural catheter placed just prior to surgery and a preperitoneal catheter placed at the end of the surgical procedure. Patients were instructed to use the epidural patient-controlled analgesia (PCA) device freely and were randomized into two groups after obtaining the approval of the Institutional Review Board: Group A received 10 ml of levobupivacaine twice a day postoperatively via preperitoneal catheter and group B received only 10 ml of saline. Demographics, surgical characteristics, pain scores recorded four days following surgery, analgesic volume used from the epidural PCA, clinical outcomes (length of stay, time to first bowel movement, time to first passage of gas or stool, time to first oral intake) and respiratory function test results (preoperative vs. postoperative) were compared. RESULTS: There were no significant differences in demographics or surgical characteristics between both groups. Pain scores were similar. Clinical outcomes and respiratory functions were comparable. The use of analgesic volume via epidural catheter was significantly lower in group A than in group B (P = 0.032). CONCLUSIONS: Preperitoneal catheter analgesia significantly decreased the need for epidural drug consumption and proved to be a beneficial adjunct for postoperative pain management of patients who underwent colon and rectal resections.

FloSeal reduces the incidence of lymphoceles after lymphadenectomies in laparoscopic and robot-assisted extraperitoneal radical prostatectomy.

PURPOSE: To evaluate the efficacy and cost-effectiveness of FloSeal(®) hemostatic matrix in preventing lymphocele development after pelvic lymphadenectomy (PLA). MATERIALS AND METHODS: This was a single-center, matched comparison of lymphadenectomies in laparoscopic and robot-assisted extraperitoneal radical prostatectomy (ERP) performed with and without FloSeal between January 2008 and October 2009. FloSeal was applied topically in the lymphadenectomy zone immediately after node resection. Cost analysis for lymphocele treatment was performed. RESULTS: A total of 142 patients underwent PLA with ERP (32 with FloSeal, 110 without FloSeal). The mean number of lymph nodes removed was 6.5±4.5 (range 2-20). Median prostate-specific antigen concentration was 8.5 ng/mL (range 1.5-24 ng/mL). There was one (3.1%) symptomatic lymphocele in the FloSeal group compared with 16 (14.5%) in the non-FloSeal group. The median number of lymph nodes removed was 8 (range 5-20) in the FloSeal group and seven (range 3-25) in the non-FloSeal group. The only lymphocele in the FloSeal group was treated with percutaneous drainage alone. In the non-FloSeal group, six symptomatic lymphoceles were managed conservatively-four with percutaneous puncture and six with fenestration after percutaneous drainage. The mean cost per patient of treating symptomatic lymphoceles was €327 ($455) in the FloSeal group (total costs €10,481 [$14,559]) vs €553 ($769) (total costs €60,870 [$84,551]) in the non-FloSeal group. CONCLUSIONS: These preliminary data suggest that the use of FloSeal after lymphadenectomy can reduce the number of symptomatic lymphoceles and is cost-effective.

Assessment of acridine orange and SYTO 16 for in vivo imaging of the peritoneal tissues in mice.

The effect of peritoneal injection of acridine orange and SYTO 16 in mice was investigated. Images of peritoneal tissues stained with these dyes and obtained through a confocal micro-endoscope are presented. Seventy-five Balb/c mice were split into five groups and given peritoneal injections of dye or saline. The proportions of negative outcomes in each group were compared using confidence intervals and the Fisher's exact statistical test. A statistically significant increase in adverse events due to dye injection was not observed. These data provide an initial investigation into the safety of acridine orange and SYTO 16 for in vivo imaging.

Assessment of peritoneal tolerance of a new MR blood pool contrast agent in rabbits.

OBJECTIVE: Fast 3D MR angiography in conjunction with a new blood pool contrast agent (iron oxide crystals) is a recently described method for detection and localization of intra-abdominal bleeding sites with high sensitivity and specificity. However, peritoneal reactions to the contrast agent have not yet been investigated. The purpose of this study was to assess the peritoneal tolerance of the contrast agent in an animal experiment. METHODS: Eleven rabbits were intraperitoneally injected with 5 mL diluted NC100150 Injection; two rabbits were used as the control group. Rabbits injected with NC100150 Injection were imaged in pairs at 12, 24, and 48 hours and 3 weeks, and a single rabbit was imaged at 72 hours and 1 and 2 weeks after the intraperitoneal administration of the agent. Immediately after imaging, the rabbits were killed and an autopsy was performed. Samples of peritoneal surfaces and intra-abdominal organs were harvested for histology. MR imaging, gross pathology, and histology were evaluated. RESULTS: MR imaging and gross pathology demonstrated the presence of intraperitoneal contrast agent up to 24 hours after administration. Histology revealed a considerable amount of iron in the peritoneum, mesenteric fat, and lymph nodes within the first 24 hours. In most cases, iron was rapidly cleared from these sites within 2 days; in one animal, however, iron was detectable up to 1 week. No signs of inflammation or fibrosis were detected. CONCLUSIONS: This study shows no evidence of inflammatory reactions or signs of fibrosis after the intraperitoneal application of NC100150 Injection.

Cytohistologic assessment of antitumor effects of intraperitoneal hyperthermic perfusion with mitomycin C for patients with gastric cancer with peritoneal metastasis.

For 15 patients with refractory gastric cancer and peritoneal metastasis, intraperitoneal hyperthermic perfusion (IPHP) using mitomycin C combined with extensive surgery was prescribed. The antitumor effects were assessed cytohistologically in pre-IPHP and post-IPHP specimens of the abdominal effusion and peritoneal tissue. Gastric cancer cells in the abdominal effusion and/or lavage vanished from post-IPHP peritoneal exudate obtained from the pouch of Douglas. Peritoneal tissues from nine patients were harvested just after the IPHP treatment. All the nuclei of cancer cells were pyknotic in three of nine patients, and two of these three patients are alive with no local recurrence; one patient died of hepatic metastasis. In the remaining six patients, four with preoperative ascitic effusion and positive post-IPHP histologic findings died of peritoneal, intraabdominal, and pericardial metastases. The other two had some residual microscopic foci in the subperitoneal deep layer; one patient died of pleural recurrence, and the other is alive with no evidence of recurrence 42 months after the IPHP. Among the other six patients, whose post-IPHP peritoneal tissues were not available because of disappearance of disseminating foci as a result of the IPHP, two are living with no recurrence and, of the remaining four patients, three died of hepatic and intraabdominal metastases and the other one died of other causes. The histologic findings are suggestive of the following: (1) uniform heat and drug distribution in the abdominal cavity with IPHP treatment, except for an area adjacent to the inflow point of the perfusate; and (2) limited penetration of heat and drug through the subperitoneal layer. Thus, IPHP treatment results in complete destruction of cancer cells in the abdominal effusion and on and just beneath the peritoneum.

An assessment of the fibrogenic potential of two refractory fibres by intraperitoneal injection in rats.

Two commercially available grades of the refractory fibre SAFFIL were administered to rats by intraperitoneal injection and the tissue reaction was compared. Although the fibres differed considerably in surface properties and porosity the tissue reactions were identical and consisted of a mild chronic inflammatory response with a small amount of collagen present. The reaction was quite distinct from the marked fibrosis induced by chrysotile asbestos. As the reaction to all fibres tested had stabilised after 6 months, a longer observation period is unnecessary.