Repeat cytoreductive surgery with HIPEC for colorectal peritoneal metastases: a systematic review.

BACKGROUND: Colorectal peritoneal metastases (CRPM) are present in 10-20% of patients at the time of their initial cancer diagnosis, and affects over 20% of those who develop colorectal cancer recurrence. Cytoreductive surgery (CRS) with HIPEC is firmly established as the optimal surgical treatment, but there is very little known about the benefit of repeat or iterative CRS. The aim of this review is to provide a systematic evaluation of the perioperative complications, survival outcomes and quality of life in patients undergoing repeat CRS with HIPEC for CRPM. METHODS: A systematic review of PubMed, Ovid MEDLINE, EMBASE, Scopus and Cochrane databases was performed to identify all studies that reported outcomes for repeat CRS with or without HIPEC for CRPM. RESULTS: Four hundred and ninety-three manuscripts were screened, and 15 retrospective studies were suitable for inclusion. Sample sizes ranged from 2 to 30 participants and comprised a total of 229 patients. HIPEC was used in all studies, but exact rates were not consistently stated. Perioperative morbidity was reported in four studies, between 16.7% and 37.5%. Nine studies reported mortality rate which was consistently 0%. The median overall survival after repeat CRS ranged from 20 to 62.6 months. No studies provided quality of life metrics. CONCLUSION: Repeat CRS for CRPM has perioperative morbidity and mortality rates comparable to initial CRS, and offers a potential survival benefit in selected patients. There is however limited high-quality data in the literature.

Neoadjuvant chemotherapy does not improve survival for patients with high volume colorectal peritoneal metastases undergoing cytoreductive surgery.

BACKGROUND: Colorectal peritoneal metastases (CRPM) affects 15% of patients at initial colorectal cancer diagnosis. Neoadjuvant chemotherapy (NAC) prior to cytoreductive surgery (CRS) has been demonstrated to be a safe and feasible option, however there is limited data describing its efficacy in advanced peritoneal disease. This study evaluated the effect of NAC on survival in patients with high volume CRPM undergoing CRS with or without HIPEC. METHODS: A retrospective review of all patients who underwent CRS with or without HIPEC for CRPM from 2004 to 2019 at our institution was performed. The cohort was divided based on peritoneal carcinomatosis index (PCI) at surgery: Low Volume (PCI ≤ 16) and High Volume (PCI > 16). RESULTS: A total of 326 patients underwent CRS with HIPEC for CRPM. There were 39 patients (12%) with High Volume disease, and 15 of these (38%) received NAC. Patients with High Volume disease had significantly longer operating time, lower likelihood of complete macroscopic cytoreduction (CC-0 score), longer intensive care unit length of stay and longer hospital stay compared to Low Volume disease. In High Volume disease, the NAC group had a significantly shorter median survival of 14.4 months compared to 23.8 months in the non-NAC group (p = 0.046). CONCLUSION: Patients with High Volume CRPM achieved good median survival following CRS with HIPEC, which challenges the current PCI threshold for offering CRS. The use of NAC in this cohort did not increase perioperative morbidity but was associated with significantly shorter median survival compared to upfront surgery.

Development and Validation of Micro-Azocasein Assay for Quantifying Bromelain.

The proteolytic activity of enzymes may be evaluated by a colorimetric method with azocasein. Hence, we developed a micro-assay to quantify bromelain using azocasein. A total of 250 µL of 1.0% azocasein in dH2O was added to 250 µL of test solution, vortexed and incubated at ambient room temperature/30 min. The reaction was terminated with 1500 µL of 5% trichloroacetic acid, vortexed and centrifuged. A total of 150 µL of 0.5M NaOH was added to 150 µL of supernatant in triplicates, and absorbance was recorded at 410 nm. The linearity of the calibration curve was tested with 200-800 µg/mL serial dilutions. The detection limit, precision, accuracy, and robustness were tested along with the substrate enzyme reaction time and solvent matrix effect. Good linearity was seen with serially diluted 200 µg/mL bromelain. The limit of quantification and limit of detection were 5.412 and 16.4 µg/mL, respectively. Intra-day and inter-day analyses showed a relative standard deviation below 2.0%. The assay was robust when tested over 400-450 nm wavelengths. The assays performed using dH2O or PBS diluents indicated a higher sensitivity in dH2O. The proteolytic activity of bromelain was enhanced with L-cysteine or N-acetylcysteine. Hence, this micro-azocasein assay is reliable for quantifying bromelain.

Development and Optimization of a Subtraction-Normalized Immunocyte Profiling Signature for Prostate Cancer Active Surveillance Risk Stratification.

PURPOSE: Less invasive decision support tools are desperately needed to identify occult high-risk disease in men with prostate cancer (PCa) on active surveillance (AS). For a variety of reasons, many men on AS with low- or intermediate-risk disease forgo the necessary repeat surveillance biopsies needed to identify potentially higher-risk PCa. Here, we describe the development of a blood-based immunocyte transcriptomic signature to identify men harboring occult aggressive PCa. We then validate it on a biopsy-positive population with the goal of identifying men who should not be on AS and confirm those men with indolent disease who can safely remain on AS. This model uses subtraction-normalized immunocyte transcriptomic profiles to risk-stratify men with PCa who could be candidates for AS. MATERIALS AND METHODS: Men were eligible for enrollment in the study if they were determined by their physician to have a risk profile that warranted prostate biopsy. Both training (n = 1017) and validation cohort (n = 1198) populations had blood samples drawn coincident to their prostate biopsy. Purified CD2+ and CD14+ immune cells were obtained from peripheral blood mononuclear cells, and RNA was extracted and sequenced. To avoid overfitting and unnecessary complexity, a regularized regression model was built on the training cohort to predict PCa aggressiveness based on the National Comprehensive Cancer Network PCa guidelines. This model was then validated on an independent cohort of biopsy-positive men only, using National Comprehensive Cancer Network unfavorable intermediate risk and worse as an aggressiveness outcome, identifying patients who were not appropriate for AS. RESULTS: The best final model for the AS setting was obtained by combining an immunocyte transcriptomic profile based on 2 cell types with PSA density and age, reaching an AUC of 0.73 (95% CI: 0.69-0.77). The model significantly outperforms (P < .001) PSA density as a biomarker, which has an AUC of 0.69 (95% CI: 0.65-0.73). This model yields an individualized patient risk score with 90% negative predictive value and 50% positive predictive value. CONCLUSIONS: While further validation in an intended-use cohort is needed, the immunocyte transcriptomic model offers a promising tool for risk stratification of individual patients who are being considered for AS.

Long-Term Treatment of Unresectable Pseudomyxoma Peritonei with Multiple Treatments of Intratumoural Bromelain and Acetylcysteine (BromAc®): A Case Report.

Pseudomyxoma peritonei is a rare peritoneal malignancy characterized by the progressive accumulation of mucinous material and tumour within the abdomen and pelvis. Percutaneous drainage of mucin may be a non-surgical option for relief of symptoms; however, it remains difficult due to the high viscosity of mucin, with numerous case reports reporting difficulty removing material through medium-bore catheters alone. BromAc is a therapy currently undergoing development which dissolves mucinous tumour masses and allows for extraction. This report describes the case of a patient who has had multiple treatments with BromAc over 4 years.

Increased Incidence of Liver Metastases in Colorectal Versus Appendiceal Adenocarcinoma Peritonectomy Patients Despite Equivocal Survival.

BACKGROUND/AIM: Colorectal adenocarcinoma (CRAdenoCa) and appendiceal adenocarcinoma (AAdenoCa) are diseases of the same histopathological type that metastasise to the liver and peritoneum. In selected subgroups, peritonectomy and heated intraperitoneal chemotherapy (HIPEC) may be indicated as part of the multimodal treatment plan. However, literature comparing the survival outcomes and preoperative tumour activity and burden of CRAdenoCa and AAdenoCa peritonectomy patients without synchronous liver metastases (sLM) is scarce. Little is also known about the comparative incidence of sLM and metachronous LM (mLM) between CRAdenoCa and AAdenoCa peritonectomy patients. This study aimed to clarify the above. PATIENTS AND METHODS: A retrospective cohort study of 684 CRAdenoCa and AAdenoCa primary peritonectomy patients between 2001-2021 was conducted at St George Hospital in Sydney, Australia. RESULTS: Median overall survival (years) was equivocal between CRAdenoCa and AAdenoCa peritonectomy patients (1.7 vs. 1.9, p=0.35). Peritoneal cancer index and preoperative carcinoembryonic antigen (CEA) were significantly elevated (25 vs. 9, p<0.0001 and 7.9 vs. 5, p=0.0080) in AAdenoCa versus CRAdenoCa peritonectomy patients without sLM. The incidence of sLM and mLM was increased in CRAdenoCa peritonectomy patients (24% vs. 3.1%, p<0.0001 and 26% vs. 10%, p=0.0001). CONCLUSION: This study demonstrates similar survival outcomes between CRAdenoCa and AAdenoCa peritonectomy patients. Despite elevated preoperative tumour burden and biological activity in AAdenoCa patients, CRAdenoCa patients had higher rates of sLM and mLM. Further studies are warranted to validate and identify cellular and molecular targets that increase CRAdenoCa's ability to metastasise to the liver.

Effective Use of Bromelain and Acetylcysteine (BromAc®) for Treatment of Perigastric Pseudomyxoma Peritonei: A Case Report.

BACKGROUND/AIM: Pseudomyxoma peritonei (PMP) is a rare clinical condition of progressive peritoneal mucin accumulation. PMP has a reasonable survivability but with a notable risk of tumour recurrence. Standard treatment, including for tumour relapse, aims for a cure with complete cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. In the case of tumour recurrence, surgery becomes progressively complex, and some patients are not suitable for surgery either due to patient preference or morbidity and mortality risk. BromAc® is an emerging, novel mucolytic combination therapy composed of bromelain and acetylcysteine which can be administered intratumorally via radiologically guided drains. It represents a minimally invasive treatment for patients who have symptomatic tumour deposits but are not surgical candidates. CASE REPORT: We report the case of a 64-year-old male with a background of appendiceal PMP who presented with a gastric outlet obstruction from a perigastric tumour deposit. This was managed with BromAc® administration, following which the patient's symptoms resolved. This corresponded with an 80% reduction in the tumour volume radiologically. CONCLUSION: BromAc® is an emerging minimally invasive treatment for PMP tumour deposits that may be considered as adjunctive or alternative treatment in patients who are not surgical candidates to reduce tumour burden and improve symptomatology and quality of life.

Efficacy of National Comprehensive Cancer Network Guidelines in Identifying Pathogenic Germline Variants Among Unselected Patients with Prostate Cancer: The PROCLAIM Trial.

BACKGROUND: Prostate cancer (PCa) patients with pathogenic/likely pathogenic germline variants (PGVs) in cancer predisposition genes may be eligible for U.S. Food and Drug Administration-approved targeted therapies, clinical trials, or enhanced screening. Studies suggest that eligible patients are missing genetics-informed care due to restrictive testing criteria. OBJECTIVE: To establish the prevalence of actionable PGVs among prospectively accrued, unselected PCa patients, stratified by their guideline eligibility. DESIGN, SETTING, AND PARTICIPANTS: Consecutive, unselected PCa patients were enrolled at 15 sites in the USA from October 2019 to August 2021, and had multigene cancer panel testing. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Correlates between the prevalence of PGVs and clinician-reported demographic and clinical characteristics were examined. RESULTS AND LIMITATIONS: Among 958 patients (median [quartiles] age at diagnosis 65 [60, 71] yr), 627 (65%) had low- or intermediate-risk disease (grade group 1, 2, or 3). A total of 77 PGVs in 17 genes were identified in 74 patients (7.7%, 95% confidence interval [CI] 6.2-9.6%). No significant difference was found in the prevalence of PGVs among patients who met the 2019 National Comprehensive Cancer Network Prostate criteria (8.8%, 43/486, 95% CI 6.6-12%) versus those who did not (6.6%, 31/472, 95% CI 4.6-9.2%; odds ratio 1.38, 95% CI 0.85-2.23), indicating that these criteria would miss 42% of patients (31/74, 95% CI 31-53%) with PGVs. The criteria were less effective at predicting PGVs in patients from under-represented populations. Most PGVs (81%, 60/74) were potentially clinically actionable. Limitations include the inability to stratify analyses based on individual ethnicity due to low numbers of non-White patients with PGVs. CONCLUSIONS: Our results indicate that almost half of PCa patients with PGVs are missed by current testing guidelines. Comprehensive germline genetic testing should be offered to all patients with PCa. PATIENT SUMMARY: One in 13 patients with prostate cancer carries an inherited variant that may be actionable for the patient's current care or prevention of future cancer, and could benefit from expanded testing criteria.

External validation of prognostic scores and comparison of predictive accuracy for patients with colorectal cancer with peritoneal metastases considered for cytoreductive surgery and intraperitoneal chemotherapy.

BACKGROUND AND OBJECTIVES: Prognostic scores are developed to facilitate the selection of patients with colorectal cancer peritoneal metastases (CRPM) for treatment with cytoreductive surgery (CRS) ± intraperitoneal chemotherapy (IPC). Three prominent prognostic scores are the Peritoneal Surface Disease Severity Score (PSDSS), the Colorectal Peritoneal Metastases Prognostic Surgical Score (COMPASS), and the modified COloREctal-Pc (mCOREP). We externally validate these scores and compare their predictive accuracy. METHODS: Data from consecutive CRPM patients who underwent CRS/IPC from 1996 to 2018 was used to externally validate COMPASS, PSDSS, and mCOREP. Analysis evaluated the efficacy of each score in predicting (1) open-close laparotomy-those found at laparotomy to not be eligible for curative intent CRS/IPC, (2) surgical futility-those who underwent open-close laparotomy, palliative debulking surgery, or had an overall survival of less than 12 months, and (3) overall and recurrence-free survival (OS, RFS). RESULTS: Prognostic scores were calculated for the 174-patient external validation cohort. COMPASS was most accurate in predicting open-close laparotomy, futile surgery, and survival (OS and RFS). Area under the curve (AUC) for open-close prediction was 0.78 (95% confidence interval, CI: 0.68-0.87), representing useful discrimination. However, AUC for futility prediction was 0.62 (95% CI: 0.52-0.71), and C-statistic for OS was 0.65 indicating only possibly helpful discrimination. C-statistic for RFS was 0.59 indicating poor discrimination. CONCLUSION: While COMPASS showed the best statistical behavior, accuracy for several clinically relevant outcomes remains low, and thus applicability to clinical practice limited.

Outcomes for Colorectal Cancer Cases With Peritoneal Metastases Treated With Cytoreductive Surgery With or Without Hyperthermic Intraperitoneal Chemotherapy: A Comparative Analysis of Survival Between Peritoneal Carcinomatosis Scores - PCI in a Single Centre.

BACKGROUND/AIM: Peritoneal cancer index (PCI) has been a strong indicator of prognosis for patients receiving cytoreductive surgery. The aim of this single institution study was to compare the survival of peritoneal carcinoma cases treated with cytoreduction surgery arising from colorectal cancer grouped by PCI scores. PATIENTS AND METHODS: A retrospective study of a prospective dataset maintained from 2000 till September 2022, for peritoneal metastases from colorectal cancers was carried out. Of the total of 1,625 peritoneal metastases cases, 415 were identified with colorectal cancer and considered for analysis. Survival was followed for 60 months since the index-peritonectomy for cases in this study. RESULTS: Hazard ratio for 5-year survival using the Cox regression analysis over time (t) with a Log-rank (Mantel-Cox) test for significance between the groups indicated, <15 vs. 15 (HR=2.121, p=0.0338), <15 vs. 16-20 (HR=2.748, p<0.0001), <15 vs. >20 (HR=3.158, p<0.0001), 15 vs. 16-20 (HR=1.262, p=0.5658), 15 vs. >20 (HR=1.566, p=0.2771) and for PCI category 16-20 vs. >20 (HR=1.204, p=0.5355) for survival. Median survival for the categories of PCI <15, PCI-15, PCI-16-20, and PCI >15 was 43.967 (95%CI=28.31-59.63), 20.67 (95%CI=5.01-36.33), 19.50 (95%CI=3.84-35.16), and 14.30 (95%CI=1.36-29.96), respectively. CONCLUSION: A correlation of PCI with survival was confirmed in this study reinforcing the need for assessment of PCI at surgery to help prognostication. Detecting synchronous peritoneal metastases early and prompt treatment can help prevent recurrence and increase survival.

First steps toward a BIG change: A pilot study to implement the Brain Injury Guidelines across a 24-hospital system.

INTRODUCTION: The modified Brain Injury Guidelines (mBIG) support a subset of low-risk patients to be managed without repeat head computed tomography (RHCT), neurosurgical consult (NSC), or hospital transfer/admission. This pilot aimed to assess mBIG implementation at a single facility to inform future systemwide implementation. METHODS: Single cohort pilot trial at a level I trauma center, December 2021-August 2022. Adult patients included if tICH meeting BIG 1 or 2 criteria. BIG 3 patients excluded. RESULTS: No patients required neurosurgical intervention. 72 RHCT and 83 NSC were prevented. 21 isolated BIG 1 were safely discharged home from the ED. No hospital readmissions for tICH. Protocol adherence rate was 92%. CONCLUSION: Implementation of the mBIG at a single trauma center is feasible and optimizes resource utilization. This pilot study will inform an implementation trial of the mBIG across a 24-hospital integrated health system.

Intraperitoneal BromAc® Does Not Interfere with the Healing of Colon Anastomosis.

A combination of bromelain and acetylcysteine, BromAc®, is an efficient intraperitoneal mucolytic for thick mucus secreted in pseudomyxoma peritonei (PMP). Patients with PMP quite often undergo colon anastomosis. Hence, we investigated the effect of the intraperitoneal delivery of BromAc® on colon-anastomosis healing in a rat model. Sixteen Wistar rats were divided into two groups (N = 8). The controls received intraperitoneal saline after anastomosis, whilst the other group received BromAc®. They were monitored for body-weight and general health parameters. Half the rats in each group (N = 4) were culled at 4 or 13 days post-surgery for assessment. The healing process of the tissues was assessed by burst pressure and collagen density with histology to assess the integrity of the internal organs. The results indicated that there was a similar pattern of weight fluctuation during the experiment, although the rats treated with the BromAc® showed slightly greater weight loss during the first 4 days. Although the burst pressure was similar in both groups, the BromAc® group at day 13 showed a slightly higher burst pressure, which was complemented by a higher collagen density (albeit not statistically significant). The histology of the internal organs was comparable to those of the controls. This study indicates that the intraperitoneal delivery of BromAc® in a rat model does not interfere with the healing process of colonic anastomosis.

Shoulder complex and trunk coordination of individuals with severe hemiparesis following a constraint-induced movement therapy protocol: A case series.

INTRODUCTION: Constraint Induced Movement Therapy (CIMT) has been shown to be an effective rehabilitation technique in individuals with mild and moderate upper limb (UL) hemiparesis. The aim was to evaluate the effect the CIMT for improving paretic UL use and interjoint coordination with individuals in severe hemiparesis. METHODS: Six individuals with severe chronic hemiparesis (mean age = 55 ± 16 years) received a UL CIMT intervention for 2 weeks. UL clinical assessments were conducted five times: two assessments at pre-intervention and then, one assessment at post-intervention and 1- and 3-month follow-up using the Graded Motor Activity Log GMAL) and the Graded Wolf Motor Function Test (GWMFT). Scapula, humerus and trunk coordination variability were assessed using the 3-D kinematics during arm elevation, combing hair, turning on the switch and grasp a washcloth. A paired t-test was used to check differences between coordination variability and a one-way ANOVA repeated measures was used to check differences between GMAL and GWMFT scores. RESULTS: There were no differences in GMAL and GWMFT between the patient screening and the baseline data collection (p > 0.05). GMAL scores increased at post-intervention and at follow-ups (p < 0.02). GWMFT performance time score decreased at post-intervention and at 1-month follow-up (p < 0.04). Improvements in kinematic variability of the paretic UL at pre and post-intervention were observed in all tasks, except in the activity of turn on the light switch. CONCLUSION: Following the CIMT protocol, improvements in GMAL and GWMFT scores may reflect improvements in paretic UL performance, in real-life environment. Improvements in kinematic variability may reflect an improving of UL interjoint coordination for individuals with chronic severe hemiparesis.

Bromelain and acetylcysteine (BromAc®): a novel approach to the treatment of mucinous tumours.

Mucins are a significant extracellular component of neoplastic entities such as pseudomyxoma peritonei and several gastrointestinal adenocarcinomas. Mucinous tumours present a challenge for systemic treatments due to poor drug penetrance and increased resistance. Therefore, the development of an effective mucolytic therapy has significant therapeutic implications for these tumour types. BromAc® is a novel mucolytic agent consisting of bromelain and acetylcysteine. It has demonstrated significant mucolysis and antitumour effects in vitro and in vivo for several mucinous tumours. It has also exhibited a synergistic potentiation of the effect of several cytotoxic agents on mucinous tumours in preclinical studies. Furthermore, it demonstrates locoregional safety and efficacy in animal and clinical studies. This literature review will summarise the history of BromAc® for mucinous tumours, including its conception, preclinical development in vitro and in vivo, and clinical evidence. The implications of current data and directions for future research are then discussed.

Effect of Nebulized BromAc on Rheology of Artificial Sputum: Relevance to Muco-Obstructive Respiratory Diseases.

Respiratory diseases such as cystic fibrosis, COPD, and COVID-19 are difficult to treat owing to viscous secretions in the airways that evade mucocilliary clearance. Earlier studies have shown success with BromAc as a mucolytic agent. Hence, we tested the formulation on two gelatinous airway representative sputa models, to determine whether similar efficacy exist. Sputum lodged in an endotracheal tube was treated to aerosol N-acetylcysteine, bromelain, or their combination (BromAc). After measuring the particle size of aerosolized BromAc, the apparent viscosity was measured using a capillary tube method, whilst the sputum flow was assessed using a 0.5 mL pipette. Further, the concentration of the agents in the sputa after treatment were quantified using chromogenic assays. The interaction index of the different formulations was also determined. Results indicated that the mean particle size of BromAc was suitable for aerosol delivery. Bromelain and N-acetylcysteine affected both the viscosities and pipette flow in the two sputa models. BromAc showed a greater rheological effect on both the sputa models compared to individual agents. Further, a correlation was found between the rheological effects and the concentration of agents in the sputa. The combination index using viscosity measurements showed synergy only with 250 µg/mL bromelain + 20 mg/mL NAC whilst flow speed showed synergy for both combinations of bromelain (125 and 250 µg/mL) with 20 mg/mL NAC. Hence, this study indicates that BromAc may be used as a successful mucolytic for clearing airway congestion caused by thick mucinous immobile secretions.

Peritoneal metastasis of advanced epithelial ovarian carcinoma treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: A retrospective international multicentric data analysis.

INTRODUCTION: The purpose of our study was to evaluate outcome data after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal metastasis originating from advanced epithelial ovarian carcinoma (PMOC). PATIENTS AND METHODS: A retrospective international multi-institutional registry was established through collaborative efforts of participating units affiliated with the Peritoneal Surface Oncology Group. RESULTS: One thousand four hundred and ninety-one patients from 11 specialized units underwent CRS and HIPEC that of those 326 (21.9%) upfront surgeries, 504 (33.8%) interval surgery, and 661(44.3%) recurrent cases. Complete Cytoreduction(CC0/1) was achieved in 1213 patients (81.3%). Treatment -related mortality was 0.8%, major operative complications (Grades 3-5) was 25.1%. Factors associated with major operative complications include prior surgical score (PSS for recurrent cases; RC) PSS>2,p = 0.000), PCI(≤15, >15 cut-off level; p ≤ 0.000), completeness of cytoreduction (CC, p=0.000), high CA125 levels (>25 mg/dl), presence of ascites, high CRP (>5 mg/dl) levels and low albumin levels (below to 2.5 mg/dl) (p ≤ 0.05). The median survival was 58 months in upfront surgery(UFS), 60 months in interval surgery(IS), and 42 months in RC. The overall survival for five years was 45% for UFS, 37% for IS, 28% for RC cases. CCscore (p = 0.000), CA125, CRP and albumin levels (p ≤ 0.05) were predictors for progression free survival. PCI(p ≤ 0.000), major postoperative complications (p = 0.004), incomplete CRS(CC2/3)(p < 0.001), prior chemotherapy (hazard ratio [HR], 3-8; p < 0.001) and PSS>2 for RC were independent predictors of poor overall survival. CONCLUSION: The combined treatment strategy for PMOC may be performed safely with acceptable morbidity and mortality in the specialized units.

Use of Prognostic Factors and Scores in Selection of Patients with Colorectal Cancer Peritoneal Metastasis (CRPM) for Cytoreductive Surgery and Intraperitoneal Chemotherapy (CRS/IPC): Results of an International Survey Among Oncologic Clinicians.

BACKGROUND: No universally accepted guidelines exist for treatment of patients with colorectal cancer peritoneal metastases (CRPM) undergoing cytoreductive surgery and intraperitoneal chemotherapy (CRS/IPC). Several uncertainties remain concerning almost every aspect of this treatment modality, resulting in marked variability in patient management and likely outcomes. This survey aimed to define variations and trends in clinician decision making more clearly. METHODS: A 41-question web-based survey was distributed electronically via the Peritoneal Surface Oncology Group International (PSOGI), the International Society for the Study of Pleura and Peritoneum (ISSPP) as well as via social media (particularly Twitter). The survey sought to address and record clinician responses regarding patient workup/assessment, selection for preoperative systemic therapy, preoperative and intraoperative selection for CRS/IPC, and consideration of prognosis and complications. RESULTS: Complete responses were received from 60 clinicians from 45 centres in 22 countries. Upon assessment of survey responses, several interesting trends were noted in each section of the survey. Significant variability in surgeon practice and opinion were identified concerning almost every aspect of the treatment modality. CONCLUSION: This international survey provides the most comprehensive insight into clinician decision-making trends regarding patient assessment, selection and management. This should allow areas of variability to be more clearly defined and could potentially prompt development of initiatives for achieving consensus and standardisation of care in the future.

Comparing Survival Outcomes and Impact of EPIC in Patients Undergoing CRS/HIPEC for Mucinous Appendiceal Neoplasm.

BACKGROUND/AIM: This study sought to investigate the difference in survival outcomes in patients with complete cytoreduction (CC)-0 or CC-1 mucinous appendiceal cancer undergoing cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC). It also investigated what effect early postoperative intraperitoneal chemotherapy (EPIC) may have on survival based on CC score and histology. PATIENTS AND METHODS: This was a retrospective single centre study of patients that underwent CRS/HIPEC +/- EPIC for mucinous appendiceal neoplasms from June 2003 to February 2022. RESULTS: A total of 545 patients were identified. Although there was a survival difference between CC-0 and CC-1 on univariate analyses, this was not statistically significant on multivariate analysis. Histology, peritoneal cancer index, and EPIC status were demonstrated to be independent factors that affected overall survival (OS) on multivariate analysis. Patients with CC-1 that received EPIC had significantly improved OS (mean OS 14 years) when compared to patients that did not receive EPIC (mean OS 6 years). In CC-1, OS was significantly improved in patients that received EPIC in both low-grade (p<0.001) and high-grade (p=0.012) disease. OS for patients that received EPIC at 1, 5, and 10 years was 95%, 80%, and 59%, respectively. OS for patients that did not receive EPIC at 1, 5, and 10 years was 84%, 49%, and 30%, respectively. CONCLUSION: There was no difference in OS between CC-0 and CC-1. The implementation of EPIC in patients with CC-1 significantly improved OS in both low-grade and high-grade disease and thus we recommend its addition in CC-1 disease to achieve optimal survival outcome.

Taming the SARS-CoV-2-mediated proinflammatory response with BromAc®.

Introduction: In the present study, the impact of BromAc®, a specific combination of bromelain and acetylcysteine, on the SARS-CoV-2-specific inflammatory response was evaluated. Methods: An in vitro stimulation system was standardized using blood samples from 9 healthy donors, luminex assays and flow cytometry were performed. Results and discussion: BromAc® demonstrated robust anti-inflammatory activity in human peripheral blood cells upon SARS-CoV-2 viral stimuli, reducing the cytokine storm, composed of chemokines, growth factors, and proinflammatory and regulatory cytokines produced after short-term in vitro culture with the inactivated virus (iSARS-CoV-2). A combined reduction in vascular endothelial growth factor (VEGF) induced by SARS-CoV-2, in addition to steady-state levels of platelet recruitment-associated growth factor-PDGFbb, was observed, indicating that BromAc® may be important to reduce thromboembolism in COVID-19. The immunophenotypic analysis of the impact of BromAc® on leukocytes upon viral stimuli showed that BromAc® was able to downmodulate the populations of CD16+ neutrophils and CD14+ monocytes observed after stimulation with iSARS-CoV-2. Conversely, BromAc® treatment increased steady-state HLA-DR expression in CD14+ monocytes and preserved this activation marker in this subset upon iSARS-CoV-2 stimuli, indicating improved monocyte activation upon BromAc® treatment. Additionally, BromAc® downmodulated the iSARS-CoV-2-induced production of TNF-a by the CD19+ B-cells. System biology approaches, utilizing comprehensive correlation matrices and networks, showed distinct patterns of connectivity in groups treated with BromAc®, suggesting loss of connections promoted by the compound and by iSARS-CoV-2 stimuli. Negative correlations amongst proinflammatory axis and other soluble and cellular factors were observed in the iSARS-CoV-2 group treated with BromAc® as compared to the untreated group, demonstrating that BromAc® disengages proinflammatory responses and their interactions with other soluble factors and the axis orchestrated by SARS-CoV-2. Conclusion: These results give new insights into the mechanisms for the robust anti-inflammatory effect of BromAc® in the steady state and SARS-CoV-2-specific immune leukocyte responses, indicating its potential as a therapeutic strategy for COVID-19.

Physical and chemical factors affecting the loading and release of bromelain from DC beads.

Doxorubicin loaded DC beads (microspheres) has been used for treating un-resectable tumours by transarterial chemoembolization (TACE). We have shown that bromelain, an enzyme from the pineapple plant, enhances the cytotoxic effect of a number of chemotherapeutic drugs and in an earlier study we have demonstrated that it can be loaded into DC beads. Therefore, in the current study we have investigated how certain physical and chemical parameters affect its loading and release for future development of DC beads in cancer therapy. Aliquots of 40-60 µL of DC beads (100-300 µm) were treated to bromelain in distilled water and various parameters such as pH of solution, bromelain concentration, temperature, loading period, presence/absence of agitation and the cytotoxic effect of bromelain loaded beads were investigated. Further release kinetics was also studied with additional investigation of pH effect on the proteolytic activity of bromelain. Results indicate that higher loading of bromelin was achieved in the beads at lower pH, higher concentration of bromelain, with agitation, 24 hours loading and ambient room temperature. Proteolytic activity of bromelain was maximal at pH 4.5 whilst cytotoxicity was at par if not better in the bromelain loaded DC beads. Release kinetics indicated that bromelain can be delivered over several hours. Hence, we conclude that bromelain can be loaded more efficiently with manipulation of certain parameters with noticeable cytotoxicity in tumour cells.