Enhancing the Efficacy of HIPEC Through Bromelain: A Preclinical Investigation in Appendiceal Cancer.

INTRODUCTION: Appendiceal cancer (AC) excessive mucin production is a barrier to heated intraperitoneal chemotherapy (HIPEC) drug delivery. Bromelain is a pineapple stem extract with mucolytic properties. We explored bromelain treatment effects against mucinous AC in a patient-derived tumor organoid (PTO) model and an AC cell line. PATIENTS AND METHODS: PTOs were fabricated from tumor specimens obtained from patients with AC undergoing cytoreductive surgery with HIPEC. PTOs underwent HIPEC treatment with bromelain, cisplatin, and mitomycin C (MMC) at 37 °C and 42 °C with and without bromelain pretreatment. RESULTS: From October 2020 to May 2023, 16 specimens were collected from 13 patients with low-grade (12/16, 75%) and high-grade AC (4/16, 25%). The mucin-depleting effects of bromelain were most significant in combination with N-acetylcysteine (NAC) compared with bromelain (47% versus 10%, p = 0.0009) or NAC alone (47% versus 12.8%, p = 0.0027). Bromelain demonstrated > 31% organoid viability reduction at 60 min (p < 0.001) and > 66% in 48 h (p < 0.0001). Pretreatment with bromelain increased cytotoxicity of both cisplatin and MMC HIPEC conditions by 31.6% (p = 0.0001) and 35.5% (p = 0.0001), respectively. Ki67, CK20, and MUC2 expression decreased after bromelain treatment; while increased caspase 3/7 activity and decreased Bcl-2 (p = 0.009) and Bcl-xL (p = 0.01) suggest induction of apoptosis pathways. Furthermore, autophagy proteins LC3A/B I (p < 0.03) and II (p < 0.031) were increased; while ATG7 (p < 0.01), ATG 12 (p < 0.04), and Becline 1(p < 0.03), expression decreased in bromelain-treated PTOs. CONCLUSIONS: Bromelain demonstrates cytotoxicity and mucolytic activity against appendiceal cancer organoids. As a pretreatment agent, it potentiates the cytotoxicity of multiple HIPEC regimens, potentially mediated through programmed cell death and autophagy.

Hyperthermic intraperitoneal chemotherapy in colorectal cancer.

BACKGROUND: This study evaluated the efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer with peritoneal metastases (pmCRC) in a large international data set of patients. PATIENTS AND METHODS: Patients with pmCRC from 39 centres who underwent cytoreductive surgery with HIPEC between 1991 and 2018 were selected and compared for the HIPEC protocols received-oxaliplatin-HIPEC versus mitomycin-HIPEC. Following analysis of crude data, propensity-score matching (PSM) and Cox-proportional hazard modelling were performed. Outcomes of interest were overall survival (OS), recurrence-free survival (RFS) and the HIPEC dose-response effects (high versus low dose, dose intensification and double drug protocols) on OS, RFS and 90-day morbidity. Furthermore, the impact of the treatment time period was assessed. RESULTS: Of 2760 patients, 2093 patients were included. Median OS was 43 months (95% c.i. 41 to 46 months) with a median RFS of 12 months (95% c.i. 12 to 13 months). The oxaliplatin-HIPEC group had an OS of 47 months (95% c.i. 42 to 53 months) versus 39 months (95% c.i. 36 to 43 months) in the mitomycin-HIPEC group (P = 0.002), aHR 0.77, 95% c.i. 0.67 to 0.90, P < 0.001. The OS benefit persisted after PSM of the oxaliplatin-HIPEC group and mitomycin-HIPEC group (48 months (95% c.i. 42 to 59 months) versus 40 months (95% c.i. 37 to 44 months)), P < 0.001, aHR 0.78 (95% c.i. 0.65 to 0.94), P = 0.009. Similarly, matched RFS was significantly higher for oxaliplatin-HIPEC versus others (13 months (95% c.i. 12 to 15 months) versus 11 months (95% c.i. 10 to 12 months, P = 0.02)). High-dose mitomycin-HIPEC protocols had similar OS compared to oxaliplatin-HIPEC. HIPEC dose intensification within each protocol resulted in improved survival. Oxaliplatin + irinotecan-HIPEC resulted in the most improved OS (61 months (95% c.i. 51 to 101 months)). Ninety-day mortality in both crude and PSM analysis was worse for mitomycin-HIPEC. There was no change in treatment effect depending on the analysed time period. CONCLUSIONS: Oxaliplatin-based HIPEC provided better outcomes compared to mitomycin-based HIPEC. High-dose mitomycin-HIPEC was similar to oxaliplatin-HIPEC. The 90-day mortality difference favours the oxaliplatin-HIPEC group. A trend for dose-response between low- and high-dose HIPEC was reported.

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.

Transhepatic Bromelain and Acetylcysteine for Treatment of Posterior Gastric Pseudomyxoma Peritonei: A Case Report.

BACKGROUND/AIM: Pseudomyxoma peritonei (PMP) is a rare condition characterized by diffuse spread of mucinous tumors within the peritoneal cavity. Traditional treatment modalities, such as cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are challenging in cases of recurrent disease, owing to anatomical complexities and increasing morbidity and mortality risk. BromAc® has emerged as a novel, targeted therapy for PMP with evidence for intra-tumoral administration to break down mucin deposits. CASE REPORT: We present a 70-year-old female with confirmed diagnosis of symptomatic appendiceal PMP situated behind the stomach, refractory to prior CRS and HIPEC. Transhepatic intra-tumor injection of BromAc® was performed, guided by imaging, with catheter placement into the posterior gastric mucinous tumor. The procedure was well-tolerated, and post-treatment imaging revealed a significant 40% reduction in tumor burden. The patient had fever on cycle days two and three, which self-resolved and septic screen performed was negative. Following BromAc® administration, the patient demonstrated improvement in symptoms and quality of life. CONCLUSION: This case highlights the potential efficacy and safety of transhepatic administration of BromAc® for the treatment of recurrent PMP behind the stomach. The targeted delivery of BromAc® directly into a mucinous tumor via the transhepatic route offers a minimally invasive alternative for cases where traditional surgical interventions pose challenges. However, further research and clinical trials are warranted to validate the broader applicability of this novel approach, assess long-term outcomes, and optimize procedural parameters for enhanced therapeutic outcomes in PMP treatment.

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.

When all else fails: the colo-duodenal anastomosis.

Total enterectomy is an exceedingly rare procedure performed out of necessity due to massive intestinal infarction, trauma, or peritoneal malignancy. This case describes a 47-year-old patient who has successfully undergone the procedure to manage mesenteric ischaemia. Bowel continuity was achieved with a duodenocolonic anastomosis, and the patient has been transitioned to life-long total parental nutrition. This case highlights that carefully selected patients can achieve long-term survival with good quality of life rather than palliation.

Peritoneal Tuberculosis in Western Countries: A Rare Case With Concurrent Helminthic Infection.

This case report presents a rare case of peritoneal tuberculosis (TB) coexisting with a helminthic infection in a 25-year-old female residing in Australia, highlighting the diagnostic challenges posed by abdominal TB. Despite the low incidence of TB in Western countries, abdominal TB remains a diagnostic dilemma due to its nonspecific symptoms and potential mimicry of other abdominal pathologies. The case highlights the importance of considering TB as a differential diagnosis of unexplained abdominal symptoms, particularly in individuals with a history of travel or previous residence in high-endemic regions. A multidisciplinary approach involving infectious disease specialists, radiologists, and surgeons is essential for comprehensive management. Prompt initiation of anti-TB therapy is recommended once diagnosis is confirmed.

Malignant Peritoneal Mesothelioma: An In-Depth and Up-to-Date Review of Pathogenesis, Diagnosis, Management and Future Directions.

Malignant peritoneal mesothelioma (MPM) is an extremely rare malignancy usually confined to the abdominal cavity. With an aggressive natural history, morbidity and mortality are consequences of progressive locoregional effects within the peritoneal cavity. The first reported case was in the early 20th century, however, due to the rare nature of the disease and a large gap in understanding of the clinicopathological effects, the next reported MPM cases were only published half a decade later. Since then, there has been exponential growth in our understanding of the disease, however, there are no prospective data and a paucity of literature regarding management. Traditionally, patients were treated with systemic therapy and the outcomes were very poor, with a median survival of less than one year. However, with the advent of cytoreductive surgery and locoregional chemotherapy, there have been significant improvements in survival. Even more recently, with an improved understanding of the molecular pathogenesis of MPM, there have been reports of improved outcomes with novel therapies. Given the disastrous natural history of MPM, the limited data, and the lack of universal treatment guidelines, an in-depth review of the past, present, and future of MPM is critical to improve treatment regimens and, subsequently, patient outcomes.

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.

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.

The 'Starburst' Sign: A Novel Description of PET Images in Carcinoma of Unknown Primary.

BACKGROUND/AIM: Carcinoma of unknown primary (CUP) poses a formidable diagnostic challenge, characterised by high mortality rates and an elusive primary tumour site. While Positron emission tomography (PET) scans are routinely employed in the initial evaluation of CUP patients, identifying the primary tumour remains an ongoing struggle. In light of this, the aim of this case report is to introduce a novel radiological description, termed the 'Starburst' sign, derived from distinctive PET scan appearances associated with CUP. CASE REPORT: In this report, we present the case of a 47-year-old female patient who presented with abdominal symptoms. Upon investigation, extensive peritoneal disease was observed, yet the primary tumour source remained unidentified. Despite further diagnostic efforts, including a normal gastroscopy, a PET scan was able to confirm the presence of high-volume metastatic disease, without an identifiable primary tumour. Palliative treatment was initiated, but unfortunately, the patient's condition deteriorated rapidly, leading to her demise. CONCLUSION: The 'Starburst' sign, a unique radiological description of CUP in PET scans, has significant potential in advancing our understanding of the disease. It provides a visual analogy to a dying star, aiding comprehension of complex pathophysiology and implications of metastatic lesions. The introduction of the 'Starburst' sign benefits patients and healthcare professionals, enhancing education, assessment, and treatment of CUP. This novel description contributes to knowledge in the field and can impact clinical management.

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.

Enhancement of treatment efficacy of hepatic tumours using Trans-arterial-chemoembolization.

This review article examines the basic principle underlying trans-arterial chemoembolization (TACE) used for treating unrespectable liver cancer with discussion on the barriers that are present for efficient drug delivery with suggestions on methods that may be used to overcome these barriers and hence enhance the efficacy of the technique. Current drugs used with TACE along with inhibitors of neovascularisation are briefly discussed. It also compares the conventional method of chemoembolization with TACE and rationalizes why there is not much of a difference between the two methods on treatment efficacy. Further it also suggests alternative methods of drug delivery that may be used instead of TACE. Additionally, it discusses the disadvantages on using non degradable microspheres with recommendations for degradable microspheres within 24 hours to overcome rebound neovascularisation owing to hypoxia. Finally, the review examines some of the biomarkers that are used to assess treatment efficacy with indication that non-invasive and sensitive biomarkers should be identified for routine screening and early detection. The review concludes that, if the current barriers present in TACE can be overcome along with the use of degradable microspheres and efficient biomarkers for monitoring efficacy, then a more robust treatment would emerge that may even serve as a cure.

Overall survival and morbidity are not associated with advanced age for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: a single centre experience.

Objectives: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has enabled better prognosis for patients with peritoneal surface malignancies. However, in older age groups, short -and long-term outcomes are still perceived as poor. We evaluated patients aged 70 and over and determine if age is a predictor of morbidity, mortality and overall survival (OS). Methods: A retrospective cohort analysis was performed on CRS/HIPEC patients and categorised by age. The primary outcome was overall survival. Secondary outcomes included morbidity, mortality, hospital and incentive care unit (ICU) stay and early postoperative intraperitoneal chemotherapy (EPIC). Results: A total of 1,129 patients were identified with 134 aged 70+ and 935 under 70. There was no difference in OS (p=0.175) or major morbidity (p=0.051). Advanced age was associated with higher mortality (4.48 vs. 1.11 %, p=0.010), longer ICU stay (p<0.001) and longer hospitalisation (p<0.001). The older group was less likely to achieve complete cytoreduction (61.2 vs. 73 %, p=0.004) and receive EPIC (23.9 vs. 32.7 %, p=0.040). Conclusions: In patients undergoing CRS/HIPEC, age of 70 and above does not impact OS or major morbidity but is associated with increased mortality. Age alone should not be a limiting factor in selecting CRS/HIPEC patients. Careful multi-disciplinary approach is needed when considering those of advanced age.