Detachment of cells from the extracellular matrix into the peritoneal cavity initiates a cascade of metabolic alterations, leading usually to cell death by apoptosis, so-called anoikis . Glycolytic enzymes enable the switch from oxidative phosphorylation to aerobic glycolysis and allow resistance to anoikis of shed tumour cells. These enzymes also have moonlighting activities as protein kinases and transcription factors. Phosphoglycerate kinase (PGK) and pyruvate kinase are the only glycolytic enzymes generating ATP in the hexokinase pathway. Hypoxia, EGFR activation, expression of K-Ras G12V and B-Raf V600E induce mitochondrial translocation of phosphoglycerate kinase 1 (PGK1). Mitochondrial PGK1 acts as a protein kinase to phosphorylate pyruvate dehydrogenase kinase 1 (PDHK1), reducing mitochondrial pyruvate utilization, suppressing reactive oxygen species production, increasing lactate production and promoting tumourigenesis. PGK1 also plays a role as a transcription factor once transported into the nucleus. Resistance to anoikis is also facilitated by metabolic support provided by cancer-associated fibroblasts (CAFs). Our series of experiments in-vitro and in the animal model showed that PGK1 knock-out or inhibition is effective in controlling development and growth of peritoneal metastasis (PM) of gastric origin, establishing a causal role of PGK1 in this development. PGK1 also increases CXCR4 and CXCL12 expression, which is associated with a metastatic phenotype and plays a role in the metastatic homing of malignant cells. Thus, PGK1, its modulators and target genes may be exploited as therapeutic targets for preventing development of PM and for enhancing cytotoxic effects of conventional systemic chemotherapy.
Background The quest to cure or to contain the disease in cancer patients leads to new strategies and techniques being added to the armamentarium of oncologists. Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) is a recently described surgical technique which is being evaluated at many centers for the management of peritoneal metastasis (PM). The present study is a systematic review to evaluate the current role of PIPAC in the management of gastric cancer associated PM. Methods A systematic search was conducted in Pubmed and EMBASE database using relevant keywords and confirming to the PRISMA guidelines to identify the articles describing the role of PIPAC in gastric cancer associated PM. All the studies which were published prior to July 1, 2018 in English literature and reported the role of PIPAC in gastric cancer associated PM were included in the systematic review. Results The search yielded 79 articles; there were ten published studies which have reported the use of PIPAC in gastric cancer associated PM. A total of 129 patients with gastric cancer associated PM were treated in the studies. Only two studies had an exclusive cohort of gastric cancer patients while eight other studies had a heterogeneous population with a small proportion of gastric cancer patients. There was only one study highlighting the role of PIPAC in neoadjuvant setting to downgrade the peritoneal carcinomatosis index. All the studies revealed that PIPAC is feasible and has minimal perioperative morbidity, even after repeated applications. Conclusion There is a scarcity of English literature related to the role of PIPAC in gastric cancer associated PM. PIPAC is a safe and well-tolerated procedure which has the potential to contain spreading PM. Further studies are warranted to better define the role of PIPAC in gastric cancer associated PM.
Background Despite optimal surgery and appropriate first-line chemotherapy, ∼70–80 % of patients with epithelial ovarian cancer will develop disease relapse. The prognosis is poor especially for women with Platinum resistant ovarian cancer. The standard treatment for these groups of patients is non-platinum-containing chemotherapy like taxanes, anthracyclines, gemcitabine, topotecan, and trabectedin. These drugs in various combinations and sequences provide modest survival or symptomatic benefit but with significant side effects. Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) is a minimally-invasive drug-delivery technique specifically addressing limited tissue penetration and poor drug distribution with promising results. PIPAC is a novel method of delivering normothermic chemotherapy into the abdominal cavity as an aerosol under pressure. This concept seems to enhance the effectiveness of intra peritoneal chemotherapy by taking advantage of the physical properties of gas and pressure by generating an artificial pressure gradient and enhancing tissue uptake and distributing drugs homogeneously within the closed and expanded peritoneal cavity. Thus, due to the high local bioavailability during PIPAC, the chemotherapy dosage can be reduced which in turn largely prevents systemic side effects and organ toxicity. Methods The study aims to investigate the therapeutic efficacy measured as objective tumour response according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria, of PIPAC in comparison with conventional Intravenous chemotherapy for women with recurrent platinum resistant ovarian cancer with peritoneal metastasis (PM). Consecutive patients diagnosed with PM secondary to platinum-resistant ovarian cancer will be randomized to PIPAC group or IV chemotherapy group. The primary objective of this study is to determine the efficacy after three cycles of PIPAC with cisplatin and doxorubicin in comparison with six cycles of systemic chemotherapy. The secondary outcome measures include morbidity and mortality, overall survival and disease specific survival. Analysis is by intention to treat. Aim Assess the objective tumour response of PIPAC in comparison with systemic intravenous chemotherapy for women with platinum-resistant ovarian cancer. Study type Prospective randomized control intervention trial. Intervention model IV Chemotherapy group (Control group) PIPAC group (Experimental group) Masking Open label. Primary purpose Treatment. Sample size Calculated sample size is 97 and rounded to 100. For each treatment group sample size of 50 will be considered. Primary outcome criteria Objective tumour response according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria version 1.1. Secondary outcome criteria Morbidity; Disease-specific survival (months between inclusion and death due to ovarian cancer); OS (months between inclusion and death due to any cause); CA 125 levels. Discussion PIPAC in women with platinum resistant ovarian PM has good response owing to superior tissue penetration and better drug distribution. The procedure is safe and well tolerated owing it to its minimal invasiveness. Typical side-effects of systemic chemotherapy, such as alopecia, peripheral neurotoxicity, nausea and myelosuppression are absent. We expect reduction of ascites with symptomatic relief and CA 125 levels. PIPAC is a novel technique for selected patients with platinum resistant ovarian PM and further investigation in comparative clinical trials with conventional chemotherapy will establish its role as a good palliative treatment option. Ethics committee approval Obtained. Status Recruiting. Trial registration number REF/2018/08/021223 Registered on Clinical Trials Registry – India (CTRI); www.ctri.nic.in
Background Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) is an innovative drug delivery technique. Most common indication is palliative therapy of peritoneal metastasis of gastrointestinal and gynecological origin in the salvage situation. Access to the abdomen is the critical step of the procedure, since most patients had previous surgery. Potential pitfalls include non-access because of adhesions, bowel access lesions and postoperative subcutaneous toxic emphysema. Methods We propose a technique, the “finger-access technique” that might prevent largely these pitfalls. A minilaparotomy of 3 cm is performed in the midline, a finger introduced into the abdomen and a 5-mm double-balloon trocar (no Hasson trocar) is placed under finger protection at some distance of the first incision. The fascia of the minilaparotomy, not the skin, is then closed. The abdomen is insufflated with CO 2 and tightness is controlled with saline solution in the minilaparotomy. A second 10–12 mm trocar is then introduced under videoscopic control. The first trocar is then visualized through the second one to exclude a bowel lesion during first access. Results and conclusions In our hands, this access technique has shown to be safe and effective.
