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PURPOSE: Despite advances in systemic therapy, outcomes of patients with gastric cancer (GC) peritoneal carcinomatosis (PC) remain poor, in part because of poor penetrance of systemic therapy into peritoneal metastasis due to the plasma-peritoneal barrier and anarchic intra-tumoral circulation. Hence, regional treatment approach with administration of chemotherapy directly into the peritoneal cavity (intraperitoneal, IP) under various conditions, combined with or without cytoreductive surgery (CRS) has remained an area of significant research interest. The purpose of this review is to provide high-level evidence for regional treatment approaches in the management of GCPC with limited peritoneal disease. METHODS: A review of the current literature and ongoing clinical trials for regional IP therapies for GCPC was performed. Studies included in this review comprise of phase III randomized controlled trials, non-randomized phase II studies, high-impact retrospective studies, and active ongoing clinical trials for each available IP modality. RESULTS: The three common IP approaches are heated intraperitoneal chemotherapy (HIPEC), normothermic intraperitoneal chemotherapy (NIPEC) and more recently introduced, pressurized intraperitoneal aerosolized chemotherapy (PIPAC). These IP approaches have been combined with systemic therapy and/or CRS with varying degrees of promising results, demonstrating evidence of improvements in survival rates and peritoneal disease control. Patient selection, optimization of systemic therapy, and completeness of cytoreduction have emerged as major factors influencing the design of contemporary and ongoing trials. CONCLUSION: IP chemotherapy has a clear role in the management of patients with GCPC, and when combined with CRS in appropriately selected patients has the potential to significantly improve survival. Ongoing and upcoming IP therapy clinical trials hold great promise to shape the treatment paradigm for GCPC.

BackgroundThere is a paucity of targeted therapies for patients with pseudomyxoma peritonei (PMP) secondary to low-grade appendiceal mucinous neoplasms (LAMNs). Dysregulated metabolism has emerged as a hallmark of cancer, and the relationship of metabolomics and cancer is an area of active scientific exploration. We sought to characterize phenotypic differences found in peritoneal metastases (PM) derived from LAMN versus adenocarcinoma.MethodsTumors were washed with phosphate-buffered saline (PBS), microdissected, then dissociated in ice-cold methanol dried and reconstituted in pyridine. Samples were derivatized in tert-butyldimethylsilyl (TBDMS) and subjected to gas chromatography-coupled mass spectrometry. Metabolites were assessed based on a standard library. RNA sequencing was performed, with pathway and network analyses on differentially expressed genes.ResultsEight peritoneal tumor samples were obtained and analyzed: LAMNs (4), and moderate to poorly differentiated adenocarcinoma (colon [1], appendix [3]). Decreases in pyroglutamate, fumarate, and cysteine in PM from LAMNs were found compared with adenocarcinoma. Analyses showed the differential gene expression was dominated by the prevalence of metabolic pathways, particularly lipid metabolism. The gene retinol saturase (RETSAT), downregulated by LAMN, was involved in the multiple metabolic pathways that involve lipids. Using network mapping, we found IL1B signaling to be a potential top-level modulation candidate.ConclusionsDistinct metabolic signatures may exist for PM from LAMN versus adenocarcinoma. A multitude of genes are differentially regulated, many of which are involved in metabolic pathways. Additional research is needed to identify the significance and applicability of targeting metabolic pathways in the potential development of novel therapeutics for these challenging tumors.

BackgroundLiquid biopsies have become an integral part of cancer management as minimally invasive options to detect molecular and genetic changes. However, current options show poor sensitivity in peritoneal carcinomatosis (PC). Novel exosome-based liquid biopsies may provide critical information on these challenging tumors. In this initial feasibility analysis, we identified an exosome gene signature of 445 genes (ExoSig445) from colon cancer patients, including those with PC, that is distinct from healthy controls.MethodsPlasma exosomes from 42 patients with metastatic and non-metastatic colon cancer and 10 healthy controls were isolated and verified. RNAseq analysis of exosomal RNA was performed and differentially expressed genes (DEGs) were identified by the DESeq2 algorithm. The ability of RNA transcripts to discriminate control and cancer cases was assessed by principal component analysis (PCA) and Bayesian compound covariate predictor classification. An exosomal gene signature was compared with tumor expression profiles of The Cancer Genome Atlas.ResultsUnsupervised PCA using exosomal genes with greatest expression variance showed stark separation between controls and patient samples. Using separate training and test sets, gene classifiers were constructed capable of discriminating control and patient samples with 100% accuracy. Using a stringent statistical threshold, 445 DEGs fully delineated control from cancer samples. Furthermore, 58 of these exosomal DEGs were found to be overexpressed in colon tumors.ConclusionsPlasma exosomal RNAs can robustly discriminate colon cancer patients, including patients with PC, from healthy controls. ExoSig445 can potentially be developed as a highly sensitive liquid biopsy test in colon cancer.

Exosomes are small, lipid-bilayer bound extracellular vesicles of 40-160 nanometers in size that carry important information for intercellular communication. Exosomes are produced more by tumor cells than normal cells and carry tumor-specific content, such as DNA, RNA, and proteins, which have been implicated in tumorigenesis, tumor progression, and treatment response. Due to the critical role of exosomes in cancer development and progression, they can be exploited to develop specific biomarkers and therapeutic targets. Since exosomes are present in various biofluids, such as blood, saliva, urine, and peritoneal fluid, they are ideally suited to be developed as liquid biopsy tools for early diagnosis, molecular profiling, disease surveillance, and treatment response monitoring. In the past decade, numerous studies have been published about the functional significance of exosomes in a wide variety of cancers, with a particular focus on exosome-derived RNAs and proteins as biomarkers. In this review, utilizing human studies on exosomes, we highlight their potential as diagnostic, prognostic, and predictive biomarkers in gastrointestinal cancers.

Mucinous adenocarcinoma of the appendix is a rare form of lower gastrointestinal (GI) tract cancer. These cancers have a high tendency to progress towards peritoneal metastasis and their response to systemic treatment is typically low. Together, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have become an established form of therapy used to prolong the survival of patients with this disease. Repeat CRS and HIPEC have been shown to be feasible in selected patients with GI peritoneal carcinomatosis (PC), among which those with appendix cancer receive the greatest benefit. The peritoneal cancer index (PCI) and completeness of cytoreduction have been shown to be important predictors of outcomes. However, repeat cytoreduction in patients with a high-volume peritoneal tumor burden (peritoneal cancer index (PCI) > 30) is not typically performed due to concerns regarding morbidity and mortality. Herein, we describe a case of repeat CRS and HIPEC for extensive appendiceal mucinous peritoneal carcinomatosis after initial incomplete cytoreduction and durable remission of 28 months without adjuvant chemotherapy. In appendiceal mucinous cancers, repeat CRS can achieve a durable response despite an initial failed CRS and high-volume disease.

BackgroundStudies from Asia indicate that normothermic intraperitoneal chemotherapy (NIPEC) may confer survival benefit in patients with gastric peritoneal carcinomatosis (PC). However, data regarding this approach is lacking in western population. The current STOPGAP trial is intended to assess 1-year progression-free survival benefit of sequential systemic chemotherapy and paclitaxel NIPEC in patients with gastric/ gastroesophageal junction (GEJ) adenocarcinoma PC.MethodsThis is a prospective, single center, single arm, phase II investigator-initiated clinical trial. Patients with histologically proven gastric/GEJ (Siewert 3) adenocarcinoma with positive peritoneal cytology or PC will be eligible to participate after three months of standard of care systemic chemotherapy and with no evidence of visceral metastasis on restaging scans. The primary treatment is iterative paclitaxel NIPEC with systemic paclitaxel and 5-fluorouracil, which will be administered on days1 and 8 and repeated every three weeks for 4 cycles. Patients will undergo diagnostic laparoscopy both before and after NIPEC to assess peritoneal cancer index (PCI). Patients with PCI less than or equal to 10 in whom complete cytoreduction (CRS) is feasible may opt to undergo CRS with heated intraperitoneal chemotherapy (HIPEC). The primary endpoint is 1-year progression free survival and secondary endpoints are overall survival and patient reported quality of life outcomes measured by EuroQol- 5 dimensions-5 level (EuroQol-5D-5L) questionnaire.DiscussionIf the sequential approach of systemic chemotherapy followed by paclitaxel NIPEC proves beneficial, then this approach could be used in larger, muti-institutional randomized clinical trial of gastric PC.Trial registrationThe trial was registered on 21/02/2021, under clinical trials.gov; Identifier: NCT04762953.

IntroductionTumor agnostic circulating tumor DNA (ctDNA) is routinely used to guide treatment decisions in gastrointestinal (GI) cancers, especially metastatic cancers. The amount of ctDNA detected in plasma is affected by stage, tumor burden, and tumor vascularization. We hypothesized that peritoneal carcinomatosis (PC) is associated with lower ctDNA levels than other metastatic sites in GI cancers due to the plasma-peritoneal barrier.MethodsWe conducted a retrospective analysis of patients with stage II-IV GI cancers treated at our institution between 2015 and 2020 with available panel-based ctDNA results (Guardant 360TM). ctDNA analysis was performed on early and pretreatment samples. We compared the reported maximum variant allele frequency (mVAF) of somatic mutations across metastatic sites.ResultsOf the 279 patients with GI cancers (colorectal, upper GI, pancreaticobiliary), 212 had stage IV disease (PC: n = 61; visceral metastases: n = 138; other metastases: n = 13). Mean mVAF increased with increasing stages of disease (stage II: 3.6 ± 7; stage III: 6.4 ± 10; stage IV: 28.0 ± 51; p

Current guidelines recommend neoadjuvant (NAC) and/or adjuvant chemotherapy for locally advanced gastric cancers (LAGCs). However, the choice and duration of NAC regimen is standardized, rather than personalized to biologic response, despite the availability of several different classes of agents for the treatment of gastric cancer (GC). The current trial will use a tumor-informed ctDNA assay (Signatera™) and monitor response to NAC. Based on ctDNA kinetics, the treatment regimen is modified. This is a prospective single center, single-arm, open-label study in clinical stage IB-III GC. ctDNA is measured at baseline and repeated every 8 weeks. Imaging is performed at the same intervals. The primary end point is the feasibility of this approach, defined as percentage of patients completing gastrectomy.

BackgroundGastrointestinal (GI) malignancies represent a heterogeneous group of diseases. Traditional tumor markers, though part of standard-of-care, lack sensitivity and specificity. Tumor-informed circulating tumor DNA (ctDNA) assay-based molecular residual disease assessment as well as recurrence and treatment response monitoring can serve as a robust tool in patients with wide range of GI malignancies and ethnicities.MethodsA personalized, tumor-informed multiplex PCR-NGS assay (SignateraTM) was used for the detection and quantification of ctDNA in 258 plasma samples from 198 patients with GI cancers at two institutions. Serial time- points were collected on a subset of patients (n=64) to monitor their ctDNA levels in response to treatment. Chi-square test was used to compare ctDNA-positivity rates in different cohorts.ResultsThe study included stage I-IV patients with a median age of 62 years (61% females and 49% ethnic minorities); 92% had surgical resection, 83% received systemic treatment. ctDNA-positivity was significantly associated with advanced stage (P=0.004), and presence/extent of metastases (P

BackgroundRecent randomized controlled trials have failed to show a survival difference between adjuvant chemotherapy (CT) and adjuvant chemoradiotherapy (CRT) in patients with resected gastric cancer (GC). However, a subset of patients with lymph node (LN) positive disease may still benefit from CRT. Additional evidence is needed to help guide physicians in identifying patients in whom CRT should be considered. Our objective was then to compare survival outcomes based on lymph node ratio (LNR) (ratio of metastatic to harvested LNs) for patients with gastric and gastroesophageal junction (GEJ) adenocarcinoma treated with surgery and either CT or CRT.MethodsThis retrospective population-based study used California Cancer Registry (CCR) data from 2004 to 2013. It included 1,493 patients diagnosed with stage IB-III gastric/GEJ adenocarcinoma and treated with CT or CRT following total or partial gastrectomy. Overall survival (OS) was the primary outcome and GC-specific survival was secondary. Mortality hazards ratios (HR) for these outcomes were computed using propensity score weighted Cox regression models, stratified by LNR strata categories as 0%, 1-9%, 10-25% and >25%.ResultsOut of 1,493 patients that met inclusion criteria, 462 were treated with CT while 1,031 received CRT. Median follow-up for all subjects was 76 months and median survival was 54 months for CRT and 35 for the CT cohort, P25% [HR =0.67 (95% CI, 0.56-0.80)]. Similar findings were observed for GC-specific survival and for analyses limited to patients that had at least 15 LNs evaluated.ConclusionsLNR appears to be a simple and readily available measure that could be used in treatment planning for resected GC. CRT offers significant survival advantage over CT among patients with high LN disease burden (LNR of ≥10%).

BackgroundBoth perioperative chemotherapy (PC) and adjuvant chemoradiotherapy (CRT) improve survival in resectable gastric cancer; however, these treatments have never been formally compared. Our objective was to evaluate treatment trends and compare survival outcomes for gastric cancer patients treated with surgery and either PC or CRT.MethodsWe performed a retrospective population-based cohort study between 2007 through 2013 using California Cancer Registry data. Patients diagnosed with stage IB-III gastric adenocarcinoma and treated with total or partial gastrectomy were eligible for this study. Based on the type of treatment received, patients were grouped into surgery-only, PC, or CRT. Primary and secondary outcomes were overall survival (OS) and gastric cancer-specific survival (GCCS) respectively. Mortality hazards ratios (HRs) for each of these outcomes were computed using propensity score weighted and covariate-adjusted Cox regression models, stratified by clinical node status.ResultsOf 2,146 patients who underwent surgical resection, 1,067 had surgery-only, while 771 and 308 received PC or CRT, respectively. Median OS was 25, 33, and 52 months for surgery-only, PC, and CRT, respectively; P

In the original version of this article Sarath Sujatha- Bhaskar’s family name was misspelled. It is correct as reflected in this erratum. The original article has also been updated.

Peritoneal Carcinomatosis (PC) is a late stage manifestation of several gastrointestinal malignancies including appendiceal, colorectal, and gastric cancer. In PC, tumors metastasize to and deposit on the peritoneal surface and often leave patients with only palliative treatment options. For colorectal PC, median survival is approximately five months, and palliative systemic therapy is able to extend this to approximately 12 months. However, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) with a curative intent is possible in some patients with limited tumor burden. In well-selected patients undergoing complete cytoreduction, median survival has been reported as high as 63 month. Identifying patients earlier who are either at risk for, or who have recently developed PC may provide them with additional treatment options such as CRS/HIPEC. PC is diagnosed late by imaging findings or often times during an invasive procedures such as laparoscopy or laparotomy. In order to improve the outcomes of PC patients, a minimally invasive, accurate, and specific PC screening method needs to be developed. By utilizing circulating PC biomarkers in the serum of patients, a "liquid biopsy," may be able to be generated to allow a tailored treatment plan and early intervention. Exosomes, stable patient-derived nanovesicles present in blood, urine, and many other bodily fluids, show promise as a tool for the evaluation of labile biomarkers. If liquid biopsies can be perfected in PC, manifestations of this cancer may be more effectively treated, thus offering improved survival.

This review discusses the current state of biomarker discovery for the purposes of diagnostics and therapeutic monitoring. We underscore relevant challenges that have defined the gap between biomarker discovery and meaningful clinical use. We highlight recent advancements in and propose a way to think about future biomarker development.

Breast tumors often show profound sensitivity to exogenous oxidative stress. Investigational agent 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) induces aryl hydrocarbon receptor (AhR)-mediated DNA damage in certain breast cancer cells. Since AhR agonists often elevate intracellular oxidative stress, we hypothesize that 5F 203 increases reactive oxygen species (ROS) to induce DNA damage, which thwarts breast cancer cell growth. We found that 5F 203 induced single-strand break formation. 5F 203 enhanced oxidative DNA damage that was specific to breast cancer cells sensitive to its cytotoxic actions, as it did not increase oxidative DNA damage or ROS formation in nontumorigenic MCF-10A breast epithelial cells. In contrast, AhR agonist and procarcinogen benzo[a]pyrene and its metabolite, 1,6-benzo[a]pyrene quinone, induced oxidative DNA damage and ROS formation, respectively, in MCF-10A cells. In sensitive breast cancer cells, 5F 203 activated ROS-responsive kinases: c-Jun-N-terminal kinase (JNK) and p38 mitogen activated protein kinase (p38). AhR antagonists (alpha-naphthoflavone, CH223191) or antioxidants (N-acetyl-l-cysteine, EUK-134) attenuated 5F 203-mediated JNK and p38 activation, depending on the cell type. Pharmacological inhibition of AhR, JNK, or p38 attenuated 5F 203-mediated increases in intracellular ROS, apoptosis, and single-strand break formation. 5F 203 induced the expression of cytoglobin, an oxidative stress-responsive gene and a putative tumor suppressor, which was diminished with AhR, JNK, or p38 inhibition. Additionally, 5F 203-mediated increases in ROS production and cytoglobin were suppressed in AHR100 cells (AhR ligand-unresponsive MCF-7 breast cancer cells). Our data demonstrate 5F 203 induces ROS-mediated DNA damage at least in part via AhR, JNK, or p38 activation and modulates the expression of oxidative stress-responsive genes such as cytoglobin to confer its anticancer action.