Peritoneal Recurrence In Patients Research Articles

Peritoneal lavage cytology in patients with curative resection for stage II and III colorectal cancer: A multi-institutional prospective study.

11 Background: Although various prognostic factors in patients with colorectal cancer has been reported, the usefulness of intraoperative lavage cytology in patients with colorectal cancer is controversial. The aim of this study was to clarify the usefulness of intraoperative lavage cytology in patients with curative resection for pSage II-III colorectal cancer in a prospective multicenter study. Methods: The 20 member hospitals of the Japanese Society for the Cancer of the Colon and Rectum prospectively registered the patients diagnosed as stage II or III colorectal cancer preoperatively between 2013 and 2017. Among these patients, pStage II-III patients went through analysis. Lavage cytology was performed twice during surgery. The first procedure was performed right after laparotomy, and the second was performed right after specimen retrieval. The primary endpoint of this study was an effect of lavage cytology on 5-year relapse-free survival (RFS) in patients with pStage II-III colorectal cancer. The secondary endpoint was an effect of lavage cytology on 5-year overall survival (OS) and peritoneal recurrence in patients with pStage II-III colorectal cancer. Results: A total of 1378 patients were eligible and went through analysis. The number of patients with pStage II and III colorectal cancer were 670 and 708, respectively. Among 1378 patients, 54 (3.9%) had positive cytology. The median follow-up period of the entire cohort was 5.3 years. In pStage II patients, the 5-year RFS rate with positive and negative cytology was 61.1% and 81.6%, respectively (P = 0.023). The 5-year OS rate of pStage II patients with positive and negative cytology was 67.1% and 91.7%, respectively (P = 0.0083). However, there was no difference in RFS and OS between patients with positive and negative cytology in pStage III patients. Thirty-three patients had peritoneal recurrence. The peritoneal recurrence rate was 11.8% and 1.5% in pStage II patients with positive and negative lavage cytology, respectively (P = 0.032). That was 10.5% and 2.5% in pStage III patients with positive and negative lavage cytology, respectively (P = 0.022). In total, 11.1% of patients with positive lavage cytology had peritoneal recurrence in this cohort. Conclusions: The pStage II colorectal cancer patients with negative cytology had better RFS and OS compared to those with positive cytology. Peritoneal lavage cytology was useful in predicting peritoneal recurrence after curative resection for pStage II-III colorectal cancer. Clinical trial information: UMIN000026070 .

Tumor DNA in Peritoneal Lavage as a Novel Biomarker for Predicting Peritoneal Recurrence in Patients With Gastric Cancer.

Peritoneal lavage cytology positivity (CY1) has been identified as a prognostic factor for distant metastases that is equivalent to peritoneal dissemination in Japan. Peritoneal lavage cytology is usually diagnosed by microscopic findings; a diagnostic procedure using a liquid biopsy (LB) technique has not yet been established. We evaluated the feasibility of a LB approach using peritoneal lavage samples from 15 patients with gastric cancer. Samples were collected from both the Douglas pouch and the left subdiaphragmatic area, and cell-free DNA was extracted for analysis of TP53 mutations using droplet digital polymerase chain reaction. All 10 patients with CY1 had positive cytology for the left subdiaphragmatic specimen. However, only six out of the 10 patients had positive cytology for their Douglas pouch specimens, and these six patients had peritoneal tumor DNA (ptDNA) in these specimens. In all five patients with CY0, ptDNA was not detected. The overall survival was significantly shorter in the ptDNA-positive group than in the ptDNA-negative group. The survival of the group with a high amount of DNA from free intraperitoneal cells (ficDNA) was significantly worse than that of those with a low amount. In contrast, the group with a high amount of DNA from peritoneal cell-free DNA (pcfDNA) had significantly better survival than the group with a low amount. LB cytology showed equivalent utility to that of conventional microscopic examinations regarding its diagnostic ability. Therefore ptDNA, pcfDNA and ifcDNA are expected to be useful as prognostic factors.

Favorable control of hepatocellular carcinoma with peritoneal dissemination by surgical resection using indocyanine green fluorescence imaging: a case report and review of the literature

BackgroundThe optimal management for peritoneal dissemination in patients with hepatocellular carcinoma remains unclear. Although several reports have described the usefulness of surgical resection, the indications should be carefully considered. Herein, we report the case of a patient with hepatocellular carcinoma with peritoneal recurrence who underwent surgical resection using an indocyanine green fluorescence navigation system and achieved favorable disease control.Case presentationA 45-year-old Asian woman underwent left hemihepatectomy for a ruptured hepatocellular carcinoma. Seventeen months after the initial surgery, a single nodule near the cut surface of the liver was detected on computed tomography, along with elevation of tumor markers. The patient was diagnosed with peritoneal metastasis and underwent a surgical resection. Twelve months later, a single nodule on the dorsal side of the right hepatic lobe was detected on computed tomography, and we performed surgical resection. Indocyanine green (0.5 mg/kg) was intravenously administered 3 days before surgery, and the indocyanine green fluorescence imaging system revealed clear green fluorescence in the tumor, which helped us perform complete resection. Indocyanine green fluorescence enabled the detection of additional lesions that could not be identified by preoperative imaging, especially in the second metastasectomy. There was no further recurrence at 3 months postoperatively.ConclusionWhen considering surgical intervention for peritoneal recurrence in patients with hepatocellular carcinoma, complete resection is mandatory. Given that disseminated nodules are sometimes too small to be detected by preoperative imaging studies, intraoperative indocyanine green fluorescence may be an essential tool for determining the indications for surgical resection.

GECOP-MMC: phase IV randomized clinical trial to evaluate the efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) with mytomicin-C after complete surgical cytoreduction in patients with colon cancer peritoneal metastases

BackgroundThe French PRODIGE 7 trial, published on January 2021, has raised doubts about the specific survival benefit provided by HIPEC with oxaliplatin 460 mg/m2 (30 minutes) for the treatment of peritoneal metastases from colorectal cancer. However, several methodological flaws have been identified in PRODIGE 7, specially the HIPEC protocol or the choice of overall survival as the main endpoint, so its results have not been assumed as definitive, emphasizing the need for further research on HIPEC. It seems that the HIPEC protocol with high-dose mytomicin-C (35 mg/m2) is the preferred regime to evaluate in future clinical studies.MethodsGECOP-MMC is a prospective, open-label, randomized, multicenter phase IV clinical trial that aims to evaluate the effectiveness of HIPEC with high-dose mytomicin-C in preventing the development of peritoneal recurrence in patients with limited peritoneal metastasis from colon cancer (not rectal), after complete surgical cytoreduction. This study will be performed in 31 Spanish HIPEC centres, starting in March 2022. Additional international recruiting centres are under consideration. Two hundred sixteen patients with PCI ≤ 20, in which complete cytoreduction (CCS 0) has been obtained, will be randomized intraoperatively to arm 1 (with HIPEC) or arm 2 (without HIPEC). We will stratified randomization by surgical PCI (1–10; 11–15; 16–20). Patients in both arms will be treated with personalized systemic chemotherapy. Primary endpoint is peritoneal recurrence-free survival at 3 years. An ancillary study will evaluate the correlation between surgical and pathological PCI, comparing their respective prognostic values.DiscussionHIPEC with high-dose mytomicin-C, in patients with limited (PCI ≤ 20) and completely resected (CCS 0) peritoneal metastases, is assumed to reduce the expected risk of peritoneal recurrence from 50 to 30% at 3 years.Trial registrationEudraCT number: 2019–004679-37; Clinicaltrials.gov: NCT05250648 (registration date 02/22/2022, ).

Impact of Subclassification of Serosal Invasion on the Survival of Patients With T4a Gastric Cancer.

In the Japanese Classification of Gastric Carcinoma, T4a gastric cancer is defined as tumor invasion contiguous to the serosa or penetrating the serosa with exposure to the peritoneal cavity. The aim of this study was to assess the impact of T4a subclassification of gastric cancer on survival. A total of 326 patients with T4a cancer who had undergone gastrectomy were enrolled. The T4a tumors were classified into two groups: serosa-contiguous or serosa-exposed. The serosa-exposed group had a significantly worse prognosis, and multivariate analysis identified the T4a subclass as an independent prognostic factor. Analysis of the risk factors for recurrence identified the T4a subclass as a significant risk factor for peritoneal recurrence in patients undergoing curative gastrectomy. The serosa-contiguous and serosa-exposed subgroups of T4a gastric cancer showed different biological behaviors. These groups may need to be treated as separate.

Clinical significance of coexisting histological diffuse type in stage II/III gastric cancer.

Since 1965, the Laurén classification has been used most commonly for gastric adenocarcinoma, with two main types: intestinal type and diffuse type. Signet ring cell carcinoma (Sig) and non-solid poorly differentiated adenocarcinoma (Por2) are the histological forms of diffuse type that are often found in advanced tumors, and they seem to be associated with a poor prognosis. S-1-based adjuvant chemotherapy for patients with stage II/III gastric cancer has generally been accepted in Japan, but histological type does not alter treatment strategy. The aim of the present study was to investigate the prognostic impact of the histopathological mixture of Sig and Por2 in patients with stage II/III gastric cancer treated with S-1 adjuvant chemotherapy. The clinicopathological data of 968 patients with gastric carcinoma who underwent gastrectomy between 2007 and 2016 at Osaka City University Hospital were retrospectively analyzed. In the present study, tumors containing Sig or Por2 were classified as diffuse type, and those not containing them were classified as intestinal type. There were 307 cases of diffuse type and 661 cases of intestinal type. Diffuse type included 189 cases with Sig. A pathological diagnosis of Sig was an independent risk factor for peritoneal recurrence in patients with stage II/III gastric cancer. Patients with diffuse type had a worse overall survival rate than those with intestinal type at stage III gastric cancer. Among the patients who received S-1 adjuvant chemotherapy, the prognosis of patients with stage III gastric cancer with Sig but not Por2 was significantly worse compared with that of patients with intestinal type. Therefore, the present study revealed that the coexistence of Sig in the primary tumor was associated with a poor prognosis in patients with stage III gastric cancer. The current findings suggested that, since mixed Sig gastric cancer had a high risk of peritoneal recurrence even if adjuvant chemotherapy was performed, the pathological diagnosis should be considered when determining the therapeutic strategy for adjuvant chemotherapy in patients with stage III gastric cancer.

Clinical importance of carcinoembryonic antigen messenger RNA level in peritoneal lavage fluids measured by transcription-reverse transcription concerted reaction for advanced gastric cancer in laparoscopic surgery.

Transcription-reverse transcription concerted reaction (TRC) is recognized as a useful method for detecting free cancer cells in the peritoneal cavity and predicting peritoneal recurrence in patients with gastric cancer. Nonetheless, the clinical significance of TRC in laparoscopic surgery remains unclear. This study aimed to evaluate the clinical importance of carcinoembryonic antigen (CEA) messenger RNA (mRNA) level in peritoneal lavage fluids measured by TRC in laparoscopic surgery for locally advanced gastric cancer. We enrolled patients with locally advanced gastric cancer who underwent laparoscopic gastrectomy. Peritoneal lavage fluids were collected prior to gastrectomy, and the TRC method was employed to quantify CEA mRNA in peritoneal washes. Overall survival (OS), recurrence-free survival (RFS), and peritoneal recurrence-free survival (PRFS) were analyzed using the Kaplan-Meier method and compared using the log-rank test. Adjusted Cox proportional hazards regression models were used to calculate the hazard ratios (HRs) for CEA mRNA positivity. A total of 100 patients were analyzed in this study. Overall, 22 patients (22%) exhibited CEA mRNA positivity in peritoneal lavage fluids, as measured by TRC. No significant association between CEA mRNA levels and clinicopathological characteristics was observed. Patients who were CEA mRNA-positive in peritoneal lavage fluids had significantly worse OS, RFS, and PRFS than those who were CEA mRNA-negative (p = 0.0059, p < 0.0001, and p = 0.0022, respectively). In the univariate Cox model, the HR for all-cause mortality in CEA mRNA-positive versus CEA mRNA-negative patients was 3.60 (95% CI, 1.33-9.55; p = 0.0129). Multivariate analysis revealed that CEA mRNA positivity was a significant independent factor for recurrence. TRC enables the detection of free cancer cells in the peritoneal cavity and CEA mRNA levels can help predict the prognosis, even in laparoscopic gastrectomy.

Transcriptomic Profiling Identifies a Risk Stratification Signature for Predicting Peritoneal Recurrence and Micrometastasis in Gastric Cancer.

Gastric cancer peritoneal carcinomatosis is fatal. Delay in detection of peritoneal metastases contributes to high mortality, highlighting the need to develop biomarkers that can help identify patients at high risk for peritoneal recurrence or metastasis. We performed a systematic discovery and validation for the identification of peritoneal recurrence prediction and peritoneal metastasis detection biomarkers by analyzing expression profiling datasets from 249 patients with gastric cancer, followed by analysis of 426 patients from three cohorts for clinical validation. Genome-wide expression profiling identified a 12-gene panel for robust prediction of peritoneal recurrence in patients with gastric cancer (AUC = 0.95), which was successfully validated in a second dataset (AUC = 0.86). Examination of 216 specimens from a training cohort allowed us to establish a six gene-based risk-prediction model [AUC = 0.72; 95% confidence interval (CI): 0.66-0.78], which was subsequently validated in an independent cohort of 111 patients with gastric cancer (AUC = 0.76; 95% CI: 0.67-0.83). In both cohorts, combining tumor morphology and depth of invasion further improved the predictive accuracy of the prediction model (AUC = 0.84). Thereafter, we evaluated the performance of the identical six-gene panel for its ability to detect peritoneal metastasis by analyzing 210 gastric cancer specimens (prior 111 patients plus additional 99 cases), which discriminated patients with and without peritoneal metastasis (AUC = 0.72). Finally, our biomarker panel was also remarkably effective for identifying peritoneal micrometastasis (AUC = 0.72), and its diagnostic accuracy was significantly enhanced when depth of invasion was included in the model (AUC = 0.85). Our novel transcriptomic signature for risk stratification and identification of high-risk patients with peritoneal carcinomatosis might serve as an important clinical decision making in patients with gastric cancer.

A Multi-institutional Study of Peritoneal Recurrence Following Resection of Low-grade Appendiceal Mucinous Neoplasms.

Peritoneal dissemination of low-grade appendiceal mucinous neoplasms (LAMNs), sometimes referred to as pseudomyxoma peritonei, can result in significant morbidity and mortality. Little is known about the natural history of localized (non-disseminated) LAMNs. The goal of this study was to evaluate the risk of peritoneal recurrence in patients with localized LAMNs. We performed a multi-institutional retrospective review of patients with pathologically confirmed localized LAMNs. Baseline characteristics, pathology, and follow-up data were collected. The primary endpoint was the rate of peritoneal recurrence. We identified 217 patients with localized LAMNs. Median age was 59years (11-95) and 131 (60%) patients were female. Surgical management included appendectomy for 124 (57.1%) patients, appendectomy with partial cecectomy for 26 (12.0%) patients, and colectomy for 67 (30.9%) patients. Pathology revealed perforation in 46 patients (37.7% of 122 patients with perforation status mentioned in the report), extra-appendiceal acellular mucin (EAM) in 49 (22.6%) patients, and extra-appendiceal neoplastic cells (EAC) in 13 (6.0%) patients. Median follow-up was 51.1months (0-271). Seven (3.2%) patients developed a peritoneal recurrence, with a median time to recurrence of 14.4months (2.5-47.0). Seven (15.2%) patients with histologic evidence of perforation had recurrence, versus no patients (0%) without perforation (p < 0.001); five (10.2%) patients with EAM versus two (1.2%) patients without EAM (p = 0.007), and one (7.7%) patient with EAC versus six (2.9%) patients without EAC (p = 0.355) had recurrence. This multi-institutional study represents the largest reported series of patients with localized LAMNs. In the absence of perforation or extra-appendiceal mucin or cells, recurrence was extremely rare; however, patients with any of these pathologic findings require careful follow-up.

Abstract 3145: Clinical impact of new liquid biopsy using modified telomerase-specific adenovirus-based identification for viable-peritoneal tumor cells in peritoneal lavage fluid in resectable pancreatic cancer

Abstract Pancreatic cancer (PC) is one of the leading causes of cancer-related mortality worldwide. Although surgical resection is the only curable option, less than 20% of the patients diagnosed with localized disease are resectable. The prognosis of these patients after complete resection is extremely poor due to local and systemic recurrence. Peritoneal recurrence is a major recurrence pattern after surgery for PC. Peritoneal lavage cytology (CY) is used widely in the diagnosis and staging of gastric and pancreatic cancer to rule out patients with occult peritoneal metastasis. For gastric cancer, positive cytology (CY+), even in the absence of visible peritoneal metastasis, represents stage IV disease. However, the prognostic significance of CY+ in potentially resectable PC is controversial. We rise the question of whether CY+ status in PC has predictive value for survival and early peritoneal recurrence. Therefore, we conducted this study to evaluate use of a new genetically modified telomerase-specific replication-selective adenovirus, expressing GFP (TelomeScan F35) in rapid detection of viable peritoneal tumor cell (v-PTC) dissemination of PC. This human clinical trial sought to determine if the presence of virally-detected, rare v-PTC predict peritoneal recurrence and patient outcome. This study was approved by the IRB in Osaka Police Hospital and Rinku General Medical Center. Patients with resectable cytologically or histologically proven ductal adenocarcinoma of the pancreas were enrolled. Peritoneal lavage fluid was harvested just after a laparotomy in 53 patients with PC. Half of the fluid was examined by cytology with papanicolau staining and MOC-31 immunostaining and the remaining half was analyzed to detect v-PTC with TelomeScan F35. To distinguish between leucocyte and cells with epithelial origin, cells were stained with anti-CD45 Ab. To further distinguish cells with primary tumor origin, cells were labeled with anti-CEA, anti-CA19-9 and EpCAM Abs. GFP-positive and CD45-negative, and either CEA-, CA19-9 or EpCAM-positive cells were counted as v-PTC by automatic detection system using NIS Elements imaging software. Patients were followed after surgery to evaluate its clinical significance. Among 53 patients aged 53-87 years (30 males and 23 females), 6 were cytologically positive (CY+), other 12 were virally positive by TelomeScan F35 (v-PTC+). All 53 patients underwent a surgical resection (PD/DP/TP=32/14/7). 2 patients were double positive (CY+/v-PTC+), and peritoneal recurrence early occurred at 7 month after surgery despite adjuvant chemotherapy. 4 were CY+, but v-PTC-, and no peritoneal recurrence were observed (0%). On the other hand, other 10 were CY-, but v-PTC+, and 4 of these 10 patients occurred peritoneal recurrence (40%). Remaining 37 patients were double negative (CY-/v-PTC-), peritoneal recurrence were observed in only 4 patients. In conclusion, the TelomeScan F35-based v-PTC(+) status was associated with a significantly increased incidence of peritoneal recurrence in patients with resectable PC, resulting in impaired survival. Citation Format: Masahiro Tanemura, Kenta Furukawa, Manabu Mikamori, Tadafumi Asaoka, Yasuo Urata, Kentaro Kishi. Clinical impact of new liquid biopsy using modified telomerase-specific adenovirus-based identification for viable-peritoneal tumor cells in peritoneal lavage fluid in resectable pancreatic cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3145.

P-110 Prediction of peritoneal recurrence in patients with gastric cancer: A multicenter study

The peritoneum is the common recurrence site of gastric cancer (GC) presenting with worse survival. Although some predictive clinicopathological factors were determined, comprehensive assessment of peritoneal recurrence risk prediction for patients treated with adjuvant chemotherapy (CR) or chemoradiotherapy (CRT) after surgery is lacking. We aimed to predict peritoneal recurrence and to develop a new scoring model in GC.

Prediction of Peritoneal Recurrence in Patients with Gastric Cancer: a Multicenter Study.

The peritoneum is the common recurrence site of gastric cancer (GC) presenting with worse survival. Although some predictive clinicopathological factors have been identified, there is no comprehensive assessment of peritoneal recurrence risk prediction for patients treated with adjuvant chemotherapy (CR) or chemoradiotherapy (CRT) after surgery. We aimed to predict peritoneal recurrence and develop a new scoring model in GC. This retrospective study included 274 GC patients who presented with recurrence after curative gastrectomy followed by adjuvant chemotherapy (CT) or chemoradiotherapy (CRT). Risk factors for peritoneal recurrence were analyzed using the following parameters: age, gender, tumor location and characteristics, and differences between treatment modalities. All parameters were assessed by binary logistic regression analysis to compare the patients with and without peritoneal recurrence. Then, a new risk scoring model was developed. Peritoneal recurrence was observed in 115 (44.1%) patients. Peritoneal recurrence was higher in female gender (odds ratio (OR), 1.93; 1.07-3.49, P = 0.030, 1 point), T4a-b stage (OR, 2.47; 1.14-5.36, P = 0.022, 1 point), poor/undifferentiated (OR, 2.04; 1.31-4.06, P = 0.004, 1 point), and signet cell carcinoma (OR, 2.04; 1.04-4.02, P = 0.038, 1 point) after adjusted for resection and dissection types. The risk scoring model was developed using the related parameters: Peritoneal recurrence rates were 24.6%, 42.6%, and 71.4% for group 1 (0 point), group 2 (1-2 points), and group 3 (3-4 points), respectively. Female gender, T4 tumor stage, undifferentiated histopathology, and signet cell type had a tendency to peritoneal recurrence after adjusted for treatment modalities. Patients with 3 or 4 risk factors had an 8.8-fold increased risk for the development of peritoneal recurrence.

Laparoscopic surgery for T4 colon cancer: a risk factor for peritoneal recurrences?

BackgroundAlthough some preclinical studies have inferred that laparoscopic surgery for advanced cancer may increase the risk of peritoneal metastasis, this potential hazard has not been fully evaluated in the clinical setting. This study aimed to clarify whether laparoscopic surgery is associated with an increased risk of postoperative peritoneal recurrence after resection of T4 colon cancer. MethodsThis study included 272 patients who underwent curative resection for pathological T4a colon cancer without distant metastases at the University of Tokyo Hospital between 1997 and 2017. Multivariable Fine-Gray analysis was performed to evaluate whether the use of laparoscopy was an independent risk factor for postoperative peritoneal recurrence. Thereafter, oncological outcomes (overall and relapse-free survival, and organ-specific recurrence) were compared between laparoscopic colectomy and open colectomy using propensity score matching. ResultsMultivariable analysis found that laparoscopic surgery was a significant risk factor for postoperative peritoneal recurrence (hazard ratio: 1.89; 95% confidence interval: 1.01–3.65; P = .046). Comparison after propensity score matching revealed that the incidence of peritoneal recurrence was significantly higher after laparoscopic colectomy than after open colectomy (5-year cumulative incidence: 28.1% vs 12.1%; P = .003). ConclusionThis study suggested that laparoscopic surgery may be related to an increased risk of peritoneal recurrence in patients with pathological T4a colon cancer. Clinicians should be fully aware of this potential risk and seek an optimal treatment plan for the prevention and early detection of peritoneal metastasis.

Review of the Outcomes of Ovarian Cancer Treated with Cytoreductive Surgery and Heated Intraperitoneal Chemotherapy

Ovarian, fallopian tube and primary peritoneal carcinomas (OVCA) most commonly present in advanced stages and despite aggressive surgical resection and chemotherapy will likely recur. Although OVCA can recur in the liver, chest or brain, it most commonly recurs within the peritoneal cavity. Peritoneal spread is problematic and often results in bowel obstruction and the inability to maintain nutritional goals. Given the lethality of peritoneal disease as well as the difficulty in treating this recurrence pattern, novel tactics to treat peritoneal dissemination have been a focus of research in OVCA. Heated intraperitoneal chemotherapy (HIPEC) has been well studied and is utilized to treat appendiceal malignancies, which similarly involve the peritoneum. HIPEC has been shown to improve survival and decrease the risk of peritoneal recurrence in patients with appendiceal malignancies. This technique has also been shown to improve outcomes in patients with peritoneal metastases due to colorectal cancers and gastric cancers. Over the past three decades, HIPEC has been used to treat OVCA with mixed results. The aim of this paper is to review the use of HIPEC in the treatment of OVCA in the upfront and recurrent setting.

Plasma exosome-encapsulated microRNA-21 and microRNA-92a are promising biomarkers for the prediction of peritoneal recurrence in patients with gastric cancer.

In patients with gastric cancer (GC), peritoneal recurrence is a common risk and associated with poor prognosis. A novel biomarker for the prediction of high-risk peritoneal recurrence in patients with GC is desirable. The present study investigated the effectiveness of exosome-encapsulated microRNAs (ex-miRNAs) as minimally invasive biomarkers in patients with GC that received curative surgery. Recurrence-specific ex-miRNAs were selected following comparison of miRNA microarray data from patients with TNM stage II GC with peritoneal recurrence (n=3) and without peritoneal recurrence following curative surgery (n=3), and three healthy volunteers. In this analysis, exosome-encapsulated miRNA-21 (ex-miR-21) and exosomal miR-92a (ex-miR-92a) exhibited the greatest alterations in expression patterns. Using plasma exosome samples collected from another 129 patients with stage II and III GC, the present study investigated the potential value of ex-miR-21 and ex-miR-92a as biomarkers. Ex-miRNA levels were measured using TaqMan miRNA assays. Ex-miR-21 levels were significantly higher and ex-miR-92a levels were significantly lower in samples from patients with GC compared with healthy controls. The overall survival (OS) and peritoneal recurrence-free survival (PRFS) were poorer in stage II and III patients with high ex-miR-21 levels than in patients with low miR-21 levels. OS and PRFS of stage II and III patients with low ex-miR92a levels were significantly worse than those with high ex-miR92a levels. Cox multivariate analyses indicated that ex-miR-21 and ex-miR-92a were independent prognostic factors for OS and PRFS in stage II and III GC. A negative correlation was detected between expression levels of miR-21 and programmed cell death protein 4 mRNA, and miR-92a and prostaglandin E receptor 4 mRNA. Therefore, ex-miR-21 and ex-miR-92a may function as effective and minimally invasive biomarkers for the prediction of peritoneal recurrence and the prognosis of patients with stage II/III GC.

Mesothelin Expression Is a Predictive Factor for Peritoneal Recurrence in Curatively Resected Stage III Gastric Cancer.

Mesothelin is overexpressed in many solid tumors, and recent studies have shown that mesothelin expression is associated with poor outcomes in several malignant tumors and may play a role in cancer progression. Clinical trials of mesothelin-targeted immunotherapies are currently under way, but the correlation between mesothelin expression and gastric cancer prognosis is still unclear. Mesothelin expression in tumor cells was evaluated immunohistochemically in 958 patients with advanced gastric cancer and interpreted according to the intensity and extent of staining. Samples were scored from 0 to 2, with high expression defined as a score of 2. Clinicopathological factors, overall survival (OS), recurrence-free survival (RFS), and sites of initial recurrence, including peritoneal recurrence, were evaluated. Staging was performed according to the American Joint Committee on Cancer 7th edition. High mesothelin expression was observed in 49.7% of patients and significantly associated with high pathologic T (p = .021) and peritoneal recurrence (p = .018). Multivariate survival analysis showed that high mesothelin expression was independently associated with poor RFS (p = .001), OS (p = .001), and peritoneal recurrence (p = .002) in addition to stage, lymphovascular invasion, and Lauren classification. In a subgroup analysis of peritoneal recurrence, high mesothelin expression was also an independent prognostic factor in stage III (p = .013) and diffuse/mixed type gastric cancer (p = .010). High mesothelin expression is correlated with poor outcomes. In addition, mesothelin expression, Lauren classification, and stage are meaningful predictive factors for peritoneal recurrence. Moreover, mesothelin was a significant predictor of a high risk of peritoneal recurrence in patients with stage III gastric cancer. This study demonstrates that high mesothelin expression correlates with poor outcomes and is a significant predictor of peritoneal recurrence in patients with stage III gastric cancer. This study provides instrumental evidence for designing anti-mesothelin antibody-drug conjugate clinical trials in patients with diffuse-type gastric cancer to reduce their high risk of peritoneal carcinomatosis.

LGR5 expression predicts peritoneal recurrence after curative resection of primary colon cancer

BackgroundThe aim of this study was to clarify whether a cancer stem cell marker could be an indicator of post-operative peritoneal recurrence of colon cancer.MethodsExpression of four putative markers (CD133, CD44 variant 6, aldehyde dehydrogenase-1 and leucine-rich repeating G-protein-coupled receptor-5 (LGR5)) was evaluated immunohistochemically in primary tumour samples from 292 patients who underwent curative resection for non-metastasised pT4 colon cancer at the University of Tokyo Hospital between 1997 and 2015.ResultsPeritoneal recurrence was significantly higher in LGR5-negative cases (5-year cumulative incidence: 27.5% vs. 14.4%, p = 0.037). Multivariable analysis confirmed that negative LGR5 expression was an independent risk factor for peritoneal recurrence (hazard ratio (HR) 2.79, p = 0.005) in addition to poor differentiation, positive lymph node metastasis, preoperative carcinoembryonic antigen > 5 ng/mL and anastomotic leakage. The addition of LGR5 significantly improved the predictive value of the multivariable model (net reclassification improvement: 0.186, p = 0.028: integrated discrimination improvement: 0.047, p = 0.008).ConclusionsNegative LGR5 expression was a significant predictor of peritoneal recurrence in patients with pT4 colon cancer. Therefore, LGR5 might be a promising biomarker to identify patients at high risk of post-operative peritoneal metastasis.

Subclinical cancer cell dissemination in peritoneal lavage fluid detected by reverse-transcription polymerase chain reaction identifies patients at high risk for peritoneal recurrence and consequent impaired survival in the setting of preoperative chemoradiation therapy for pancreatic cancer

Preoperative chemoradiation therapy is a promising strategy for pancreatic cancer. Peritoneal recurrence is a major recurrence pattern after surgery for pancreatic cancer following preoperative chemoradiation therapy, even in patients with negative peritoneal lavage fluid cytology. Previous reports have indicated that the detection of carcinoembryonic antigen mRNA by reverse transcription polymerase chain reaction is useful for evaluating subclinical tumor cell dissemination in peritoneal lavage fluid. Patients with resectable and borderline resectable pancreatic cancer treated with preoperative gemcitabine-based chemoradiation therapy and subsequent surgery were enrolled in this study. In all patients, a conventional cytologic examination of peritoneal lavage fluid from laparotomy confirmed the negative peritoneal cytology status. Carcinoembryonic antigen mRNA was detected in the peritoneal lavage fluid at laparotomy using reverse transcription polymerase chain reaction. Recurrence patterns and survival were evaluated in association with the carcinoembryonic antigen mRNA status in the peritoneal lavage fluid. The peritoneal lavage fluid from 57 of the 237 patients (24%) was carcinoembryonic antigen mRNA(+). The carcinoembryonic antigen mRNA(+) patients had a significantly higher incidence of peritoneal recurrence than the carcinoembryonic antigen mRNA(-) patients (36% vs. 15%, P < .001). The 5-year survival rates of the carcinoembryonic antigen mRNA(+) and carcinoembryonic antigen mRNA(-) patients were 31% and 51%, respectively (P = .037). A multivariable analysis for survival revealed that borderline resectability, positive nodal status, and positive carcinoembryonic antigen mRNA status were independent variables for impaired survival. Carcinoembryonic antigen mRNA(+) status was associated with a significantly increased incidence of peritoneal recurrence in patients with pancreatic cancer treated with preoperative chemoradiation therapy, resulting in impaired survival.

Risk Factors for Peritoneal Recurrence in Stage II to III Colon Cancer.

BACKGROUND:Most previous reports to analyze risk factors for peritoneal recurrence in patients with colon cancer have been observational studies of a population-based cohort.OBJECTIVE:This study aimed to determine the risk factors for peritoneal recurrence in patients with stage II to III colon cancer who underwent curative resection.DESIGN:This was a pooled analysis using a combined database obtained from 3 large phase III randomized trials (N = 3714).SETTINGS:Individual patient data were collected from the Japanese Foundation for Multidisciplinary Treatment of Cancer clinical trials 7, 15, and 33, which evaluated the benefits of postoperative 5-fluorouracil–based adjuvant therapies in patients with locally advanced colorectal cancer.PATIENTS:We included patients who had stage II to III colon cancer and underwent curative resection with over D2 lymph node dissection.MAIN OUTCOME MEASURES:Main outcomes measured were risk factors for peritoneal recurrence without other organ metastasis after curative surgery.RESULTS:Peritoneal recurrence occurred in 2.3% (86/3714) of all patients undergoing curative resection. Mean duration from operation to peritoneal recurrence was 17.0 ± 10.3 months. Of these patients with peritoneal recurrence, 29 patients (34%) had recurrence in ≥1 other organ. Multivariate analysis showed that age (≥60 y: HR = 0.531; p = 0.0182), pathological T4 (HR = 3.802; p < 0.0001), lymph node involvement (HR = 3.491; p = 0.0002), and lymphadenectomy (D2: HR = 1.801; p = 0.0356) were independent predictors of peritoneal recurrence. The overall survival was lower in patients who developed peritoneal recurrence than in those with other recurrence (HR = 1.594; p = 0.002).LIMITATIONS:The regimens of adjuvant chemotherapy were limited to oral 5-fluorouracil.CONCLUSIONS:Our findings clarified the risk factors for peritoneal recurrence in patients who underwent curative resection for colon cancer. See Video at http://links.lww.com/DCR/A609.

Intraperitoneal chemotherapy for locally advanced gastric cancer to prevent and treat peritoneal carcinomatosis.

Gastric cancer (GC) is one of the leading causes of cancer death in both sexes in the world. The overall survival (OS) of GC patients is still unsatisfactory. The peritoneal dissemination is the most common type of recurrence in advanced GC. The rationale for administering chemotherapeutic drugs directly into peritoneal cavity is supported by the relative transport barrier that is formed by the tissue surrounding the peritoneal space. Intraperitoneal (IP) chemotherapy with taxanes is safe and feasible. Further randomized phase III clinical trials are needed to validate IP chemotherapy with taxanes for peritoneal carcinomatosis (PC) from GC. Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) used as prophylaxis against peritoneal recurrence in patients with high risk GC is safe, significantly improves the survival and reduces the risk of peritoneal recurrence. A drug delivery system with anticancer drugs seem to be have a pharmacokinetic advantage but further randomized clinical trials are needed to validate its effect.