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Objective: We sought to define criteria associated with low lymph node metastasis risk in patients with submucosal (pT1b) gastric cancer from 3 Western and 3 Eastern countries. Summary Background Data: Accurate prediction of lymph node metastasis risk is essential when determining the need for gastrectomy with lymph node dissection following endoscopic resection. Under present guidelines, endoscopic resection is considered definitive treatment if submucosal invasion is only superficial, but this is not routinely assessed. Methods: Lymph node metastasis rates were determined for patient groups defined according to tumor pathological characteristics. Clinicopathological predictors of lymph node metastasis were determined by multivariable logistic regression and used to develop a nomogram in a randomly selected subset that was validated in the remainder. Overall survival was compared between Eastern and Western countries. Results: Lymph node metastasis was found in 701 of 3166 (22.1%) Eastern and 153 of 560 (27.3%) Western patients. Independent predictors of lymph node metastasis were female sex, tumor size, distal stomach location, lymphovascular invasion, and moderate or poor differentiation. Patients fulfilling the National Comprehensive Cancer Network guideline criteria, excluding the requirement that invasion not extend beyond the superficial submucosa, had a lymph node metastasis rate of 8.9% (53/594). Excluding moderately differentiated tumors lowered the rate to 3.4% (10/296). The nomogram's area under the curve was 0.690. Regardless of lymph node status, overall survival was better in Eastern patients. Conclusions: The lymph node metastasis rate was lowest in patients with well differentiated tumors that were 3 cm and lacked lymphovascular invasion. These criteria may be useful in decisions regarding endoscopic resection as definitive treatment for pT1b gastric cancer.

Endoscopic submucosal dissection (ESD) has gained popularity in recent decades as a reliable and curative resection technique for early gastrointestinal tract neoplasms worldwide. Recent advances in multiple devices have enabled ESD to be a more accessible and safer procedure in the US. For esophageal ESD, it is crucial to expand our knowledge of the differences between esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). This article describes the diagnosis, ESD devices/techniques, and post-ESD management for ESCC.

Identifying colorectal cancer patient populations responsive to chemotherapy or chemoradiation therapy before surgery remains a challenge. Recently validated mouse protocols for organoid irradiation employ the single hit multi-target (SHMT) algorithm, which yields a single value, the D0, as a measure of inherent tissue radiosensitivity. Here, we translate these protocols to human tissue to evaluate radioresponsiveness of patient-derived organoids (PDO) generated from normal human intestines and rectal tumors of patients undergoing neoadjuvant therapy. While PDOs from adenomas with a logarithmically expanded Lgr5+ intestinal stem cell population retain the radioresistant phenotype of normal colorectal PDOs, malignant transformation yields PDOs from a large patient subpopulation displaying marked radiosensitivity due to reduced homologous recombination–mediated DNA repair. A proof-of-principle pilot clinical trial demonstrated that rectal cancer patient responses to neoadjuvant chemoradiation, including complete response, correlate closely with their PDO D0 values. Overall, upon transformation to colorectal adenocarcinoma, broad radiation sensitivity occurs in a large subset of patients that can be identified using SHMT analysis of PDO radiation responses.Significance:Analysis of inherent tissue radiosensitivity of patient-derived organoids may provide a readout predictive of neoadjuvant therapy response to radiation in rectal cancer, potentially allowing pretreatment stratification of patients likely to benefit from this approach.

Supplementary Data from Colorectal Cancer Develops Inherent Radiosensitivity That Can Be Predicted Using Patient-Derived Organoids

Identifying colorectal cancer patient populations responsive to chemotherapy or chemoradiation therapy before surgery remains a challenge. Recently validated mouse protocols for organoid irradiation employ the single hit multi-target (SHMT) algorithm, which yields a single value, the D0, as a measure of inherent tissue radiosensitivity. Here, we translate these protocols to human tissue to evaluate radioresponsiveness of patient-derived organoids (PDO) generated from normal human intestines and rectal tumors of patients undergoing neoadjuvant therapy. While PDOs from adenomas with a logarithmically expanded Lgr5+ intestinal stem cell population retain the radioresistant phenotype of normal colorectal PDOs, malignant transformation yields PDOs from a large patient subpopulation displaying marked radiosensitivity due to reduced homologous recombination–mediated DNA repair. A proof-of-principle pilot clinical trial demonstrated that rectal cancer patient responses to neoadjuvant chemoradiation, including complete response, correlate closely with their PDO D0 values. Overall, upon transformation to colorectal adenocarcinoma, broad radiation sensitivity occurs in a large subset of patients that can be identified using SHMT analysis of PDO radiation responses. Significance: Analysis of inherent tissue radiosensitivity of patient-derived organoids may provide a readout predictive of neoadjuvant therapy response to radiation in rectal cancer, potentially allowing pretreatment stratification of patients likely to benefit from this approach.

The impact of stroma-targeting therapy on tumor immune suppression is largely unexplored. An RNA oligonucleotide, STNM01, has been shown to repress carbohydrate sulfotransferase 15 (CHST15) responsible for tumor proteoglycan synthesis and matrix remodeling. This phase I/IIa study aimed to evaluate the safety and efficacy of STNM01 in patients with unresectable pancreatic ductal adenocarcinoma (PDAC).This was an open-label, dose-escalation study of STNM01 as second-line therapy in gemcitabine plusA total of 22 patients were enrolled, and 3 cycles were repeated at maximum; no DLT was observed. The median OS was 7.8 months. The disease control rate was 77.3%; 1 patient showed complete disappearance of visible lesions in the pancreas and tumor-draining lymph nodes. Higher tumoral CHST15 expression was associated with poor CD3Locoregional injection of STNM01 was well tolerated in patients with unresectable PDAC as combined second-line therapy. It prolonged survival by enhancing T cell infiltration in tumor microenvironment.The present study was supported by the Japan Agency for Medical Research and Development (AMED).

Few Western studies have evaluated the long-term oncologic outcomes of minimally invasive surgery (MIS) approaches to gastrectomy for gastric cancer. This study aimed to compare the outcomes between minimally invasive and open gastrectomies and between laparoscopic and robotic gastrectomies at a high-volume cancer center in the United States. The study analyzed data for all patients undergoing curative gastrectomy for gastric adenocarcinoma from January 2007 to June 2017. Postoperative complications and disease-specific survival (DSS) were compared between surgical approaches. The median follow-up period for the 845 patients in this study was 38.5 months. The stage-stratified 5-year DSS did not differ significantly between open surgery (n = 534) and MIS (n = 311). The MIS approach resulted in significantly fewer complications, as confirmed by adjusted comparison (odds ratio [OR], 0.70; range, 0.49–1.00; p = 0.049). After adjustment, the two groups did not differ in terms of DSS (hazard ratio [HR], 0.83; range, 0.55–1.25; p = 0.362). The robotic operations (n = 190) had fewer conversions to open procedure (p = 0.010), a shorter operative time (212 vs 240 min; p < 0.001), more dissected nodes (27 vs 22; p < 0.001), fewer Clavien-Dindo grade ≥3 complications (5.8% vs 13.2%; p = 0.023), and a shorter postoperative stay (5 vs 6 days; p = 0.045) than the laparoscopic operations (n = 121). The DSS rate did not differ between the laparoscopic and robotic groups. The study findings demonstrated the long-term survival and oncologic equivalency of MIS gastrectomy and the open approach in a Western cohort, supporting the use of MIS at centers that have adequate experience with appropriately selected patients.

Background and study aims The risk of aerosolization of body fluids during endoscopic procedures should be evaluated during the COVID-19 era, as this may contribute to serious disease transmission. Here, we aimed to investigate if use of endoscopic tools during flexible endoscopy may permit gas leakage from the scope or tools. Material and methods Using a fresh 35-cm porcine rectal segment, a colonoscope tip, and manometer were placed intraluminally at opposite ends of the segment. The colonoscope handle, including the biopsy valve, was submerged in a water bath. Sequentially, various endoscopic devices (forceps, clips, snares, endoscopic submucosal dissection (ESD) knives) were inserted into the biopsy valve, simultaneously submerging the device handle in a water bath. The bowel was slowly inflated up to 74.7 mmHg (40 inH2O) and presence of gas leakage, leak pressure, and gas leakage volume were measured. Results Gas leakage was observed from the biopsy valve upon insertion and removal of all endoscopic device tips with jaws, even at 0 mmHg (60/60 trials). The insertion angle of the tool affected extent of gas leakage. In addition, gas leakage was observed from the device handles (8 of 10 devices) with continuous gas leakage at low pressures, especially two snares at 0 mmHg, and an injectable ESD knife at 0.7 ± 0.8 mmHg). Conclusions Gas leakage from the biopsy valve and device handles commonly occur during endoscopic procedures. We recommend protective measures be considered during use of any tools during endoscopy.

The purpose of this study was to identify factors associated with quality-of-life recovery after gastrectomy. Patients anticipated to undergo gastric cancer resection were invited to complete the European Organisation for Research and Treatment of Cancer (EORTC) QLQ C30 and STO22 surveys in the preoperative setting and at 0–1.5 months (early), > 1.5–6 months (intermediate), and > 6–18 months (late) following resection. Quality-of-life recovery was measured as paired differences between pre- and postoperative results. Multivariable linear regression identified factors associated with preoperative quality of life and degree of change following resection. Across 393 participants, response rates at the intermediate and late postoperative time points were 58% (n = 228) and 71% (n = 277), respectively. Relative to baseline, median global health scale decreased in the early (− 15.1 pts, p

With the aim of using side‐scan sonar (SSS) in marine monitoring at offshore CO2 storage sites, an experiment was conducted in a bay with a flat seabed, approximately 32 m deep. CO2 bubbles released at regulated rates between 500 and 5000 mL min−1 were searched for with SSS to elucidate the detection limit, which depends on the towing speed and the altitude of SSS, and the horizontal distance between the release point and SSS. When the towing speed was less than 6 knots, SSS was able to detect CO2 bubbles released at 1000 mL min−1 (approximately 4 tonnes year−1), which is an extremely small rate compared with injection rates in commercial scale storage, O(106) tonnes year−1. The time required for searching an area of 1 km2 with SSS was estimated to be between 1.7 and 3.4 hours, assuming that SSS was towed at an altitude of 27 m. Thus, SSS was demonstrated to be serviceable for marine monitoring. pH measured at 5 m away from the release point dropped by larger than 0.05 four times during the experiment. Only one of them might have been due to the CO2 release, and the others were due to intrusion of water from deeper layers because temperature, salinity and dissolved oxygen simultaneously changed. This indicates that bubble searching with SSS could detect smaller‐scale CO2 leakages than locating anomalous carbonate values, although the latter is still important in case all or most of CO2 dissolve before the emission to the sea. © 2020 Society of Chemical Industry and John Wiley & Sons, Ltd.

The standard treatment of locally advanced rectal cancer is chemoradiation (CRT) followed by proctectomy and adjuvant chemotherapy. However, there is an emerging role for nonsurgical management after CRT or total neoadjuvant therapy (TNT) consisting of CRT and neoadjuvant chemotherapy. Endoscopic submucosal dissection (ESD) after CRT or TNT for rectal cancer, termed "salvage ESD," may be a viable nonsurgical option for carefully selected patients. We aimed to evaluate the feasibility and safety of salvage ESD.A retrospective chart review of cases of salvage ESD for locally advanced rectal cancer and standard ESD for rectal tumors without prior CRT from July 2018 to August 2020 at our institution was performed. Clinical factors and imaging, procedural, and pathology results were collected and compared.Twelve salvage ESD cases were compared with 27 standard ESD cases. Before CRT, 83.3% of lesions in the salvage ESD group were initially clinically staged as T3. The en-bloc resection rates were 92.7% and 91.7% (P = 1.00) and R0 resection rates 66.7% and 75.0% (P = .55) for the standard and salvage groups, respectively. In the salvage ESD group, no adverse events were observed, and 75.0% of the adenocarcinomas in the salvage ESD group had morphologically changed to hyperplasia or adenoma after CRT, with no identifiable lesions greater than T1 tumor depth.Salvage ESD for locally advanced rectal cancer is technically feasible with low adverse event rates. There may be a diagnostic role in salvage ESD in assessing pathologic response to CRT and a possible therapeutic role in resection of residual lesions with the potential to avoid surgery.

Water and energy are essential for the human body. The doubly labeled water (DLW) method measures water turnover (WT) and total energy expenditure (TEE), which serves as a benchmark for the adequate intake (AI) of water and estimated energy requirements (EER). The objective of the current study was to examine the association of WT and TEE with physical activity and body composition in Japanese preschool children. We included 41 preschool children (22 girls, 19 boys) aged 3–6 in this study. WT, TEE, and fat-free mass (FFM) were obtained using DLW. Physical activity was measured using a triaxial accelerometer and categorized as light (LPA; 1.5–2.9 Metabolic equivalents, METs) and of moderate-to-vigorous intensity (MVPA; ≥3.0 METs). Exercise duration (Ex) was defined as ≥4.0 METs of physical activity. WT and TEE moderately positively correlated with Ex, but not with LPA. WT moderately positively correlated with BW and FFM while TEE strongly. We established predictive equations for WT and TEE using body weight (BW), FFM, step count, and Ex to guide the AI of water and EER in Japanese preschool children. We found that FFM and step count are the determinants of TEE, and that BW and Ex are the determinants of WT in preschool children.

Endoscopic submucosal dissection can remove large superficial gastrointestinal lesions in en bloc. A detailed pathological evaluation of the resected specimen is required to assess the risk of recurrence after treatment. However, the current method of sectioning specimens to a thickness of a few millimeters does not provide information between the sections that are lost during the preparation. In this study, we have produced three-dimensional images of the entire dissected lesion for nine samples by using micro-CT imaging system. Although it was difficult to diagnose histological type on micro-CT images, it successfully evaluates the extent of the lesion and its surgical margins. Micro-CT images can depict sites that cannot be observed by the conventional pathological diagnostic process, suggesting that it may be useful to use in a complementary manner.

4144 Background: Carbohydrate sulfotransferase 15 (CHST15) is a proteoglycan biosynthetic enzyme and responsible for tumor matrix remodeling. We reported last year the top-line clinical results of Phase I/IIa (PI/IIa) trial of STNM01, a synthetic RNA oligonucleotide to CHST15, as a second-line (2L) therapy in patients with progressive, unresectable pancreatic ductal adenocarcinoma (PDAC). Here we report the final PI/IIa results and follow-up clinical results investigating the changes of tumor microenvironmental parameters and the correlation with overall survival (OS). Methods: An additional clinical study was followed by PI/IIa trial (jRCT2031190055), which was a multicenter, open-label study of locoregional injections with STNM01 three times at 2 week-interval in 4 weeks as one cycle. A total of 3 cycles were repeated at maximum in combination with systemic 2L chemotherapy, oral fluoropyrimidine S-1 in the PI/IIa trial. The primary objective of this additional clinical study was OS. The secondary objectives were relations of tumor microenvironmental parameters evaluated by immunohistochemistry with OS. For comparison analyses, two-tailed unpaired t-test was performed. For correlation analyses, the Pearson coefficient analyses were performed. Results: A total of 22 patients were enrolled in the study. The average number of tumor-infiltrating CD3+ (13.8/mm2) and CD8+ T cells (8.0/mm2) at baseline in the evaluable population (n = 20) was at most one tenth or less, compared to historical data, indicating 2L population contained more T cell-immune suppressive patients. Baseline CD3+ and CD8+ T cells negatively correlated with tumoral CHST15 expression (p = 0.0051, p = 0.0478, respectively). As the final PI/IIa results, the median OS was 7.8 months with 6 and 12 months-survival rates of 68.2% and 31.8%, respectively. Disease control rate was 76.2% including 1 complete response. STNM01 led to a significant reduction in CHST15 at the end of cycle 1 compared to baseline (p = 0.0095, n = 19), and this was associated with increased CD3+ (p = 0.0331) and CD8+ T cells (p = 0.0146) and reduced CD33+ myeloid-derived suppressor cells (MDSCs) (p = 0.0281) in the tumor. Patient subpopulation who survived over 1 year (n = 5) showed a significant fold increase of CD3+ (p = 0.0033) and CD8+ T cells (p = 0.0147) and decrease of CD33+ MDSCs (p = 0.0403) at the end of cycle 1 compared to another subpopulation who survived less than 1 year (n = 13-14). Higher fold increase of CD3+ T cells (p = 0.0035, n = 19) or fold decrease of CD33+ MDSCs (p = 0.0212, n = 15) at the end of cycle 1 significantly correlated with longer OS. Conclusions: Locoregional injection of STNM01 was able to reactivate and augment tumor-infiltrating T cells while repress MDSCs. These changes in tumor immune cell profiles correlate with prolong prognosis in patients with first-line refractory, unresectable PDAC. Clinical trial information: jRCT2031190055.

Background Accurate diagnosis of malignant and benign pancreatic lesions can be challenging, especially with endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) samples that are small and/or degraded. In the present study, we determined how to best evaluate abnormal SMAD4 expression by immunohistochemical staining on cell block specimens from EUS-FNA samples. Results In surgically resected pancreas, when abnormal SMAD4 immunolabelling was evaluated as negative SMAD4 expression, the sensitivity was low (33%), but when it was evaluated as decreased SMAD4 expression, the sensitivity improved (53%). Specificity and positive predictive value were high for both evaluations. There were no false-positive cases. In cell block specimens, decreased SMAD4 expression showed 47% sensitivity and 72% specificity, while negative SMAD4 expression showed lower sensitivity (20%) and higher specificity (100%). Both evaluations in cell block specimens showed lower sensitivity and specificity compared to resected specimens. False-positive and -negative rates were higher for cell blocks than for resected specimens. Conclusions Decreased SMAD4 immunolabelling provided improved sensitivity as compared to negative SMAD4 immunolabelling; therefore, it is important to compare SMAD4 expression in a sample to its expression in normal cells. Abnormal SMAD4 labelling showed low sensitivity and high specificity; therefore, SMAD4 staining using EUS-FNA samples might be helpful to detect malignancies that possess SMAD4 gene abnormalities.

Endoscopic submucosal dissection (ESD) is challenging in the right colon. Traction devices can make it technically easier. In this study, we evaluated a flexible grasper with articulating tip and elbow-like bending (IgE) through a double-balloon surgical platform (DESP), compared with an earlier generation grasper without elbow-like bending (Ig). The reach of Ig/IgE was investigated at eight locations using a synthetic colon within a 3D model. Using a fresh porcine colorectum, 4 cm pseudo-polyps were created at the posterior wall of the ascending colon. Fifty-four ESD procedures were performed using three techniques: standard ESD (STD), ESD using Ig (DESP+Ig), and ESD using IgE (DESP+IgE). IgE was able to reach the full circumference at all the locations, whereas the medial walls proximal to the descending colon were out of Ig’s reach. Compared with the STD, both DESP+Ig and DESP+IgE showed significantly shorter procedure time (STD vs. DESP+Ig vs. DESP+IgE = median 48.9 min vs. 38.6 vs. 29.9) and fewer injuries (1.5 vs. 0 vs. 0). Moreover, the DESP+IgE had a shorter procedure time than the DESP+Ig (p=0.0025). The IgE with DESP increased instrument reach compared to Ig, and likely represented a traction tool for excision of large pseudo-polyps in the right colon.

Endoscopic submucosal dissection (ESD) is challenging in the right colon. Traction devices can make it technically easier. In this study, we evaluated a flexible grasper with articulating tip and elbow-like bending (IgE) through a double-balloon surgical platform (DESP), compared with an earlier generation grasper without elbow-like bending (Ig). The reach of Ig/IgE was investigated at eight locations using a synthetic colon within a 3D model. Using a fresh porcine colorectum, 4 cm pseudo-polyps were created at the posterior wall of the ascending colon. Fifty-four ESD procedures were performed using three techniques: standard ESD (STD), ESD using Ig (DESP + Ig), and ESD using IgE (DESP + IgE). IgE was able to reach the full circumference at all the locations, whereas the medial walls proximal to the descending colon were out of Ig’s reach. Compared with the STD, both DESP + Ig and DESP + IgE showed significantly shorter procedure time (STD vs. DESP + Ig vs. DESP + IgE = median 48.9 min vs. 38.6 vs. 29.9) and fewer injuries (1.5 vs. 0 vs. 0). Moreover, the DESP + IgE had a shorter procedure time than the DESP + Ig (p = 0.0025). The IgE with DESP increased instrument reach compared to Ig, and likely represented a traction tool for excision of large pseudo-polyps in the right colon.

Femoral shaft nonunion after the intramedullary nailing has been successfully treated with advances in surgical technique. Nonetheless, the techniques cause morbidity to periosteum at the fracture site. We report the case of a 67-year-old man who underwent endoscopic surgery for refractory nonunion following the fracture of the distal femoral shaft, despite two fixations using an interlocking nail. In addition, the patient had uncontrolled diabetic mellitus. Endoscopy allowed us to acquire a clear view of the nonunion site, in which the resection of scar tissues and the packing of the cancellous bone were performed. At the final follow-up, bone healing was observed, and the patient was able to return to normal daily and social activity.

103 Background: According to the National Comprehensive Cancer Network guideline, locally advanced rectal cancer is treated with chemotherapy with or without radiation, followed by transabdominal resection. However, there has been an emerging role for nonoperative management after chemoradiotherapy, and there is significant morbidity and risks associated with surgical resection. Endoscopic submucosal dissection (ESD) after chemoradiotherapy (CRT) for rectal cancer, which is termed “salvage ESD,” may be a viable option for patients, in terms of evaluating pathological response and providing potential curative resection. We aim to evaluate the feasibility and safety of salvage ESD. Methods: Retrospective chart review of cases of salvage ESD after CRT for locally advanced rectal cancer (salvage group) and standard ESD cases for rectal tumors without prior CRT (standard group) from July 2018 to August 2020 at our institution was performed. Clinical factors, imaging, procedural, and pathology results were collected and compared between the two groups. Results: 12 salvage ESD cases were compared to 27 standard ESD cases. 83.3% of the lesions in the salvage ESD group were initially staged as T3 prior to CRT. 100% of the lesions in the salvage ESD group were scarred down, compared to 33.3% in the standard ESD group (p

Background & Aims Endoscopic submucosal dissection (ESD) is a widely accepted treatment option for superficial gastric neoplasia in Asia, but there are few data on outcomes of gastric ESD from North America. We aimed to evaluate the safety and efficacy of gastric ESD in North America. Methods We analyzed data from 347 patients who underwent gastric ESD at 25 centers, from 2010 through 2019. We collected data on patient demographics, lesion characteristics, procedure details and related adverse events, treatment outcomes, local recurrence, and vital status at the last follow up. For the 277 patients with available follow-up data, the median interval between initial ESD and last clinical or endoscopic evaluation was 364 days. The primary endpoint was the rate of en bloc and R0 resection. Secondary outcomes included curative resection, rates of adverse events and recurrence, and gastric cancer-related death. Results Ninety patients (26%) had low-grade adenomas or dysplasia, 82 patients (24%) had high-grade dysplasia, 139 patients (40%) had early gastric cancer, and 36 patients (10%) had neuroendocrine tumors. Proportions of en bloc and R0 resection for all lesions were 92%/82%, for early gastric cancers were 94%/75%, for adenomas and low-grade dysplasia were 93%/ 92%, for high-grade dysplasia were 89%/ 87%, and for neuroendocrine tumors were 92%/75%. Intraprocedural perforation occurred in 6.6% of patients; 82% of these were treated successfully with endoscopic therapy. Delayed bleeding occurred in 2.6% of patients. No delayed perforation or procedure-related deaths were observed. There were local recurrences in 3.9% of cases; all occurred after non-curative ESD resection. Metachronous lesions were identified in 14 patients (6.9%). One of 277 patients with clinical follow up died of metachronous gastric cancer that occurred 2.5 years after the initial ESD. Conclusions ESD is a highly effective treatment for superficial gastric neoplasia and should be considered as a viable option for patients in North America. The risk of local recurrence is low and occurs exclusively after non-curative resection. Careful endoscopic surveillance is necessary to identify and treat metachronous lesions.

An option to detect CO2 leakage from deep geological storage under the seabed is monitoring the partial pressure of CO2 (pCO2) in the sea. One of the challenges of this technique is to differentiate pCO2 elevations caused by CO2 leakage from variations in the natural baseline (which varies due to seasonal and other factors). This paper compares a covariance threshold for anomalous pCO2 (a threshold based on pCO2 and dissolved oxygen), with annual and seasonal constant thresholds, using data observed in two hydrologically contrasting areas in Osaka Bay, Japan. In one of these locations the water column is typically stratified throughout the year, whereas at the other it is vertically mixed. The covariance threshold often but not consistently outperforms the constant thresholds, but is effective in all the cases analyzed in the present study. In any season in the mixed area, and in winter in the stratified area, the possibility of false-negatives in the seasonal threshold method is smaller than or comparable with that in the covariance threshold one. In areas with large natural pCO2 variations, such as during summer in the stratified area, the covariance threshold method is efficient in detecting CO2 leakage whereas the seasonal threshold method is of little use. With a good understanding of local conditions, monitoring pCO2 with the covariance threshold method is a potentially useful but not sufficient option for leakage detection in the marine environment.

Objective We sought to identify clinicopathological characteristics of high-grade pancreatic intraepithelial neoplasia (PanIN)/carcinoma in situ to facilitate screening for pancreatic ductal adenocarcinoma. Methods We evaluated PanIN lesions in 173 consecutive autopsy cases with no evidence of pancreatic ductal adenocarcinoma and/or intraductal papillary mucinous neoplasm (mean age, 80.5 years) by submitting the entire pancreas for microscopic examination. Results PanIN-3 was found in 4% of examined cases, whereas PanIN-1 and PanIN-2 were present in 77% and 28%, respectively. PanIN-3 was more frequently identified in patients with diabetes mellitus and/or older age. PanIN-3 lesions were always multifocal, and the number of PanIN-3 foci was positively associated with those of PanIN-1 or PanIN-2. PanIN-3 was located more frequently in the pancreatic body and tail than in the head and predominantly involved small interlobular/intralobular ducts rather than the main duct. Notably, 71% of pancreata with PanIN-3 showed cystic changes in PanIN-3 and lower grade PanIN lesions. PanIN-3 was also accompanied by higher grade extralobular fibrosis. Conclusions We found that 4% of the examined pancreata harbored PanIN-3 lesions that were associated with several unique clinicopathological features. The cystic change along with fibrotic pancreatic parenchyma may be detected by imaging studies such as endoscopic ultrasound.