Pathophysiological Implications of Protein Lactylation in Pancreatic Epithelial Tumors.

Protein lactylation is a post-translational modification associated with glycolysis. Although recent evidence indicates that protein lactylation is involved in epigenetic gene regulation, its pathophysiological significance remains unclear, particularly in neoplasms. Herein, we investigated the potential involvement of protein lactylation in the molecular mechanisms underlying benign and malignant pancreatic epithelial tumors, as well as its role in the response of pancreatic cancer (PC) cells to gemcitabine. Increased lactylation was observed in the nuclei of intraductal papillary mucinous adenoma, non-invasive intraductal papillary mucinous carcinoma, and invasive carcinoma, in parallel to the upregulation of hypoxia-inducible factor-1α. This observation indicated that a hypoxia-associated increase in nuclear protein lactylation could be a biochemical hallmark in pancreatic epithelial tumors. The standard PC chemotherapy drug gemcitabine suppressed histone lactylation in vitro, suggesting that histone lactylation might be relevant to its mechanism of action. Taken together, our findings suggest that protein lactylation may be involved in the development of pancreatic epithelial tumors and could represent a potential therapeutic target for PC.

Genomic profile and clinical features of MSI-H and TMB-high pancreatic cancers: real-world data from C-CAT database.

BACKGROUND: Microsatellite instability high (MSI-H) and tumor mutational burden high (TMB-high) pancreatic cancer are rare, and information is lacking. Based on the C-CAT database, we analyzed the clinical and genomic characteristics of patients with these subtypes. METHODS: We retrospectively reviewed data on 2206 patients with unresectable pancreatic adenocarcinoma enrolled in C-CAT between July 2019 and January 2022. The clinical features, proportion of genomic variants classified as oncogenic/pathogenic in C-CAT, overall response rate (ORR), disease control rate (DCR), and time to treatment failure (TTF) of chemotherapy as first-line treatment were evaluated. RESULTS: Numbers of patients with MSI-H and TMB-high were 7 (0.3%) and 39 (1.8%), respectively. All MSI-H patients were TMB-high. MSI-H and TMB-high patients harbored more mismatch repair genes, such as MSH2, homologous recombination-related genes, such as ATR and BRCA2, and other genes including BRAF, KMT2D, and SMARCA4. None of the 6 MSI-H patients who received chemotherapy achieved a clinical response, including 4 patients treated with gemcitabine plus nab-paclitaxel (GnP) therapy, whose DCR was significantly lower than that of microsatellite stable (MSS) patients (0 vs. 67.0%, respectively, p = 0.01). Among the TMB-high and TMB-low groups, no significant differences were shown in ORR, DCR (17.1 vs. 23.1% and 57.1 vs. 63.1%, respectively), or median TTF (25.9 vs. 28.0 weeks, respectively) of overall first-line chemotherapy. CONCLUSIONS: MSI-H and TMB-high pancreatic cancers showed some distinct genomic and clinical features from our real-world data. These results suggest the importance of adapting optimal treatment strategies according to the genomic alterations.

Genomic landscape and clinical features of rare subtypes of pancreatic cancer: analysis with the national database of Japan.

BACKGROUND: Special subtypes of pancreatic cancer, such as acinar cell carcinoma (ACC), adenosquamous carcinoma (ASC), and anaplastic carcinoma of the pancreas (ACP), are rare, and so data on them are limited. Using the C-CAT database, we analyzed clinical and genomic characteristics of patients with these and evaluated differences on comparison with pancreatic ductal adenocarcinoma (PDAC) patients. METHODS: We retrospectively reviewed data on 2691 patients with unresectable pancreatic cancer: ACC, ASC, ACP, and PDAC, entered into C-CAT from June 2019 to December 2021. The clinical features, MSI/TMB status, genomic alterations, overall response rate (ORR), disease control rate (DCR), and time to treatment failure (TTF) on receiving FOLFIRINOX (FFX) or GEM + nab-PTX (GnP) therapy as first-line treatment were evaluated. RESULTS: Numbers of patients with ACC, ASC, ACP, and PDAC were 44 (1.6%), 54 (2.0%), 25 (0.9%), and 2,568 (95.4%), respectively. KRAS and TP53 mutations were prevalent in ASC, ACP, and PDAC (90.7/85.2, 76.0/68.0, and 85.1/69.1%, respectively), while their rates were both significantly lower in ACC (13.6/15.9%, respectively). Conversely, the rate of homologous recombination-related (HRR) genes, including ATM and BRCA1/2, was significantly higher in ACC (11.4/15.9%) than PDAC (2.5/3.7%). In ASC and ACP, no significant differences in ORR, DCR, or TTF between FFX and GnP were noted, while ACC patients showed a trend toward higher ORR with FFX than GnP (61.5 vs. 23.5%, p = 0.06) and significantly more favorable TTF (median 42.3 vs. 21.0 weeks, respectively, p = 0.004). CONCLUSIONS: ACC clearly harbors different genomics compared with PDAC, possibly accounting for differences in treatment efficacy.

Spontaneous regression in solid pseudopapillary neoplasm of pancreas.

A solid pseudopapillary neoplasm (SPN) of the pancreas is a rare neoplasm that mainly occurs in young women. We herein report the case of spontaneous regression in SPN of the pancreas. A 48-years-old female was found to have a mass in the head of the pancreas on examination for her back pain and referred to our hospital in 20XX. Laboratory data showed no abnormalities in serum levels of pancreatic enzymes and tumor markers. A contrast CT scan of upper abdomen showed a slightly enhanced lesion (23 × 19 mm in diameter) without cystic component or fibrous capsule in the head of the pancreas. An MRI scan showed the mass as low-intensity in T1-WI and high-intensity in T2-WI. She admitted to our hospital for further examination of a pancreatic mass by EUS-FNA in 20XX + 4. EUS showed a slightly hypoechoic mass (30 × 19 mm in diameter) compared with the neighboring normal pancreas. Tumor margin was relatively clear and the internal echo image was homogenous. Histological findings revealed a solid and pseudopapillary proliferation of eosinophilic polygonal cells with oval nuclei. The tumor cells were positive for vimentin and CD10 in the cytoplasm and ß-catenin in the nuclei, which led to the diagnosis of SPN. We recommended this patient to undergo surgical resection, however, the patient chose follow-up examinations. Follow-up study after 1 year using MRI scan showed spontaneous regression, which was coincided with her menopause. These findings suggest that the natural regression of SPN may occur and female sex hormone changes may regulate the growth of SPN.

Autopsy of a Patient with Primary Pancreatic Lymphoma with Findings Resembling Severe Acute Pancreatitis.

Primary pancreatic lymphoma is a rare pancreatic malignancy, reportedly accounting for only 0.2-0.7% of all primary pancreatic tumors. Primary pancreatic lymphoma is often difficult to distinguish from other diseases, such as acute pancreatitis. We herein report the autopsy of a patient with primary pancreatic lymphoma with imaging findings resembling those of severe acute pancreatitis, with a focus on the gross and histological features.

Correction: Association of fatty pancreas with pancreatic endocrine and exocrine function.

[This corrects the article DOI: 10.1371/journal.pone.0209448.].

Usefulness of urinary trypsinogen-2 and trypsinogen activation peptide in acute pancreatitis: A multicenter study in Japan.

BACKGROUND: Rapid urinary trypsinogen-2 dipstick test and levels of urinary trypsinogen-2 and trypsinogen activation peptide (TAP) concentration have been reported as prognostic markers for the diagnosis of acute pancreatitis. AIM: To reconfirm the validity of all these markers in the diagnosis of acute pancreatitis by undertaking a multi-center study in Japan. METHODS: Patients with acute abdominal pain were recruited from 17 medical institutions in Japan from April 2009 to December 2012. Urinary and serum samples were collected twice, at enrollment and on the following day for measuring target markers. The diagnosis and severity assessment of acute pancreatitis were assessed based on prognostic factors and computed tomography (CT) Grade of the Japanese Ministry of Health, Labour, and Welfare criteria. RESULTS: A total of 94 patients were enrolled during the study period. The trypsinogen-2 dipstick test was positive in 57 of 78 patients with acute pancreatitis (sensitivity, 73.1%) and in 6 of 16 patients with abdominal pain but without any evidence of acute pancreatitis (specificity, 62.5%). The area under the curve (AUC) score of urinary trypsinogen-2 according to prognostic factors was 0.704, which was highest in all parameter. The AUC scores of urinary trypsinogen-2 and TAP according to CT Grade were 0.701 and 0.692, respectively, which shows higher than other pancreatic enzymes. The levels of urinary trypsinogen-2 and TAP were significantly higher in patients with extended extra-pancreatic inflammation as evaluated by CT Grade. CONCLUSION: We reconfirmed urinary trypsinogen-2 dipstick test is useful as a marker for the diagnosis of acute pancreatitis. Urinary trypsinogen-2 and TAP may be considered as useful markers to determine extra-pancreatic inflammation in acute pancreatitis.

Association of fatty pancreas with pancreatic endocrine and exocrine function.

AIM: The purpose of this study was to clarify whether fatty pancreas might lead to impaired pancreatic endocrine or exocrine function. MATERIAL AND METHODS: The study involved 109 participants who had undergone the glucagon stimulation test and N-benzoyl-L-tyros-p-amino benzoic acid (BT-PABA) test to assess pancreatic function as well as unenhanced abdominal computed tomography (CT). Pancreatic endocrine impairment was defined as ΔC peptide immunoreactivity less than 2 [mmol/L] in the glucagon stimulation test, and pancreatic exocrine impairment was defined as a urinary PABA excretion rate less than 70% on the BT-PABA test. We defined as the mean CT value of pancreas / CT value of spleen (P/S ratio) as a marker to assess fatty pancreas. We analyzed the association between fatty pancreas and pancreatic impairment using the logistic regression model. The odds ratio (OR) is shown per 0.1 unit. RESULTS: Pancreatic endocrine function was impaired in 33.0% of the participants, and 56.9% of those were regarded as having pancreatic exocrine impairment. The P/S ratio was significantly correlated with pancreatic endocrine impairment in univariate analysis (OR = 0.61, 95% confidence interval (CI) = 0.43-0.83, P = 0.0013) and multivariate analysis (OR = 0.38, 95% CI = 0.22-0.61, P < .0001) for all participants. Similar significant relationships were observed in both univariate (OR = 0.70, 95% CI = 0.49-0.99, P = 0.04) and multivariate (OR = 0.39, 95% CI = 0.21-0.66, P = 0.0002) analyses for the participants without diabetes (n = 93). The amount of pancreatic fat was not associated with exocrine impairment in univariate analysis (OR = 0.80, 95% CI = 0.59-1.06, P = 0.12). CONCLUSION: Fatty pancreas was associated with pancreatic endocrine impairment but did not have a clear relationship with pancreatic exocrine impairment.

[Outcome and Problems of Nab-Paclitaxel Therapy for Gastric Cancer in Clinical Practice].

Nanoparticle albumin-bound paclitaxel(nab-PTX)was approved for the treatment of gastric cancer without a large-scale clinical trial in Japan. Its safety and efficacy should be validated in clinical practice. We retrospectively investigated prognostic factors related to time to treatment failure(TTF)in 11 patients with unresectable or recurrent gastric cancer treated with nab- PTX in our hospital. In univariate analysis, Onodera's prognostic nutritional index(PNI)and the time from the start of first-line chemotherapy to the start of nab-PTX were related to TTF. In multivariate analysis, Onodera's PNI was identified as an independent predictive factor for TTF (hazard ratio 0.056, p=0.022). PNI could contribute to adequate patient selection and the improvement of nab-PTX therapy efficacy ingastric cancer.

Evidence-based clinical practice guidelines for chronic pancreatitis 2015.

Chronic pancreatitis is considered to be an irreversible progressive chronic inflammatory disease. The etiology and pathology of chronic pancreatitis are complex; therefore, it is important to correctly understand the stage and pathology and provide appropriate treatment accordingly. The newly revised Clinical Practice Guidelines of Chronic Pancreatitis 2015 consist of four chapters, i.e., diagnosis, staging, treatment, and prognosis, and includes a total of 65 clinical questions. These guidelines have aimed at providing certain directions and clinically practical contents for the management of chronic pancreatitis, preferentially adopting clinically useful articles. These revised guidelines also refer to early chronic pancreatitis based on the Criteria for the Diagnosis of Chronic Pancreatitis 2009. They include such items as health insurance coverage of high-titer lipase preparations and extracorporeal shock wave lithotripsy, new antidiabetic drugs, and the definition of and treatment approach to pancreatic pseudocyst. The accuracy of these guidelines has been improved by examining and adopting new evidence obtained after the publication of the first edition.

[A case of hypervascular hyperplastic nodule in chronic alcoholic liver disease with corona-like enhancement in the late phase image of CT during hepatic arteriography].

A 46-year-old woman was admitted to our hospital with hepatic encephalopathy due to alcoholic liver disease. A hepatic nodule (20 mm in diameter) in S7 was enhanced in the early phase of contrast CT. No significant findings were observed in the late phase of contrast CT and SPIO MRI. The late phase of CT during hepatic arteriography showed corona-like enhancement of the nodule. The nodule was diagnosed as a hypervascular hyperplastic nodule, based on histological examinations and immunohistochemical results with antibodies against CD68 and CD34.

Endoscopic resection for the diagnosis of visceral Kaposi's sarcoma.

Kaposi's sarcoma is an uncommon neoplasm that occasionally involves the gastrointestinal tract in immunosuppressed individuals. Infection with human herpes virus 8 is known to be necessary for developing all forms of Kaposi's sarcoma. We report a renal transplant recipient who developed visceral Kaposi's sarcoma 18 months after the transplantation. In Oriental countries, the incidence of Kaposi's sarcoma is extremely low, and this is the first case of Kaposi's sarcoma arising from a transplant recipient in Japan. Standard forceps biopsies of the gastric lesions failed to make the correct diagnosis. However, endoscopic resection successfully led to the correct diagnosis of Kaposi's sarcoma and herpes simplex virus 8 infection as well. This is the first report of a patient with visceral Kaposi's sarcoma who underwent endoscopic resection that reliably confirmed histological diagnosis and the viral genome at the same time.

Solid pseudopapillary tumor as a possible cause of acute pancreatitis.

CONTEXT: Acute pancreatitis is not commonly seen in the first presentation of pancreatic neoplasms. Solid pseudopapillary tumor as a cause of acute pancreatitis has not yet been reported. This is the first report of acute pancreatitis resulting from solid pseudopapillary tumor. CASE REPORT: We report the case of a 21-year-old female who presented with a sudden onset of severe abdominal pain associated with elevated serum pancreatic enzyme concentration. The initial diagnosis was acute pancreatitis. However, subsequent ultrasonography and computed tomography showed an abdominal mass in the tail of the pancreas, retroperitoneal fluid and left pleural effusion. There was scarce pain relief even with large doses of analgesics. A distal pancreatectomy was then performed and a final diagnosis of solid pseudopapillary tumor was made histologically. The surrounding pancreatic tissue was characterized as hemorrhagic edematous pancreatitis. CONCLUSIONS: Solid pseudopapillary tumor is generally known as a slow-growing pancreatic neoplasm with few, if any, symptoms. However, solid pseudopapillary tumors should be kept in mind as a possible cause of acute pancreatitis, especially in cases of non-alcoholic young women having an acute pancreatitis attack.

Increased QT dispersion in patients with alcoholic pancreatitis.

OBJECTIVES: Increased dispersion of the QT interval has been proposed to be a novel marker for increased risk of ventricular arrhythmia and sudden cardiac death. This study examined whether QT dispersion is affected in patients with alcoholic pancreatitis. METHODS: We measured the QT interval, corrected QT interval, activation recovery interval, activation time, recovery time, and their respective dispersions in 3 age- and gender-matched groups: patients with alcoholic pancreatitis [age, 58.9 +/- 11.8 years; male/female (M/F), 33/3], patients with alcohol dependence (age, 59.3 +/- 8.9 years; M/F, 33/4), and a healthy control group (age, 55.8 +/- 8.8 years; M/F, 33/3). RESULTS: The QT dispersions in patients with alcoholic pancreatitis (62.4 +/- 19.9 milliseconds; P < 0.001) or alcohol dependence (58.2 +/- 19.6 milliseconds; P < 0.001) were significantly greater than in the control group (41.4 +/- 13.3 milliseconds). Similarly, the corrected QT dispersions in patients with alcoholic pancreatitis (68.5 +/- 22.8 milliseconds; P < 0.001) or alcohol dependence (65.3 +/- 23.6 milliseconds; P < 0.001) were significantly greater than in the control group (42.8 +/- 13.2 milliseconds). Both QT dispersion and QTc dispersion were longer in patients with alcoholic pancreatitis than those with alcohol dependence (P = 0.011 and P = 0.039, respectively). Simple linear regression analysis of the relationship between the RR and QT intervals revealed that the regression lines for patients with alcoholic pancreatitis and alcohol dependence were almost parallel. However, the slope of the regression line for the control group was significantly greater (P < 0.05) than for the other 2 lines. CONCLUSION: The findings demonstrate increased QT and QTc dispersions in patients with either alcoholic pancreatitis or alcohol dependence. The QT dispersion and QTc dispersion were longer in patients with alcoholic pancreatitis than those with alcohol dependence.

Molecular cloning and characterization of chymopasin, a novel serine protease from rat pancreas.

INTRODUCTION: Pancreas secretes many enzymes for food digestion into the pancreatic juice. We cloned a novel serine protease, chymopasin, from rat pancreas. AIMS: To know the localization of this enzyme in the pancreas and to analyze the enzymatic characteristics. METHODOLOGY: We cloned chymopasin cDNA using 3' and 5' RACEs. Northern blot and in situ hybridization were used to study the expression of this enzyme. Recombinant chymopasin protein produced by was analyzed by Western blot using specific antibody, and its enzymatic characteristics were examined using commercially available synthetic substrates, fibrin and gelatin. RESULTS: The open reading frame of rat chymopasin consisted of 792 bp encoding 264 amino acid residues. The deduced amino acid sequence contained the essential catalytic triad characteristic of the serine protease family. There was no putative N-glycosylation site. The amino acid sequence of rat chymopasin showed 54.5% identity to rat chymotrypsin B. Northern blot analysis showed that the transcript was strongly expressed in the pancreas. In situ hybridization with digoxigenin-labeled cRNA probe showed that the positive signals were observed in the acinar cells, but not in the islet or duct cells. Chymopasin protein was detected in the pancreas homogenate and bile-pancreatic juice. Further, cerulein stimulated the secretion of rat chymopasin into bile-pancreatic juice. CONCLUSION: These results suggested that rat chymopasin might be a digestive enzyme secreted from the acinar cells. From the enzyme assay using synthetic substrates, the purified recombinant chymopasin expressed in showed chymotrypsin-like activity. In addition, rat recombinant chymopasin showed fibrinolytic and gelatinolytic activities. These results suggested a role in the pathogenesis of pancreatic damage.

Relation between morphologic changes in the main pancreatic duct and exocrine pancreatic function after a secretin test.

INTRODUCTION: Because pancreatic exocrine function testing methods are problematic, both imaging and functional tests are important in the diagnosis of chronic pancreatitis. AIM: To evaluate the usefulness of ultrasonographic monitoring of the main pancreatic duct after a secretin test. METHODOLOGY: A total of 70 subjects (30 control subjects, 26 patients with probable chronic pancreatitis, and 14 patients with definite chronic pancreatitis) were selected. The main pancreatic duct diameters were measured serially after an injection of secretin (100 IU/body). The relation between the magnitude of the duct dilation and exocrine pancreatic function on the secretin test was evaluated. RESULTS: The main pancreatic duct dilated immediately after a bolus injection of secretin, showed a peak after 2-5 minutes, and recovered gradually. The response curve of the definite group had a flatter pattern than that of the other groups. For the maximal to basal duct diameter ratio, statistically significant differences were found between the control and definite groups and between the control and probable groups. In addition, the ratio correlated significantly with the maximal bicarbonate concentration and secretory volume on the secretin test. CONCLUSIONS: The results of the current study indicate that exocrine pancreatic function and the morphologic changes of the main pancreatic duct are significantly related. Dynamic ultrasonographic findings may reflect pancreatic function; consequently, this test may be a useful tool in the diagnosis of chronic pancreatitis.

Ultrasonographic splanchnic arterial flow measurement in severe acute pancreatitis.

INTRODUCTION: Duplex ultrasonographic technology is now capable of detecting flow signals in the various splanchnic vessels and calculating the concomitant flow velocities using fast-Fourier transformation. AIM: To use Doppler sonography to investigate how splanchnic hemodynamics vary during the early stage of severe acute pancreatitis. METHODOLOGY: Six patients with severe acute pancreatitis (age, 59.0 +/- 6.57 years; four men, two women) and seven with mild to moderate acute pancreatitis (age, 60.1 +/- 7.41 years; five men, two women) were examined with Doppler sonography immediately after disease onset. The maximum velocity, minimum velocity, mean velocity, pulsatility index, and resistive index were determined from the Doppler spectra from the proper hepatic artery, celiac artery, and superior mesenteric artery. We also examined 15 healthy subjects (age, 59.3 +/- 4.60 years; 10 men, five women) as controls. RESULTS: The maximum velocity of the proper hepatic artery in patients with severe acute pancreatitis was significantly higher than that in patients with mild to moderate acute pancreatitis (p = 0.011) and in control subjects (p = 0.0047). Similarly, significant increases in both the minimum velocity and the mean velocity of the proper hepatic artery were observed in patients with severe acute pancreatitis. Neither pulsatility index nor resistive index of the proper hepatic artery showed a significant difference among the three groups. There were no significant differences among the three groups with respect to the flow velocity of the superior mesenteric artery. In contrast, the pulsatility index of the superior mesenteric artery in patients with severe acute pancreatitis was significantly lower than that in patients with mild to moderate acute pancreatitis (p = 0.0058) or in control subjects (p = 0.0024). For patients with acute pancreatitis, a significant inverse correlation was obtained between the maximum velocity of the proper hepatic artery and the pulsatility index of the superior mesenteric artery (r = -0.658, p = 0.0145). CONCLUSION: The increase in the hepatic arterial flow velocity and the decrease in the superior mesenteric arterial pulsatility index may represent early events of the severe type of acute pancreatitis.