Maintenance steroid therapy is associated with decreased risk of malignancy and better prognosis of patients with autoimmune pancreatitis: A multicenter cohort study in Japan.

BACKGROUND/OBJECTIVES: The association between autoimmune pancreatitis (AIP) and pancreatic cancer (PC) remains controversial. This study aimed to clarify the long-term prognosis and risk of malignancies in AIP patients in Japan. METHODS: We conducted a multicenter retrospective cohort study on 1364 patients with type 1 AIP from 20 institutions in Japan. We calculated the standardized incidence ratio (SIR) for malignancies compared to that in the general population. We analyzed factors associated with overall survival, pancreatic exocrine insufficiency, diabetes mellitus, and osteoporosis. RESULTS: The SIR for all malignancies was increased (1.21 [95 % confidence interval: 1.05-1.41]) in patients with AIP. Among all malignancies, the SIR was highest for PC (3.22 [1.99-5.13]) and increased within 2 years and after 5 years of AIP diagnosis. Steroid use for ≥6 months and ≥50 months increased the risk of subsequent development of diabetes mellitus and osteoporosis, respectively. Age ≥65 years at AIP diagnosis (hazard ratio [HR] = 3.73) and the development of malignancies (HR = 2.63), including PC (HR = 7.81), were associated with a poor prognosis, whereas maintenance steroid therapy was associated with a better prognosis (HR = 0.35) in the multivariate analysis. Maintenance steroid therapy was associated with a better prognosis even after propensity score matching for age and sex. CONCLUSIONS: Patients with AIP are at increased risk of developing malignancy, especially PC. PC is a critical prognostic factor for patients with AIP. Although maintenance steroid therapy negatively impacts diabetes mellitus and osteoporosis, it is associated with decreased cancer risk and improved overall survival.

Viscosity and Characteristics of Malignant Ascites.

BACKGROUND/AIM: Malignant ascites is a common condition in patients with terminal cancer. Treatments, such as diuretics, percutaneous drainage of ascites, and abdominal vein shunting have been advocated. However, these treatments have not achieved sufficient palliative effects. Therefore, the development of innovative therapies is mandated, especially for new therapies that require the creation of a fluid simulation of malignant ascites. However, there have been no previous studies on the physical properties of malignant ascites, including viscosity, which are necessary for the development of such a fluid. Therefore, we prospectively investigated the physical properties of malignant ascites. PATIENTS AND METHODS: This single-center, prospective, observational study included 30 patients between November 2021 and January 2023. The primary endpoint was the viscosity of the malignant ascites, and the secondary endpoints included other viscosity studies, biochemical tests, and the presence of malignant cells in the ascites. RESULTS: The median viscosity was 1.105 mPa*S. The viscosity of malignant ascites tended to decrease with increasing temperature, which is common for liquids. Malignant ascites fluid containing malignant cells tended to be more viscous than ascites fluid without malignant cells; furthermore, albumin levels tended to be higher in the former than in the latter. CONCLUSION: Malignant ascites' median viscosity was 1.105 mPa*S. Correlation between viscosity and temperature showed a decreasing trend. These findings contribute valuable insights for future malignant ascites management and device development.

The history of endoscopic ultrasound-guided fine-needle aspiration: development and progress.

Endoscopic ultrasonography (EUS) is an important diagnostic technique to accurately diagnose diseases originating from organs near the gastrointestinal tract. EUS-guided fine-needle aspiration (FNA) has improved the histopathological diagnosis. EUS-FNA has been further developed over a long period of 40 years. The history of the development of endosonographic scopes, ultrasonographic observation systems, puncture needles, and puncture methods will provide a springboard for future development.

Is preoperative pancreatic juice cytology useful for determining therapeutic strategies for patients with intraductal papillary mucinous neoplasm of the pancreas?

BACKGROUND: We compared the results of preoperative pancreatic juice cytology (PJC) and final pathological diagnosis after resection in patients who underwent resection of intraductal papillary mucinous neoplasm (IPMN) of the pancreas to determine whether preoperative PJC can help determine therapeutic strategies. METHODS: Of 1130 patients who underwent surgical resection IPMN at 11 Japanese tertiary institutions, the study included 852 patients who underwent preoperative PJC guided by endoscopic retrograde cholangiopancreatography (ERCP). RESULTS: The accuracy of preoperative PJC for differentiation between cancerous and noncancerous lesions were 55% for IPMN overall; 59% for the branch duct type; 49% for the main pancreatic duct type; 53% for the mixed type, respectively. On classifying IPMN according to the diameters of the mural nodule (MN) and main pancreatic duct (MPD), the corresponding values for diagnostic performance were 40% for type 1 (MN ≥5 mm and MPD ≥ 10 mm); 46% for type 2 (MN ≥5 mm and MPD < 10 mm); 61% for type 3 (MN < 5 mm and MPD ≥ 10 mm); 72% for type 4 (MN < 5 mm and MPD < 10 mm), respectively. CONCLUSIONS: PJC in IPMN is not a recommended examination because of its low overall sensitivity and no significant difference in diagnostic performance by type, location, or subclassification. Although the sensitivity is low, the positive predictive value is high, so we suggest that pancreatic juice cytology be performed only in cases where the patient is not sure about surgery.

Immune Checkpoint Inhibitor-induced Pancreatitis with Pancreatic Enlargement Mimicking Autoimmune Pancreatitis: A Case Report and Review of the Literature.

A 61-year-old woman was administered 35 cycles of pembrolizumab for the treatment of recurrent endometrial cancer, achieving a complete response. She presented with asymptomatic pancreatic enlargement and elevated hepatobiliary enzymes, but amylase and lipase levels were within the normal ranges. Intrapancreatic bile duct stenosis due to pancreatic enlargement was present, mimicking autoimmune pancreatitis on computed tomography performed before the onset of clinical manifestations. A histological examination of a biopsy specimen showed lymphocyte and plasma cell infiltration with dense fibrosis in the stroma. The patient was successfully treated with oral prednisolone. There were no manifestations of recurrent pancreatitis after tapering the prednisolone dose.

The Ki67 index evaluation of pancreatic neuroendocrine tumors using 3D immunohistochemistry in small tissue specimens.

BACKGROUND: /Objectives: This study aimed to evaluate the usefulness of three-dimensional (3D) immunohistochemistry for the Ki67 index of small tissue specimens of pancreatic neuroendocrine tumor (PanNET). METHODS: Clinicopathological materials from 17 patients with PanNET who underwent surgical resection at Jichi Medical University Hospital were analyzed. We compared the Ki67 index of endoscopic ultrasonography-fine-needle aspiration biopsy (EUS-FNAB) specimens, surgical specimens, and small tissue specimens hollowed from paraffin blocks of surgical specimens that were substituted for EUS-FNAB specimens ("sub-FNAB"). The sub-FNAB specimens were optically cleared using LUCID (IlLUmination of Cleared organs to IDentify target molecules) and analyzed using 3D immunohistochemistry. RESULTS: The median Ki67 index in FNAB, sub-FNAB, and surgical specimens with conventional immunohistochemistry were 1.2% (0.7-5.0), 2.0% (0.5-14.6), and 5.4% (1.0-19.4), respectively. The median Ki67 index in sub-FNAB specimens with tissue clearing was calculated separately using the total number of cells on multiple images ("multiple slice"), with the image of the fewest positive cells ("coldspot"), and with the image of most positive cells ("hotspot"), which were 2.7% (0.2-8.2), 0.8% (0-4.8), and 5.5% (2.3-12.4), respectively. PanNET grade evaluated for the hotspot of the surgical specimens was significantly more consistent with those of the hotspot than multiple images of sub-FNAB specimens (16/17 vs. 10/17, p = 0.015). Hotspot evaluation using 3D immunohistochemistry of the sub-FNAB specimens showed agreement with the assessment of the surgical specimens (Kappa coefficient: 0.82). CONCLUSIONS: Tissue clearing and 3D immunohistochemistry for the Ki67 index can potentially improve the preoperative evaluation of EUS-FNAB specimens of PanNET in routine clinical practice.

Cholangiocarcinoma Resembling IgG4-related Sclerosing Cholangitis.

A 66-year-old man diagnosed with immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) with diffuse intrahepatic bile duct stenosis and elevated serum IgG4 levels was referred for a further examination because of elevated serum carbohydrate antigen 19-9 levels despite treatment with corticosteroids. An umbilical nodule was found on a physical examination and a biopsy showed adenocarcinoma. Although several imaging studies revealed no changes from prior studies, bile cytology collected by endoscopic retrograde cholangiopancreatography showed adenocarcinoma. Consequently, the patient was diagnosed with cholangiocarcinoma resembling IgG4-SC after detecting an umbilical metastasis, also known as Sister Mary Joseph's nodule.

Steroid therapy has an acceptable role as the initial treatment in autoimmune pancreatitis patients with pancreatic cyst formation: Based on a Japanese nationwide study.

BACKGROUND: We attempted to determine the indications and limitations of steroid therapy as the first-line therapy in patients with autoimmune pancreatitis (AIP) with cyst formation (ACF). METHODS: This Japanese multicenter survey was conducted to examine the merits/demerits of steroid treatment as the initial therapy for ACF. RESULTS: Data of a total of 115 patients with ACF were analyzed. Complete remission was achieved in 86% (86/100) of patients who had received steroid treatment, but only 33.3% (5/15) of patients who had not received steroids. Relapse after the remission (n = 86) occurred in 7.6% (6/86) of patients who had received steroid therapy, but 40% (2/5) of patients who had not received steroid therapy. Multivariate analysis identified adoption of the wait and watch approach without steroid treatment (odds ratio = 0.126, P < .001) as a significant and independent negative predictor of remission of ACF. As for predictors of relapse, the presence of varix (odds ratio = 5.83, P = .036) was identified as an independent risk factor. CONCLUSION: Steroid therapy plays an important role as first-line therapy in AIP patients with pancreatic cyst formation, however, varix formation, besides the diameter of the cyst(s), is a risk factor for refractoriness to steroid therapy.

Fifth-generation new radio millimeter-wave radio signal transmission over a seamless fiber-terahertz mobile fronthaul system for an ultra-dense small cell network.

This Letter demonstrates the transmission of fifth-generation new radio (5G NR) millimeter-wave signals over a seamless fiber-terahertz-wave mobile fronthaul system in the 350 GHz band for an ultra-dense small cell network. The system utilizes a simple optical heterodyne method at the transmitter and direct detection at the receiver. As a proof-of-concept demonstration, we successfully transmitted 256- and 64-quadrature amplitude modulation 5G-NR-compliant signals at 24.2 and 38 GHz over a seamless fiber-terahertz system in the 350 GHz band. The proposed system can provide a simple solution to facilitate the deployment of ultra-dense small cells in high-frequency bands in 5G networks and beyond.

Efficacy of Contrast-Enhanced Endoscopic Ultrasonography for the Diagnosis of Pancreatic Tumors.

Endoscopic ultrasound can be useful for obtaining detailed diagnostic images for pancreatic disease. Contrast-enhanced harmonic endoscopic ultrasound has allowed to demonstrate not only microvasculature but also real perfusion imaging using second-generation contrast agents. Furthermore, endoscopic ultrasound fine-needle aspiration cytology and histology have become more ubiquitous; however, the risk of dissemination caused by paracentesis has yet to be resolved, and the application of less invasive contrast-enhanced endoscopic ultrasound for the differential diagnosis of pancreatic tumors has been anticipated. Contrast-enhanced harmonic endoscopic ultrasound can contribute to the differential diagnosis of pancreatic tumors.

Endoscopic ultrasound-guided pancreatic sampling for the histopathological diagnosis of autoimmune pancreatitis.

Autoimmune pancreatitis (AIP), which is characterized by pancreatic enlargement and irregular narrowing of the main pancreatic duct, is difficult to differentiate from malignancy. The irregular narrowing of the pancreatic duct, which can be detected via endoscopic retrograde cholangiopancreatography, is a characteristic feature of AIP; however, distinguishing between localized AIP and pancreatic cancer based on pancreatic duct imaging is difficult. This study overviews the efficacy of endoscopic ultrasound (EUS)-guided pancreatic sampling for the histopathological diagnosis of AIP. Recent enhancements in needle biopsy methodologies and technologies have contributed to improvement in the diagnostic efficacy of this technique. The guidance provided in this study for the histological diagnosis of AIP is anticipated to further advance in the histopathological diagnosis of AIP using EUS-guided pancreatic sampling.

Tissue harmonic versus contrast-enhanced harmonic endoscopic ultrasonography for the diagnosis of pancreatic tumors: Prospective multicenter study.

OBJECTIVES: This prospective multicenter study aimed to assess and compare the accuracy of tissue harmonic endoscopic ultrasonography (TH-EUS) and contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) for differentiating pancreatic carcinoma from other pancreatic tumors. METHODS: Consecutive patients with solid pancreatic tumors were prospectively enrolled between August 2013 and December 2014. To assess the accuracy of TH-EUS and CH-EUS, we compared four parameters of TH-EUS (fuzzy edge, irregular periphery, hypoechogenicity, and heterogeneous internal echogenicity) and four parameters of CH-EUS (hypoenhancement and heterogeneous enhancement in the early and late phases, respectively) to investigate which parameter of each method was most suitable to diagnose pancreatic carcinomas. Interobserver agreement and the diagnostic ability of pancreatic carcinoma using TH-EUS and CH-EUS were assessed and compared. RESULTS: A total of 204 patients were enrolled. For the diagnosis of pancreatic carcinoma, interobserver agreement by experts and nonexperts was 0.33-0.50 and 0.35-0.50 for TH-EUS, respectively, and 0.72-0.74 and 0.20-0.54 for CH-EUS, respectively. Irregular periphery was the most accurate diagnostic parameter among TH-EUS findings for differentiating pancreatic carcinomas, with sensitivity, specificity, and accuracy of 95.0%, 42.9%, and 78.9%, respectively. Late phase hypoenhancement was the most accurate diagnostic parameter among CH-EUS findings for differentiating pancreatic carcinomas, with sensitivity, specificity, and accuracy of 90.8%, 74.6%, and 85.8%, respectively. The accuracy of CH-EUS (late phase hypoenhancement) for diagnosis of pancreatic carcinoma was significantly higher than that of TH-EUS (irregular periphery) (p < 0.001). CONCLUSION: In comparison with TH-EUS, CH-EUS increased the diagnostic ability and reproducibility for the diagnosis of pancreatic carcinoma. UMIN (000011124).

Concordance of the histological diagnosis of type 1 autoimmune pancreatitis and its distinction from pancreatic ductal adenocarcinoma with endoscopic ultrasound-guided fine needle biopsy specimens: an interobserver agreement study.

The histological diagnosis of type 1 autoimmune pancreatitis (AIP) based on the findings obtained by an endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) is feasible, but the diagnostic consistency of this method has not been confirmed. We determined the interobserver agreement among 20 pathologists regarding the diagnosis of type 1 AIP, including the distinction from pancreatic ductal adenocarcinoma (PDAC) using large tissue samples obtained by EUS-FNB. After guidance for diagnosing AIP with biopsy tissues was provided, a round 2 was performed. The median sensitivity and specificity for diagnosing PDAC vs. non-neoplastic diseases were 95.2% and 100%, respectively. In groups of specialists (n = 7) and the generalists (n = 13), Fleiss' к-values increased from 0.886 to 0.958 and from 0.750 to 0.816 in round 2. The concordance was fair or moderate for obliterative phlebitis and storiform fibrosis but slight for ductal lesion of type 1 AIP. Discordant results were due to ambiguous findings and biopsy tissue limitations. Among the specialists, the ratio of cases with perfect agreement regarding the presence of storiform fibrosis increased in round 2, but agreement regarding obliterative phlebitis or ductal lesions was not improved. Although the histological definite diagnosis of type 1 AIP was achieved by most observers in > 60% of the cases, the confidence levels varied. Because some ambiguities exist, the histological diagnostic levels based on the diagnostic criteria of type 1 AIP should not be taken for granted. Guidance is effective for improving accurate PDAC diagnoses (notably by recognizing acinar-ductal metaplasia) and for evaluating storiform fibrosis.

Endoscopic ultrasound-guided tissue acquisition for the histopathological diagnosis of autoimmune pancreatitis.

Autoimmune pancreatitis (AIP) is a disease concept that originated in Japan. It is characterized by diffuse pancreatic enlargement and irregular narrowing of the main pancreatic duct. Although the usefulness of the histological diagnosis of AIP using endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) and EUS-guided fine-needle biopsy (FNB) has been reported, enhanced diagnostic performance is expected with improvements in tissue collection methods and fine-needle techniques. Guidance for establishing the tissue diagnosis of AIP has been developed and is useful for histological evaluation. Histopathological diagnosis by EUS-FNA/FNB is expected to play a central role in AIP diagnosis in the future.

Millimeter-wave radio-over-fiber system using optical phase modulation and photonic downconversion for uplink fronthaul transmission.

This Letter proposes a high-performance radio-over-fiber (RoF) system for high-speed and high-fidelity analog waveform transmission of radio signals in the millimeter-wave band in the uplink direction. At the antenna site, the system utilizes a newly fabricated low half-wave voltage broadband phase modulator to convert a millimeter-wave radio signal into an optical signal. At the receiver, by using photonic downconversion and optical filtering technology, a simple direct detection and downconversion of the signal to the microwave band can be achieved simultaneously. As a demonstration of proof of concept, we successfully transmitted a 1024-quadrature amplitude modulation (QAM) narrowband orthogonal frequency-division multiplexing signal at 38 GHz and a 60 Gb/s 64-QAM single-carrier signal at 26.5 GHz over a 20 km RoF system. The system is promising for facilitating the deployment of ultra-dense small cells in high-frequency bands in 5G and beyond networks.

Pancreatic Ductal Adenocarcinoma: Epidemiology and Risk Factors.

The number of new cases of pancreatic ductal adenocarcinoma is increasing with a cumulative total of 495,773 cases worldwide, making it the fourteenth most common malignancy. However, it accounts for 466,003 deaths per year and is the seventh leading cause of cancer deaths. Regional differences in the number of patients with pancreatic ductal adenocarcinoma appear to reflect differences in medical care, as well as racial differences. Compared to the prevalence of other organ cancers in Japan, pancreatic ductal adenocarcinoma ranks seventh based on the number of patients, eighth based on morbidity, and fourth based on the number of deaths, with a continuing increase in the mortality rate. Risk factors for developing pancreatic ductal adenocarcinoma include family history, genetic disorders, diabetes, chronic pancreatitis, and intraductal papillary mucinous neoplasms. An issue that hinders improvement in the prognosis of patients with pancreatic ductal adenocarcinoma is the development of a strategy to identify patients with these risk factors to facilitate detection of the disease at a stage when intervention will improve survival.

High-fidelity indoor MIMO radio access for 5G and beyond based on legacy multimode fiber and real-time analog-to-digital-compression.

Dedicated indoor radio access network (RAN, such as C-RAN with fronthaul) will be in urgent demand for 5G and beyond ((B)5G), as it becomes more difficult for outdoor base stations to serve indoor mobile/IoT terminals due to the loss issue induced by higher carrier frequency. One cost-effective and time-saving strategy for indoor (B)5G RAN is to reuse the legacy multimode fibers (MMF) deployed in buildings and premises worldwide. In this work, we introduce the concept of indoor (B)5G fronthaul over legacy MMF based on analog-to-digital-compression (ADX), termed as ADX-RoMMF. Enabled by ADX for MIMO data compression, both high radio signal fidelity and fronthaul bandwidth efficiency can be achieved, which alleviates the limitation of low MMF bandwidth-distance product and supports decent indoor coverage. Meanwhile, its digital nature is highly compatible with low-cost optical transceivers (with nonlinearity and/or imperfection) and packet-based fronthaul networking such as time-sensitive networking. Furthermore, the ultralow latency of ADX processing meets the requirement of low-delay (B)5G fronthauling. We experimentally demonstrate an ADX-RoMMF link serving 16-channel MIMO signals with NR-class bandwidth and 1024QAM, leveraging a real-time ADX prototyped on a single-chip field-programmable radio platform. Results show that this 32Gb/s CPRI-equivalent rate can be transported over MMF distance of 850m within 1024QAM EVM requirement, which is 4-fold larger than that of conventional fronthaul compression scheme. Moreover, 500ns ADX latency overhead is also verified.

Intracholecystic papillary neoplasm arising in the cystic duct and extending into common bile duct: a case report.

An 83-year-old man without specific symptoms was referred to our hospital for further evaluation and treatment of apparent double primary tumors of the cystic duct and common bile duct. Computed tomography showed contrast-enhanced solid tumors in the cystic duct and common bile duct. Magnetic resonance imaging showed that the bile duct tumor was isointense on T1-weighted images and had low intensity on T2-weighted images. In addition, the bile duct tumor showed high intensity on diffusion-weighted images. Endoscopic ultrasonography revealed the tumor of the common bile duct and endoscopic retrograde cholangiopancreatography demonstrated a filling defect in the bile duct. The cystic duct was not identified on endoscopic ultrasonography or endoscopic retrograde cholangiopancreatography. Transpapillary biopsy of the bile duct tumor showed adenocarcinoma. The patient was diagnosed with double primary tumors of the cystic duct and the common bile duct and underwent subtotal stomach-preserving pancreaticoduodenectomy. Microscopic examination with molecular profiling of the tumors revealed a high-grade noninvasive intracholecystic papillary neoplasm of the cystic duct extending into the common bile duct and forming a tubulopapillary neoplasm with invasion of the common bile duct.