Endoscopic Papillectomy for Ampullary Gangliocytic Paraganglioma: A Case Series and Literature Review.

Background Gangliocytic paraganglioma (GP) significantly affects patients' quality of life. However, studies on endoscopic papillectomy (EP) for ampullary GP are limited. We therefore evaluated the safety and efficacy of EP for treating ampullary GP. Methods We retrospectively reviewed the clinicopathological characteristics of patients with GP who underwent EP at Nagoya University Hospital and conducted a literature survey. Results We enrolled six patients with a median tumor diameter of 17 mm. Complications related to EP were observed in three patients: two experienced bleeding, one had mild acute pancreatitis, and one had perforation (duplicate patients included), all of whom improved conservatively. Five resected specimens were confined to the submucosal layer, and one was beyond the submucosal layer. All patients were monitored without surgery, and no disease recurrence was observed after a median follow-up of 73 months. A literature review identified 14 patients, and additional surgery due to a positive vertical margin after EP revealed lymph node metastasis in 2 patients. There was no disease recurrence or death. Conclusion EP led to good long-term outcomes and effectively treated ampullary GP. Considering the potential for lymph node metastasis, additional surgery is recommended if the tumor exceeds the submucosal layer.

An atypical case of isolated immunoglobulin G4-related sclerosing cholangitis with a cholangiogram resembling primary sclerosing cholangitis.

An asymptomatic 77-year-old man with intrahepatic bile duct dilation was referred to our hospital. Cholangiography revealed alternations between strictures and dilated segments from the right and left hepatic ducts to the lower bile ducts, with findings of a pruned tree, beaded, shaggy appearance, and diverticulum-like outpouching. Histopathology revealed abundant immunoglobulin G4 (IgG4)-positive plasma cells (> 10 per high-power field) with an IgG4/IgG-positive cell ratio of 40-50%. After 2 weeks of steroid therapy, the cholangiography markedly improved. Because the cholangiographic findings resembled those of primary sclerosing cholangitis, steroid therapy proved useful in differentiating IgG4-related sclerosing cholangitis from primary sclerosing cholangitis.

Outcomes of endoscopic papillectomy of ampullary carcinoma and factors affecting additional surgery.

BACKGROUND/PURPOSE: Data on the prognosis of endoscopic papillectomy (EP) for ampullary carcinoma (AC) is limited; therefore, we aimed to identify the factors associated with endoscopically controlled AC. METHODS: Between January 2003 and October 2022, 75 patients underwent EP for ampullary tumors and were diagnosed with AC based on the pathological features of the resected tissue. The factors associated with additional surgery after EP were also evaluated. RESULTS: A total of 67 patients had ACs ranging from carcinoma in situ to tumors limited to the mucosa (M group), and eight patients had ACs ranging from those limited to the sphincter of Oddi to those invading the duodenal muscularis propria (OD group). The 3-year endoscopic tumor control (condition not requiring additional surgery) rates in the M and OD groups were 90.8% and 84.6% (p = .033), respectively. In the M group, the presence of tumor components in the resection margins was the only significant factor associated with additional surgeries (p = .010) in the univariate analysis. The 3-year endoscopic tumor control rates were 100% for negative and uncertain resection margins and 76.6% for positive margins (p = .009). CONCLUSIONS: If the AC is confined to the mucosa and the resection margins are negative or uncertain, the tumor can be well-controlled endoscopically.

The role of EUS elastography-guided fine needle biopsy in the histological diagnosis of solid pancreatic lesions: a prospective exploratory study.

This study aimed to evaluate the feasibility and efficacy of Endoscopic ultrasound elastography-guided fine needle biopsy (EUS-EG-FNB) for the diagnosis of pancreatic mass lesions. EUS-EG images were classified into heterogeneous and homogeneous groups. For the heterogeneous group, EUS-FNB was separately performed in both hard areas and soft areas. Only samples obtained during the first two passes (hard/soft areas) were used to compare the diagnostic accuracy as well as the quality and quantity of the specimens. We investigated the association of EUS-EG findings using strain histogram analysis with the histological findings. Fifty-five patients were enrolled including 25 patients with heterogeneous group. The homogeneous group had significantly lower mean strain value (hard) lesions. The adequate sampling rates from hard and soft areas were 88 and 92%, respectively (P = 0.6374). Comparison of the diagnostic accuracy and the quality and quantity of the histological core between hard and soft areas showed no significant differences. In pancreatic adenocarcinoma cases, the proportion of fibrous stroma in the core tissue was significantly correlated with the elasticity of the region. (R2 = 0.1226: P = 0.0022) EUS-EG may reflect tissue composition in pancreatic tumors, however, EUS-EG did not affect either the quality and quantity of the tissues obtained.Clinical Trial Registry No: UMIN-000033073.

The impact of the age-adjusted Charlson comorbidity index as a prognostic factor for endoscopic papillectomy in ampullary tumors.

BACKGROUND: The prognostic nutritional index (PNI) and Charlson comorbidity index (CCI) have been useful for predicting the prognosis based on nutritional condition and comorbidities in surgery and endoscopic mucosal dissection. The age-adjusted CCI (ACCI) has also been reported to be useful in surgery, but it has not been applied to endoscopic treatment. We therefore clarified the prognostic factors associated with ampullary tumors treated with endoscopic papillectomy (EP). METHODS: From January 2003 to December 2020, 236 patients who underwent EP for sporadic ampullary tumors at Nagoya University Hospital were included in this study. The 5-year survival and ability to predict the prognosis were evaluated in terms of the sex, PNI, ACCI, final pathological diagnosis, and intraductal extension. RESULTS: During a median follow-up period of 1558 days, 17 patients died. No patient died of the primary disease. The 5-year survival rate was 91.1%. In a univariate analysis, only a high ACCI (≥ 5) was extracted as a significant prognostic factor (Odds ratio, 12.2; 95% confidence interval, 3.81-39.3; p < 0.001). The 5-year survival rates for a low ACCI (≤ 4) and high ACCI were 96.6% and 73.5%, respectively (p < 0.001). CONCLUSIONS: A high ACCI is an important prognostic factor associated with the 5-year survival and a risk of death from other illness. Ampullary tumors suitable for EP are less likely to be a prognostic factor, and treatment-free follow-up may be acceptable in patients with a high ACCI.

Usefulness of Macroscopic On-Site Evaluation Using a Stereomicroscope during EUS-FNB for Diagnosing Solid Pancreatic Lesions.

METHODS: We reviewed a total of 60 consecutive patients who underwent both S-MOSE and rapid on-site cytopathological evaluation (ROSE) during EUS-FNB between July 2019 and October 2020, and the usefulness of S-MOSE in comparison with histology was evaluated. A 22-gauge Franseen needle was used to perform EUS-FNB in all patients, and only the specimens obtained by the first pass were evaluated. The final diagnosis was based on the surgical specimen or the clinical course consistent with the EUS-FNB results. RESULTS: The final diagnoses of the 60 patients included 45 patients with pancreatic ductal adenocarcinoma, 6 with autoimmune pancreatitis, 4 with mass-forming pancreatitis, 1 with pancreatic metastasis, 2 with pancreatic neuroendocrine tumor, and 2 with intraductal papillary mucinous carcinoma. The histological diagnostic accuracy of the first pass of EUS-FNB was 83.3% (50/60). The agreement between the S-MOSE and the histological diagnosis was 90% (54/60). The positive predictive value of S-MOSE for histological diagnosis was 90.7%, which can be an indicator of when to stop the EUS-FNB procedure. There were no immediate or delayed adverse events reported after the FNB based on the chart and medical visit history review. CONCLUSION: In the EUS-FNB of SPLs, S-MOSE can be an alternative to ROSE for specimen evaluation and has the potential to shorten the procedure time.

Fish bone migration after pancreaticoduodenectomy: Incidence and treatment options.

OBJECTIVE: Migration of a fish bone to the bile duct or pancreatic duct is a possible complication after pancreaticoduodenectomy (PD). The aim of this study was to clarify the incidence and indications for intervention in such cases. METHODS: We reviewed the cases with fish bone migration after PD detected on computed tomography (CT) scan between October 2000 and October 2020 were reviewed and the incidence of fish bone migration, presence of symptoms and signs, therapeutic modalities and patient outcomes were analyzed. RESULTS: Among the 1475 PD procedures performed at our institution during the study period, 14 cases of fish bone migration were noted on CT, the incidence of which was 0.95% (14/1475). The time duration from surgery to the detection of fish bone ranged from 88 to 5902 days (median 917 d). Ten patients remained asymptomatic without therapeutic intervention for up to 2919 days (median 509 d). Four patients were treated by endoscopy, either at the patient's request (n = 1) or because of their symptoms (n = 3), and removal was successful in three cases but failed in one case in which the fish bone migrated to the right intrahepatic bile duct. No surgical treatment was required in any case. CONCLUSIONS: The incidence of fish bone migration on CT after PD was about 1%. Some cases resolved spontaneously, and most of the asymptomatic cases required no intervention. For symptomatic cases, endoscopic treatment should be considered first. It is important to confirm the location of the fish bone by CT and determine whether it can be removed.

Fecal incontinence and oral regurgitation during duodenal endoscopic submucosal dissection using the water pressure method.

OBJECTIVES: Endoscopic submucosal dissection (ESD) in the duodenum is challenging. The water pressure method (WP-ESD) has been developed with a decreased rate of perforation. However, details of perioperative adverse events of WP-ESD are unknown. The purpose of this study was to clarify the frequency and related factors of fecal incontinence and oral regurgitation during WP-ESD. METHODS: A chart-based retrospective analysis was performed on 43 patients who underwent duodenal WP-ESD. The saline volume given into the body was calculated in all cases. All adverse events during WP-ESD until 6 weeks were extracted, and factors related to intraoperative fecal incontinence or oral regurgitation were analyzed. The frequency of fecal incontinence and oral regurgitation was also compared to those of 83 conventional ESD cases. RESULTS: In WP-ESD, intraoperative fecal incontinence occurred in 12 (28%), oral regurgitation in six (14%), and aspiration pneumonia in one patient. For fecal incontinence, the infusion speed (saline volume divided by resection time) around 17 mL/min was a significant factor in multivariable analysis. For oral regurgitation, only tumor size was a significant factor in univariate analysis (P = 0.027). Significant difference was observed in the frequency of fecal incontinence between WP-ESD and conventional ESD (28% vs. 0%, P < 0.001), but no difference was observed in oral regurgitation or aspiration pneumonia. CONCLUSIONS: Intraoperative fecal incontinence is a unique adverse event of WP-ESD related to the infusion speed. WP-ESD did not pose a risk for oral regurgitation, but we should be aware of the risk in large tumor cases.

Comparison of insulin degludec (IDeg)/insulin Aspart (IAsp) co-formulation therapy twice-daily with free combination of GLP-1 receptor agonist liraglutide plus insulin degludec in Tochigi: IDEAL Trial.

AIM: We compared the efficacy and safety of insulin degludec/insulin aspart co-formulation (IDegAsp) twice-daily to a free combination of basal insulin degludec and GLP-1 receptor agonist liraglutide (IDeg + Lira) once-daily for patients with inadequately controlled type 2 diabetes on insulin therapy and oral antidiabetic drugs. SUBJECTS AND METHODS: Eligible patients were randomly allocated at a 1:1 ratio to receive either the once-daily dual injection of IDeg + Lira (n = 24) or twice-daily single injection of IDegAsp (n = 28). The primary endpoints were as follows: HbA1c changes over 52 weeks of treatment and the percentage of participants achieving HbA1c < 7.0% at week 52. RESULTS: After 52 weeks, HbA1c decreased by 0.3% in the IDegAsp group and by 0.7% in the IDeg + Lira group. The HbA1c reduction was greater in the IDeg + Lira group than in the IDegAsp group. 19% of patients on IDegAsp versus 40% on IDeg + Lira achieved HbA1c < 7.0%. Pre-breakfast and pre-dinner blood glucose at 52 weeks were significantly lower in the IDeg + Lira group than in the IDegAsp group. The reduction in body mass index (BMI) was greater in the IDeg + Lira group than in the IDegAsp group throughout the study period. The confirmed hypoglycaemia rates were 1.32 and 0.69 per patient/year of exposure to IDegAsp and IDeg + Lira, respectively. CONCLUSIONS: In patients with inadequately controlled type 2 diabetes on insulin therapy and oral antidiabetic drugs, treatment with the once-daily dual injection of IDeg + Lira compared with the twice-daily single injection of IDegAsp showed no significant difference in glycaemic control but statistically superior weight loss.

Effect of insulin degludec versus insulin glargine on glycemic control and daily fasting blood glucose variability in insulin-naïve Japanese patients with type 2 diabetes: I'D GOT trial.

AIMS: Insulin degludec (IDeg) is an ultra-long-acting insulin that has a smooth time/action profile over more than 42h. The present study compared the effects of IDeg and insulin glargine (IGlar) on HbA1c reduction and on within-subject day-to-day variability of fasting blood glucose (FBG) in insulin-naïve patients with type 2 diabetes. SUBJECTS AND METHODS: Eligible patients were randomly allocated at a 3:1 ratio to receive once-daily IDeg (n=31) or IGlar (n=12). Both basal insulins were administered before breakfast and titrated to achieve a target FBG <110mg/dl. The primary endpoints were the change in HbA1c from baseline to 24weeks of treatment, as well as the standard deviation (SD) and coefficient of variation (CV) of FBG from 8 to 12weeks and from 20 to 24weeks. Secondary endpoints included the QOL evaluated by the Diabetes Therapy-Related QOL questionnaire. RESULTS: After 24weeks, HbA1c was decreased by 1.6% in the IDeg group and 1.7% in the IGlar at the same insulin dosage. At 24weeks, FBG was significantly lower in the IDeg group than in the IGlar group and the CV of FBG was significantly smaller in the IDeg group. The frequency of total and severe hypoglycemic episodes did not differ between the groups. In the IDeg group, QOL showed significant improvement regarding anxiety and dissatisfaction with treatment. CONCLUSIONS: Treatment with IDeg or IGlar achieved similar improvement in glycemic control in insulin-naïve patients with type 2 diabetes. The day-to-day variation of FBG was smaller in patients receiving IDeg.

Application of dose kernel calculation using a simplified Monte Carlo method to treatment plan for scanned proton beams.

Full Monte Carlo (FMC) calculation of dose distribution has been recognized to have superior accuracy, compared with the pencil beam algorithm (PBA). However, since the FMC methods require long calculation time, it is difficult to apply them to routine treatment planning at present. In order to improve the situation, a simplified Monte Carlo (SMC) method has been introduced to the dose kernel calculation applicable to dose optimization procedure for the proton pencil beam scanning. We have evaluated accuracy of the SMC calculation by comparing a result of the dose kernel calculation using the SMC method with that using the FMC method in an inhomogeneous phantom. The dose distribution obtained by the SMC method was in good agreement with that obtained by the FMC method. To assess the usefulness of SMC calculation in clinical situations, we have compared results of the dose calculation using the SMC with those using the PBA method for three clinical cases of tumor treatment. The dose distributions calculated with the PBA dose kernels appear to be homogeneous in the planning target volumes (PTVs). In practice, the dose distributions calculated with the SMC dose kernels with the spot weights optimized with the PBA method show largely inhomogeneous dose distributions in the PTVs, while those with the spot weights optimized with the SMC method have moderately homogeneous distributions in the PTVs. Calculation using the SMC method is faster than that using the GEANT4 by three orders of magnitude. In addition, the graphic processing unit (GPU) boosts the calculation speed by 13 times for the treatment planning using the SMC method. Thence, the SMC method will be applicable to routine clinical treatment planning for reproduction of the complex dose distribution more accurately than the PBA method in a reasonably short time by use of the GPU-based calculation engine.

Evaluation of monitor unit calculation based on measurement and calculation with a simplified Monte Carlo method for passive beam delivery system in proton beam therapy.

Calibrating the dose per monitor unit (DMU) for individual patients is important to deliver the prescribed dose in radiation therapy. We have developed a DMU calculation method combining measurement data and calculation with a simplified Monte Carlo method for the double scattering system in proton beam therapy at the National Cancer Center Hospital East in Japan. The DMU calculation method determines the clinical DMU by the multiplication of three factors: a beam spreading device factor FBSD, a patient-specific device factor FPSD, and a field-size correction factor FFS(A). We compared the calculated and the measured DMU for 75 dose fields in clinical cases. The calculated DMUs were in agreement with measurements in ± 1.5% for all of 25 fields in prostate cancer cases, and in ± 3% for 94% of 50 fields in head and neck (H&N) and lung cancer cases, including irregular shape fields and small fields. Although the FBSD in the DMU calculations is dominant as expected, we found that the patient-specific device factor and field-size correction also contribute significantly to the calculated DMU. This DMU calculation method will be able to substitute the conventional DMU measurement for the majority of clinical cases with a reasonable calculation time required for clinical use.

Modification of physical properties of poly(L-lactic acid) by addition of methyl-ß-cyclodextrin.

Poly(L-lactic acid) (PLLA) is a biodegradable plastic and one of the most famous plastics made from biobased materials. However, its physical strength is insufficient compared to general-purpose plastics. In this study, the effect of methylcyclodextrin (MeCD) addition on the structure and physical properties, especially the drawing behavior, of PLLA was investigated. Through thermal analysis, it was found that MeCD addition lowers the crystallinity and enhances the mobility of PLLA. The sample containing approximately 17% MeCD was drawn to more than 1000% at 60 °C, although PLLA fractured at a strain of less than 100%. Differential scanning calorimetry (DSC)-Raman in situ measurements also revealed decreases in the glass transition temperature (T g), cold crystallization temperature (T c), and melting point (T m), and improvement in structural distribution with temperature. DSC-Raman measurements simultaneously supplied information about crystallinity and thermal properties. Thus, it was concluded that MeCD had high affinity for PLLA, and the addition of MeCD increased the amorphous component of PLLA and enhanced the drawability.

Experimental verification of dose calculation using the simplified Monte Carlo method with an improved initial beam model for a beam-wobbling system.

A beam delivery system using a single-radius-beam-wobbling method has been used to form a conformal irradiation field for proton radiotherapy in Japan. A proton beam broadened by the beam-wobbling system provides a non-Gaussian distribution of projection angle different in two mutually orthogonal planes with a common beam central axis, at a certain position. However, the conventional initial beam model for dose calculations has been using an approximation of symmetric Gaussian angular distribution with the same variance in both planes (called here a Gaussian model with symmetric variance (GMSV)), instead of the accurate one. We have developed a more accurate initial beam model defined as a non-Gaussian model with asymmetric variance (NonGMAV), and applied it to dose calculations using the simplified Monte Carlo (SMC) method. The initial beam model takes into account the different distances of two beam-wobbling magnets from the iso-center and also the different amplitudes of kick angle given by each magnet. We have confirmed that the calculation using the SMC with NonGMAV reproduced the measured dose distribution formed in air by a mono-energetic proton beam passing through a square aperture collimator better than with the GMSV and with a Gaussian model with asymmetric variance (GMAV) in which different variances of angular distributions are used in the two mutually orthogonal planes. Measured dose distributions in a homogeneous phantom formed by a modulated proton beam passing through a range shifter and an L-shaped range compensator, were consistent with calculations using the SMC with GMAV and NonGMAV, but in disagreement with calculations using the SMC with GMSV. Measured lateral penumbrae in a lateral direction were reproduced better by calculations using the SMC with NonGMAV than by those with GMAV, when an aperture collimator with a smaller opening was used. We found that such a difference can be attributed to the non-Gaussian angular distribution of the initial beam at a lateral position for the beam-wobbling system. Calculations using the SMC with NonGMAV are effective to reproduce dose distributions formed by a beam-wobbling system more accurately than that with GMSV or that with GMAV.

Improvement of spread-out Bragg peak flatness for a carbon-ion beam by the use of a ridge filter with a ripple filter.

We have developed a novel design method of ridge filters for carbon-ion therapy using a broad-beam delivery system to improve the flatness of a biologically effective dose in the spread-out Bragg peak (SOBP). So far, the flatness of the SOBP is limited to about ±5% for carbon beams since the weight control of component Bragg curves composing the SOBP is difficult. This difficulty arises from using a large number of ridge-bar steps (e.g. about 100 for a SOBP width of 60 mm) required to form the SOBP for the pristine Bragg curve with an extremely sharp distal falloff. Instead of using a single ridge filter, we introduce a ripple filter to broaden the Bragg peak so that the number of ridge-bar steps can be reduced to about 30 for SOBP with of 60 mm for the ridge filter designed for the broadened Bragg peak. Thus we can manufacture the ridge filter more accurately and then attain a better flatness of the SOBP due to well-controlled weights of the component Bragg curves. We placed the ripple filter on the same frame of the ridge filter and arranged the direction of the ripple-filter-bar array perpendicular to that of the ridge-filter-bar array. We applied this method to a 290 MeV u(-1) carbon-ion beam in Heavy Ion Medical Accelerator in Chiba and verified the effectiveness by measurements.

Improved dose-calculation accuracy in proton treatment planning using a simplified Monte Carlo method verified with three-dimensional measurements in an anthropomorphic phantom.

Treatment planning for proton tumor therapy requires a fast and accurate dose-calculation method. We have implemented a simplified Monte Carlo (SMC) method in the treatment planning system of the National Cancer Center Hospital East for the double-scattering beam delivery scheme. The SMC method takes into account the scattering effect in materials more accurately than the pencil beam algorithm by tracking individual proton paths. We confirmed that the SMC method reproduced measured dose distributions in a heterogeneous slab phantom better than the pencil beam method. When applied to a complex anthropomorphic phantom, the SMC method reproduced the measured dose distribution well, satisfying an accuracy tolerance of 3 mm and 3% in the gamma index analysis. The SMC method required approximately 30 min to complete the calculation over a target volume of 500 cc, much less than the time required for the full Monte Carlo calculation. The SMC method is a candidate for a practical calculation technique with sufficient accuracy for clinical application.

The basic study of a bi-material range compensator for improving dose uniformity for proton therapy.

A range compensator (abbreviated as a RC hereafter) is used to form a conformal dose distribution for heavy-charged-particle therapy. However, it induces distortion of the dose distribution. The induced inhomogeneity may result in a calibration error of a monitor unit (MU) assigned to a transmission ionization chamber. By using a bi-material RC made from a low-Z material and a high-Z material instead of the regular RC, the dose inhomogeneity has been obviously reduced by equalizing the lateral dose distributions formed by pencil beams traversing elements of the RC with different base thicknesses at the same water-equivalent depth. We designed and manufactured a 4 x 4 matrix-shaped single-material RC and a bi-material RC with the same range losses at corresponding elements of the RCs. The bi-material RC is made from chemical wood (the main chemical component is an ABS resin) as a low-Z material and from brass as a high-Z material. Sixteen segments of the RC are designed so that the range-loss differences of the adjacent segments of the RC range from 0 to 50 mm in steps of 5 mm. We measured dose distributions in water formed by a 160 MeV proton beam traversing the single-material RC or the bi-material RC, using the HIMAC biology beam port. Large dips and bumps were observed in the dose distribution formed by the use of the single-material RC; the dose uniformity has been significantly improved in the target region by the use of the bi-material RC. The improvement has been obtained at the expense of blurring lateral penumbra. For clinical application of this method to a patient with large density inhomogeneity, a simple modification method of the original calculation model has been given.

Analytical design method of optimum ridge filters for wobbled and collimated proton beams.

A novel design method of ridge filters (RFs) has been developed for general proton beam lines which use a single-radius beam wobbling method. It can be applied to beam lines that transport both protons and carbon ions which are about three times longer than regular beam lines dedicated to protons. We designed an RF with an SOBP (spread-out Bragg peak) width of 60 mm in water for the 160-MeV proton beam of the HIMAC (Heavy Ion Medical Accelerator in Chiba) biology beam line using an existing model of the RF. Yet we observed a slope in the SOBP region when we used the RF. To elucidate the source of the slope, we have developed a new calculation model taking into account the geometry of the RF and a beam-limiting device. The source for the slope was found to be the large scattering effect of protons in the RF and beam restriction by a ring collimator (aperture diameter: 160 mm) placed just before the RF. When both fluence reduction by the scattering effect of protons in the RF and the beam-collimation effect are taken into account, proper RFs can be designed universally for a given beam line arrangement using the single-radius beam-wobbling method from the start without any trial-and-error process. This will serve to reduce the commissioning time of newly designed beam delivery systems.

Waveform simulation based on 3D dose distribution for acoustic wave generated by proton beam irradiation.

A pulsed proton beam is capable of generating an acoustic wave when it is absorbed by a medium. This phenomenon suggests that the acoustic waveform produced may well include information on the three-dimensional (3D) dose distribution of the proton beam. We simulated acoustic waveforms by using a transmission model based on the Green function and the 3D dose distribution. There was reasonable agreement between the calculated and measured results. The results obtained confirm that the acoustic waveform includes information on the dose distribution.