Endovascular treatment for a ruptured lumbar artery aneurysm in a patient with neurofibromatosis type 1.

The present medical case report describes successful endovascular treatment via stent graft and coil packing for a ruptured lumbar artery aneurysm in a 55-year-old woman with neurofibromatosis type 1. Although less common, vasculopathy, such as an aneurysm, stenosis, rupture, and arteriovenous fistula, have been reported and can be a cause of death for patients with this disorder. However, only a few cases of a ruptured lumbar aneurysm have been reported.

Open surgical repair of a giant common hepatic artery pseudoaneurysm that perforated into the duodenum and common bile duct.

This is a case of 60-year-old male patient with a history of heavy alcohol consumption and liver dysfunction who presented with a giant hepatic aneurysm. The incidence of giant hepatic aneurysms exceeding 10 cm in diameter is rare, particularly in the context of pseudoaneurysms. Furthermore, simultaneous perforation into the bile duct and duodenum is highly unusual. This case report elucidates the successful surgical management of a large pseudoaneurysm of the common hepatic artery that concurrently perforated the bile duct and duodenum, without any complications or deterioration of liver function.

The renoprotective effect of once-weekly GLP-1 receptor agonist dulaglutide on progression of nephropathy in Japanese patients with type 2 diabetes and moderate to severe chronic kidney disease (JDDM67).

AIMS/INTRODUCTION: Few studies have investigated the renoprotective effect of glucagon-like peptide-1 (GLP-1) receptor in patients with chronic kidney disease (CKD). This study evaluated the effect of dulaglutide 0.75 mg on renal function in Japanese patients with type 2 diabetes and CKD stage 3 to 4. MATERIALS AND METHODS: Dulaglutide (group A) and non-dulaglutide (group B) were compared using data collected from a computerized diabetes care database. For group B, propensity score weighting based on propensity scores was performed. Evaluation items were a change from baseline in hemoglobin A1c (HbA1c), body weight, urine albumin-to-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR), for 3 years. RESULTS: In total, the data obtained from 255 patients (125 and 130 patients for group A and B, respectively) were analyzed. Propensity score-adjusted patient background characteristics (group A vs B) were age 70.8 vs 69.4 years, body weight 70.2 vs 72.9 kg, body mass index 27.3 vs 28.1 kg/m2 , HbA1c 8.4 vs 8.5%, eGFR 47.9 vs 47.7 mL/min/1.73 m2 , and UACR 218 vs 251 mg/gCr. Although there were no statistically significant differences in the change from baseline between groups A and B at most time points in eGFR, a statistically significant eGFR decline in group B was observed in slope analysis for 3 years. This renoprotective effect was marked in patients with macro-albuminuria and/or concomitant SGLT2 inhibitor use. CONCLUSIONS: Dulaglutide slowed the eGFR decline in patients with type 2 diabetes and CKD stage 3 to 4.

Prospective clinical study for claudication after endovascular aneurysm repair involving hypogastric artery embolization.

PURPOSE: This prospective study aimed to assess the prognosis of claudication after endovascular aneurysm repair (EVAR) involving hypogastric artery (HGA) embolization. METHODS: Patients who were scheduled to undergo EVAR involving bilateral or unilateral HGA embolization (BHE or UHE, respectively) between May 2017 and January 2019 were included in this study. Patients underwent the walk test preoperatively, one week postoperatively, and monthly thereafter for six months. The presence of claudication and the maximum walking distance (MWD) were recorded. A near-infrared spectroscopy monitor was placed on the buttocks, and the recovery time (RT) was determined. A walking impairment questionnaire (WIQ) was completed to determine subjective symptoms. RESULTS: Of the 13 patients who completed the protocol, 12 experienced claudication in the 6-min walk test. The MWD was significantly lower at one week postoperatively than preoperatively. The claudication prevalence was significantly higher at five and six months postoperatively after BHE than after UHE. BHE was associated with longer RTs and lower WIQ scores than UHE. CONCLUSIONS: We noted a trend in adverse effects on the gluteal circulation and subjective symptoms ameliorating within six months postoperatively, with more effects being associated with BHE than with UHE. These findings should be used to make decisions concerning management strategies for HGA reconstruction.

[Pharmacological and clinical profile of Onasemnogene Aveparvovec, the first gene therapy for spinal muscular atrophy (SMA)].

Onasemnogene abeparvovec (Zolgensma®; formerly AVXS-101) is a one-time gene therapy designed to address the genetic root cause of spinal muscular atrophy (SMA) by replacing the function of the missing or nonworking SMN1 gene via an adeno-associated AAV9 viral vector. On March 19, 2020, the Japanese Ministry of Health, Labor and Welfare approved onasemnogene abeparvovec for the treatment of SMA patients <2 years of age, including presymptomatic patients with a genetic diagnosis. Patients must be negative for elevated anti-AAV9 antibodies. Onasemnogene abeparvovec is administered through a single intravenous infusion, delivering a new working copy of the SMN gene into a patient's cells. Intravenous administration of onasemnogene abeparvovec to SMA model mice resulted in sustained expression of survival motor neuron (SMN) protein, weight gain, improvement of motor function, and prolongation of survival. Its clinical efficacy and safety have been demonstrated through the Phase I START and Phase III STR1VE-US, STR1VE-EU, and SPR1NT trials, and their long-term extension studies. SMA and presymptomatic patients treated with onasemnogene abeparvovec have achieved rates of survival not observed in the natural history of SMA. Treatment has led to rapid motor function improvement, often within one month of dosing, and developmental milestone achievement, including the ability to sit without support. The most commonly observed adverse effects after treatment were elevated liver enzymes, which often resolved with a course of prednisolone, and vomiting. This review discusses the rationale underlying gene replacement therapy for SMA, and describes the basic science, clinical trial experience, and use of onasemnogene abeparvovec.

Comparison of Edoxaban and Warfarin for the Treatment of Cancer-Associated Venous Thromboembolism　- A Retrospective Observational Study.

BACKGROUND: Because anticoagulant drugs for ambulatory patients with cancer-associated venous thromboembolism (CAT) are limited to warfarin and direct oral anticoagulants (DOACs) in Japan, it is important to assess the outcomes of both drugs.Methods and Results:We retrospectively assessed the outcomes of CAT patients who were treated with warfarin or edoxaban between 2011 and 2017. The assessment was limited to the duration of anticoagulant administration. CAT patients who did not receive anticoagulation therapy were also compared with the warfarin and edoxaban groups. We enrolled 111 CAT patients treated with warfarin (n=58, mean age 62.6 years, mean time in therapeutic range [TTR] % 61.1) or edoxaban (n=53, mean age 64.6 years). Although venous thromboembolism (VTE) recurred in 2 warfarin-treated patients, the 2 treatment groups were not significantly different (P=0.18). Bleeding during anticoagulation therapy occurred in 6 warfarin-treated patients (2 with major bleeding) and in 5 edoxaban-treated patients (no major bleeding) (P=1.0). The non-anticoagulation group (n=37) showed a high recurrence rate (P<0.01) compared with the anticoagulant group. CONCLUSIONS: This study showed that warfarin and edoxaban are equally effective in preventing VTE recurrence and bleeding. However, warfarin control in CAT patients presented some difficulties. This study also demonstrated the efficacy of anticoagulant drugs, compared with no anticoagulation, for CAT patients to prevent VTE recurrence.

Midaortic Syndrome due to Takayasu Arteritis in a Child with Acute Decompensated Cardiac Failure Managed by an Emergency Axillo-External Iliac Artery Bypass: A Follow-Up Case Report of Long-Term Outcomes.

Midaortic syndrome (MAS) is characterized by a diffuse narrowing of the distal thoracic or abdominal aorta and is concomitant with various etiologies. The common symptoms of MAS include severe hypertension or arterial insufficiency distal to the stenosis. This includes lower extremity claudication and heart failure due to afterload mismatch. We present the case of an 8-year-old girl who developed acute decompensated cardiac, respiratory, and renal failures because of the occlusion of the descending aorta secondary to Takayasu arteritis (TA). Although thoracoabdominal-aortic bypass is usually performed for patients with MAS, the procedure was considered too invasive, given the patient's condition. Therefore, we performed an emergency axillo-external iliac artery bypass for revascularization. Subsequently, organ failure improved and she was discharged. At postoperative 10 years, an asymptomatic pseudoaneurysm was detected at the distal anastomosis, for which revision surgery was performed. Overall, the long-term prognosis was satisfactory, suggesting that this procedure is less invasive and effective for treatment of MAS due to TA, in emergencies.

Long-Term Outcomes of Acute Limb Ischemia: A Retrospective Analysis of 93 Consecutive Limbs.

Objective: To examine the medium- to long-term outcomes of acute limb ischemia (ALI), which are unclear at present. Methods: We analyzed 93 consecutive limbs in 77 patients with ALI between January 2005 and December 2015 treated at our vascular center. We categorized the cases into four groups according to etiology (embolism, thrombosis, graft thrombosis, and dissection groups) to assess survival, limb salvage, and freedom from re-intervention rates. Results: The mean age at onset was 72±15 years. The median follow-up length was 2.90 years. The Rutherford categories I, IIa, IIb, and III included 1, 38, 51, and 3 cases, respectively. Thromboembolectomy was performed in all patients in the embolism and thrombosis groups. In addition, endovascular treatment was performed in 25 (37.3%) patients, especially in the thrombosis group (81.3%). A major amputation could not be avoided in 10 patients. The 5-year limb salvage rates for categories IIa and IIb were 97.1% and 83.1%, respectively. The 5-year freedom from re-intervention rate was 89.2%. The survival rates at 1, 3, and 5 years were 87.9%, 75.2%, and 60.6%, respectively. Conclusion: The 5-year survival rates of patients with ALI were equivalent to those with chronic limb threatening ischemia (CLTI). The intervention and long-term outcomes were distinguishable according to etiology.

T-448, a specific inhibitor of LSD1 enzyme activity, improves learning function without causing thrombocytopenia in mice.

Dysregulation of histone H3 lysine 4 (H3K4) methylation has been implicated in the pathogenesis of several neurodevelopmental disorders. Targeting lysine-specific demethylase 1 (LSD1), an H3K4 demethylase, is therefore a promising approach to treat these disorders. However, LSD1 forms complexes with cofactors including growth factor independent 1B (GFI1B), a critical regulator of hematopoietic differentiation. Known tranylcypromine-based irreversible LSD1 inhibitors bind to coenzyme flavin adenine dinucleotide (FAD) and disrupt the LSD1-GFI1B complex, which is associated with hematotoxicity such as thrombocytopenia, representing a major hurdle in the development of LSD1 inhibitors as therapeutic agents. To discover LSD1 inhibitors with potent epigenetic modulation and lower risk of hematotoxicity, we screened small molecules that enhance H3K4 methylation by the inhibition of LSD1 enzyme activity in primary cultured rat neurons but have little impact on LSD1-GFI1B complex in human TF-1a erythroblasts. Here we report the discovery of a specific inhibitor of LSD1 enzyme activity, T-448 (3-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide fumarate). T-448 has minimal impact on the LSD1-GFI1B complex and a superior hematological safety profile in mice via the generation of a compact formyl-FAD adduct. T-448 increased brain H3K4 methylation and partially restored learning function in mice with NMDA receptor hypofunction. T-448-type LSD1 inhibitors with improved safety profiles may provide unique therapeutic approaches for central nervous system disorders associated with epigenetic dysregulation.

Long-Term Outcomes of Surgical Treatment by In Situ Graft Reconstruction for Infected Abdominal Aortic Aneurysm.

Objectives: The optimal surgical management for primary infected abdominal aortic aneurysm (IAAA) is controversial. Here, we report the early and long-term results of surgical treatments with the resection of the IAAA and in situ graft reconstruction with pedicled omental coverage that was performed at out hospital. Methods: Between 2010 and 2017, 27 consecutive patients (26 males, 1 female, median age 69 years) with IAAA were surgically treated with the resection of the IAAA, in situ graft reconstruction and covered with a pedicled omental flap. Perioperative and long-term outcomes were reviewed retrospectively by medical records. Results: Clinical manifestations, including pyrexia, fever and abdominal pain, were observed during the treatment of the patients. Aneurysm excision and in situ graft reconstruction with omental coverage were performed for all cases. In 13 cases (48.1%), tissue culture was positive. The antibiotic was administered intravenously for 9 to 47 days (median 18 days) postoperatively, and after confirming the reduction of the inflammatory response, it was administered as oral agents for 24 to 443 days (median 169 days).There was no perioperative death or re-infection. Perioperative complications were found in 8 cases (29.6%) of minor spinal cord infarction, ileus, chylous ascites, and cholangitis due to choledochlithiasis. During the observation period of median 1,147 days, there was no recurrence of infection, graft infection, or disease-related death. There were six deaths due to other diseases. And the overall survival rate was 76.2%. Conclusion: According to our study, the long-term outcomes of surgical treatment with in situ graft reconstruction for IAAA were considered satisfactory. (This is a translation of Jpn J Vasc Surg 2019; 28: 35-40.).

Oral Steroid Use and Abdominal Aortic Aneurysm Expansion　- Positive Association.

BACKGROUND: The maximum axial diameter (MAD) of a fusiform abdominal aortic aneurysm (AAA) is an indicator of the risk of expansion or rupture. Apart from smoking and MAD itself, few expansion risk factors have been reported. In this study, we investigated expansion risk factors for AAA.Methods and Results:This retrospective cohort study included 176 patients who attended Tohoku University Hospital with infrarenal fusiform AAA. AAA expansion rate was determined on multidetector computed tomography, and the correlations between expansion rate and the clinical data were analyzed. The median expansion rate was 2.405 mm/year. On univariate analysis, a significant positive correlation with expansion rate was observed for the initial MAD (P<0.001) and significant negative correlations for oral angiotensin receptor blocker usage (P=0.025), height (P=0.005), body weight (P=0.017), total cholesterol (P=0.007), low-density lipoprotein cholesterol (P=0.004), and HbA1c (P=0.037). On logistic regression analysis, significant positive associations with expansion rate were observed for initial MAD (P<0.001) and oral steroid usage (P=0.029) and a negative association for height (P=0.041). CONCLUSIONS: Oral steroid usage is an important risk factor for AAA expansion, independent of other risk factors of atherosclerosis and MAD.

Inclusion bodies of aggregated hemosiderins in liver macrophages.

Hemosiderin formation is a structural indication of iron overload. We investigated further adaptations of the liver to excess iron. Five patients with livers showing iron-rich inclusions larger than 2 µm were selected from our database. The clinical features of patients and structures of the inclusions were compared with those of 2 controls with mild iron overload. All patients had severe iron overload with more than 5000 ng/mL of serum ferritin. Etiologies were variable, from hemochromatosis to iatrogenic iron overload. Their histological stages were either portal fibrosis or cirrhosis. Inclusion bodies were ultra-structurally visualized as aggregated hemosiderins in the periportal macrophages. X-ray analysis always identified, in addition to a large amount of iron complexes including oxygen and phosphorus, a small amount of copper and sulfur in the mosaic matrixes of inclusions. There were no inclusions in the control livers. Inclusion bodies, when the liver is loaded with excess iron, may appear in the macrophages as isolated organella of aggregated hemosiderins. Trace amounts of copper-sulfur complexes were always identified in the mosaic matrices of the inclusions, suggesting cuproprotein induction against excess iron. In conclusion, inclusion formation in macrophages may be an adaptation of the liver loaded with excess iron.

Histological Analysis of a New Route after Subintimal Crural Angioplasty.

BACKGROUND: Subintimal angioplasty is an alternative approach in treating critical limb ischemia with crural artery disease. However, route or location of the newly created channel is not understood. CASE PRESENTATION: A 68-year-old man was referred to our hospital with ischemic gangrene of the right big toe. We performed endovascular treatment because he was a poor candidate for bypass surgery. The posterior tibial artery was treated using subintimal angioplasty, although it resulted in early occlusion. We decided that he was not able to receive any further limb salvage treatment and performed amputation below the knee 7 days after treatment. The specimen from the origin of posterior tibial artery to plantar artery bifurcation was resected and the formalin-fixed vessel was cut into 39 segments. Histological analysis showed that the newly formed lumen was comparatively well dilated and created in the media by tearing internal elastic lamina in almost the whole of its length. The severely poor runoff vessels below the ankle were thought to be a main cause of early occlusion. CONCLUSIONS: The newly formed lumen by subintimal crural angioplasty could be well dilated and created in the media.

Efficacy of iliac inflow repair in patients with concomitant iliac and superficial femoral artery occlusive disease.

BACKGROUND: In multilevel arterial disease, whether complete revascularization or staged runoff repair should be performed remains controversial. The aim of this study was to evaluate the efficacy of iliac inflow repair and to identify clinical conditions that are associated with the need for runoff repair in concomitant iliac and superficial femoral artery (SFA) occlusive disease. METHODS: Patients undergoing inflow repair for complicated flow-limiting iliac lesions with diffuse SFA disease between 2007 and 2013 were retrospectively reviewed. Patients with poor response to inflow repair underwent infrainguinal revascularization (IIR). RESULTS: The 29 ischemic limbs examined in this study represent 26 different patients (22 males; mean age, 77 ± 8 years). Indications for inflow repair were Rutherford Classifications III (31%), IV (31%), V (31%), and VI (7%). Severity of the complicated SFA disease was either TASC (TransAtlantic Inter-Society Consensus) type C (14%) or type D (86%). Overall, freedom from IIR was 90% after 30 days and 83% after 1 year. Patients having claudication, rest pain, and shallow ischemic ulcers experienced the relief of symptoms, whereas patients with deep gangrene that needed minor amputation required IIR more frequently (p < 0.01). Anatomical risk factors for poor response to inflow repair were poor quality of the deep femoral artery (p < 0.01) and the flow-limiting popliteal artery (p = 0.02), and poor below-knee runoff (≤ 1 vessel, p < 0.01). CONCLUSION: Iliac inflow repair can reverse the symptoms in patients with multilevel arterial occlusive disease that are not associated with gangrenous toes.

A Novel LSD1 Inhibitor T-3775440 Disrupts GFI1B-Containing Complex Leading to Transdifferentiation and Impaired Growth of AML Cells.

Dysregulation of lysine (K)-specific demethylase 1A (LSD1), also known as KDM1A, has been implicated in the development of various cancers, including leukemia. Here, we describe the antileukemic activity and mechanism of action of T-3775440, a novel irreversible LSD1 inhibitor. Cell growth analysis of leukemia cell lines revealed that acute erythroid leukemia (AEL) and acute megakaryoblastic leukemia cells (AMKL) were highly sensitive to this compound. T-3775440 treatment enforced transdifferentiation of erythroid/megakaryocytic lineages into granulomonocytic-like lineage cells. Mechanistically, T-3775440 disrupted the interaction between LSD1 and growth factor-independent 1B (GFI1B), a transcription factor critical for the differentiation processes of erythroid and megakaryocytic lineage cells. Knockdown of LSD1 and GFI1B recapitulated T-3775440-induced transdifferentiation and cell growth suppression, highlighting the significance of LSD1-GFI1B axis inhibition with regard to the anti-AML effects of T-3775440. Moreover, T-3775440 exhibited significant antitumor efficacy in AEL and AMKL xenograft models. Our findings provide a rationale for evaluating LSD1 inhibitors as potential treatments and indicate a novel mechanism of action against AML, particularly AEL and AMKL. Mol Cancer Ther; 16(2); 273-84. ©2016 AACR.

Natural History and Chronological Growth Rate of Renal Artery Aneurysms.

Objective: Renal artery aneurysm (RAA) is an uncommon disease, the natural course of which is still not well known. The objective of this study is to define factors that affect the growth rate of RAAs. Materials and Methods: We retrospectively reviewed 32 aneurysms in 26 patients at our institute between January 2010 and March 2016. Basal demographics, comorbidities, reason for diagnosis, and details of the aneurysms and interventions were recorded. The chronological changes in the diameter of the RAA using multiplanar reconstructions of computed tomography images were measured and analyzed. Results: The baseline mean diameter was 20.1±8.4 mm (range: 9.9-41). The mean follow-up period was 3.13±2.1 y (range: 0.5-7.1). The median growth rate was 0.35 mm/y (interquartile range: 0.05, 0.62). The growth rate was slower when the initial diameter was <20 mm than when it was >20 mm (p=0.036). Also, whole-completed calcification was a significant factor for slower growth (p=0.016). We performed ex-vivo surgery in two cases and coil packing with stenting in one. No ruptures occurred during the study period. Conclusion: Our results suggest that cases with an RAA diameter <20 mm do not require intervention. The interval period can be longer in whole-completed calcification types.

Long-Term Outcomes of Surgical Treatment with In Situ Graft Reconstruction for Secondary Aorto-Enteric Fistula.

Objectives: The optimal surgical management for secondary aorto-enteric fistula (sAEF) is controversial. Here, we report the long-term outcomes of a surgical treatment with in situ graft reconstruction for sAEF that was performed at our hospital. Methods: Between 2009 and 2012, 10 consecutive patients (8 males, 2 females, mean age 75.9 years) with sAEF were surgically treated with in situ graft reconstruction. Perioperative and long-term outcomes were reviewed retrospectively by medical records. Results: Clinical manifestations, including gastrointestinal bleeding, shock, sepsis, and back and abdominal pain, were observed during the treatment of the patients. In all the cases, the fistula was found between the duodenum or small intestine and the graft anastomosis, the graft itself, or pseudoaneurysm. Total graft excision and in situ graft reconstruction with omental coverage and digestive tract reconstruction was performed for all cases. There were two operative deaths because of multiple organ dysfunction syndrome and sepsis. The other patients showed no sAEF related complications, such as graft infection, and were alive during the 54-month mean follow-up period (33-76 months). Conclusion: According to our study, the long-term outcomes of surgical treatment with in situ graft reconstruction for sAEF were considered satisfactory. (This article is a translation of Jpn J Vasc Surg 2016; 25: 1-6.).

Surgical resection and inferior vena cava reconstruction for treatment of the malignant tumor: technical success and outcomes.

OBJECTIVE: The purpose of this study was to review patients who underwent inferior vena cava (IVC) resection with concomitant malignant tumor resection and to consider the operative procedures and the outcomes. MATERIALS AND METHODS: Between 2000 and 2012, 41 patients underwent resection of malignant tumors concomitant with surgical resection of the IVC at our institute. The records of these patients were retrospectively reviewed. RESULTS: Primary tumor resections included nephrectomy, hepatectomy, retroperitoneal tumor extirpation, lymph node dissection, and pancreaticoduodenectomy. The IVC interventions were partial resection in 23 patients and total resection in 18 patients. Four patients underwent IVC replacement. Operation-related complications included pulmonary embolism, acute myocardial infarction, deep vein thrombosis, leg edema and temporary hemodialysis. There were no operative deaths. The mean follow-up period was 24.9 months (range: 2-98 months). The prognosis depended on the type and stage of the tumor. CONCLUSION: Resection and reconstruction of the IVC can be performed safely if the preoperative evaluations and surgical procedures are performed properly. The IVC resection without reconstruction was permissive if the IVC was completely obstructed preoperatively, but it may also be considered in cases where the IVC is not completely obstructed.

Sudden cardiac arrest immediately after stent graft deployment during treatment of iliac aneurysm with iliocaval fistula.

An 84-year-old woman with heaviness of the right lower extremity had an iliocaval fistula related to a right internal iliac aneurysm. Immediately after deployment of an endovascular device, cardiac arrest occurred because of severely decreased sympathetic activity. After surgery, the patient recovered well and has been followed up with exclusion of the arteriovenous fistula and resolution of the type II endoleak. Endovascular treatment for large arteriovenous fistulas induces rapid closure of the fistula together with restoration of blood supply to the lower extremity. Markedly deactivated sympathetic nerve traffic could result in a critical hemodynamic status in association with endograft deployment.

Intraductal papillary mucinous neoplasm originating from a jejunal heterotopic pancreas: report of a case.

We report a rare case of an intraductal papillary mucinous neoplasm (IPMN) originating from a jejunal heterotopic pancreas, found incidentally during surgery. A 75-year-old woman was referred to our department for surgical treatment of an abdominal aortic aneurysm (AAA) and a concurrent oropharyngeal tumor. During surgery to correct the AAA, we found a jejunal tumor incidentally and performed partial resection of the jejunum. Microscopically, the jejunal tumor showed dilated ducts containing intraluminal papillae lined with mucinous epithelium with low-grade cytological and architectural atypia within the pancreatic tissue. Immunohistochemical staining revealed MUC1 (-), MUC2 (-), MUC5AC (+), and MUC6 (-) proteins. To the best of our knowledge, only six cases of IPMN originating from a heterotopic pancreas have been reported in English, and this is the first report of an IPMN originating from a jejunal heterotopic pancreas.