Nanocarriers targeting the diseases of the pancreas.

Diseases of the pancreas include acute and chronic pancreatitis, exocrine pancreatic insufficiency, diabetes and pancreatic cancer. These pathologies can be difficult to treat due to the innate properties of the pancreas, its structure and localization. The need for effective targeting of the pancreatic tissue by means of nanoparticles delivering therapeutics is a major focus area covered and discussed in this review. Most common diseases of the pancreas do not have specific and direct medical treatment option, and existing treatment options are generally aimed at relieving symptoms. Diabetes has different treatment options for different subtypes based on insulin having stability problems and requiring injections reducing patient compliance. Pancreatic cancer progresses silently and can only be diagnosed in advanced stages. Therefore, survival rate of patients is very low. Gemcitabine and FOLFIRINOX treatment regimens, the most commonly used clinical standard treatments, are generally insufficient due to the chemoresistance that develops in cancer cells and also various side effects. Therefore new treatment options for pancreatic cancer are also under focus. Overcoming drug resistance and pancreatic targeting can be achieved with active and passive targeting methods, and a more effective and safer treatment regimen can be provided at lower drug doses. This review covers the current literature and clinical trials concerning pancreatic drug delivery systems in the nanoscale focusing on the challenges and opportunities provided by these smart delivery systems.

Ferulic acid promotes muscle glucose uptake and modulate dysregulated redox balance and metabolic pathways in ferric-induced pancreatic oxidative injury.

The antidiabetic properties of ferulic acid and its protective role against Fe2+ -induced oxidative pancreatic injury were investigated in this study using in vitro and ex vivo models. Induction of oxidative injury in the pancreas was achieved by incubating normal pancreatic tissue with 0.1 mM FeSO4 and treated by co-incubating with different concentrations of ferulic acid for 30 min at 37°C. Ferulic acid inhibited the activities of α-glucosidase, α-amylase, and pancreatic lipase significantly (p < .05) and promoted glucose uptake in isolated rat psoas muscles. Induction of oxidative pancreatic injury caused significant (p < .05) depletion of glutathione (GSH) level, superoxide dismutase (SOD), and catalase activities, as well as elevation of malondialdehyde (MDA) and nitric oxide (NO) levels, acetylcholinesterase and chymotrypsin activities. Treatment of tissues with ferulic acid significantly (p < .05) reversed these levels and activities. LC-MS analysis of the extracted metabolites revealed 25% depletion of the normal metabolites with concomitant generation of m-Chlorohippuric acid, triglyceride, fructose 1,6-bisphosphate, and ganglioside GM1 in oxidative-injured pancreatic tissues. Treatment with ferulic acid restored uridine diphosphate glucuronic acid and adenosine tetraphosphate and generated P1,P4-Bis(5'-uridyl) tetraphosphate and L-Homocysteic acid, while totally inactivating oxidative-generated metabolites. Ferulic acid also inactivated oxidative-activated pathways, with concomitant reactivation of nucleotide sugars metabolism, starch and sucrose metabolism, and rostenedione metabolism, estrone metabolism, androgen and estrogen metabolism, porphyrin metabolism, and purine metabolism pathways. Taken together, our results indicate the antidiabetic and protective potential of ferulic acid as depicted by its ability to facilitate muscle glucose uptake, inhibit carbohydrate and lipid hydrolyzing enzymes, and modulate oxidative-mediated dysregulated metabolisms. PRACTICAL APPLICATIONS: There have been increasing concerns on the side effects associated with the use of synthetic antidiabetic drug, coupled with their expenses particularly in developing countries. This has necessitated continuous search for alternative treatments especially from natural products having less or no side effects and are readily available. Ferulic acid is among the common phenolics commonly found in fruits and vegetables. In this present study, ferulic acid was able to attenuate oxidative stress, cholinergic dysfunction, and proteolysis in oxidative pancreatic injury, as well as inhibit carbohydrate digesting enzymes. Thus, indicating the ability of the phenolic to protect against complications linked to diabetes. Crops rich in ferulic acid maybe beneficial in managing this disease.

Granulomatosis with polyangiitis presenting as pancreatic disease.

Granulomatosis with polyangiitis (GPA) is a rare necrotising small vessel vasculitis typically associated with oronasal, pulmonary and renal manifestations. Pancreatic disease is an exceedingly rare initial presentation and is associated with delayed diagnosis and rapid progression. We discuss a 66-year-old woman presenting with epigastric pain, elevated lipase and radiographic evidence of focal pancreatitis. She had no relevant medical history and no lithiasis seen on imaging. Pertinent findings include strawberry gingivitis, positive proteinase-antineutrophil cytoplasm antibody (98% specificity) and focal nodular parenchymal lung lesions on CT chest-all of which are consistent with a diagnosis of GPA. She was promptly started on high-dose steroids which resulted in significant clinical and biochemical improvement. Cyclophosphamide was added once biopsy confirmed the absence of malignancy. In order to optimise the clinical outcomes of GPA, physicians must keep a wide differential and high index of suspicion in the setting of unexplained pancreatitis with systemic features.

Inhibition of thioredoxin-interacting protein and inflammasome assembly using verapamil mitigates diabetic retinopathy and pancreatic injury.

It has been previously demonstrated by our group that genetic inhibition of thioredoxin-interacting-protein (TXNIP) preserved retinal neuronal function in chemically-induced retinopathy. Moreover, elevated intracellular levels of TXNIP and calcium ions play important roles in hyperglycemia-induced oxidative stress and inflammation. Current study aimed to appraise the potential therapeutic benefits of pharmacological inhibition of TXNIP using verapamil in diabetic retinopathy. Diabetic retinopathy was assessed in type-1 diabetes rat model induced by a single intravenous injection of streptozotocin (45 mg/kg), with or without daily treatment with verapamil (10 mg/kg, oral) for 4 months. Verapamil treatment commenced 48 h post-streptozotocin insult and continued for 16 weeks. Untreated diabetic rats exhibited higher expression of toll-like-receptor-4 (TLR4), TXNIP, nucleotide-binding domain-like receptor protein-3 (NLRP3), caspase-1, cytochrome-c, and ssDNA as assessed immunohistochemically in both retinal and pancreatic tissues 16 weeks post-diabetes induction. This was associated with a reduced thioredoxin reductase (Trx-R) activity, increased release of TNF-α and IL-1ß into vitreous fluid along with retinal ganglion cell (RGC) loss, pancreatic islets shrinkage, and enhanced CD34 expression. The treatment with verapamil enhanced Trx-R activity, significantly inhibited TLR4 mediated NLRP3-inflammasome assembly with subsequent diminishing of inflammatory markers (TNF-α and IL-1ß) release into the vitreous, suppression of pathological angiogenesis, and preservation of RGC count and pancreatic islets diameter. Current study showed that using the calcium channel blocker, verapamil, interferes with the pathogenesis of diabetic retinopathy and pancreatic islets damage at multiple levels mainly through the inhibition of TLR4, TXNIP and NLRP3-inflammasome, suggesting its promising role as an anti-diabetic and a neuroprotective agent.

Undiagnosed sarcoidosis presenting as acute pancreatitis: a rare presentation of a known disease.

A 43-year-old African American man presented with right upper quadrant pain and elevated blood pressure. Investigations revealed elevated lipase, hypercalcaemia and elevated creatinine. CT abdomen with contrast revealed extensive intraabdominal lymphadenopathy with an initial suspicion for a lymphoproliferative malignancy. Patient was managed for acute pancreatitis, with further workup of hypercalcaemia revealing an elevated ACE level. Inguinal lymph node biopsy confirmed a non-caseating granuloma leading to the diagnosis of sarcoidosis.

Pancreatic tuberculosis in immunocompetent patients. At the University Hospital in Kingdom of Saudi Arabia.

OBJECTIVES: To raise awareness of practitioners on benign treatable conditions such as pancreatic tuberculosis (TB). Methods: A retrospective study at King Khaled University Hospital, Riyadh, Saudi Arabia of all patient charts presented with pancreatic mass for a period of 10 years (2007-2017) with a study duration of 4 years between 2013 and 2017. Patients with confirmed diagnosis of pancreatic cancer were excluded. A written ethical approval was obtained accordingly. Results: All adult patient charts were retrospectively reviewed with a pancreatic mass for a period of 10 years (2007-2017). Nine patients were identified with proven diagnosis of TB. The data were obtained based on demographic features, sign and symptoms, duration of illness, imaging, ultrasound, contrast enhanced computed tomography scan, cytology or histopathology, polymerase chain reaction, culture and follow up with anti-tuberculous therapy and samples for cytology or histology. The histological findings of granuloma with caseation or positive culture were used confirming the diagnosis of TB. All patients were immunocompetent and screened for human immunodeficiency viruses before starting anti-TB treatment. Results were negative. All patients who underwent fine needle aspiration (FNA) and endoscopic ultrasound (EUS) for suspicious pancreatic mass were provided trial of antibiotics as cases of pancreatic tuberculosis showed dramatic improvement during follow up and cured from the disease. Conclusion: The EUS and FNA are good tools to confirm malignancy and rule out benign treatable conditions like TB for any patient with a pancreatic mass suspicious for carcinoma.

Late pancreatic panniculitis in a simultaneous pancreas kidney transplant patient with failed allografts.

We present a rare case of pancreatic panniculitis in a 59-year-old male simultaneous pancreas-kidney (SPK) recipient with failed allografts. The patient presented with fever and painful erythematous nodules on his leg 1 month after stopping all immunosuppression. A thorough infectious and rheumatological workup was negative. He had pancreas rejection 4 years after SKP transplant and was restarted on dialysis after 14 years when his renal allograft failed due to chronic allograft nephropathy. His chronic immunosuppression (tacrolimus, azathioprine) was stopped and prednisone was weaned over 3 months at that time. A skin biopsy revealed saponification of the subcutaneous fat with inflammation pathognomonic of pancreatic panniculitis. Concurrent allograft pancreatitis confirmed with elevated lipase and a computed tomography scan finding of peripancreatic graft stranding and atrophic native pancreas. He was started on pulse steroid therapy for 3 days followed by oral taper. This resulted in dramatic resolution of all skin lesions and normalization of lipase levels within 1 week, followed by resumption of low-dose tacrolimus and azathioprine. This is an extremely rare occurrence of panniculitis in pancreas allograft after 10 years of pancreatic failure associated with stopping immunosuppression.

[Diagnosis and treatment of pancreatic tuberculosis: experiences of 10 cases].

Objectives: To study the clinical characteristics of pancreatic tuberculosis, and therefore to improve the diagnosis and treatment of this disease. Methods: The clinical data of 10 patients with pancreatic tuberculosis form 1990 to 2017 were reviewed, including clinical characteristics, laboratory tests and imaging features. Results: The ten patients aged 28 to 71 (median 56) years. All of them presented varying degrees of abdominal pain and weight loss (3 to 8 kg). Hypo-echoic pancreatic masses were shown by abdominal ultra-sound in 7 cases, and cystic-solid masses with thick wall was shown by abdominal CT scan in 4 cases, but dilatation of the pancreatic duct was found in none of the 10 cases. Hemoglobin levels lower than 12 g/L were found in 6 cases, and ESR more than 20 mm/1 h was present in 7 cases. Four cases received PPD test, but only one was positive. CA19-9 was found to be higher than normal (27 IU/ml) in 3 cases (39.2 IU/ml, 125.7 IU/ml, 88.9 IU/ml respectively). Three cases received T-spot.TB tests, and all the results were positive. Seven cases received laparotomy, and the other 3 received endoscopic ultrasound-guided biopsy. Caseous necrosis and Langerhans cells were found in all the 10 cases. Nine patients were treated by 6 to 12 months' anti-tuberculosis therapies, and at 1-5 years' follow-up, 8 were cured and 1 improved. Conclusions: The manifestations of pancreatic tuberculosis were easy to be confused with other diseases, and therefore a comprehensive understanding of history and careful examinations were important for a correct diagnosis. Once the diagnosis was made, prompt standard anti-tuberculosis therapy could lead to a favorable outcome.

Tuberculosis of pancreas, the first case reported from Qatar.

Despite the high prevalence of tuberculosis (TB) in developing countries, primary pancreatic TB is a rare entity. We present a case of pancreatic TB in an immunocompetent patient who was found to have pancreatic mass resembling malignancy. A 40-year-old Indian male presented to the medical emergency room with complaints of abdominal pain and fever for 2 weeks' duration. He had a history of unintentional weight loss of about 20 pounds in the past 2 months. There was no significant history of exposure to TB patient. Family history was unremarkable for any malignancy. On examination, the significant finding was epigastric tenderness. He was thoroughly investigated, his purified protein derivative and QuantiFERON were negative. Chest X-ray was unremarkable. Computed tomography scan abdomen was performed that revealed large heterogenous necrotic mass in the lesser sac likely arising from pancreatic body with possible infiltration of the stomach, left lobe of the liver and encasing celiac vessels and portal vein with multiple peripancreatic and retroperitoneal necrotic lymph nodes. Endoscopic ultrasound with fine-needle aspiration of pancreatic mass was done, biopsy specimen revealed the presence of inflammation with no evidence of malignancy. TB polymerase chain reaction and culture came positive for Mycobacterium tuberculosis. He was started on antituberculosis treatment with isoniazid, rifampicin, pyrazinamide, and ethambutol with a plan to continue for total 6 months. However, follow-up of the patient could not be done as he traveled back to his home country.

Transforming growth factor-ß in pancreatic diseases: Mechanisms and therapeutic potential.

Pancreatic diseases, such as acute pancreatitis, chronic pancreatitis, and pancreatic cancer, are common gastrointestinal diseases resulting in the development of local and systemic complications with a high risk of death. Numerous studies have examined pancreatic diseases over the past few decades; however, the pathogenesis remains unclear, and there is a lack of effective treatment options. Recently, emerging evidence has suggested that transforming growth factor beta (TGF-ß) exerts controversial functions in apoptosis, inflammatory responses, and carcinogenesis, indicating its complex role in the pathogenesis of pancreas-associated disease. Therefore, a further understanding of relevant TGF-ß signalling will provide new ideas and potential therapeutic targets for preventing disease progression. This is the first systematic review of recent data from animal and human clinical studies focusing on TGF-ß signalling in pancreas damage and diseases. This information may aid in the development of therapeutic agents for regulating TGF-ß in this pathology to prevent or treat pancreatic diseases.

Isolated pancreatic tuberculosis with elevated CA 19-9 levels masquerading as a malignancy: A rare case report and literature review.

RATIONALE: Primary pancreatic tuberculosis is extremely rare, it presents with non-specific clinical symptoms and imaging features; it may be falsely identified as a malignancy of the pancreas. PATIENT CONCERNS: A 41-year-old male with no history of tuberculosis presented to our hospital with a 2-week history of jaundice. DIAGNOSES: Abdominal computed tomography (CT) showed a heterogeneous irregular hypodense mass in the head of the pancreas causing dilatation of the common bile duct (CBD), and it was enhanced after infusion of contrast material. Serum cancer antigen (CA) 19-9 was 124 U/mL (normal: 0-40 U/mL). He was preoperatively diagnosed as having a pancreatic carcinoma. INTERVENTIONS: A Whipple procedure (pancreaticoduodenectomy) was performed. The pancreatic tuberculosis was confirmed based on the postoperative histopathologic specimens and acid-fast stain of the drainage. Then isoniazid, rifampicin, and ethambutol were given for 6 months. OUTCOMES: The patient recovered very well. There was no evidence of tuberculosis recurrence, and the patient remained free of symptoms during the follow-up examination 1 year after surgery. LESSONS: Pancreatic tuberculosis should be considered when the mass is located on the head of the pancreas even with elevated serum CA19-9 levels.

Multivisceral IgG4-related disease presenting as recurrent massive gastrointestinal bleeding: a case report and literature review.

BACKGROUND: IgG4-related disease (IgG4-RD) is a newly recognized autoimmune systemic disorder characterized by elevated levels of serum IgG4 and abundant infiltration of IgG4-positive plasmacytes in the affected organs. The liver, biliary system and pancreas are the most commonly affected organs. However, involvement of the digestive tract is very rare. To date, only a few cases of isolated gastric IgG4-RD have been reported. CASE PRESENTATION: We present a case of IgG4-RD of the liver, gallbladder, pancreas and duodenum, which was clinically misinterpreted and thereafter over-treated. A 52-year-old male presented with obstructive jaundice for 3 years, melena for 5 months and hematemesis for 10 days. Three years prior, the patient had undergone biopsies of pancreatic lesions, liver lesions, cholecystectomy and choledochojejunostomy. Histopathology showed chronic inflammatory changes. Endoscopy at admission revealed a duodenal ulcer with active bleeding. Despite medical management, the patient presented with repeated gastrointestinal bleeding. Upon evaluation, serum IgG4 levels were found to be elevated. Histopathology of the duodenal ulcer biopsy and repeated examination of the gallbladder and pancreatic and liver biopsies confirmed IgG4 positive plasma cell infiltration. A definitive diagnosis of IgG4-RD was made and steroid administration was initiated. At last follow up, 11 months to-the-day after initiating steroid treatment, the patient was asymptomatic. CONCLUSIONS: Notably, IgG4-RD of multiple digestive organs is still very rare. As a systemic disease, it is characterized by the infiltration of IgG4-bearing plasma cells and raised IgG4 levels. Histopathology findings remain the diagnostic gold standard for this disorder.

Calcified peripancreatic lymph nodes in pancreatic and hepatic tuberculosis mimicking pancreatic malignancy: A case report and review of literature.

RATIONALE: Tuberculosis remains a serious menace to the health of people. Isolated hepatic tuberculosis is rare and pancreatic tuberculosis is extremely rare. The preoperative diagnosis of pancreatic tuberculosis remains a great challenge. PATIENT CONCERNS: A 58-year-old Asian woman was referred to our hospital for evaluation of low back pain for 4 years and abdominal pain for 1 month. DIAGNOSES: Computed tomography (CT) of the abdomen showed a hypodense mass in the pancreatic head and neck with abundant calcifications, a hypodense lesion in the liver without calcification, peripancreatic lymphadenopathy, calcifications in some lymph nodes. CT-guided fine needle aspiration biopsy of the hepatic lesion was carried out and the cytological examination revealed hepatic tuberculosis. INTERVENTIONS: The patient was treated with antituberculous therapy for 1 year. OUTCOMES: Low back pain and abdominal pain disappeared 3 months after initial treatment and after 2 year of follow-up, the patient was asymptomatic. LESSONS: Our data hint that calcifications in both pancreatic lesions and peripancreatic lymph nodes may suggest pancreatic tuberculosis rather than pancreatic malignancy.

A study of a pancreatic mass: not all is what it seems.

We report the case of a male with no medical history with acute cholangitis secondary to a pancreatic head´s mass suggestive of neoplasm. An EUS-FNA was performed where no atypical cells were identified but a granulomatous component did. The patient was finally diagnosed of disseminated tuberculosis with pancreatic involvement. Pancreatic tuberculosis is an infrequent entity that requires a high index of suspicion due to the variability of its forms of presentation and the high morbidity and mortality without targeted therapy.

Alveolar echinococcosis in the head of pancreas: A case report.

RATIONALE: Pancreatic alveolar echinococcosis (AE) is an exceptionally rare disease; no more than 10 cases have been published to date. It is characterized as extensive local tissue infringement and destruction; thus, extended surgical resection, such as duodenopancreatectomy, is often needed to obtain a negative resection margin so as to improve the long-term outcome and prognosis. PATIENT CONCERNS: A middle-aged Tibetan man was admitted due to a 16-year history of recurrent pain in the right upper abdomen. Magnetic resonance imaging scan showed a cystic lesion in the VI segment of his liver and several cystic lesions in the head of pancreas. DIAGNOSES: Pancreatic AE. INTERVENTIONS: The patient adopted a preserved surgery of partial cystectomy and completely removing the content of the cyst and then soaking by hypertonic saline combined with adjuvant medical therapy of albendazole. OUTCOMES: The patient was monitored on a regular basis at the outpatient department; the patient is still alive and has already survived 8 years till now. LESSONS: A preserved surgery combined with adjuvant medical therapy of albendazole can also contribute to a good survival outcome for AE located at the head of pancreas.

Prospective Evaluation of Pasireotide in Patients Undergoing Pancreaticoduodenectomy: The Washington University Experience.

BACKGROUND: Pasireotide is a newer generation somatostatin analogue that led to a significant reduction in pancreatic fistula after pancreatectomy in a single-center randomized controlled trial. We sought to determine if pasireotide reduces the incidence of pancreatic fistula and other complications after pancreaticoduodenectomy at our high volume center. STUDY DESIGN: All patients undergoing pancreaticoduodenectomy between April 2011 and January 2017 were prospectively followed, and their complications were graded using the Modified Accordion Grading System (MAGS) in our institutional complications database. For 18 months, 5 pancreatic surgeons used pasireotide routinely in patients undergoing pancreaticoduodenectomy. Patients receiving pasireotide were then propensity score-matched to patients who did not receive pasireotide, and their outcomes were compared. RESULTS: There were 459 patients who underwent pancreaticoduodenectomy, and 127 patients (28%) received pasireotide. Patients who received pasireotide were significantly more likely to have dilated pancreatic ducts and have a drain left at the time of surgery. Patients who received pasireotide had no difference in pancreatic fistula, overall complications, 90-day readmission, or 90-day mortality. However, patients who received pasireotide had a significantly reduced rate of postoperative bleeding/anemia (8.7% vs 16.9%, p = 0.03). Among 112 propensity score-matched pairs, patients who received pasireotide did not have significantly different rates of pancreatic fistula, and the rates of severe (MAGS grades 3 to 6) pancreatic fistula were identical between the 2 groups (7.1% vs 7.1%, p = 1.00). Matched patients who received pasireotide had significantly decreased postoperative bleeding/anemia (9.8% vs 19.6%, p = 0.04). CONCLUSIONS: Pasireotide did not reduce the incidence or severity of pancreatic fistulas after pancreaticoduodenectomy, but was associated with a decrease in postoperative bleeding/anemia. A multicenter randomized trial is needed to accurately define the role of pasireotide in the postoperative management of pancreaticoduodenectomy patients.

Pancreatic gout and the role of multimodality imaging in its management.

Uric acid deposition in the pancreas is very rare and neither an endoscopic ultrasound (EUS) nor a contrast-enhanced CT image of this condition has ever been published. We describe a case of asymptomatic pancreatic gout that was detected incidentally on CT. Imaging features mimicked pancreatic neoplasm, warranting further evaluation with EUS-guided fine-needle aspiration. Samples revealed debris encrusted with monosodium urate crystals. Follow-up CT showed complete resolution with urate-lowering therapy. We aim to augment current knowledge on the imaging of pancreatic gout and discuss its management.

Antiviral Activity of Oroxylin A against Coxsackievirus B3 Alleviates Virus-Induced Acute Pancreatic Damage in Mice.

The flavonoids mosloflavone, oroxylin A, and norwogonin, which were purified from Scutellaria baicalensis Georgi, significantly protected Vero cells against Coxsackievirus B3 (CVB3)-induced cell death. To investigate the in vivo antiviral activity of oroxylin A, we intraperitoneally inoculated CVB3 into 4-week-old BALB/c mice. Body weights and blood glucose levels of the mice were decreased after CVB3 infection, and these changes were attenuated by the administration of oroxylin A. Importantly, treatment of mice with oroxylin A reduced viral titers in the pancreas and decreased the serum levels of the inflammatory cytokines including interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α. Additionally, the administration of oroxylin A mitigated the histological pancreatic lesions and apoptotic cell death induced by CVB3 infection and increased the levels of phospho-eIF2α in infected pancreata. The results suggest that oroxylin A may represent a potent antiviral agent against CVB3 infection.