Increase In Pancreatic Enzymes Research Articles

Effect Of Pentavalent Antimony Compounds On The İnflammatory, Hematological and Biochemical Parameters İn Patients With Cutaneous Leishmaniasis

Objective This study aimed to evaluate how systemic antimony treatment in cutaneous leishmaniasis (CL) patients affects biochemical, hematological, and inflammatory parameters in child and adult patient groups. Methods A total of 50 patients (29 adults, 21 children) who received systemic meglumine antimonate (MA) treatment in the skin and venereal diseases clinic between September 2022 and January 2024 and were diagnosed with CL by microscopic examination were included in the study. The medical records of the patients were examined retrospectively. Before and after treatment, neutrophil count, leukocyte count, lymphocyte count, hemoglobin concentration, platelet count, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), mean platelet volume (MPV), amylase, lipase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen and serum creatinine levels were recorded. Results In the children group, lymphocyte and platelet values decreased statistically significantly; and lipase value increased statistically significantly after treatment. In the adult group; hemoglobin, neutrophil, lymphocyte and leukocyte values decreased statistically significantly; ALT, AST, amylase, lipase, NLR and PLR values increased statistically significantly after treatment. Conclusion Based on the data in our study, it was stated that systemic meglumine antimonate treatment may lead to an increase in pancreatic enzymes and transaminases and bone marrow suppression. We also think that patients in the adult age group should be followed more closely regarding pancreatic enzymes and kidney function tests than the pediatric age group.

Gastrointestinal involvement in STEC-associated hemolytic uremic syndrome: 10 years in a pediatric center

BackgroundThe gastrointestinal (GI) tract represents one of the main targets of typical hemolytic uremic syndrome (HUS) in children. In this observational study, we tried to establish (1) the main features of GI complications during STEC-HUS and (2) the relationship between Escherichia coli serotypes and Shiga toxin (Stx) variants with hepatopancreatic involvement.MethodsA total of 79 STEC-HUS patients were admitted to our pediatric nephrology department between January 2012 and June 2021. Evidence of intestinal, hepatobiliary, and pancreatic involvements was reported for each patient, alongside demographic, clinical, and laboratory features. Frequency of gastrointestinal complications across groups of patients infected by specific E. coli serotypes and Stx gene variants was evaluated.ResultsSix patients developed a bowel complication: two developed rectal prolapse, and four developed bowel perforation which resulted in death for three of them and in bowel stenosis in one patient. Acute pancreatitis was diagnosed in 13 patients. An isolated increase in pancreatic enzymes and/or liver transaminases was observed in 41 and 15 patients, respectively. Biliary sludge was detected in three, cholelithiasis in one. Forty-seven patients developed direct hyperbilirubinemia. Neither E. coli serotypes nor Shiga toxin variants correlated with hepatic or pancreatic involvement.ConclusionsDuring STEC-HUS, GI complications are common, ranging from self-limited elevation of laboratory markers to bowel perforation, a severe complication with a relevant impact on morbidity and mortality. Hepatopancreatic involvement is frequent, but usually short-lasting and self-limiting.Graphical abstractA higher resolution version of the Graphical abstract is available asSupplementary information

Use of Ponatinib Alone or Combined with Other Therapies in Relapsed/Refractory Ph-like Acute Lymphoblastic Leukemia. a Campus ALL Real-Life Study

Introduction. Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) employed in relapsed/refractory (R/R) and, more recently, also in newly diagnosed Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Ph-like ALL is a genetically heterogenous subgroup that shares a common transcriptional profile, similar to that of true Ph+ ALL, though lacking the BCR::ABL1 rearrangement. Ph-like ALL is characterized by a poor prognosis, a high relapse rate and a worse overall survival if treated with standard chemotherapy. Several molecular pathways are involved, including JAK/STAT, CRLF2 and ABL-class mutations, providing a heterogeneous genetic landscape with very limited data on the subsequent clinical outcome. Few isolated cases of successful treatment of R/R Ph-like ALL with ponatinib have been reported, including also patients with lesions different from ABL-class mutations. Currently, ponatinib prescription in Italy is not allowed for Ph-like ALL. Patients and Methods. Between January 2019 and July 2023, 17 patients were candidate to receive ponatinib on a nominate compassionate use basis; data were collected in the context of the Campus ALL network in Italy. The criteria for inclusion were a diagnosis of Ph-like ALL, with either hematological or molecular evidence of disease, and a treatment period of at least 28 consecutive days of ponatinib. The Ph-like signature was based on the BCR/ABL1 like-predictor (Chiaretti et al, BJH 2018) and, whenever possible, targeted RNA sequencing. Final data were collected for 15 patients (2 patients were excluded due to a treatment period <28 days) treated with ponatinib either as a single agent or in association with immuno and/or chemotherapy. Results. All patients had common ALL. Eight of the 15 cases were classified as high risk or very high risk ALL at diagnosis; 10 were males, the median age was 28 years (14-66) and the median white blood count at diagnosis was 25.6 x10 9/l (2.7-317 x10 9/l). Targeted RNA sequencing was carried out in 10/15 cases: 7 presented gene fusions ( ABL-class mutations in 2, JAK2 mutations in 2, and CRLF2::P2RY8, IKZF1::DDC and RB1::RCBTB2 in 1 case each); 2 additional cases had a CRLF2 rearrangement, evaluated by FISH. Copy number aberrations analysis by multiplex ligation-dependent probe amplification (MLPA) technology was performed in 12/15 cases: 5 cases had a IKZF1 plus signature, 6 had a IZKF1 loss, while 1 case was IKZF1 wild type. Ponatinib was started in first (n=2) or second (n=5) hematologic relapse in 7 patients (46%), with 3 also having an extramedullary disease; 7 additional patients (46%) were treated in first (n=5) or second (n=2) minimal residual disease (MRD) persistence/recurrence; finally, 1 patient was refractory to 3 subsequent lines of treatment. In 8/15 patients ponatinib was used as single agent or in association with steroids or intrathecal chemotherapy only, in 4 it was administered in combination with chemotherapy and in 3 with blinatumomab; 7 patients started ponatinib after having failed an allogeneic transplant (6 hematologic relapses and 1 molecular relapse). A complete hematological and molecular remission (MRD- CR) was achieved in 6 patients (40%); notably, 4 of these 6 cases carried a gene fusion (1 JAK2 rearrangement, 1 ABL-class fusion, 1 IKZF1::DDC and 1 RB1::RCBTB2); 2 further patients in hematologic relapse at the start of treatment achieved a MRD+ CR (1 patient had a ABL-class gene fusion). Thus, the overall response rate was 53%. Four patients were refractory, while 2 maintained a stable disease. After ponatinib-based treatment, 6 patients were allografted and 1 received a CAR-T cell infusion. The toxicity profile was mild: 3 patients developed a transaminitis, 1 also had a fungal pneumonia, and 1 an increase in pancreatic enzymes. At a median follow-up of 3 months (1-5), 10 patients are alive, 8 being in continuous complete remission. Conclusions. Treatment with ponatinib showed promising results in terms of CR achievement in a heavily pre-treated population of Ph-like ALL patients, with an acceptable toxicity profile. In a pre-transplant setting, ponatinib was effective as a bridge to cellular therapies in 7 out of 8 patients as intention-to-treat (ITT), thus suggesting that this strategy may represent an effective bridge to further therapies. To our knowledge, this is the largest cohort of adult Ph-like ALL cases treated with ponatinib so far reported.

P171 CARDIOTOXICITY IN A PATIENT WITH UROTHELIAL CARCINOMA TREATED WITH DURVALUMAB AND CARBOZANTINIB

Abstract We present the clinical case of a 53–year–old patient with urothelial carcinoma enrolled in the ARCADIA study since April 2020, in therapy with Durvalumab and Carbozantinib (24 cycles). Durvalumab was suspended in October 2022 due to the increase in pancreatic enzymes and the probable autoimmune genesis of pancreatitis. On 04/12/2022, due to the onset of epigastralgia with ECG finding of sinus tachycardia and ST elevation in the lower site with HS–TnI 18883.8, he performed emergency coronary angiography which was negative for significant stenosis. On the Echocardiogram: Severe left ventricular systolic dysfunction (FE 25%). The patient presented increased inflammation indices and acute renal failure with Exitus.

Pancreatic Stones in Children with Chronic Pancreatitis: A Case Report

Background: Chronic pancreatitis is a continuous progressive inflammation of the pancreas that can cause recurrent abdominal pain. The incidence of chronic pancreatitis in children is on an upward trend in recent years. The purpose of this case report is to enhance clinician's insight in considering chronic pancreatitis as a differential diagnosis in cases of recurrent abdominal pain in children. Case: We reported a case of chronic pancreatitis with pancreatic stones in a 12-year-old child. The patient came with complaints of recurrent upper left abdominal and heartburn accompanied by nausea and vomiting. Epigastric and left hypochondriac tenderness were found. Laboratory examination showed an increase in pancreatic enzymes up to 6x the normal value. The results of abdominal CT-scan and MRCP showed multiple pancreatic stones with pseudocysts. The patient then underwent the Puestow procedure. Postoperatively, the complaints of abdominal pain resolved and the pancreatic enzymes improved significantly. Discussion: The diagnosis of pancreatitis must meet 2 out of the 3 criteria that have been determined. Primary management includes fluids, analgesics, early nutrition, and surgery in cases of chronic pancreatitis accompanied by complications such as pseudocysts or pancreatic stones. Conclusion: This case teaches the need for a careful clinical approach and consideration of chronic pancreatitis as a differential diagnosis in a child with recurrent abdominal pain.

Early Increases in Posttransplant Pancreatic Enzymes Are Associated With Surgical Complications But Not Graft Failure Among Pancreas Transplant Recipients.

This study aimed to find the association between immediate postoperative increases in pancreatic enzymes and posttransplant complications among pancreas transplant recipients (PTRs). We analyzed all PTRs transplanted at the University of Wisconsin between June 2009 and September 2018. Enzyme levels were presented as a ratio of absolute numbers to the upper limit of normal value, with value >1 considered as abnormal. We specifically evaluated bleeding, fluid collections, and thrombosis complications based on the amylase or lipase ratios on day 1 (Amylase1, Lipase1) and maximum ratios within 5 days of transplant (Amylasemax, Lipasemax). For early complications, we focused on technical complications that occurred within 90 days of transplant. For long-term outcomes, we assessed patient and graft survival, and rejections. There were a total of 443 PTRs, 287 were simultaneous pancreas and kidney recipients, and 156 were solitary pancreas recipients. Higher Amylase1, Liplase1, Amylasemax, and Lipasemax were associated with an increase in early complications, mainly need for pancreatectomy, fluid collections, bleeding complications, or graft thrombosis, particularly in the solitary pancreas group. Our finding suggests that cases of early perioperative enzyme increase merit consideration for early imaging investigation to mitigate detrimental outcomes.

Безсимптомна гіперамілаземія в дебюті запальних захворювань кишечника у дітей: випадок із практики

У статті проаналізовані дані літературних джерел щодо епідеміології, етіології, механізмів розвитку уражень підшлункової залози при запальних захворюваннях кишечника в дітей. Проілюстровано спектр патологічних станів підшлункової залози у хворих на запальні захворювання кишечника. Наведено алгоритм диференційної діагностики безсимптомної елевації панкреатичних ферментів у дітей. Проведено ретельний аналіз клініко-анамнестичних, лабораторно-інструментальних даних, продемонстровано алгоритм діагностичного пошуку при безсимптомній гіперамілаземії у хлопчика, хворого на виразковий коліт.

Favipiravir Induced Acute Pancreatitis in a COVID-19 Patient

There are a number of gastrointestinal symptoms and complications of COVID-19. Asymptomatic increase in pancreatic enzymes and rarely symptomatic pancreatitis are observed in this disease. This article describes a 37-year-old male suffering from mildly symptomatic COVID-19 infection, who received tablet favipiravir for his management. His condition was improving, when he developed acute pancreatitis, diagnosed clinically, biochemically and also with help of abdominal ultrasound. When he developed this, all typical symptoms of COVID-19 were improved. As a result, role of favipiravir in the development of this pancreatitis was suspected.
 J MEDICINE JAN 2021; 22 (1) : 69-71

Increase in pancreatic enzymes following spinal alignment changes in the thoracolumbar junction: Potential for acute pancreatitis after kyphosis correction

BackgroundDespite the identification of various risk factors for pancreatitis and hyperamylasemia following spinal surgery, no report has investigated the relationship between spinal alignment changes and elevated serum amylase levels. The purpose of this study was to investigate the relationship between spinal alignment changes and hyperamylasemia after spinal fusion. MethodsA total of 222 patients whose serum pancreatic amylase levels were measured before and after spinal surgery from December 2017 to May 2019 were included. Inclusion criteria were (1) spinal fusion including the thoracolumbar junction (T10-L2) and (2) serum pancreatic amylase measurements before, immediately after surgery (day 0), the day after surgery (day 1), and 1 week after surgery. Ultimately, 37 patients who met the criteria were analyzed. Patients with hyperamylasemia at day 0 and/or day 1 (H group) were then compared with those without hyperamylasemia (N group). ResultsNo significant differences in age, sex, surgical procedure, number of fused segments, intraoperative blood loss, operative time or American Society of Anesthesiologists physical status classification were observed between both groups. The H group had significantly larger preoperative thoracolumbar kyphosis (TLK) (H group: 22.6°, N group: 6.4°), postoperative TLK (H group: 16.8°, N group: 7.6°), and preoperative T12–L1 kyphosis angles (H group: 16.2°, N group: 7.9°) compared with the N group. Moreover, the H group demonstrated a significant decrease in TLK after surgery (H group: −5.8°, N group: 1.6°). ConclusionsRisk factors for hyperamylasemia included a large preoperative TLK angle and a greater postoperative decrease in TLK. Thus, decreased TLK after spinal fusion surgery should prompt careful attention to abdominal symptoms and elevated pancreatic amylase levels.

355-OR: Effects of a Six-Week Intervention with Glucagon-Like Peptide-1 Analogue on Pancreatic Volume, Edema, and DNA Synthesis in Obese Men

Plasma concentrations of the two pancreatic enzymes, amylase and lipase, are increased within the normal physiological range after initiation of glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment. An association between the use of GLR-1RA and incidence of acute pancreatitis or pancreatic cancer has not been found - neither in rodent studies nor in preclinical studies or in the large cardiovascular outcome trials with GLP-1RAs. The increased concentrations of pancreatic enzymes have been suggested to be explained by increased DNA or protein synthesis found in rodent and acinar cell studies. However, whether this translates into humans is unknown. We therefore investigated the effect of liraglutide, a GLP-1RA, on pancreatic volume, edema and DNA synthesis reflected by 18F-flourothymidine (FLT)-uptake using state-of-the-art positron emission tomography (PET)-magnetic resonance imaging (MRI) before initiation, after four weeks during titration of liraglutide and after six weeks during steady state on maximum dose of liraglutide 3.0 mg in 14 obese men (age 38 ± 3 years, BMI 32 ± 1 kg/m2) without diabetes. Plasma concentrations of amylase and lipase were assessed in parallel. Amylase (+7 U/L [95% confidence intervals, 3 - 11] p<0.01) and lipase (+19 U/L [7-30] p<0.01) increased during liraglutide treatment while body weight decreased (-4.5 kg [-5,9 - -3,1] p<0.01). Pancreatic volume did not change from baseline to steady state of treatment (+2.1 cm3 [-10 - 14] p=0.72]) and no signs of change in cellular infiltration of the pancreas were found (p=0.22). During titration of liraglutide, FLT-uptake increased (+0.09 g/mL [0.000 - 0.17], p=0.05). In conclusion, six weeks of treatment with liraglutide did not affect pancreatic volume, edema or cellularity in obese individuals. Increased DNA synthesis reflected by FLT-uptake in the pancreas seen after four weeks of liraglutide treatment may be responsible for the increase in pancreatic enzymes. Disclosure M.S. Svane: None. H.H. Johannesen: None. C. Martinussen: None. K.N. Bojsen-Moller: None. M.L. Hansen: None. A.E. Hansen: None. C.F. Deacon: Employee; Spouse/Partner; Merck & Co., Inc. Stock/Shareholder; Spouse/Partner; Merck & Co., Inc. Other Relationship; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novartis AG, Novo Nordisk A/S. B. Hartmann: None. S.H. Keller: None. T.L. Klausen: None. A. Loft: None. A. Kjaer: None. S. Madsbad: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. J.O. Löfgren: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S, Novo Nordisk Foundation. Speaker’s Bureau; Self; Merck Sharp & Dohme Corp.

Acalculous Acute Pancreatitis in a COVID-19 Patient.

Coronavirus disease 2019 (COVID-19) is a multisystemic condition caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with manifestations ranging from mild upper respiratory symptoms to cytokine storm causing acute respiratory distress syndrome. Pancreatic exocrine tissue and endocrine islets both express angiotensin-converting enzyme 2 (ACE2), the proven receptor for SARS-CoV-2 cell internalization. An increase in pancreatic enzymes has been increasingly recognized in patients with COVID-19, but little is known about the real prevalence of acute pancreatitis in this population. We report a case of acute acalculous pancreatitis in a COVID-19 patient.LEARNING POINTSAcute pancreatitis may be a manifestation of SARS-CoV-2 infection.Future studies must address the real impact of pancreatic involvement in COVID-19 patients.

Effect of triploidy on digestive enzyme activity of early stages of turbot (Scophthalmus maximus).

In the present work, growth and digestive enzyme activities of total acid and alkaline proteases, pepsin, trypsin, lipase, and α-amylase, as well as partial characterization of enzyme activity, were studied in diploid and triploid turbot. Growth was similar between both groups. Acid protease activity increased consistently during the experiment, for both diploid (2n) and triploid (3n) fish. The alkaline protease activity was always higher for triploids throughout the experiment. Proteolytic acid activity (pH2) was generally higher for diploids, at all temperatures tested. Higher activity was at pH2 and 3 for 2n and 3n fish, respectively. Regarding temperature, acid and alkaline protease activity was higher at 37°C and 60°C, respectively, for both groups. The general increase in pancreatic enzymes (trypsin and amylase) before 35days after hatching (DAH) and posterior decrease until 60 DAH. There was a marked effect on enzyme activity when changing from live prey to pellets (35 DAH), especially on triploids.

Quantitative ultrasound and the pancreas

Pancreatitis is inflammation of the pancreas. Cerulein-induced pancreatitis in animal models can cause a significant increase in pancreatic enzymes in blood, as well as interstitial edema and inflammatory cell infiltration in the pancreas. This degree of pancreatitis is mild; all animals survive the induction of pancreatitis and resolves within ~6 days after induction, making this an excellent model to study the attenuation coefficient (AC: dB/cm-MHz) and backscatter coefficient (BSC: 1/cm-sr) of the pancreas temporally. The edematous stroma and shrinkage and dedifferentiation of acinar cells, has certain similarities with the morphology in some forms of pancreatic carcinoma. The pancreas’ AC and BSC (20-50 MHz) were estimated in vivo and ex vivo at baseline (before cerulein injections) and at 24 h, 48 h and 72 h after cerulein injections in Sprague-Dawley rats (N = 24). AC and BSC showed the same trends whereby (relative to baseline values) the 24-h AC decreased ~0.3 dB/cm-MHz and BSC decreased ~1-2 dB w...

Thrombosis of pancreatic arteriovenous malformation induced by diagnostic angiography: case report

BackgroundWe report on a case of pancreatic arteriovenous malformation (PAVM) that obliterated shortly after diagnostic angiography (DSA). PAVM is a rare anomaly that presents with upper abdominal pain, signs of acute pancreatitis and massive gastrointestinal bleeding. The management of PAVM is rather complex, with complete treatment usually accomplished only by a total extirpation of the affected organ or at least its involved portion. DSA prior to treatment decisions is helpful for characterizing symptomatic PAVM, since it can clearly depict the related vascular networks. In addition, interventional therapy can be performed immediately after diagnosis.Case presentationA 39-old male was admitted due to recurring upper abdominal pain that lasted several weeks. Initial examination revealed the absence of fever or jaundice, and the laboratory tests, including that for pancreatic enzymes, were unremarkable. An abdominal ultrasound (US) showed morphological and Doppler anomalies in the pancreas that were consistent with a vascular formation. A subsequent DSA depicted a medium-sized nidus, receiving blood supply from multiple origins but with no dominant artery. Coil embolization was not possible due to the small caliber of the feeding vessels. In addition, sclerotherapy was not performed so as to avoid an unnecessary wash out to the non-targeted duodenum. Consequently, the patient received no specific treatment for his symptomatic PAVM. A large increase in pancreatic enzymes was noticed shortly after the DSA procedure. Imaging follow-up by means of CT and MRI showed small amounts of peripancreatic fluid along with a limited area of intra-parenchymal necrosis, indicating necrotizing pancreatitis. In the post-angiography follow-up the patient was hemodynamically stable the entire time and was treated conservatively. The symptoms of pancreatitis improved over a few days, and the laboratory findings returned to normal ranges. Long-term follow-up by way of a contrast-enhanced CT revealed no recanalization of the thrombosed PAVM.ConclusionThe factors associated with the obliteration of PAVM during or after DSA are poorly understood. In our case it may be attributed to the low flow dynamics of PAVM, as well as to the local administration of a contrast agent. Asymptomatic PAVM, as diagnosed with non-invasive imaging techniques, should not be evaluated with DSA due to the potential risk of severe complications, such as acute pancreatitis.

Development of Non-alcoholic Fatty Liver Disease Following Pancreatectomy

Introduction: Non-alcoholic fatty liver disease (NAFLD) is defined as fat in the hepatocytes in excess of 5% of total liver weight or fatty degeneration of more than one-third of the total number of cells in the liver with the absence of alcohol use. NAFLD is usually associated with obesity, hyperlipidemia, or insulin resistance. The development of NAFLD may be due to pancreatic exocrine dysfunction and NAFLD has been shown to be influenced by the volume of remnant pancreas. We present a case of a patient with NAFLD after a pancreatectomy. Case Report: A 36 year old female presented with refractory epigastric and left upper quadrant abdominal pain associated with 2 days of vomiting and inability to tolerate a diet. Her past medical history is significant for diabetes mellitus type 1 (present since childhood, last Hgb A1C: 6.6), and chronic pancreatitis secondary to sphincter of oddi dysfunction which required a total pancreatectomy 6 months prior. Following her pancreatectomy the patient was symptom free for 3 months, after which she developed recurrent and persistent abdominal pain with nausea, vomiting, and diarrhea. She admitted to a weight loss of more than 50 pounds since her surgery. She denied alcohol intake and stated compliance with medications including insulin and pancreatic enzymes. On evaluation her vital signs included a blood pressure of 105/54, heart rate of 80, and temperature of 36.3C. Her BMI had decreased from 31 prior to the surgery to 22 after the surgery. Her abdomen was soft but she had tenderness to palpation in the epigastric area and bilateral upper quadrants with hepatomegaly. Her laboratory studies were significant for elevated AST and ALT of 98 and 71 respectively, which were normal prior to surgery. Her lipid panel revealed triglycerides, 93; cholesterol, 59; HDL, 16; and LDL, 27. Computed tomography of the abdomen was performed and showed new hepatomegaly with the largest diameter of 25 cm with fat deposition. She was treated with in an increase in pancreatic enzymes. Discussion: This case illustrates a less common cause of NAFLD. Patients with post pancreatectomy NAFLD can develop non-alcoholic steatohepatitis (NASH) and should be monitored for progression of this disease. Further research is needed to evaluate etiology and treatment options in this unique population, as there are currently limited recommendations for treatment.

Efficacy and Safety of Once-Weekly Dulaglutide Versus Insulin Glargine in Patients With Type 2 Diabetes on Metformin and Glimepiride (AWARD-2).

This study compared the efficacy and safety of once-weekly dulaglutide, a glucagon-like peptide-1 receptor agonist, with daily insulin glargine, both combined with maximally tolerated doses of metformin and glimepiride in patients with type 2 diabetes. The primary objective was noninferiority of dulaglutide 1.5 mg to glargine in the HbA1c change from baseline at 52 weeks. In this 78-week, open-label study, 810 patients were randomized to dulaglutide 1.5 mg, dulaglutide 0.75 mg, or glargine. The baseline mean ± SD HbA1c was 8.1 ± 1.0% (65.5 ± 10.8 mmol/mol). The least squares mean ± SE HbA1c change from baseline to the primary end point was -1.08 ± 0.06% (-11.8 ± 0.7 mmol/mol) for dulaglutide 1.5 mg, -0.76 ± 0.06% (-8.3 ± 0.7 mmol/mol) for dulaglutide 0.75 mg, and -0.63 ± 0.06% (-6.9 ± 0.7 mmol/mol) for glargine, with an end point mean ± SD dose of 29 ± 26 units (0.33 ± 0.24 units/kg), and a fasting plasma glucose (mean ± SD) of 118 ± 23 mg/dL from self-monitored plasma glucose. Statistical criteria for superiority were met with dulaglutide 1.5 mg and for noninferiority with dulaglutide 0.75 mg. More patients on dulaglutide 1.5 mg achieved HbA1c targets <7.0% (53 mmol/mol) versus glargine (P < 0.001). Body weight decreased with dulaglutide and increased with glargine. Total hypoglycemia rates were lower with dulaglutide; severe hypoglycemia was minimal. Increases in pancreatic enzymes were observed for dulaglutide. Incidence of nausea (15.4, 7.7, and 1.5%) and diarrhea (10.6, 9.2, and 5.7%) were more common with dulaglutide 1.5 mg and 0.75 mg than with glargine. Once-weekly dulaglutide 1.5 mg, compared with daily insulin glargine without forced titration, demonstrated greater HbA1c reduction and weight loss, with a higher incidence of gastrointestinal adverse events and a lower risk of hypoglycemia.

Effect of double-balloon enteroscopy on pancreas: an experimental porcine model.

To evaluate the effect of double-balloon enteroscopy (DBE) on pancreas histology and levels of pancreatic enzymes. Conventional upper gastrointestinal endoscopy was performed on five control pigs. Oral DBE was performed with an EN-450T5 enteroscope on 20 pigs. Two experimental groups (10 pigs each) were defined according to DBE duration: 90 min for Group 1 and 140 min for group 2. During oral insertion, the balloons were not inflated in the descending part of the duodenum to avoid the minor duodenal papilla. Serum amylase, lipase and C-reactive protein (CRP) levels were monitored before the procedure and repeated every 30 min until the exploration was finished, as well as 24 h and 7 d after. After the procedure and for a total of 7 d, the pigs were observed twice a day for signs of decreased activity, irritability, vomiting or anorexia. Gross and microscopic examination of the pancreas was performed on day 7. All animals tolerated DBE without clinical manifestations of acute pancreatitis. Experimental groups had higher levels of enzymes than the control group at 24 h. Throughout the exploration, the amylase levels increased significantly above the baseline 24 h after DBE, although the increase was not statistically significant and did not reach 20% of the baseline. An increase in lipase and CRP was observed at 24 h after the procedure, although by day 7, all enzymatic levels had returned to baseline. No differences between groups 1 and 2 were found for any enzyme and sampling site during and after the procedure. Similarly, no correlation between insertion depth and enzyme levels was observed. Direct in situ and post-removal inspection of the pancreas did not show any evidence of fluid collection, abscesses or hemorrhage. Histological examination of the pancreas from groups 1 and 2 revealed the existence of focal areas (0.14-0.26 mm2) of ischemic necrosis in 47.4% of the animals. In the pigs with damaged pancreas, the left lobe (tail) was always affected. However, this only happened in 83.3% of the samples from the right lobe (head) and in 33.3% of the samples from the body of the pancreas. Significant differences were found between the left lobe (tail) and the body for the percentage of affected pancreas. Both the size of the lesions and the percentage of affected pancreas were higher in the left pancreatic lobe (tail). The presence of the lesions was not related to the exploration length. The increase in pancreatic enzymes after DBE could be related to focal points of pancreatic ischemic necrosis due to mechanical stress.

Next Generation Therapy in Chronic Myeloid Leukemia

TKIs Imatinib is an established first-line therapy CP of CML. Before Imatinib therapy, IFN-alpha was a treatment option for CML because it induced durable remissions in a subset of CP patients. However, because of IFN toxicity, and its limited and unpredictable efficacy, IFN-alpha was displaced by Imatinib, with its limited toxicity and marked efficacy in the treatment of most CML patients. Imatinib has limitations, but the 5-year survival rate with Imatinib is approx. 89% compared with Interferon and Cytarabin (70%). About 15–20% CML become resistant to Imatinib, and the resistance is found in association with a BCR/ABL mutation T315I or with G250E mutations. Treatment of Imatinib-resistance CML is thus a challenge in clinical hematology. In addition, clinical evaluation of Imatinib has shown adverse effects, such as fatigue, severe nausea, vomiting, oedema, fluid retention, muscle cramps, muscular skeletal pain, and cutaneous disorders. With the prolonged survival time in CML, which with Imatinib is a median 40 months, BCC, SCC, melanoma (30% cases), breast cancer (the authors have found 1 case), prostate cancer (1 case), GI cancer, GU bladder cancer including RCC, a few pancreatic and cholangiocarcinomas, and metastatic carcinoma of unknown origin have also been reported in various literature [1]. These investigators concluded that increased rates of cancers were found at a large range of sites and there was immune deficiency, regardless of the mechanism of deficiency. There have also been scattered reports of co-existence of CML with other lymphoid malignancies such as CLL and multiple myeloma [1, 2]. It has also been shown that heart failure occurs in 1 in 1,000 patients receiving Imatinib, and that it also alters bone metabolism. Imatinib costs more than the Interferon + Cytarabin combination. The effects of Imatinib (as well as other kinase inhibitors) on leukemic stem or initiating cells are limited, and so it has been advisable to take a low dose of Imatinib over a long period. Now, the second generation TKIs, such as Dasatinib and Nilotinib, have appeared. A unique spectrum of adverse events has occurred and been reported for both these TKIs [3, 4]. For Dasatinib-treated patients, the occurrence of pleural effusion has been a clinical challenge, especially when pleural effusion becomes recurrent or is accompanied by pericardial effusion, pulmonary hypertension, or an infection. Also, potential risk factors such as a pre-existing cardiac disease, arterial hypertension, or auto-immune disorders have been described for these TKIs. Several non-hematologic adverse events have been described for Dasatinib, including diarrhea, skin rash, bleeding, viral re-activation, and sometimes also many opportunistic infections, which have been reported in patients receiving Dasatinib at a dose of 270 mg daily. Nilotinib-treated patients have developed increases in pancreatic enzymes, bilirubin, and fasting glucose levels. Other non-hematologic adverse events of Nilotinib include diarrhea, folliculitis-like skin rash, and bleeding. There are a few reports of severe peripheral arterial occlusive disease (PAOD) and other vascular occlusive events (infarction) in patients receiving Nilotinib [3, 4]. Several of these patients developed a rapidly progressive and highly resistant form of PAOD after switching from Imatinib to Nilotinib [3, 4]. The question is whether patients, who had a complete molecular response (CMR or MCyR) to Imatinib or Imatinib in combination with Interferon, could safely stop drug treatment? What should be done with relapses? Do TKIs act then? SCT is still the treatment for CML that is considered to be curative in patients with AP or blast-crisis CML. Other choices which are still in clinical trial include a vaccine called CMLVAX100 which is given along with Imatinib to see if there is an increase in its effectiveness. Research into this and other cancer vaccines is continuing. The oral agent AP24534 also appears to have some activity independent of Bcr-Abl mutation. Cortes and colleagues [5] conducted a trial of AP24534 in patients with refractory CML and other hematologic malignancies. This agent inhibits survival of cell lines expressing Bcr-Abl variants at an inhibitory concentration of less than 40 nM. It also inhibits Flt-3 and c-Src. And this agent has the advantage of being orally administered.

Nilotinib Exerts Direct Effects on Vascular Endothelial Cells and May Act As a Co-Trigger of Atherosclerosis in Patients with Ph+ CML

Abstract▪2753▪This icon denotes a clinically relevant abstractThe second-generation BCR/ABL tyrosine kinase inhibitor nilotinib is increasingly used for the treatment of patients (pts) with newly diagnosed Ph+ CML or imatinib-resistant CML. So far, nilotinib has been considered a well-tolerated drug that shows little if any relevant side effects. However, long-term results are not available yet. Known recurrent side effect of nilotinib include an increase in pancreatic enzymes (lipase, amylase) and an increase in fasting glucose levels. More recently, several centers have reported on the occurrence of progressive peripheral arterial occlusive disease (PAOD) in some of their pts treated with nilotinib. The exact relationship with drug intake and the potential mechanisms underlying PAOD development remain unknown. To address these questions, we have extended and updated our retrospective analysis and examined the in vitro effects of nilotinib. A total number of 34 pts (second line nilotinib, n=33; first line nilotinib, n=1; females, n=15; males, n=19, median age: 57.5 years) receiving nilotinib in our center were examined (observation period 2006–2011). Vascular events related to atherosclerosis were recorded in 9 pts (26.5%). Of these, 6 (17.6%) had PAOD, including 2 cases of severe PAOD requiring repeated surgical interventions or amputation (n=1). One patient had a myocardial infarction, one an acute coronary artery syndrome requiring bypass surgery, and one a spinal infarction. Although in all 9 pts, one or more pre-existing risk factors for atherosclerosis were identified, none of these pts had developed a vascular event during prior imatinib therapy. The JAK2 V617F mutant was not found in any of the 9 pts. Three pts died during the observation period, two from major bleeding episodes, and one from sudden death of unknown etiology. In 5 cases, an increase in blood glucose levels was found, and 1 patient developed overt diabetes mellitus. The frequency of PAOD development in age-, observation time-, and risk factor-matched control cohorts (CML pts receiving imatinib, lymphoproliferative neoplasms, JAK2 V617F+ myeloproliferative neoplasms, each n=34 pts) was significantly lower (<5%) than in the nilotinib group (p<0.05 by Chi Square test with Boneferroni correction). As assessed by 3H-thymidine uptake, nilotinib was found to inhibit the growth of the human microvascular endothelial cell line HMEC-1 (IC50: 0.5–1.5 μM), whereas no substantial effect was seen with imatinib. Furthermore, nilotinib, but not imatinib, was found to inhibit umbilical vein endothelial cell (HUVEC) migration and sprouting in a scratch-wound healing assay. Finally, nilotinib but not imatinib, was found to block the growth of various human pancreatic cell lines, including PANC-1 and the insulin- producing cell line 1.4E7. Together, our data show that nilotinib exerts direct inhibitory effects on endothelial cells and pancreatic cells. Whether these drug effects contribute to vascular events seen in our nilotinib-treated pts remains at present unknown. In addition, the exact pro-atherogenic effect of nilotinib in second-line and first-line treated patients with CML remains unknown since no data from prospective clinical trials focusing on this issue, are available. Until these questions and safety-issues have been clarified, it may be advisable to take certain co-morbidities into account when considering the use of nilotinib in CML patients. In addition, the follow up of long-term treated patients should include parameters that can detect vascular events and predisposing co-morbidities as early as possible. Disclosures:Valent:Novartis: Consultancy, Honoraria, Research Funding.

Abstract A1: Phase 1 study of PF-03446962, a fully human mAb against activin receptor-like kinase 1 (ALK 1), a TGFβ receptor involved in tumor angiogenesis.

Abstract Background: Transforming Growth Factor β (TGF β) is a cytokine able to regulate many biological processes in cancer. At the vascular level, the activity of TGFβ is exerted by selectively binding to its receptor, activin receptor like kinase 1 (ALK-1), triggering a downstream signaling involving intracellular and nuclear proteins (SMADs and Id1) and leading to transcriptional upregulation of proangiogenic factors. ALK-1 deficiency is related to a clinical syndrome called hereditary hemorrhagic telangectasia. PF-03446962 is a fully human mAb against ALK-1 with dose dependent antiangiogenic activity as demonstrated preclinically in human tumour xenografts. Mechanistic studies indicated that ALK 1 and VEGF signalling pathways may promote angiogenesis in a collaborative manner. Methods: We conducted a Phase 1 trial in patients (pts) with solid tumors. Primary objectives: identify MTD and a recommended phase 2 dose (RP2D); secondary objectives included safety profile, PK, antitumor activity, soluble proteins TGFβ related and blood flow by contrast enhanced ultrasound (CE-US). Results: 44 pts have been enrolled on 8 dose levels (0.5–15 mg/kg). PF-03446962 is administered iv on Day 1, 29 and then q 2 weeks. 15 mg/kg was defined as maximum administered dose, with DLTs represented by G3 thrombocytopenia and increase in pancreatic enzymes in 2/6 pts. Noteworthy 3 pts developed telangectasia suggesting an in vivo knock-out of the ALK-1 function. The dose of 6.75 mg/kg was defined as RP2D and PK data support the proposed regimen with drug concentration above the estimated therapeutic concentrations during each cycles. 3 PRs were observed, one hepatocellular carcinoma (HCC) resistant to anti-VEGF therapy, one NSCLC and one RCC (both NSCLC and RCC still ongoing). SD lasting for at least 16 weeks was observed in 7/44 pts, with 2 patients (adrenocortical ca. and mesothelioma) lasting for approximately 12 months from treatment start. 2/5 HCC pts showed a TTP of 5.5–6 months similar to those observed with sorafenib in first line. Of note all patients with PR and most of SDs were treated with prior antiangiogenic therapy. In preclinical models, PF-03446962 exerted antitumor activity in tumors resistant to VEGFRTKIs thus suggesting ALK 1 as potential mechanism of escape from VEGF blockade. CE-US showed changes consistent with reduced blood flow in 2/3 pts assessed at this time. Conclusions: PF-03446962 is a first in class mAb anti ALK-1, safe and with manageable toxicities, mainly characterized by asymptomatic elevation of pancreatic enzymes and transient platelet decreases. Based on clinical activity, anti ALK 1 may be a promising novel antiangiogenic strategy with particular interest for pts who failed anti VEGF/VEGFRTKI in clinic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A1.