Elevated Pancreatic Enzymes Research Articles

Pancreatic duct drainage using EUS-guided rendezvous technique for stenotic pancreaticojejunostomy

The patient was a 30-year-old female who had undergone excision of the extrahepatic bile duct and Roux-en-Y hepaticojejunostomy for congenital biliary dilatation at the age of 7. Thereafter, she suffered from recurrent acute pancreatitis due to pancreaticobiliary maljunction and received subtotal stomach-preserving pancreaticoduodenectomy. She developed a pancreatic fistula and an intra-abdominal abscess after the operation. These complications were improved by percutaneous abscess drainage and antibiotic therapy. However, upper abdominal discomfort and the elevation of serum pancreatic enzymes persisted due to stenosis from the pancreaticojejunostomy. Because we could not accomplish dilation of the stenosis by endoscopic retrograde cholangiopancreatography, we tried an endoscopic ultrasonography (EUS) guided rendezvous technique for pancreatic duct drainage. After transgastric puncture of the pancreatic duct using an EUS-fine needle aspiration needle, the guidewire was inserted into the pancreatic duct and finally reached to the jejunum through the stenotic anastomosis. We changed the echoendoscope to an oblique-viewing endoscope, then grasped the guidewire and withdrew it through the scope. The stenosis of the pancreaticojejunostomy was dilated up to 4 mm, and a pancreatic stent was put in place. Though the pancreatic stent was removed after three months, the patient remained symptom-free. Pancreatic duct drainage using an EUS-guided rendezvous technique was useful for the treatment of a stenotic pancreaticojejunostomy after pancreaticoduodenectomy.

Marked elevation of transaminases and pancreatic enzymes in severe malnourished male with eating disorder.

We report a case of a 45 year old Caucasian malnourished male with an history of eating disorder who developed severe liver and pancreatic damage and multiorgan disfunction. At admission to our department, his body mass index (BMI) was 11.1. Biochemical evaluation showed elevated serum levels of transaminases (AST= 2291 U/L, ALT= 1792 U/L), amylase (3620 U/L), lipase (4102 U/L), CPK= 1370 U/L, LDH= 2082 U/L. No other cause of acute liver and pancreatic damage was evidenced. Haematological disorders (anemia, thrombocytopenia, leukopenia) found on admission seem related to bone marrow hypoplasia and to gelatinous marrow transformation described in severe state of malnutrition. Although a moderate increase in liver and pancreatic enzymes are a common finding in malnourished patients, only a small number of reports describes severe liver injury and multiorgan dysfunction. After a few days of treatment (hydration and nutritional support) a marked decrease of serum transaminases, lipase, amylase, CPK, LDH occurred, despite a transient increase in these levels secondary to refeeding syndrome. The association of chronic malnutrition and a decrease in systemic perfusion may be responsible for multiorgan dysfunction. In our patient the high levels of transaminases and pancreatic enzymes were the most important biochemical abnormalities normalized after refeeding.

Increased variability and abnormalities in pancreatic enzyme concentrations in otherwise asymptomatic subjects with type 2 diabetes

BackgroundRecent studies have demonstrated an increased incidence of pancreatitis in patients with type 2 diabetes compared with obese nondiabetic individuals. Serum lipase and pancreatic amylase concentrations are used in conjunction with clinical findings to diagnose pancreatitis.MethodsIn two large clinical trials of overweight/obese nondiabetic and type 2 diabetic subjects, lipase and pancreatic amylase were measured at screening and 2–5 weeks later at baseline (prior to treatment with study medication).ResultsLipase and pancreatic amylase concentrations were above the upper limit of normal (ULN) in 13% and 6% of type 2 diabetic subjects, respectively, and were approximately three-fold (3 ×) higher than the proportion of nondiabetic subjects with levels above ULN. Elevations exceeding ULN were seen in many subjects asymptomatic for pancreatitis; however, elevations >2 × ULN and >3 × ULN were uncommon, and elevations >3 × ULN were often associated with a history of dyslipidemia, hyperlipidemia, and gastrointestinal disorders. Additionally, enzyme concentrations varied within this 2–5-week screening period, including shifts between elevated and normal levels.ConclusionResults from this post hoc analysis suggest that, although pancreatic enzymes can be a useful marker for pancreatitis within the proper clinical context, diagnosis of pancreatitis may be confounded in populations known to have asymptomatic elevations associated with disease, such as type 2 diabetes. Further effort is needed to clarify the etiology and epidemiology of pancreatic enzyme elevations in type 2 diabetes.

A Rapidly Progressive Case of Hemorrhagic Pancreatitis in a Patient with Polycythemia Vera, or Not?

Introduction: Acute pancreatitis and polycythemia vera are risk factors for mesenteric vein thrombosis. Rates of significant thrombosis and hemorrhage are reported as approximately 25% for either in patients with PCV. The case describes the difficult dilemma that occurs when clinical presentation includes both thrombo-hemorrhagic complications simultaneously. Case: A 62-year-old woman with a history of polycythemia vera was admitted for severe upper abdominal pain, nausea, vomiting and CT findings consistent with acute pancreatitis and small pelvic hematoma. She had no other risk factors for pancreatitis such as gallstones, alcohol use, hypertriglyceridemia, drugs, or autoimmune phenomena. Admission laboratory evaluation was notable for white blood cell count of 50,000, platelet count of 2.4 million, and a normal lactate. Interestingly, amylase and lipase were also normal as well as CT abdomen/pelvis obtained 3 days prior. Conservative management for pancreatitis was initiated. Unfortunately, the patient deteriorated over the next 2 days, with worsening pain and peritoneal signs. A repeat CT abdomen/pelvis showed a peripancreatic hematoma compressing the portal vein, progressive pelvic hematoma, superior mesenteric vein thrombus, and new ileus. She was taken emergently to the operating room for evacuation of peripancreatic hematoma, oversewing of bleeding vessels in right retroperitoneum, and packing of abdomen with temporary closure. Plasma exchange (PLEX) and hydroxyurea were initiated for cytoreduction of the dysfunctional platelet load in hopes of preventing further bleeding or thrombotic complications. Platelets improved to 1 million. Anticoagulation was held despite her prothrombotic state and mesenteric thrombosis in the setting of large retroperitoneal hematoma. Discussion: The diagnostic criteria for pancreatitis include two of the following: characteristic abdominal pain, elevated pancreatic enzymes, or imaging consistent with the diagnosis. Our patient met the criteria without an elevated amylase or lipase. However, upon review of the clinical picture and laparotomy findings, the peripancreatic changes were not consistent with acute pancreatitis. Instead, local hemorrhage and inflammatory changes related to the disease process of polycythemia vera were mimicking pancreatitis. In evaluating patients with presumed pancreatitis special attention should be paid to the overall clinical picture to avoid overdiagnosis. Similarly, early recognition of alternative diagnoses would allow prompt institution of appropriate therapy.

Chylomicronemia Syndrome in Pregnancy: a Case Report of an Acute Necrotizing Pancreatitis.

Introduction: Chylomicronemia syndrome (CS) is a rare disorder characterized by a high level of triglycerides in plasma. We present a case of a pregnant woman with a severe acute pancreatitis (AP) affected by a CS. Case: A 38-year-old gravida 2, para 0 with an uneventful course of pregnancy was referred with an AP at 37 0/7 weeks of gestation. This diagnosis was made from a nearby hospital where the chemical analysis showed elevated pancreatic enzymes with significant hypertriglyceridemia. Because of a pathological fetal heart tracing a caesarean delivery was performed. The APGAR score of the female newborn was 5/8/8 at 1, 5 and 10 minutes, respectively. The pH from the umbilical cord were 7.26 (artery) and 7.59 (vein). Once transferred to our intensive care unit a computer tomography scan confirmed an onset of a necrotizing AP. A conservative treatment was tried without success. For this reason a surgical debridement of the infected and necrosic parts was performed. After a long hospitalisation the patient could be dismissed after 2.5 months in good general condition. Discussion: Lipid profile changes in normal pregnancy are characterized by an elevation of total plasma cholesterol and triglyceride levels. This is normally caused by an increased liver synthesis of triglycerides in response to elevated estrogen levels. When a CS is diagnosed the main goal is to maintain fasting triglyceride levels at less than 500 mg/dL to reduce the risk for AP. Conclusion: Practitioners have an important role in evaluating chylomicronemic patients and implementing therapeutic lifestyle and pharmaceutic interventions aimed to reduce the risk for AP.

Fulminant Type 1 diabetes in a pregnant woman as an initial manifestation of the insulin autoimmune syndrome

Fulminant Type 1 diabetes is a subtype of Type 1 diabetes characterized by (1) abrupt onset of diabetes, (2) very short duration of hyperglycaemia with mildly elevated HbA(1c) (< 69 mmol/mol, 8.5%), (3) rapid progression to diabetic ketoacidosis, (4) very low C-peptide level, and (5) often associated with elevated serum pancreatic enzymes, and absence of diabetes-related autoantibodies. We encountered a case of fulminant Type 1 diabetes that developed with an initial manifestation of the insulin autoimmune syndrome and rapidly progressed to diabetic ketoacidosis during pregnancy. A 31-year-old Korean woman presented with recurrent sudden onset of sweating and change of consciousness during sleep at 19 weeks gestation. During a 72-h fasting test, hypoglycaemia (1.72 mmol/l) occurred at 4 h after the start of the test. At that time, there was a high insulin level (370.2 μU/ml), a paradoxically low C-peptide level (0.01 nmol/l) and a positive insulin autoantibody test. An oral glucose tolerance test revealed postprandial hyperglycaemia. She was initially diagnosed as the insulin autoimmune syndrome. On the day 5 of admission, she developed diabetic ketoacidosis. Her HbA(1c) was 62 mmol/mol (7.8%). The rapid progression of diabetic ketoacidosis altered the diagnosis to fulminant Type 1 diabetes. This case differed from typical fulminant Type 1 diabetes because it presented with hypoglycaemia, and positive insulin and anti-phospholipid antibody tests. Her HLA typing was HLA-DQA1*0302, 0501, HLA-DRB1*0301 (DR3), 0901(DR9). Her glucose level was subsequently very well controlled with multiple insulin injections and she successfully delivered a healthy baby.

La pancréatite lupique : une série de six cas

PurposeThe occurrence of acute pancreatitis in systemic lupus erythematosus (SLE) is known but rare, and is exceptionally the presenting manifestation. Its pathogenesis is multifactorial, and it is difficult to separate what belongs to vasculitis, thrombotic phenomena in the context of an associated antiphospholipid syndrome, or iatrogenic complications. We report on six cases of lupus pancreatitis. MethodsThis is a retrospective monocenter study of 110 patients with SLE. The diagnosis of lupus pancreatitis was established after exclusion of other causes of pancreatitis. ResultsFive women and one man (5.4%) with a mean age of 36.3years presented with lupus pancreatitis. In four patients the pancreatitis was concurrent with the diagnosis of SLE and it occurred later during an exacerbation of the disease in the two remaining patients. In all patients, pancreatic manifestations were associated with other organ involvement. Clinical manifestations were: abdominal pain (n=6), vomiting (n=3), and fever (n=3). Elevated pancreatic enzyme was noted in all cases. All patients were treated by high doses of glucocorticoids. The outcome was favorable in five patients, and one patient died. ConclusionPancreatitis may be the presenting manifestation of SLE. Its pathogenesis is often multifactorial. The outcome is usually favorable with corticosteroids.

Metastatic Embryonal Rhabdomyosarcoma to the Pancreas Presenting as Acute Pancreatitis Detected by FDG PET/CT

An 8-year-old boy with history of embryonal rhabdomyosarcoma resected 2 years ago presented with abdominal pain and elevated pancreatic enzymes. Acute pancreatitis was diagnosed, and appropriate therapy was started. An FDG PET/CT scan revealed a hypermetabolic region in the pancreas suspicious for malignancy; however, the patient's condition improved after therapy. A repeat PET/CT scan performed 3 weeks later for recurrent symptoms showed interval disease progression, consistent with metastatic disease. Our case indicates that pancreatitis can accompany malignancy or be related to the obstruction caused by tumor, and patient's response to therapy for acute pancreatitis does not rule out malignancy.

Acute Pancreatitis Associated With Campylobacter jejuni Enteritis: A Case Report

A 62-year-old male developed pancreatitis including elevation of pancreatic enzymes and evidence of pancreatic inflammation on imaging in association with Campylobacter jejuni enteritis. Hyperamylasemia in association with C. jejuni enteritis has been reported occasionally. Though many reports in the literature are incomplete, to our knowledge, only a single prior report of pancreatitis associated with Campylobacter jejuni enteritis included radiographic evidence of pancreatic inflammation. doi:10.4021/jmc541w

A Randomized Trial of Rectal Indomethacin to Prevent Post-ERCP Pancreatitis

BackgroundPreliminary research suggests that rectally administered nonsteroidal antiinflammatory drugs may reduce the incidence of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP).MethodsIn this multicenter, randomized, placebo-controlled, double-blind clinical trial, we assigned patients at elevated risk for post-ERCP pancreatitis to receive a single dose of rectal indomethacin or placebo immediately after ERCP. Patients were determined to be at high risk on the basis of validated patient- and procedure-related risk factors. The primary outcome was post-ERCP pancreatitis, which was defined as new upper abdominal pain, an elevation in pancreatic enzymes to at least three times the upper limit of the normal range 24 hours after the procedure, and hospitalization for at least 2 nights.ResultsA total of 602 patients were enrolled and completed follow-up. The majority of patients (82%) had a clinical suspicion of sphincter of Oddi dysfunction. Post-ERCP pancreatitis developed in 27 of 295 patients (9.2%) in the indomethacin group and in 52 of 307 patients (16.9%) in the placebo group (P=0.005). Moderate-to-severe pancreatitis developed in 13 patients (4.4%) in the indomethacin group and in 27 patients (8.8%) in the placebo group (P=0.03).ConclusionsAmong patients at high risk for post-ERCP pancreatitis, rectal indomethacin significantly reduced the incidence of the condition. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00820612.)

KOLELİTİYAZİSE SEKONDER OLARAK GELİŞEN AKUT PANKREATİTE BAĞLI PSÖDOKİST OLGUSU

ABSTRACT Acute pancteatitis is defined as sudden onset of abdominal pain and elevation of pancreatic enzymes in blood and/or urine, and radiographic changes of pancreas. Acute pancreatitis is uncommon in children when compared with adults. We reported the case of acute pancreatitis in a 12 years old boy with pseudocyst formation and pancreatic necrosis secondary to acute cholelithiasis. Key words: Acute pancreatit; child; cholelithiasis; pancreatic necrosis; pseudocyst. OZET Akut pankreatit ani baslangicli karin agrisi, kan ve/veya idrarda pankreatik enzimlerde artma ve pankreasta radyolojik degisiklikler seklinde tanimlanir. Eriskinlere kiyasla cocuklarda akut pankreatit sik gorulmez. Psodokist ve pankreatik nekroz bulgulari olan 12 bildirilmistir. Anahtar Kelimeler: Akut pankreatit; cocuk;karinagrisi;kolelitiyazis;p ankreatik nekroz; psodokist . INTRODUCTION Although paediatric pancreatitis is not common, the incidence of acute pancreatitis in children has increased over the past 10–15 years (1-4). Most children recover uneventfully, but some develop severe disease, and some die (5). Unlike acute pancreatitis in the adult population, paediatric pancreatitis is rarely to biliary stone disorders or alcoholism. Instead, the leading causes of pancreatitis tend to be idiopathic, trauma, infections, systemic diseases (e.g. HUS), drugs, congenital disorders (e.g. pancreatic divisum, choledochal cyst and cystic fibrosis) (2,3). Most of the cases are presented as abdominal pain or vomiting. Pain is usualy epigastric, in the right upper quadrant. Nausea and vomiting are

Acute Pancreatitis Associated With Campylobacter jejuni Enteritis: A Case Report

A 62-year-old male developed pancreatitis including elevation of pancreatic enzymes and evidence of pancreatic inflammation on imaging in association with Campylobacter jejuni enteritis. Hyperamylasemia in association with C. jejuni enteritis has been reported occasionally. Though many reports in the literature are incomplete, to our knowledge, only a single prior report of pancreatitis associated with Campylobacter jejuni enteritis included radiographic evidence of pancreatic inflammation. J Med Cases. 2012;3(3):167-168 doi: https://doi.org/10.4021/jmc541w

A Rare Cause of Acute Pancreatitis: Intramural Duodenal Hematoma

We describe an interesting case of intramural duodenal hematoma in an otherwise healthy male who presented to emergency room with gradually progressive abdominal pain, nausea, and vomiting. This condition was missed on initial evaluation and patient was discharged from emergency room with diagnosis of acute gastritis. After 3 days, patient came back to emergency room and abdominal imaging studies were conducted which showed that patient had intramural duodenal hematoma associated with gastric outlet obstruction and pancreatitis. Hematoma was the cause of acute pancreatitis as pancreatic enzymes levels were normal at the time of first presentation, but later as the hematoma grew in size, it caused compression of pancreas and subsequent elevation of pancreatic enzymes. We experienced a case of pancreatitis which was caused by intramural duodenal hematoma. This case was missed on initial evaluation. We suggest that physicians should be more vigilant about this condition.

Alta frecuencia de pancreatitis aguda asociada a patología biliar en niños chilenos

Elevated frequency of Acute Pancreatitis Associated to biliary Illness in Chilean Children Acute Pancreatitis (AP) in children presents signifi cant morbimortality. Most common etiologies in this age group are trauma, systemic illness and idiopathic pancreatitis. This is different from adult AP, where lithiasis and alcohol consumption are the predominant causes. In Chile, where billiary disease is highly prevalent, there is little information regarding AP among children. Objective: To determine the main clinical characteristics of acute pancreatitis in a group of chilean children. Patients and Methods: A retrospective study (1998-2008) of patients hospitalized with the diagnosis of AP. The diagnosis was confi rmed by elevation of pancreatic enzymes and through images. Demographic data, etiology, complications and resolutions, need for parenteral nutrition, and use of antibiotics were examined. Results: Eighteen patients were identifi ed (8,3 ± 4 y.o.). Etiology of AP was listed as: lithiasis and alterations of biliary duct: 38,8%, idiopathic: 22,2%, secondary to medications: 22,2% and other: 16.8%. Two patients presented peripancreatic infected collections; a similar number formed pancreatic pseudocysts. Six patients (33,3%) required one type of surgical procedure as part of their treatment. Two-thirds of all patients required treatment in ICU. One half of the patients required parenteral nutrition, and two thirds received IV antibiotics. The median length of hospital stay was 20 days (ave 24,9 ± 14,3 ds). There was no mortality in this serie. Conclusions: Unlike previously described, biliary AP was the most common cause in this serie. Biliary pathology should be actively studied among chilean children with AP. (Key words: Acute pancreatitis, cholelithiasis, children). (Rev Chil Pediatr 2011; 82 (6): 525-530

Histiocytis Sarcoma-Targeted Therapy: Novel Therapeutic Options? A Series of 4 Cases

Abstract 5005Case 1: A 23-year old man presented with a newly diagnosed Histiocytic Sarcoma (HS) of the neck. Tracheotomy had to be performed due to a massive swelling of the neck and pharynx. Chemotherapy was initiated in combination with local irradiation therapy with the aim of stabilization of the fulminate disease course.To gain further insight in the tumour's biology an extensive immunohistochemistry exploration was done. A positive reaction with antibodies (AB) against PDGFRalpha and VEGFR2 and VEGFR3 was detected with variable staining intensities and number of tumor cells. According to this marker profile the tyrosinkinase inhibitor Imatinib and the immunomodulating agent thalidomide were added to the chemotherapy regimen. The therapy regime of both agents, which can only be applied orally, could only partially be followed due to the massive pharyngeal mass and repeated emesis. After two cycles of chemotherapy the patient showed progressive disease and succumbed to fulminant pericardial effusions and progressive disease.Case 2: A 53-years old female with a history of exogenous allergic asthma bronchiale was admitted to a hospital. CT scan was performed and the presumption diagnosis of pneumonia was made. Due to thickened pleura with suspect pericardial infiltrations the differential diagnosis of mesothelioma was reported and a video assisted thoracoscopy with biopsies were obtained. Immunohistochemistry was positive for EGFR, PDGFRalpha, PDGFRbeta, and VEGFA20. Two cycles of an experimental therapy regime containing Imatinib and Bevacizumab, combined with chemotherapy were applied. Restaging imaging studies showed a stable tumour load in the CT and PET scans. The patient could be discharged under continuation of daily imatinib therapy and bevacizumab every 14 days. Five months later the patient showed progressive disease and succumbed.Case 3: A 48-year old male patient presented with a newly diagnosed HS of the right upper leg. Tumour tissue could not be removed in sano due to infiltration of the surrounding fat tissue. Seven months later the patient was hospitalised again with a local recurrent tumor. According to the literature two cycles of chemotherapy for extramedullary myeloid leukaemia was applied and the patient was discharged in a complete remission. Seven months later the patient developed severe back pain and a biopsy of the spine was taken. Histology reported metastasis of HS. A polychemotherapy was applied coming up with a no change course of the disease. An immunohistochemical workup showed a positive reaction with antibodies against EGFR, PDGFRalpha PDGFRbeta and VEGFC1. A Bevacizumab monotherapy was applied for three times, however showing no response. Finally, the patient died due to progressive disease.Case 4: A 68-year old female was admitted to hospital after diagnosis of a HS of the intestinal tract. A tumor of the terminal ileum of six cm in greatest diameter had been surgically removed in sano. Five weeks later the patient presented with pathologically enlarged mediastinal and abdominal lymph nodes in CT scan. Progressive disease was confirmed by a PET scan. An immunohistochemical workup showed a positive reaction with AB against PDGFRalpha, PDGFRbeta, VEGFR2 and VEGFR3 An experimental treatment approach of two cycles with a combination of Bevacizumab and chemotherapy was applied. In addition a low dose maintenance therapy with Sorafenib 2×400mg daily was administered due to pancytopenia. Therapy had to be discontinued after one month due to elevation of pancreatic enzymes. A restaging CT scan showed no pathological enlarged lymph nodes and a PET scan, two months after initiation of therapy, revealed a complete metabolic remission. Five months later on control revaluation remission was stable by CT and PET scan. Nowadays, almost two years later, the patient is still in an ongoing complete remission without any further therapy. Disclosures:No relevant conflicts of interest to declare.

Abstract C18: A phase I study of enavatuzumab (PDL192, ABT-361), a first-in-class human monoclonal antibody targeting TWEAK (tumor necrosis factor-like inducer of apoptosis) receptor, in patients (Pts) with advanced solid tumors.

Abstract Background: TWEAK receptor (TweakR, TNFRSF12A, CD266) is a member of the TNF receptor superfamily and is expressed on a range of solid tumors. Enavatuzumab is a humanized IgG1 antibody to TweakR that exhibits anti-tumor activity in preclinical models through two mechanisms: direct signaling through TweakR and antibody-dependent cellular cytotoxicity. Methods: This phase I, multicenter study was designed to determine the maximum tolerated dose (MTD) and to evaluate the safety and pharmacokinetic (PK) profiles of enavatuzumab, given intravenously over 60 minutes on days 1 and 15 of each 28-day cycle. Pts with advanced solid tumors; ECOG ≤1; adequate hematologic, renal, and hepatic function; no brain metastasis; no history of cirrhosis or pancreatitis; no recent history of acute cholecystitis; and not on immunosuppressive drugs were enrolled. Cohorts of 3–6 pts were treated at escalating dose levels of enavatuzumab ranging from 0.1 mg/kg to 1.5 mg/kg. Dose limiting toxicity (DLT) was defined as grade (G) 3 AST or ALT lasting &amp;gt;14 days or associated with clinical hepatitis and/or bilirubin ≥G2; G3 amylase or lipase lasting &amp;gt;14 days; ≥G3 bilirubin; any G4 AST, ALT, amylase, or lipase; acute pancreatitis; ≥G3 hematologic and non-hematologic toxicities; G4 cytokine release syndrome (CRS) or G3 CRS despite premedication. MTD was defined as the highest dose level with 0/3 or ≤1 of 6 pts experiencing a first-cycle DLT. PK sampling was performed on cycle 1 day 1 (C1D1), C1D2, C1D8, Day 15 of all cycles, C1D16, C2D1, and C3D1. Response was assessed by RECIST every 8 weeks. Results: Thirty pts [12 male, 18 female; median age 64.5 (range 36–82)] were enrolled at 6 dose levels: 0.1, 0.3, 0.5, 0.7, 1.0, and 1.5 mg/kg. Tumor types included colorectal (15); pancreas (4); ovarian (4); and tongue, cervical, prostate, endometrial, breast, hepatocellular, and thyroid (1 each). Sixteen pts had liver metastases. DLTs included G4 lipase and G3 bilirubin in 1 of 6 pts at the 1.0 mg/kg level and G4 lipase and G4 amylase in 1 pt at the 1.5 mg/kg level. Grade 3/4 toxicities in ≥5% of subjects included fatigue, pneumonia, hyponatremia, hypoxia, dyspnea, and elevated AST, ALT, GGT, lipase, and amylase. There was no apparent correlation of liver or pancreatic enzyme elevation with tumor type or presence of liver metastases. Of the disease evaluable pts, 11 had disease progression as their best response and 2 had stable disease (2 and 4 month duration). Enavatuzumab followed a two-compartment linear PK model. The estimated clearance was 23–33 mL/hr and elimination half-life was 7–18 days. The mean Cmax after the first dose was 2.0 mcg/mL and 28.1 mcg/mL for the 0.1 mg/kg and 1.0 mg/kg cohorts, respectively. Mean Css was reached following the second dose and was within the target efficacious peak and trough levels for the 1.0 mg/kg cohort. Conclusions: The MTD for this first-in-class drug was reached at 1.0 mg/kg. Six of 7 pts at 1.0 mg/kg and 1 of 1 pts at 1.5 mg/kg had ≥G3 liver and/or pancreatic enzyme elevations; therefore higher doses are not being tested. The mechanisms of liver and pancreatic enzyme toxicity are currently being investigated and preclinical studies are ongoing to assess potential combination strategies. 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 C18.

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.

JAK inhibitors in myeloproliferative neoplasms: Rationale, current data and perspective

JAK-STAT is an appealing but also problematic drug target in BCR-ABL1-negative myeloproliferative neoplasms (MPN) – it is appealing because the majority of patients with MPN harbor gain-of-function JAK2 or MPL mutations – it is problematic because currently available JAK inhibitors do not distinguish between oncogenic and physiologic JAK-STAT activation. Furthermore, JAK-STAT-relevant mutations in MPN do not always constitute the predominant or ancestral mutant clone. Such complexities undermine the value of JAK-STAT as a robust drug target in MPN and partly explain the hitherto lack of histologic or molecular remissions associated with currently available JAK inhibitors. Most of these drugs were, however, effective in alleviating constitutional symptoms and reducing spleen size; the mechanism of action in this instance includes drug-induced down-regulation of inflammatory cytokine activity. In addition, non-specific myelosuppression contributes to both their salutary and detrimental effects on peripheral blood count. Non-hematologic side effects include gastrointestinal disturbances, asymptomatic elevation of liver and pancreatic enzymes, peripheral neuropathy and hyperacute relapse of symptoms during treatment interruption. It is our impression that many more JAK inhibitors need to be evaluated in order to identify the best-in-class in terms of efficacy, toxicity and suitability for future combination treatment programs.

Phase I study of PF-03446962, a fully human mAb against ALK 1, a TGFβ receptor involved in tumor angiogenesis.

3009 Background: Transforming growth factor β (TGF β) is a cytokine able to regulate many biological processes in cancer. At 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. 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 I trial in patients (pts) with solid tumors. Primary objectives: identify MTD and a recommended phase II dose (RP2D); secondary objectives included safety profile, PK, antitumor activity, soluble proteins TGFβ related and blood flow by contrast enhanced ultrasound (CE-US). Results: 41 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. 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. 2 PRs were observed, one hepatocellular carcinoma (HCC) resistant to anti-VEGF therapy and one NSCLC (still ongoing). SD lasting for at least 12 weeks was observed in 9/41 pts, with 2 patients (adrenocortical ca. and mesothelioma) still ongoing after 11 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. 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 for pts who failed anti VEGF/VEGFRTKI in clinic.

Tyrosine Kinase Inhibitors, Pancreatic Hyperenzymemia and Acute Pancreatitis: A Review

The advent of new drugs can rapidly increase the number of substances causing acute pancreatitis. This is the case of tyrosine kinase inhibitors; these drugs are currently used for chronic myeloid leukemia, gastrointestinal stromal tumors, unresectable hepatocellular carcinomas and advanced renal cell carcinomas that and they have been reported to cause acute pancreatitis or asymptomatic elevations of serum pancreatic enzymes. Of the classes of drugs capable of inducing acute pancreatitis, we aimed to evaluate, in which class tyrosine kinase inhibitors can be allocated. A search was carried out using the MEDLINE database in order to select the data existing in the literature on pyrimidines and acute pancreatitis or serum lipase/amylase elevation covering the period from January 1966 to January 2010; thirteen papers were found and utilized for this review. Based on the data in the literature, we found that tyrosine kinase inhibitors may often cause an increase in pancreatic enzymes in plasma and patients treated with these drugs, especially those who are treated with sorafenib, might be at risk of developing acute pancreatitis. Whether acute pancreatitis due to tyrosine kinase inhibitors is associated only with sorafenib or may also be caused by other drugs of the same class remains an open question. Recent patents on tyrosine kinase inhibitors and acute pancreatitis are pointed out in this review.