C.M. Schmidt

EUS-guided ethanol versus saline solution lavage for pancreatic cysts: a randomized, double-blind study

BACKGROUND Surgery for pancreatic cysts is associated with significant morbidity. A pilot study previously demonstrated the safety of EUS-guided ethanol lavage of pancreatic cysts. OBJECTIVE To determine whether EUS-guided ethanol lavage would decrease pancreatic cyst size more than saline solution lavage. DESIGN Prospective, multicenter, randomized trial. SETTING Two tertiary referral hospitals in the United States. PATIENTS Patients referred for EUS with a 1- to 5-cm unilocular pancreatic cyst were randomized to blinded ethanol or saline solution lavage. Three months later, the cyst diameter was remeasured by EUS, and a second unblinded ethanol lavage was performed. INTERVENTIONS EUS-guided pancreatic cyst lavage. MAIN OUTCOME MEASUREMENTS Cyst ablation based on size changes from follow-up EUS, CT, and histology of resected specimens. RESULTS Of 58 patients randomized, 16 were excluded and 42 underwent initial ethanol (n = 25) or saline solution (n = 17) lavage. Ethanol lavage resulted in a greater mean percentage of decrease in cyst surface area (-42.9; 95% CI, -58.4 to -27.4) compared with saline solution alone (-11.4; 95% CI, -25.0 to 2.2; P = .009). Nineteen (76.0%) of 25 and 14 (82.3%) of 17 patients randomized to ethanol and saline solution, respectively, underwent a second ethanol lavage. A follow-up CT scan demonstrated resolution in 12 (33.3%) of 36 cysts. Histology of 4 resected cysts demonstrated epithelial ablation ranging from 0% (saline solution alone) to 50% to 100% (1 or 2 ethanol lavages). Complication rates were similar in all groups. LIMITATION Short-term follow-up. CONCLUSIONS EUS-guided ethanol lavage results in a greater decrease in pancreatic cyst size compared with saline solution lavage with a similar safety profile. Overall CT-defined complete pancreatic cyst ablation was 33.3%.

Pancreatic Enucleation: Improved Outcomes Compared to Resection

IntroductionPancreatic enucleation is associated with a low operative mortality and preserved pancreatic parenchyma. However, enucleation is an uncommon operation, and good comparative data with resection are lacking. Therefore, the aim of this analysis was to compare the outcomes of pancreatic enucleation and resection.Material and MethodsFrom 1998 through 2010, 45 consecutive patients with small (mean, 2.3 cm) pancreatic lesions underwent enucleation. These patients were matched with 90 patients undergoing pancreatoduodenectomy (n = 38) or distal pancreatectomy (n = 52). Serious morbidity was defined in accordance with the American College of Surgeons–National Surgical Quality Improvement Program. Outcomes were compared with standard statistical analyses.ResultsOperative time was shorter (183 vs. 271 min, p < 0.01), and operative blood loss was significantly lower (160 vs. 691 ml, p < 0.01) with enucleation. Fewer patients undergoing enucleation required monitoring in an intensive care unit (20% vs. 41%, p < 0.02). Serious morbidity was less common among patients who underwent enucleation compared to those who had a resection (13% vs. 29%, p = 0.05). Pancreatic endocrine (4% vs. 17%, p = 0.05) and exocrine (2% vs. 17%, p < 0.05) insufficiency were less common with enucleation. Ten-year survival was no different between enucleation and resection.ConclusionCompared to resection, pancreatic enucleation is associated with improved operative as well as short- and long-term postoperative outcomes. For small benign and premalignant pancreatic lesions, enucleation should be considered the procedure of choice when technically appropriate.

Diffusion-weighted imaging in characterization of cystic pancreatic lesions

AIM To evaluate whether apparent diffusion coefficient (ADC) measurements from diffusion-weighted imaging (DWI) can characterize or predict the malignant potential of cystic pancreatic lesions. MATERIALS AND METHODS Retrospective review of the magnetic resonance imaging (MRI) database over a 2-year period revealed 136 patients with cystic pancreatic lesions. Patients with DWI studies and histological confirmation of cystic mass were included. In patients with known pancreatitis, lesions with amylase content of >1000 IU/l that resolved on subsequent scans were included as pseudocysts. ADC of cystic lesions was measured by two independent reviewers. These values were then compared to categorize these lesions as benign or malignant using conventional MRI sequences. RESULTS Seventy lesions were analysed: adenocarcinoma (n=4), intraductal papillary mucinous neoplasm (IPMN; n=28), mucinous cystic neoplasm (MCN; n=9), serous cystadenoma (n=16), and pseudocysts (n=13). There was no difference between ADC values of malignant and non-malignant lesions (p=0.06), between mucinous and serous tumours (p=0.12), or between IPMN and MCN (p=0.42). ADC values for low-grade IPMN were significantly higher than those for high-grade or invasive IPMN (p=0.03). CONCLUSION ADC values may be helpful in deciding the malignant potential of IPMN. However, they are not useful in differentiating malignant from benign lesions or for characterizing cystic pancreatic lesions.

Alterations in cyst fluid genetics following endoscopic ultrasound-guided pancreatic cyst ablation with ethanol and paclitaxel.

BACKGROUND AND STUDY AIMS Endoscopic ultrasound (EUS)-guided ethanol lavage with paclitaxel injection has been shown to be effective for the treatment of pancreatic cystic neoplasms; however, the evidence for effectiveness is based primarily on cyst resolution on imaging. The aim of this study was to evaluate changes in pancreatic cyst fluid DNA following EUS-guided pancreatic cyst ablation (PCA) with ethanol and paclitaxel. PATIENTS AND METHODS In a single-center, prospective study, patients with suspected benign pancreatic cysts (15 - 50 mm in diameter; ≤ 5 compartments) underwent EUS-PCA with ethanol and paclitaxel followed 3 months later by repeat EUS-FNA, cyst aspiration for repeat DNA analysis, and possible repeat EUS-PCA. Abdominal imaging was repeated 3 - 4 months and 12 months after the second EUS. Changes in baseline pancreatic cyst fluid DNA, procedural complications, and radiographic changes in cyst volume were evaluated. RESULTS A total of 22 patients (median age 67 years; 15 women) with cysts in the head or uncinate (n = 10), body or neck (n = 8), and tail (n = 4), measuring a median diameter of 25 mm (range 15 - 43 mm), underwent one (n = 22) or two (n = 9) EUS-PCA procedures. Baseline cyst DNA included mutations in 11 patients (50 %). Postablation cyst fluid (n = 19) showed elimination of all baseline mutations in eight patients, new mutations in three, and no changes in eight without a baseline mutation. The largest per-protocol postablation image-defined volume change (n = 20) from either of the follow-up abdominal imaging studies (n = 20) demonstrated complete response ( < 5 % original volume) in 10 patients (50 %), partial response (5 % - 25 % original volume) in 5 (25 %), and a persistent cyst (> 25 % original volume) in 5 (25 %). During a median follow-up of 27 months (range 17 - 42 months), adverse events from all EUS-PCAs (n = 31) included abdominal pain alone in four patients (13 %), pancreatitis in three (10 %), peritonitis in one (3 %), and gastric wall cyst in one (3 %). The adverse events were classified as moderately severe in four patients (three with pancreatitis, one with peritonitis). CONCLUSION EUS-PCA with ethanol and paclitaxel may possibly eliminate mutant DNA in neoplastic pancreatic cysts. This technique leads to complete or partial image-defined resolution in 75 % of cysts but may lead to rare adverse events. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov (NCT01643460).

Phase II Trial of Temsirolimus for Relapsed/Refractory Primary CNS Lymphoma

PURPOSE In this phase II study (NCT00942747), temsirolimus was tested in patients with relapsed or refractory primary CNS lymphoma (PCNSL). PATIENTS AND METHODS Immunocompetent adults with histologically confirmed PCNSL after experiencing high-dose methotrexate-based chemotherapy failure who were not eligible for or had experienced high-dose chemotherapy with autologous stem-cell transplant failure were included. The first cohort (n = 6) received 25 mg temsirolimus intravenously once per week. All consecutive patients received 75 mg intravenously once per week. RESULTS Thirty-seven eligible patients (median age, 70 years) were included whose median time since their last treatment was 3.9 months (range, 0.1 to 14.6 months). Complete response was seen in five patients (13.5%), complete response unconfirmed in three (8%), and partial response in 12 (32.4%) for an overall response rate of 54%. Median progression-free survival was 2.1 months (95% CI, 1.1 to 3.0 months). The most frequent Common Toxicity Criteria ≥ 3° adverse event was hyperglycemia in 11 (29.7%) patients, thrombocytopenia in eight (21.6%), infection in seven (19%), anemia in four (10.8%), and rash in three (8.1%). Fourteen blood/CSF pairs were collected in nine patients (10 pairs in five patients in the 25-mg cohort and four pairs in four patients in the 75-mg cohort). The mean maximum blood concentration was 292 ng/mL for temsirolimus and 37.2 ng/mL for its metabolite sirolimus in the 25-mg cohort and 484 ng/mL and 91.1 ng/mL, respectively, in the 75-mg cohort. Temsirolimus CSF concentration was 2 ng/mL in one patient in the 75-mg cohort; in all others, no drug was found in their CSF. CONCLUSION Single-agent temsirolimus at a weekly dose of 75 mg was found to be active in relapsed/refractory patients with PCNSL; however, responses were usually short lived.

Efficacy of dimethylaminoparthenolide and sulindac in combination with gemcitabine in a genetically engineered mouse model of pancreatic cancer

Objectives Pancreatic cancer remains one of the deadliest diseases, with limited surgical and treatment options. Two targets of interest include the transcription factor nuclear factor-&kgr;B and cyclooxygenase-2, which are constitutively activated and overexpressed, respectively, in human pancreatic adenocarcinoma. We have previously shown that dimethylaminoparthenolide (DMAPT), a bioavailable nuclear factor-&kgr;B inhibitor, and the cyclooxygenase inhibitors sulindac and celecoxib have potential chemotherapeutic efficacy. The current study evaluates the efficacy of intervention with DMAPT and sulindac in the LSL-KrasG12D;Pdx-1-Cre genetically engineered mouse model. Gemcitabine, traditionally a chemotherapeutic agent, has relatively low toxicity; thus, combinations with low-dose gemcitabine were also explored. Methods LSL-KrasG12D;Pdx-1-Cre mice at 7 months of age were randomized into placebo, DMAPT (40 mg/kg per day), sulindac (20 mg/kg per day), gemcitabine (50 mg/kg twice weekly), and combination treatment groups. After 3 months of treatment, the mice were killed. Results The percentage of normal pancreatic ducts was significantly increased by the combinations of DMAPT/sulindac, DMAPT/gemcitabine, sulindac/gemcitabine, and DMAPT/sulindac/gemcitabine compared to placebo. Additionally, the percentage of mouse pancreatic intraepithelial neoplasia-2 lesions was significantly decreased by DMAPT/gemcitabine. Conclusions Intervention with DMAPT and sulindac in combination with gemcitabine may delay or prevent progression of premalignant pancreatic lesions in the LSL-KrasG12D;Pdx-1-Cre mouse model of pancreatic cancer.

A Prospective Randomized Multicenter Trial of Distal Pancreatectomy with and Without Routine Intraperitoneal Drainage

Objective: The objective of this study was to test the hypothesis that distal pancreatectomy (DP) without intraperitoneal drainage does not affect the frequency of grade 2 or higher grade complications. Background: The use of routine intraperitoneal drains during DP is controversial. Prior to this study, no prospective trial focusing on DP without intraperitoneal drainage has been reported. Methods: Patients undergoing DP for all causes at 14 high-volume pancreas centers were preoperatively randomized to placement of a drain or no drain. Complications and their severity were tracked for 60 days and mortality for 90 days. The study was powered to detect a 15% positive or negative difference in the rate of grade 2 or higher grade complications. All data were collected prospectively and source documents were reviewed at the coordinating center to confirm completeness and accuracy. Results: A total of 344 patients underwent DP with (N = 174) and without (N = 170) the use of intraperitoneal drainage. There were no differences between cohorts in demographics, comorbidities, pathology, pancreatic duct size, pancreas texture, or operative technique. There was no difference in the rate of grade 2 or higher grade complications (44% vs. 42%, P = 0.80). There was no difference in clinically relevant postoperative pancreatic fistula (18% vs 12%, P = 0.11) or mortality (0% vs 1%, P = 0.24). DP without routine intraperitoneal drainage was associated with a higher incidence of intra-abdominal fluid collection (9% vs 22%, P = 0.0004). There was no difference in the frequency of postoperative imaging, percutaneous drain placement, reoperation, readmission, or quality of life scores. Conclusions: This prospective randomized multicenter trial provides evidence that clinical outcomes are comparable in DP with or without intraperitoneal drainage.

Treatment of Indolent Lymphoma in Germany - Results of a Representative Population-Based Survey

BACKGROUND In advanced-stage indolent lymphoma, therapeutic approaches may vary from watch and wait, antibody monotherapy, immunochemotherapy, or dose-intensified consolidation up to allogeneic strategies. In this nationwide survey, representative hematologic/oncologic centers monitored current treatment strategies in indolent lymphoma in general practice. METHODS Four hundred ninety-five centers involved in the treatment of indolent lymphoma including university hospitals, community hospitals, and oncologists in practice were identified and contacted. Thirteen percent of centers provided information on 741 patients, which corresponds to 10% of the expected national prevalence. Detailed data on 576 unselected patients from 46 representative centers (2 university hospitals, 25 community hospitals, and 19 oncologists in practice) for whom a treatment decision took place in the fourth quarter of 2006 (start, change, or end of therapy) were included in this analysis. Data were verified by monitoring the pseudonymized patient documents. RESULTS Median age was 67 years (range, 17 to 95 years) and 65% of patients were 60 years of age or older. Concomitant disease was frequent with cardiac disease (29%), hypertension (28%), diabetes (11%), and renal impairment (7%) being the most typical combinations. Histologies included 39% follicular lymphoma, 26% chronic lymphocytic leukemia (CLL), 10% marginal zone, 9% mantle cell lymphoma (MCL), and 16% other. Only 10% of the overall patient population were treated within these studies. The aim of initial therapy was curative in 35%, and physicians aimed at improved survival in 62% and palliation only in 54% of patients. Radiation (10%), antibody monotherapy (4%), chemotherapy (33%), and combined immunochemotherapy (31%) were the most frequent approaches. Applied chemotherapies included cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) (46%), fludarabine combinations (F/FC/FCM: 15%), chlorambucil (14%), CVP/COP (9%) and bendamustin (4%). Maintenance was used in 12% and autologous/allogeneic stem cell consolidation were rarely applied (both in 3% of patients). At first relapse, combined approaches including immunochemotherapy (49%), maintenance therapy (16%), and autologous/allogeneic transplantation (14%/4%) were more frequently administered. As expected, different treatment strategies and response rates were observed in follicular lymphoma (FL), MCL, and CLL. Interestingly, supportive measures including antibiotics (34%), erythrocyte transfusions (32%), granulocyte colony-stimulating factor (22%), immunoglobulines (19%), antifungal drugs (13%), and erythropoetin (10%) were frequently applied even in first-line therapy. Overall response was 83% (FL: 97%, MCL: 95%, CLL: 74%) with a 39% complete response (FL 63%, MCL 54%, CLL 15%) rate. DISCUSSION In this population-based survey, patients characteristics differed significantly from published study cohorts as did clinical strategies and therapeutic approaches. Thus, clinically more relevant studies in medically compromised patients are urgently warranted.

Extended distal pancreatectomy for pancreatic adenocarcinoma with splenic vein thrombosis and/or adjacent organ invasion

BACKGROUND Patients with adenocarcinoma of the pancreatic body/tail and associated vascular thrombosis or adjacent organ invasion are suboptimal candidates for resection. We hypothesized that extended distal pancreatectomy (EDP) for locally advanced adenocarcinoma is associated with a survival benefit. METHODS We retrospectively reviewed a prospectively collected database of patients who underwent distal pancreatectomy (DP) for adenocarcinoma at a single academic institution (1996 to 2011) with greater than or equal to 2 years of follow-up. RESULTS Among 680 DP patients, 93 were indicated for pancreatic adenocarcinoma. Splenic vein thrombosis (n = 26) did not significantly affect morbidity, mortality, or survival. Standard DP was performed in 70 patients and 23 underwent EDP with no difference in morbidity/mortality. Patients with EDP had a survival comparable with patients with standard DP (disease-free survival 18 vs 12 months = .8; overall survival 23 vs 17 months, P =.6). There was no difference in survival between EDP patients with versus without pathologic invasion of adjacent organs, but a trend favored those without. CONCLUSION EDP is safe and should be considered in fit patients with locally advanced adenocarcinoma.

Transforming growth factor α levels in pancreatic fluid

Objective: To determine if the level of transforming growth factor &agr; (TGF-&agr;) in the pancreatic fluid (PF) can diagnose intraductal papillary mucinous neoplasm (IPMN) versus other cystic lesions of the pancreas in patients. Methods: Pancreatic fluid was prospectively obtained from patients during routine endoscopy and/or operation at Indiana University Hospital. Pancreatic fluid TGF-&agr; levels were analyzed by enzyme-linked immunosorbent assay. Intraductal papillary mucinous neoplasm tissue was also analyzed by TGF-&agr; immunohistochemistry. Results: Sixty-nine fluid samples from 58 patients with the following pathologically confirmed pancreatic disorders were analyzed: IPMN (26 patients), serous cystadenoma (6), mucinous cystic neoplasm (9), pseudocysts (5), non-IPMN-associated pancreatic ductal adenocarcinoma (6), and sphincter of Oddi dysfunction (6). There was no significant difference between the mean PF-TGF-&agr; levels in each category or between different dysplastic grades of IPMN. However, of all the diagnoses examined, only IPMN demonstrated PF-TGF-&agr; levels greater than 95 pg/mL. In low-grade IPMN specimens, TGF-&agr; immunohistochemistry correlated with enzyme-linked immunosorbent assay levels. Conclusions: The mean PF-TGF-&agr; levels are not significantly different in IPMN lesions compared with those in other cystic pancreatic lesions, pancreatic ductal adenocarcinoma, or sphincter of Oddi dysfunction. However, PF-TGF-&agr; levels more than 95 pg/mL may be useful in diagnosing IPMN. This assertion requires prospective validation.