The antioxidant and anti-inflammatory activities of avasopasem manganese in age-associated, cisplatin-induced renal injury.

PURPOSE: Cisplatin contributes to acute kidney injury (AKI) and chronic kidney disease (CKD) that occurs with greater frequency and severity in older patients. Age-associated cisplatin sensitivity in human fibroblasts involves increased mitochondrial superoxide produced by older donor cells. EXPERIMENTAL DESIGN: Young and old C57BL/6 J murine models of cisplatin-induced AKI and CKD were treated with the SOD mimetic avasopasem manganese to investigate the potential antioxidant and anti-inflammatory effects. Adverse event reporting from a phase 2 and a phase 3 randomized clinical trial (NCT02508389 and NCT03689712) conducted in patients treated with cisplatin and AVA was determined to have established the incidence and severity of AKI. RESULTS: Cisplatin-induced AKI and CKD occurred in all mice, however, was more pronounced in older mice. AVA reduced cisplatin-induced mortality, AKI, and CKD, in older animals. AVA also alleviated cisplatin-induced alterations in mitochondrial electron transport chain (ETC) complex activities and NADPH Oxidase 4 (NOX4) and inhibited the increased levels of the inflammation markers, TNFα, IL1, ICAM-1, and VCAM-1. Analysis of age-stratified subjects treated with cisplatin from clinical trials (NCT02508389, NCT03689712) also supported that the incidence of AKI increased with age and AVA reduced age-associated therapy-induced adverse events (AE), including hypomagnesemia, increased creatinine, and AKI. CONCLUSIONS: Older mice and humans are more susceptible to cisplatin-induced kidney injury, and treatment with AVA mitigates age-associated damage. Mitochondrial ETC and NOX4 activities represent sources of superoxide production contributing to cisplatin-induced kidney injury, and pro-inflammatory cytokine production and endothelial dysfunction may also be increased by superoxide formation.

Stereotactic body radiotherapy plus rucosopasem in locally advanced or borderline resectable pancreatic cancer: GRECO-2 phase II study design.

Ablative doses of stereotactic body radiotherapy (SBRT) may improve pancreatic cancer outcomes but may carry greater potential for gastrointestinal toxicity. Rucosopasem, an investigational selective dismutase mimetic that converts superoxide to hydrogen peroxide, can potentially increase tumor control of SBRT without compromising safety. GRECO-2 is a phase II, multicenter, randomized, double-blind, placebo-controlled trial of rucosopasem in combination with SBRT in locally advanced or borderline resectable pancreatic cancer. Patients will be randomized to rucosopasem 100 mg or placebo via intravenous infusion over 15 min, before each SBRT fraction (5 × 10 Gy). The primary end point is overall survival. Secondary end points include progression-free survival, locoregional control, time to metastasis, surgical resection rate, best overall response, in-field local response and acute and long-term toxicity.

The use of high doses of radiation delivered directly to tumors (stereotactic body radiation therapy [SBRT]) may improve survival compared with lower doses of radiation in patients with pancreatic cancer, but it may increase side effects. Rucosopasem, an investigational new drug being developed, can potentially improve the ability of SBRT to treat tumors without decreasing safety. In a previous study, median overall survival was improved when patients were treated with SBRT plus avasopasem, a drug that works the same way as rucosopasem. GRECO-2 is a clinical trial of rucosopasem used in combination with SBRT for treatment of localized pancreatic cancer. Patients will be randomly selected to receive either rucosopasem 100 mg or placebo via intravenous infusion over 15 min, before each SBRT treatment. The main result being studied is overall survival. Additional results include amount of time before tumors start to grow, how often patients get tumors surgically removed, best overall response and long-term safety. Clinical Trial Registration: NCT04698915 (ClinicalTrials.gov).

Indoximod-based chemo-immunotherapy for pediatric brain tumors: A first-in-children phase I trial.

BACKGROUND: Recurrent brain tumors are the leading cause of cancer death in children. Indoleamine 2,3-dioxygenase (IDO) is a targetable metabolic checkpoint that, in preclinical models, inhibits anti-tumor immunity following chemotherapy. METHODS: We conducted a phase I trial (NCT02502708) of the oral IDO-pathway inhibitor indoximod in children with recurrent brain tumors or newly diagnosed diffuse intrinsic pontine glioma (DIPG). Separate dose-finding arms were performed for indoximod in combination with oral temozolomide (200 mg/m2/day x 5 days in 28-day cycles), or with palliative conformal radiation. Blood samples were collected at baseline and monthly for single-cell RNA-sequencing with paired single-cell T cell receptor sequencing. RESULTS: Eighty-one patients were treated with indoximod-based combination therapy. Median follow-up was 52 months (range 39-77 months). Maximum tolerated dose was not reached, and the pediatric dose of indoximod was determined as 19.2 mg/kg/dose, twice daily. Median overall survival was 13.3 months (n = 68, range 0.2-62.7) for all patients with recurrent disease and 14.4 months (n = 13, range 4.7-29.7) for DIPG. The subset of n = 26 patients who showed evidence of objective response (even a partial or mixed response) had over 3-fold longer median OS (25.2 months, range 5.4-61.9, p = 0.006) compared to n = 37 nonresponders (7.3 months, range 0.2-62.7). Four patients remain free of active disease longer than 36 months. Single-cell sequencing confirmed emergence of new circulating CD8 T cell clonotypes with late effector phenotype. CONCLUSIONS: Indoximod was well tolerated and could be safely combined with chemotherapy and radiation. Encouraging preliminary evidence of efficacy supports advancing to Phase II/III trials for pediatric brain tumors.

Treatment Response in First-Line Metastatic Pancreatic Ductal Adenocarcinoma Is Stratified By a Composite Index of Tumor Proliferation and CD8 T-Cell Infiltration.

PURPOSE: Determinants of treatment outcomes to chemotherapy-based regimens in metastatic pancreatic ductal adenocarcinoma (PDA) remain ill-defined. Our aim was to examine tissue-based correlates of treatment response and resistance using matched baseline and on-treatment biopsies collected from patients with PDA treated in the first-line metastatic setting. EXPERIMENTAL DESIGN: Patients with treatment-naïve metastatic PDA were enrolled in a Phase II trial (NCT02077881) investigating gemcitabine plus nab-paclitaxel in combination with indoximod, an orally administered small-molecule inhibitor of the IDO pathway. Baseline and on-treatment biopsies (week 8) of metastatic lesions (88% liver) were collected from a cohort of responders (N = 8) and non-responders (N = 8) based on RECIST v1.1 and examined by multiplex IHC and mRNA sequencing. RESULTS: Treatment altered the transcriptional profile of metastatic lesions with a decrease in tumor cell proliferation independent of treatment response. The antiproliferative response was seen in both basal and classical PDA subtypes. PDA subtype was not associated with survival outcomes; instead, genes involved in immune activation distinguished responders from non-responders. Tumor response was associated with an increase in CD3+ and CD8+ T-cell infiltrates into metastatic lesions. A composite of decreased tumor proliferation in response to treatment and increased CD8 T-cell infiltration in metastatic lesions identified responders and associated with a favorable survival outcome. CONCLUSIONS: Our findings suggest that inhibiting cancer cell proliferation alone in PDA is insufficient to produce tumor responses and support a role for tumor-extrinsic mechanisms, such as CD8+ T cells, which combine with the cancer cell proliferation index to define treatment outcomes.

Phase II trial of the IDO pathway inhibitor indoximod plus pembrolizumab for the treatment of patients with advanced melanoma.

BACKGROUND: The indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to evade antitumor immunity. Indoximod is a small-molecule IDO pathway inhibitor that reverses the immunosuppressive effects of low tryptophan (Trp) and high kynurenine (Kyn) that result from IDO activity. In this study, indoximod was used in combination with a checkpoint inhibitor (CPI) pembrolizumab for the treatment for advanced melanoma. METHODS: Patients with advanced melanoma were enrolled in a single-arm phase II clinical trial evaluating the addition of indoximod to standard of care CPI approved for melanoma. Investigators administered their choice of CPI including pembrolizumab (P), nivolumab (N), or ipilimumab (I). Indoximod was administered continuously (1200 mg orally two times per day), with concurrent CPI dosed per US Food and Drug Administration (FDA)-approved label. RESULTS: Between July 2014 and July 2017, 131 patients were enrolled. (P) was used more frequently (n=114, 87%) per investigator's choice. The efficacy evaluable population consisted of 89 patients from the phase II cohort with non-ocular melanoma who received indoximod combined with (P).The objective response rate (ORR) for the evaluable population was 51% with confirmed complete response of 20% and disease control rate of 70%. Median progression-free survival was 12.4 months (95% CI 6.4 to 24.9). The ORR for Programmed Death-Ligand 1 (PD-L1)-positive patients was 70% compared with 46% for PD-L1-negative patients. The combination was well tolerated, and side effects were similar to what was expected from single agent (P). CONCLUSION: In this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma.

Symptom Clusters in Patients With Pancreatic Cancer Undergoing Surgical Resection: Part I.

OBJECTIVES: To describe patient-reported symptoms and symptom clusters in patients with pancreatic cancer (PC) undergoing surgical resection. SAMPLE & SETTING: 143 patients with stage II PC undergoing surgical resection alone or with subsequent adjuvant chemoradiation or chemotherapy were recruited to participate in a nested, longitudinal, exploratory study through convenience sampling techniques from Thomas Jefferson University Hospital, a National Cancer Institute-designated cancer center. METHODS & VARIABLES: The Functional Assessment in Cancer Therapy-Hepatobiliary questionnaire was used to assess 17 PC symptoms preoperatively and at three, six, and nine months postoperatively. Exploratory and confirmatory factor analyses were used to identify symptom clusters. RESULTS: Fatigue, trouble sleeping, poor appetite, trouble digesting food, and weight loss were consistently reported as the most prevalent and severe symptoms. Sixteen distinct symptom clusters were identified within nine months of surgery. Four core symptom clusters persisted over time. IMPLICATIONS FOR NURSING: Findings may be used to provide anticipatory patient and family guidance and to inform clinical assessments of symptoms and symptom clusters in this population.

Symptom Clusters in Patients With Pancreatic Cancer Undergoing Surgical Resection: Part II.

OBJECTIVES: To explore the relationship between 16 symptom clusters (SCs), clinical and demographic influencing factors, and clinical outcomes over time in patients with pancreatic cancer (PC) undergoing surgical resection. SAMPLE & SETTING: 143 patients with stage II PC undergoing surgical resection were recruited to participate in this longitudinal, exploratory study conducted at Thomas Jefferson University Hospital, a National Cancer Institute-designated cancer center. METHODS & VARIABLES: Quality of life was measured preoperatively and at three, six, and nine months postoperatively. Statistical methods included simple linear and Cox proportional hazard regression. RESULTS: Preoperative pain was significantly associated with the pain-gastrointestinal SC, and preoperative worry was significantly associated with the mood SC. The strongest negative association with emotional well-being across all study time points was found with the preoperative mood SC. The insomnia-digestive problems SC and the nutritional problems SC demonstrated a trend toward poor survival. IMPLICATIONS FOR NURSING: Findings provide evidence that preoperative worry and pain are associated with SC severity and that SCs may have a detrimental effect on quality of life and survival in patients with PC undergoing surgical resection.

A prospective, randomized, double-blind, placebo controlled trial on the efficacy of ethanol celiac plexus neurolysis in patients with operable pancreatic and periampullary adenocarcinoma.

BACKGROUND: Ethanol celiac plexus neurolysis (ECPN) has been shown to be effective in reducing cancer-related pain in patients with locally advanced pancreatic and periampullary adenocarcinoma (PPA). This study examined its efficacy in patients undergoing PPA resection. STUDY DESIGN: There were 485 patients who participated in this prospective, randomized, double-blind placebo controlled trial. Patients were stratified by preoperative pain and disease resectability. They received either ECPN (50% ethanol) or 0.9% normal saline placebo control. The primary endpoint was short- and long-term pain and secondary endpoints included postoperative morbidity, quality of life, and overall survival. RESULTS: Data from 467 patients were analyzed. The primary endpoint, the percentage of PPA patients experiencing a worsening of pain compared with preoperative baseline for resectable patients, was not different between the ethanol and saline groups in either the resectable/pain stratum (22% vs 18%, relative risk [RR] 1.23 [0.34, 4.46]), or the resectable/no pain stratum (37% vs 34%, RR 1.10 [0.67, 1.81]). In multivariable analysis of resected pancreatic ductal adenocarcinoma (PDA) patients, there was a significant reduction in pain in the resectable/pain group, suggesting that surgical resection of the malignancy alone (independent of ECPN) decreases pain to a significant degree. CONCLUSIONS: In this study, we demonstrated a significant reduction in pain after surgical resection of PPA. However, the addition of ECPN did not synergize to result in a further reduction in pain, and in fact, its effect may have been masked by surgical resection. Given this, we cannot recommend the use of ECPN to mitigate cancer-related pain in resectable PPA patients.

Non-neoplastic epithelial cysts of the pancreas: a rare, benign entity.

OBJECTIVES: With the increased use of cross-sectional radiologic imaging in recent years, cystic lesions of the pancreas are being diagnosed with greater frequency. While pseuodocysts have historically accounted for the majority of benign pancreatic cysts, there are a number of rare, benign cystic lesions of the pancreas that can mimic neoplastic cysts. The objective of this study was to review a single institution's experience with these benign cystic lesions of the pancreas. METHODS: We conducted a retrospective analysis of all patients who underwent surgical resection for pancreatic disease from 2005 to 2012 at our institution. Out of a total of 947 pancreatic resections, we identified those cases performed for cystic disease, and focused upon the clinicopathologic data of patients with non-neoplastic pancreatic cysts. RESULTS: Of the 947 pancreatic resections, 256 (27%) were performed for cystic disease. Sixteen cases (6.3%) out of the total of 256 pancreatic operations performed for cystic disease were found to have non-neoplastic cystic lesions of the pancreas. Preoperative imaging revealed primary lesions in all patients, eight of which were found incidentally. Of these lesions, 14 were suspected preoperatively to be mucinous neoplasms and two to harbor pancreatic adenocarcinoma. However, postoperative pathology revealed eight patients with ductal retention cysts, three squamoid cysts, one mucinous non-neoplastic cyst, one congenital ciliated foregut cyst, one lymphoepithelial cyst, and two endometrial cysts. Two patients had complications postoperatively, one pancreatic fistula and one SMV thrombosis. Both complications resolved with conservative management. CONCLUSIONS: Non-neoplastic epithelial pancreatic cysts are rare, benign lesions. In our institutional experience, these lesions are often indistinguishable from cystic neoplasms of the pancreas preoperatively. As such, many of these lesions are resected unknowingly. It is important for the clinician to be well informed of the nature of these lesions, in the hopes to avoid unnecessary resection whenever possible.

Does resident experience affect outcomes in complex abdominal surgery? Pancreaticoduodenectomy as an example.

OBJECTIVES: Understanding the factors contributing to improved postoperative patient outcomes remains paramount. For complex abdominal operations such as pancreaticoduodenectomy (PD), the influence of provider and hospital volume on surgical outcomes has been described. The impact of resident experience is less well understood. METHODS: We reviewed perioperative outcomes after PD at a single high-volume center between 2006 and 2012. Resident participation and outcomes were collected in a prospectively maintained database. Resident experience was defined as postgraduate year (PGY) and number of PDs performed. RESULTS: Forty-three residents and four attending surgeons completed 686 PDs. The overall complication rate was 44 %; PD-specific complications (defined as pancreatic fistula, delayed gastric emptying, intraabdominal abscess, wound infection, and bile leak) occurred in 28 % of patients. The overall complication rates were similar when comparing PGY 4 to PGY 5 residents (55.3 vs. 43.0 %; p > 0.05). On univariate analysis, there was a difference in PD-specific complications seen between a PGY 4 as compared to a PGY 5 resident (44 vs. 27 %, respectively; p = 0.016). However, this was not statistically significant when adjusted for attending surgeon. Logistic regression demonstrated that as residents perform more cases, PD-specific complications decrease (OR = 0.97; p < 0.01). For a resident's first PD case, the predicted probability of a PD-specific complication is 27 %; this rate decreases to 19 % by resident case number 15. CONCLUSIONS: Complex cases, such as PD, provide unparalleled learning opportunities and remain an important component of surgical training. We highlight the impact of resident involvement in complex abdominal operations, demonstrating for the first time that as residents build experience with PD, patient outcomes improve. This is consistent with volume-outcome relationships for attending physicians and high-volume hospitals. Maximizing resident repetitive exposure to complex procedures benefits both the patient and the trainee.

Safety of perioperative aspirin therapy in pancreatic operations.

BACKGROUND: Antiplatelet therapy with aspirin is prevalent among patients presenting for operative treatment of pancreatic disorders. Operative practice has called for the cessation of aspirin 7-10 days before elective procedures because of the perceived increased risk of procedure-related bleeding. Our practice at Thomas Jefferson University has been to continue aspirin therapy throughout the perioperative period in patients undergoing elective pancreatic surgery. STUDY DESIGN: Records for patients undergoing pancreatoduodenectomy, distal pancreatectomy, or total pancreatectomy between October 2005 and February 2012 were queried for perioperative aspirin use in this institutional research board-approved retrospective study. Statistical analyses were performed with Stata software. RESULTS: During the study period, 1,017 patients underwent pancreatic resection, of whom 289 patients (28.4%) were maintained on aspirin through the morning of the operation. Patients in the aspirin group were older than those not taking aspirin (median 69 years vs 62 years, P < .0001). The estimated intraoperative blood loss was similar between the two groups, aspirin versus no aspirin (median 400 mL vs 400 mL, P = .661), as was the rate of blood transfusion anytime during the index admission (29% vs 26%, P = 0.37) and the postoperative duration of hospital stay (median 7 days vs 6 days, P = .103). The aspirin group had a slightly increased rate of cardiovascular complications (10.1% vs 7.0%, P = .107), likely reflecting their increased cardiovascular comorbidities that led to their physicians recommending aspirin therapy. Rates of pancreatic fistula (15.1% vs 13.5%, P = .490) and hospital readmissions were similar (16.9% vs 14.9%, P = .451). CONCLUSION: This is the first study to report that aspirin therapy is not associated with increased rates of perioperative bleeding, transfusion requirement, or major procedure related complications after elective pancreatic surgery. These data suggest that continuation of aspirin is safe and that the continuation of aspirin should be considered acceptable and preferable, particularly in patients with perceived substantial medical need for treatment with antiplatelet therapy.

Trial watch: IDO inhibitors in cancer therapy.

Indoleamine 2,3-dioxigenase 1 (IDO1) is the main enzyme that catalyzes the first, rate-limiting step of the so-called "kynurenine pathway", i.e., the metabolic cascade that converts the essential amino acid L-tryptophan (Trp) into L-kynurenine (Kyn). IDO1, which is expressed constitutively by some tissues and in an inducible manner by specific subsets of antigen-presenting cells, has been shown to play a role in the establishment and maintenance of peripheral tolerance. At least in part, this reflects the capacity of IDO1 to restrict the microenvironmental availability of Trp and to favor the accumulation of Kyn and some of its derivatives. Also, several neoplastic lesions express IDO1, providing them with a means to evade anticancer immunosurveillance. This consideration has driven the development of several IDO1 inhibitors, some of which (including 1-methyltryptophan) have nowadays entered clinical evaluation. In animal tumor models, the inhibition of IDO1 by chemical or genetic interventions is indeed associated with the (re)activation of therapeutically relevant anticancer immune responses. This said, several immunotherapeutic regimens exert robust clinical activity in spite of their ability to promote the expression of IDO1. Moreover, 1-methyltryptophan has recently been shown to exert IDO1-independent immunostimulatory effects. Here, we summarize the preclinical and clinical studies testing the antineoplastic activity of IDO1-targeting interventions.

Tumor recurrence is independent of pancreatic fistula in patients after pancreaticoduodenectomy for pancreatic ductal adenocarcinoma.

BACKGROUND: Recurrence of pancreatic adenocarcinoma after pancreaticoduodenectomy (PD) can be increased in patients with pancreatic fistula (PF). The purpose of our study was to determine if a relationship exists between PF and tumor recurrence (both peritoneal and local) in patients after PD for pancreatic ductal adenocarcinoma. STUDY DESIGN: A single-institution, retrospective analysis of 221 patients who underwent PD from January 2001 to December 2009 was conducted. Electronic charts and medical records were queried for tumor characteristics, recurrence, and complications. Presence and grading of PF was determined using the criteria of the International Study Group on Pancreatic Fistula. Data were analyzed using chi-square and Kaplan-Meier survival statistics. RESULTS: There were 114 male and 107 female patients. Mean age was 66 years (range 35 to 91 years). The vast majority (84%) of patients had stage II disease; 143 (65%) had positive lymph nodes (median 2 positive nodes; range 1 to 17 positive nodes). Pancreatic fistula developed in 23 patients (grade A, n = 9; grade B, n = 13; grade C, n = 1; 10.2%). Peritoneal recurrence was noted in 20 patients (9%). Of the 23 patients with PF, peritoneal recurrence developed in 3 (13%). Of the 198 patients without PF, peritoneal recurrence developed in 17 (10%). Local recurrence occurred in 47 patients (21%), 5 (2%) in patients with PF and 42 (21%) in those without PF (p = NS). In Kaplan-Meier survival analysis, there was no significant difference in recurrence-free survival (p = 0.4) and overall survival (p = 0.3) for those with PF vs those without PF. CONCLUSIONS: Patients with PF after PD were not found to have a significant increase in local or peritoneal recurrence. Therefore, in this analysis, postoperative PF does not appear to serve as an adverse prognostic marker.

Preoperative imaging for resectable periampullary cancer: clinicopathologic implications of reported radiographic findings.

BACKGROUND: High-resolution, multiphase, computed tomography (CT) is a standard preoperative test prior to pancreatectomy, yet the clinical significance of routinely reported findings remains unknown. METHODS: We identified patients who underwent a pancreaticoduodenectomy for a periampullary adenocarcinoma (PA) over the previous 5 years and had a pancreas protocol CT at our institution. Clinicopathologic implications of reported CT findings were evaluated. RESULTS: There were 155 pancreatic ductal adenocarcinomas (PDA) and 47 non-pancreatic PAs. No mass was visualized on CT in 6 % of PDAs and 23 % of non-pancreatic PA. A size discrepancy of ≥1 cm between radiographic and pathologic tumor diameters was observed in 40 % of PAs, with CT underestimating the size in most instances (75 %). Radiographically enlarged lymph nodes were not associated with true lymph node metastases in PDAs (70 % lymph node positive cases were enlarged on CT vs 74 % lymph node negative, p = 0.5), but were associated with a preoperatively placed biliary endoprosthesis (63 % with endoprosthesis were enlarged vs 37 % no endoprosthesis, p = 0.013). Major visceral vessel involvement on CT was not associated with a vascular resection (3 % with CT vessel involvement vs 2 % without, p = 0.8) or a positive uncinate resection margin (24 vs 20 %, respectively, p = 0.6). DISCUSSION: While dedicated pancreas protocol CT provides unprecedented detail, the test may lead to overinterpretation of the extent of disease in some instances. A radiographic suggestion of enlarged lymph nodes and vascular involvement does not necessarily preclude exploration with curative intent. CTs with local disease should be reported in an objective template and carefully reviewed by a multidisciplinary group of surgeons, radiologists, and oncologists to avoid missing an opportunity for neoadjuvant therapy or cure by resection.

Defining treatment and outcomes of hepaticojejunostomy failure following pancreaticoduodenectomy.

BACKGROUND: The overall complication rate after pancreaticoduodenectomy (PD) approaches 50 %, with anastomotic failure being the most frequent cause of serious postoperative morbidity. Hepaticojejunostomy leaks (also called bile leaks) are the second most common type of leak, behind pancreaticojejunostomy leaks, yet have been the focus of only a single study as reported by Suzuki et al. (Hepatogastroenterology 50:254-257, 12). METHODS: We reviewed the recent experience with bile leaks at a single, high-volume pancreatic surgery center over a six-year time period. RESULTS: Bile leaks were identified in 16 out of 715 patients (2.2 %). Low preoperative albumin was associated with an increased risk. Bile leaks typically manifested within the first week after surgery as bilious drainage in a surgically placed drain. Associated warning signs included fever and leukocytosis. Patients with a bile leak frequently developed other complications, including a pancreatic fistula, wound infection, delayed gastric emptying, and sepsis. The impact on perioperative outcomes was comparable to patients with a pancreatic leak. A grading system is proposed based on the International Study Group on Pancreatic Fistula model. Grade A bile leaks were classified as those managed with prolonged drainage by operatively placed drains, grade B bile leaks with percutaneous abdominal drainage, and grade C bile leaks with insertion of a percutaneous transhepatic biliary drainage. CONCLUSIONS: Hepaticojejunostomy leaks are rare after PD. The complication severity ranges from trivial to life threatening and is comparable overall to pancreaticojejunostomy leaks. Surgical intervention is rarely, if ever, required. With prompt and aggressive management, a full recovery can be expected.

A dual-institution randomized controlled trial of remnant closure after distal pancreatectomy: does the addition of a falciform patch and fibrin glue improve outcomes?

OBJECTIVE: The objective of the study was to assess the efficacy of two pancreatic remnant closure techniques following distal pancreatectomy: (1) stapled or sutured closure versus (2) stapled or sutured closure plus falciform patch and fibrin glue reinforcement in the setting of a prospective randomized trial, with the primary endpoint being pancreatic fistula. Pancreatic stump leak following left-sided pancreatic resection (distal pancreatectomy) remains common. Despite multiple and varied techniques for closure, the reported leak rate varies up to 30 %. A retrospective analysis by Iannitti et al. (J Am Coll Surg 203(6):857-864, 2006) detected a decreased leak rate in patients receiving a traditional closure buttressed with an autologous falciform ligament patch and fibrin glue. METHODS: Between April 2008 and October 2011, all willing patients scheduled to undergo distal pancreatectomy at the authors' institutions were consented and enrolled at the preoperative office visit. Patients were intraoperatively stratified as having hard or soft glands and randomized to one of two groups: (1) closure utilizing stapling or suturing (SS) versus (2) stapled or sutured plus falciform ligament patch and fibrin glue (FF). The trial design and power analysis (α = 0.05, ß = 0.2, power 80 %, chi-square test) hypothesized that the FF intervention would reduce the primary endpoint (pancreatic fistula) from 30 % to 15 % and targeted an accrual goal of 190 patients. Secondary endpoints included length of postoperative hospital stay, 30-day mortality, hospital readmission, and ISGPF fistula grade (A, B, and C). RESULTS: The trial accrued 109 patients, 55 in the SS group and 54 in the FF group. Enrollment was closed prior to the target accrual, following an interim analysis and futility calculation. Due to insufficient enrollment, patients stratified as having a hard gland were excluded (n = 8) from analysis, leaving 101 patients in the soft stratum. The overall pancreatic leak rate was 19.8 % (20 patients) for patients with soft glands. Patients randomized to the FF group had a leak rate of 20 %, as compared with 19.6 % in the SS group (p = 1.000). Fistula grades in both groups were identical: 1A, 8B, and 1C in the FF group as compared to 1A, 8B, and 1C in the SS group. Complication rates were comparable between the two groups. The median length of postoperative hospital stay was 5 days in both groups. There was a trend towards a higher 30-day readmission rate in the FF group (28 % vs. 17.6 %, p = 0.243). CONCLUSION: The addition of a falciform ligament patch and fibrin glue to standard stapled or sutured remnant closure did not reduce the rate or severity of pancreatic fistula in patients undergoing distal pancreatectomy (ClinicalTrials.gov NCT00889213).

Serum blood urea nitrogen and serum albumin on the first postoperative day predict pancreatic fistula and major complications after pancreaticoduodenectomy.

INTRODUCTION: Pancreaticoduodenectomy (PD) has a high morbidity rate. Previous work has shown that hypoalbuminemia on postoperative day 1 (POD) to be contributory to post-esophagectomy complications. We set out to determine the impact of blood urea nitrogen (BUN) and albumin on POD 1 for patients undergoing PD. METHODS: We examined 446 consecutive patients who underwent PD at the Thomas Jefferson University Hospital between January 1, 2000 and December 31, 2008. Complications were graded using the Clavien scale. We examined the incidence of complications based on POD 1 albumin <2.5 versus ≥2.5 mg/dl, as well as POD 1 BUN <10 vs. ≥10 g/dL. RESULTS: Patients with a BUN <10 had a significantly decreased risk of any complication (p < 0.001), serious complication (p < 0.001), and pancreatic fistula (p = 0.011). On multivariate analysis, BUN ≥ 10 was the most significant predictor of grade III or above complication (p = 0.0019, hazard ration (HR) = 2.7) and pancreatic fistula (p = 0.016, HR = 2.6). POD 1 albumin <2.5 mg/dl was also an independent predictor of serious complication (p = 0.01, HR = 2.3). Patients with both risk factors had a 31 % chance of developing serious complications and 18.5 % risk of developing pancreatic fistula, while those patients with neither risk factor had a 6.5 and 3.6 % risk, respectively. CONCLUSION: Serum albumin and BUN on POD 1 are important predictors of perioperative morbidity following PD. These low-cost and easily accessible tests can be used as a prognostic tool to predict adverse surgical outcomes.

A progressive postresection walking program significantly improves fatigue and health-related quality of life in pancreas and periampullary cancer patients.

BACKGROUND: As patients with pancreas and periampullary cancer (PPC) experience improved survival rates and longevity, the focus shifts toward living life while surviving cancer. Fatigue is the most commonly reported symptom in all cancer patients. Exercise has been found to effectively decrease fatigue levels and improve physical functioning in cancer patients. STUDY DESIGN: One hundred two patients with resected PPC consented to participate in this study and were randomized to either an intervention group (IG) or a usual care group (UCG). Subjects completed visual analog scales, the FACIT-Fatigue Scale and the Short Form-36v2 after surgery and again 3 to 6 months after hospital discharge. RESULTS: Patients in the IG and UCG were comparable with regard to demographics, comorbidities, cancer type and staging, type of resection, preoperative fatigue and pain levels, adjuvant therapy, and baseline walking distance. Patients in the IG had significantly improved scores on the FACIT-Fatigue Scale at study completion, improved fatigue and pain scores, as well as overall physical functioning and mental health composite scores. At study completion, participants in the IG were walking twice as far and were significantly more likely to have continued walking or another form of exercise as compared with the UCG. Using hierarchical cluster analysis, 3 mutually exclusive symptom groupings were identified in the cohort. Kaplan-Meier survival analysis did not indicate an overall survival benefit for the IG. CONCLUSIONS: This is the first prospective, randomized controlled trial to report that participation in a home walking program confers a significant benefit in resected PPC patients with regard to fatigue levels, physical functioning, and health-related quality of life.

Intraductal papillary mucinous neoplasm (IPMN) with extra-pancreatic mucin: a case series and review of the literature.

BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN) is an increasingly recognized pancreatic neoplasm characterized by excessive mucin secretion by ductal epithelial cells resulting in a cystic dilation of the pancreatic duct. AIM: The objective of this study was to review Thomas Jefferson University's experience and the literature to determine the significance of extra-pancreatic mucin when associated with an IPMN. RESULTS: A retrospective analysis at our institution revealed only two cases of IPMN associated with extra-pancreatic mucin, which were classic IPMNs with rupture of the pancreatic duct and peritoneal mucin spillage. This specific finding is not previously described, although is assumed as five cases were reported in the literature with IPMN and mucin extension demonstrated by pseudomyxoma peritonei (PMP). We propose IPMN of the pancreas may be grossly compared to a mucocele of the appendix, as both are characterized by excessive secretion of mucin by ductal epithelial cells. A morbid complication of a mucocele is PMP. The presence of extra-pancreatic mucin with an IPMN could present a rare but important marker of the eventual seeding of tumor outside the primary IPMN. This has been documented with cases of iatrogenic spilling of pancreatic mucin, as well as multiple cases of IPMN associated with pseudomyxoma peritonei. CONCLUSIONS: At this time, there is scant reporting and consensus for the treatment of IPMN with extra-pancreatic mucin.

Perioperative surgical care bundle reduces pancreaticoduodenectomy wound infections.

BACKGROUND: Pancreaticoduodenectomy (PD) is a complex surgical procedure with a historically high morbidity rate. The goal of this study was to determine if the implementation of a 12-measure perioperative surgical care bundle (SCB) was successful in reducing infectious and other complications in patients undergoing PD compared with a routine preoperative preparation group (RPP). METHODS: In this retrospective cohort study utilizing the HPB surgery database at the Thomas Jefferson University, we analyzed clinical data from 233 consecutive PDs from October 2005 to May 2008 on patients who underwent RPP, and compared them with 233 consecutive PDs from May 2008 to May 2010 following the implementation of the SCB. The SCB was the product of multidisciplinary discussion and extensive literature review. RESULTS: The RPP group and the SCB group had similar demographic characteristics. The overall rate of postoperative morbidity was similar between groups (42.1% versus 37.8%). However, wound infections were significantly lower in the SCB group (15.0% versus 7.7%, P = 0.01).The rates of other common complications, as well as postoperative hospital length of stay, readmissions, and 30-d postoperative mortality were similar between groups. CONCLUSIONS: The implementation of a SCB was followed by a significant decline in wound infection in patients undergoing PD.