Mark P. Callery

Pretreatment Assessment of Resectable and Borderline Resectable Pancreatic Cancer: Expert Consensus Statement

Preoperative Staging and Defining Resectability From a surgical perspective, the first objective in the management of suspected or confirmed pancreatic cancer is to determine the potential for resection. Routine exploratory laparotomy for the purpose of operatively determining resectability has been diminished by modern 3-D radiographic imaging, along with effective and sustainable nonoperative methods of palliation. Careful correlation between preoperative CT findings and surgical results has better-defined CT criteria for resectability. The critical aspects that need be evaluated in a thorough radiographic assessment are the presence or absence of peritoneal or hepatic metastases; the potential involvement of the SMV and portal vein and the relationship of these vessels and their tributaries to the tumor; the relationship of the tumor to the SMA, celiac axis, hepatic artery, and gastroduodenal artery; and the presence of any aberrant vascular anatomy. Unequivocal radiographic findings contraindicating resection include distant metastases, major venous thrombosis of the portal vein or SMV extending for several centimeters, and circumferential encasement of the SMA, celiac axis or proximal hepatic artery. Recent revisions of the National Comprehensive Cancer Network (NCCN) guidelines were an attempt to distinguish locally advanced unresectable tumors from potentially resectable tumors.22 Ambiguity exists in these guidelines because of the lack of clarity in defining clearly resectable situations from “borderline resectable” tumors and because of the subjective criteria used to define “borderline” tumors relative to locally advanced, unresectable lesions. The NCCN guidelines do offer a definition of what should be considered a radiographically resectable tumor. Patients without distant metastases and no evidence of tumor extension to the SMV and portal vein and clear fat planes around the celiac axis, the hepatic artery, and SMA should be categorized as having localized and resectable cancers. More refined and objective criteria have been proposed by the M. D. Anderson Cancer Center Pancreas Cancer Group in an attempt to better define the term “borderline resectable” and to guide treatment decisions regarding the use of neoadjuvant therapy and the high likelihood of vein resection and reconstruction as a means to improve the rate of a complete and margin-negative resection.23 Radiographic findings of tumor abutment on the portal vein or SMV with or without venous deformity, and limited encasement of the mesenteric vein and portal vein (i.e., short segment occlusion with suitable vessel for anastomosis above and below) represent the extent of venous involvement that would categorize a tumor as borderline resectable. Radiographic findings suggesting borderline arterial involvement as defined by M. D. Anderson Cancer Center include encasement of a short segment of the hepatic artery, without evidence of tumor extension to the celiac axis and/or tumor abutment of the SMA involving < 180° of the artery circumference. In patients without clinically important major comorbidities, and in the absence of radiographic findings to suggest metastatic disease or locally advanced unresectable disease as outlined above, surgical resection should be considered feasible and likely to be achievable. Whether these resections would result in a higher-than-expected rate of margin-positive resections, and whether such resections would affect survival would best be determined by careful examination of outcomes relative to extent of vascular involvement using objective criteria to determine categorization of extent of disease. Consensus Statement 1. Tumors considered localized and resectable should demonstrate the following: a. No distant metastases. b. No radiographic evidence of SMV and portal vein abutment, distortion, tumor thrombus, or venous encasement. c. Clear fat planes around the celiac axis, hepatic artery, and SMA. 2. Tumors considered borderline resectable include the following: a. No distant metastases. b. Venous involvement of the SMV/portal vein demonstrating tumor abutment with or without impingement and narrowing of the lumen, encasement of the SMV/portal vein but without encasement of the nearby arteries, or short segment venous occlusion resulting from either tumor thrombus or encasement but with suitable vessel proximal and distal to the area of vessel involvement, allowing for safe resection and reconstruction. c. Gastroduodenal artery encasement up to the hepatic artery with either short segment encasement or direct abutment of the hepatic artery, without extension to the celiac axis. d. Tumor abutment of the SMA not to exceed >180° of the circumference of the vessel wall.

Severe hypoglycaemia post-gastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia.

Aims/hypothesisPostprandial hypoglycaemia following gastric bypass for obesity is considered a late manifestation of the dumping syndrome and can usually be managed with dietary modification. We investigated three patients with severe postprandial hypoglycaemia and hyperinsulinaemia unresponsive to diet, octreotide and diazoxide with the aim of elucidating the pathological mechanisms involved.MethodsGlucose, insulin, and C-peptide were measured in the fasting and postprandial state, and insulin secretion was assessed following selective intra-arterial calcium injection. Pancreas histopathology was assessed in all three patients.ResultsAll three patients had evidence of severe postprandial hyperinsulinaemia and hypoglycaemia. In one patient, reversal of gastric bypass was ineffective in reversing hypoglycaemia. All three patients ultimately required partial pancreatectomy for control of neuroglycopenia; pancreas pathology of all patients revealed diffuse islet hyperplasia and expansion of beta cell mass.Conclusions/interpretationThese findings suggest that gastric bypass-induced weight loss may unmask an underlying beta cell defect or contribute to pathological islet hyperplasia, perhaps via glucagon-like peptide 1-mediated pathways.

Laparoscopic surgery and the systemic immune response.

OBJECTIVE The authors review studies relating to the immune responses evoked by laparoscopic surgery. SUMMARY BACKGROUND DATA Laparoscopic surgery has gained rapid acceptance based on clinical grounds. Patients benefit from faster recovery, decreased pain, and quicker return to normal activities. Only more recently have attempts been made to identify the metabolic and immune responses that may underlie this clinical success. The immune responses to laparoscopy are now being evaluated in relation to the present knowledge of immune responses to traditional laparotomy and surgery in general. METHODS A review of the published literature of the immune and metabolic responses to laparoscopy was performed. Laparoscopic surgery is compared with the traditional laparotomy on the basis of local and systemic immune responses and patterns of tumor growth. The impact of pneumoperitoneum and insufflation gases on the immune response is also reviewed. CONCLUSIONS The systemic immune responses for surgery in general may not apply to laparoscopic surgery. The bodys response to laparoscopy is one of lesser immune activation as opposed to immunosuppression.

Clinical and Economic Validation of the International Study Group of Pancreatic Fistula (ISGPF) Classification Scheme

Objective:The authors sought to validate the ISGPF classification scheme in a large cohort of patients following pancreaticoduodenectomy (PD) in a pancreaticobiliary surgical specialty unit. Summary Background Data:Definitions of postoperative pancreatic fistula vary widely, precluding accurate comparisons of surgical techniques and experiences. The ISGPF has proposed a classification scheme for pancreatic fistula based on clinical parameters; yet it has not been rigorously tested or validated. Methods:Between October 2001 and 2005, 176 consecutive patients underwent PD with a single drain placed. Pancreatic fistula was defined by ISGPF criteria. Cases were divided into four categories: no fistula; biochemical fistula without clinical sequelae (grade A), fistula requiring any therapeutic intervention (grade B), and fistula with severe clinical sequelae (grade C). Clinical and economic outcomes were analyzed across all grades. Results:More than two thirds of all patients had no evidence of fistula. Grade A fistulas occurred 15% of the time, grade B 12%, and grade C 3%. All measurable outcomes were equivalent between the no fistula and grade A classes. Conversely, costs, duration of stay, ICU duration, and disposition acuity progressively increased from grade A to C. Resource utilization similarly escalated by grade. Conclusions:Biochemical evidence of pancreatic fistula alone has no clinical consequence and does not result in increased resource utilization. Increasing fistula grades have negative clinical and economic impacts on patients and their healthcare resources. These findings validate the ISGPF classification scheme for pancreatic fistula.

A prospectively validated clinical risk score accurately predicts pancreatic fistula after pancreatoduodenectomy.

BACKGROUND Clinically relevant postoperative pancreatic fistulas (CR-POPF) are serious inherent risks of pancreatic resection. Preoperative CR-POPF risk assessment is currently inadequate and rarely disqualifies patients who need resection. The best evaluation of risk occurs intraoperatively, and should guide fistula prevention and response measures thereafter. We sought to develop a risk prediction tool for CR-POPF that features intraoperative assessment and reveals associated clinical and economic significance. STUDY DESIGN Based on International Study Group of Pancreatic Fistula classification, recognized risk factors for CR-POPF (small duct, soft pancreas, high-risk pathology, excessive blood loss) were evaluated during pancreaticoduodenectomy. An optimal risk score range model, selected from 3 different constructs, was first derived (n = 233) and then validated prospectively (n = 212). Clinical and economic outcomes were evaluated across 4 ranges of scores (negligible risk, 0 points; low risk, 1 to 2; intermediate risk, 3 to 6; high risk, 7 to 10). RESULTS Clinically relevant postoperative pancreatic fistulas occurred in 13% of patients. The incidence was greatest with excessive blood loss. Duct size <5 mm was associated with increased fistula rates that rose with even smaller ducts. These factors, together with soft pancreatic parenchyma and certain disease pathologies, afforded a highly predictive 10-point Fistula Risk Score. Risk scores strongly correlated with fistula development (p < 0.001). Notably, patients with scores of 0 points never developed a CR-POPF, while fistulas occurred in all patients with scores of 9 or 10. Other clinical and economic outcomes segregated by risk profile across the 4 risk strata. CONCLUSIONS A simple 10-point Fistula Risk Score derived during pancreaticoduodenectomy accurately predicts subsequent CR-POPF. It can be readily learned and broadly deployed. This prediction tool can help surgeons anticipate, identify, and manage this ominous complication from the outset.

26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer

The 26S proteasome degrades proteins that regulate transcription factor activation, cell cycle progression, and apoptosis. In cancer, this may allow for uncontrolled cell division, promoting tumor growth, and spread. We examined whether selective inhibition of the 26S proteasome with PS‐341, a dipeptide boronic acid analogue, would block proliferation and induce apoptosis in human pancreatic cancer. Proteasome inhibition significantly blocked mitogen (FCS) induced proliferation of BxPC3 human pancreatic cancer cells in vitro, while arresting cell cycle progression and inducing apoptosis by 24 h. Accumulation of p21Cip1‐Waf‐1, a cyclin dependent kinase (CDK) inhibitor normally degraded by the 26S proteasome, occurred by 3 h and correlated with cell cycle arrest. When BxPC3 pancreatic cancer xenografts were established in athymic nu/nu mice, weekly administration of 1 mg/kg PS‐341 significantly inhibited tumor growth. Both cellular apoptosis and p21Cip1‐Waf‐1 protein levels were increased in PS‐341 treated xenografts. Inhibition of tumor xenograft growth was greatest (89%) when PS‐341 was combined with the tumoricidal agent CPT‐11. Combined CPT‐11/PS‐341 therapy, but not single agent therapy, yielded highly apoptotic tumors, significantly inhibited tumor cell proliferation, and blocked NF‐κB activation indicating this systemic therapy was effective at the cancer cell level. 26S proteasome inhibition may represent a new therapeutic approach against this highly resistant and lethal malignancy. J. Cell. Biochem. 82: 110–122, 2001.

The net immunologic advantage of laparoscopic surgery

The trauma of surgery evokes a variety of physiologic and immunologic alterations that should contribute to host defense. However, an exaggerated response to injury may result in immunosuppression and lead to significant postoperative morbidity and mortality. Laparoscopic surgery may result in less induced surgical trauma than conventional open surgery. Decreased postoperative pain and speedy functional recovery of laparoscopic patients may be attributable to the reduced inflammatory response and minimal immunosuppression. Inflammation, an early protective homeostatic immune response to injury, is characterized by the production of proinflammatory cytokines and by activation of cellular and humoral immune mechanisms. Postoperative levels of the inflammatory cytokines have been consistently lower after laparoscopic procedures, indicating a smaller degree of surgical insult and acute inflammatory reaction. Surgical stress derails the functions of both polymorphonuclear and mononuclear cells, which may lead to an increased risk of postoperative infection. Comparative studies of cellular immunity after laparoscopic and conventional surgery demonstrate immunologic advantage conferred by laparoscopy. Exaggerated activation of peritoneal immunity may lead to a relative local immunosuppression, resulting in ineffective intraperitoneal bacterial clearance and serious postoperative infections. Functions of the peritoneal macrophages are better preserved when laparotomy is avoided. Decreased perioperative stress may be particularly important for oncologic patients. Laparoscopic approaches may result in diminished perioperative tumor dissemination and better cancer outcomes. Although laparoscopy is “minimally invasive,” systemic immune responses still are undeniably activated. However, laparoscopic surgery appears to induce a smaller injury, resulting in proportionally decreased immunologic changes. In addition to improved cosmesis and faster functional recovery, a patient undergoing laparoscopic surgery may benefit most from a net immunologic advantage.

Staging laparoscopy with laparoscopic ultrasonography: optimizing resectability in hepatobiliary and pancreatic malignancy

BACKGROUND Open laparotomy has traditionally been required to stage hepatobiliary and pancreatic (HBP) cancers accurately. For unresectable patients, costs and morbidity have been high. Today, laparoscopy alone or combined with laparoscopic ultrasonography (LUS) is being examined for its value in defining the extent of malignancy. STUDY DESIGN We have analyzed the effect of routine implementation of this new staging technique in our HBP center. Staging laparoscopy (SL) with LUS was performed in 50 consecutive patients with HBP malignancies. All patients were considered to have resectable tumors as determined by traditional preoperative staging modalities. Primary tumors were located in the liver (n = 7), biliary tract (n = 11), or pancreas (n = 32). An average of 2.7 preoperative studies per patient were performed prior to SL-LUS. RESULTS Staging laparoscopy with laparoscopic ultrasonography predicted resectable tumors in 28 patients (56%). At laparotomy, 26 of 28 were actually resectable: the false-negative rate was 4%. Staging laparoscopy with laparoscopic ultrasonography indicated unresectability in 22 patients (44%). Staging laparoscopy alone demonstrated previously unrecognized occult metastases in 11 patients (22%). In 11 other patients (22%) in whom SL alone was negative, LUS established unresectability from vascular invasion (n = 5), lymph node metastases (n = 5), or intraparenchymal hepatic tumor (n = 1). All cases of unresectability due to vascular invasion were validated by laparotomy. Five of six lymph node or hepatic metastases were proved histologically by LUS-guided needle biopsy rather than laparotomy. CONCLUSIONS Unnecessary laparotomy can be safely avoided by SL-LUS in many patients with HPB malignancies, reducing costs and morbidity.

Stereotactic Body Radiotherapy and Gemcitabine for Locally Advanced Pancreatic Cancer

PURPOSE Patients with nonmetastatic locally advanced unresectable pancreatic cancer have a dismal prognosis. Conventional concurrent chemoradiotherapy requires 6 weeks of daily treatment and can be arduous. We explored the safety and effectiveness of a 3-day course of hypofractionated stereotactic body radiotherapy (SBRT) followed by gemcitabine in this population. PATIENTS AND METHODS A total of 36 patients with nonmetastatic, locally advanced, unresectable pancreatic cancer with ≥12 months of follow-up were included. They received three fractions of 8, 10, or 12 Gy (total dose, 24-36 Gy) of SBRT according to the tumor location in relation to the stomach and duodenum, using fiducial-based respiratory motion tracking on a robotic radiosurgery system. The patients were then offered gemcitabine for 6 months or until tolerance or disease progression. RESULTS With an overall median follow-up of 24 months (range, 12-33), the local control rate was 78%, the median overall survival time was 14.3 months, the median carbohydrate antigen 19-9-determined progression-free survival time was 7.9 months, and the median computed tomography-determined progression-free survival time was 9.6 months. Of the 36 patients, 28 (78%) eventually developed distant metastases. Six patients (17%) were free of progression at the last follow-up visit (range, 13-30 months) as determined by normalized tumor markers with stable computed tomography findings. Nine Grade 2 (25%) and five Grade 3 (14%) toxicities attributable to SBRT occurred. CONCLUSION Hypofractionated SBRT can be delivered quickly and effectively in patients with nonmetastatic, locally advanced, unresectable pancreatic cancer with acceptable side effects and minimal interference with gemcitabine chemotherapy.

Induction gemcitabine and stereotactic body radiotherapy for locally advanced nonmetastatic pancreas cancer.

PURPOSE Stereotactic body radiotherapy (SBRT) has been used successfully to treat patients with locally advanced pancreas cancer. However, many patients develop metastatic disease soon after diagnosis and may receive little benefit from such therapy. We therefore retrospectively analyzed a planned strategy of initial chemotherapy with restaging and then treatment for those patients with no evidence of metastatic progression with SBRT. METHODS AND MATERIALS Forty-seven patients received gemcitabine (1,000 mg/m(2) per week for 3 weeks then 1 week off) until tolerance, at least six cycles, or progression. Patients without metastases after two cycles were treated with SBRT (tolerance-based dose of 24-36 Gy in 3 fractions) between the third and fourth cycles without interrupting the chemotherapy cycles. RESULTS Eight of the 47 patients (17%) were found to have metastatic disease after two cycles of gemcitabine; the remaining 39 patients received SBRT. The median follow-up for survivors was 21 months (range, 6-36 months). The median overall survival for all patients who received SBRT was 20 months, and the median progression-free survival was 15 months. The local control rate was 85% (33 of 39 patients); and 54% of patients (21 of 39) developed metastases. Late Grade III toxicities such as GI bleeding and obstruction were observed in 9% (3/39) of patients. CONCLUSION For patients with locally advanced pancreas cancer, this strategy uses local therapy for those who are most likely to benefit from it and spares those patients with early metastatic progression from treatment. SBRT delivers such local therapy safely with minimal interruption to systemic chemotherapy, thereby potentially improving the outcome in these patients.