Search

The management of localized pancreatic cancer (PC) has evolved significantly in the last decade, moving away from prioritizing surgery as the primary treatment modality to embracing the need for preoperative (neoadjuvant) multimodality therapy to achieve durable disease-free control. Neoadjuvant therapy is currently recommended for all patients with borderline and locally advanced PC, and is being increasingly utilized in patients with resectable disease as well. When assessing operability the following 3 factors should be considered: clinical stage of disease, response to neoadjuvant therapy, and patient performance status. Patients who demonstrate a response to neoadjuvant therapy may benefit significant from surgical resection.

Background:18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) imaging is not routine in patients with localized pancreatic cancer (PC). We evaluated the prognostic value of PET/CT in patients who received neoadjuvant therapy.Methods: Patients with localized PC underwent pretreatment PET/CT with or without posttreatment (preop) PET/CT. Maximum standardized uptake values (SUV) were classified as high or low based on a cut point of 7.5 at diagnosis (SUVdx) and 3.5 after neoadjuvant therapy (preoperative; SUVpreop). Preop carbohydrate antigen 19-9 (CA19-9) was classified as normal ( ≤ 35 U/mL) or elevated.Results: Pretreatment PET/CT imaging was performed on 201 consecutive patients; SUVdx was high in 98 (49%) and low in 103 (51%). Preop PET/CT was available in 104 (52%) of the 201 patients; SUVpreop was high in 60 (58%) and low in 44 (42%). Following neoadjuvant therapy, preop CA19-9 was normal in 90 (45%) patients and elevated in 111 (55%). Median overall survival (OS) of all patients was 27 months; 33 months for the 103 patients with a low SUVdx and 22 months for the 98 patients with a high SUVdx (p = 0.03). Median OS for patients with low SUVdx/normal preop CA19-9, high SUVdx/normal preop CA19-9, low SUVdx/elevated preop CA19-9, and high SUVdx/elevated preop CA19-9 were 66, 34, 23, and 17 months, respectively (p < 0.0001). OS was 44 months for the 148 (74%) patients who completed all intended neoadjuvant therapy and surgery and 13 months for the 53 (26%) who did not undergo surgery (p < 0.001).Conclusion: Pretreatment PET/CT avidity and preop CA19-9 are clinically significant prognostic markers in patients with PC.

Introduction/Background: Multimodal neoadjuvant therapy has resulted in increased rates of histologic response in pancreatic tumors and adjacent lymph nodes. The biologic significance of the collective response in the primary tumor and lymph nodes is not understood. Methods: Patients with localized PC who received neoadjuvant therapy and surgery with histologic assessment of the primary tumor and local-regional lymph nodes were included. Histopathologic response was classified using the modified Ryan score as follows: no viable cancer cells (CR), rare groups of cancer cells (nCR), residual cancer with evident tumor regression (PR), and extensive residual cancer with no evident tumor regression (NR). Nodal status was defined by number of lymph nodes (LN) with tumor metastases: N0 (0 LN), N1 (1-3), N2 (≥4). Results: Of 341 patients with localized PC who received neoadjuvant therapy and surgery, 107 (31%) received chemoradiation alone, 44 (13%) received chemotherapy alone, and 190 (56%) received chemotherapy and chemoradiation. Histopathologic response consisted of 15 (4%) CRs, 59 (17%) nCRs, 188 (55%) PRs, and 79 (23%) NRs. Patients who received chemotherapy alone had the worst responses (n = 21 for NR, 48%) as compared to patients who received chemoradiation alone (n = 25 for NR, 24%) or patients who received both therapies (n = 33 for NR, 17%) (Table 1; p = 0.001). Median overall survival for all 341 patients was 39 months; OS by histopathologic subtype was not reached (CR), 49 months (nCR), 38 months (PR), and 34 months (NR), respectively (p = 0.004). Of the 341 patients, 208 (61%) had N0 disease, 97 (28%) had N1 disease, and 36 (11%) had N2 disease. In an adjusted hazards model, modified Ryan score of PR or NR (HR: 1.71; 95% CI: 1.15-2.54; p = 0.008) and N1 (HR: 1.42; 95% CI: 1.1.02-2.01; p = 0.04), or N2 disease (HR: 2.54, 95% CI: 1.64-3.93; p < 0.001) were associated with increased risk of death. Conclusions: Neoadjuvant chemotherapy alone is associated with lower rates of pathologic response. Patients with CR or nCR have a significantly improved OS as compared to patients with PR or NR. Nodal status is the most important pathologic prognostic factor. Neoadjuvant chemoradiation may be an important driver of pathologic response.

Background More than 70% of patients with localized pancreatic cancer treated with upfront surgery develop disease recurrence. Herein we describe the radiographic patterns and timing of disease recurrence after neoadjuvant therapy and surgery in patients with pancreatic cancer. Methods Radiographic patterns of first disease recurrence were examined in patients with localized pancreatic cancer who completed neoadjuvant therapy and surgery. Disease recurrence was classified as local (pancreas, resection bed, or peripancreatic vasculature); regional (peritoneum or abdominal wall); or distant (liver, lung, bone). Progression-free survival was calculated from the date of diagnosis to the date of recurrence. Results Of 306 consecutive patients who completed neoadjuvant therapy and surgery, 149 (49%) had resectable pancreatic cancer and 157 (51%) had borderline resectable disease. Neoadjuvant therapy consisted of chemoradiation (32%), chemotherapy (14%), or both therapies (54%). Overall, primary therapy (including preoperative and postoperative therapy) consisted of chemoradiation alone in 29 (9%), chemotherapy alone in 14 (5%), and both therapies in 263 (86%) patients. At a median follow-up of 27 months, 186 (61%) of the 306 patients had recurrent pancreatic cancer. Sites of first recurrence were local-only in 29 (9%), regional-only in 19 (6%), distant-only in 87 (28%), and multisite in 51 (17%). The overall median progression-free survival for all patients was 24 months. Neoadjuvant chemoradiation reduced the odds of local-only recurrence (odds ratio: 0.21; 95% confidence interval: 0.06–0.77; P = .02). Conclusion After neoadjuvant therapy and surgery, 9% of patients were found to have local-only recurrence. Treatment sequencing that incorporates neoadjuvant chemoradiation may improve local disease control.

Background Patients with locally advanced pancreatic cancer have historically been considered inoperable. The purpose of this report was to determine resectability rates for patients with locally advanced pancreatic cancer based on our recently described definitions of type A and type B locally advanced pancreatic cancer. Methods An institutional prospective pancreas cancer database was queried for consecutive patients with locally advanced pancreatic cancer treated between January 2009 and June 2017. All pretreatment imaging was re-reviewed and patients were categorized as locally advanced pancreatic cancer type A or type B. Demographics, induction therapy, resection type, and outcomes were reviewed. Results We identified 108 consecutive patients; 12 were excluded from analysis due to the absence of available pretreatment imaging or they had not yet completed all intended neoadjuvant therapy. Of the remaining 96 patients (45 type A, 51 type B), disease progression occurred in 19 (20%) during induction therapy and 30 (31%) were deemed inoperable at final preoperative restaging. Therefore, 47 (49%) of 96 patients were taken to surgery and 40 (42%) underwent successful resection (28 [62%] of 45 type A and 12 [24%] of 51 type B); an RO resection was achieved in 32 (80%). Metastatic disease was found intraoperatively (6 at laparoscopy, 1 at laparotomy) in 7 (15%) of 47 patients. There were no mortalities; 6 (15%) patients experienced major postoperative complications. Resected patients had a median overall survival of 38.9 months. Conclusion Locally advanced pancreatic cancer can be dichotomized into type A and B with distinctly different probabilities of completing all therapy to include surgery; thereby allowing goals of therapy to be established at the time of diagnosis. Multimodality therapy that includes surgery can be accomplished in selected patients with locally advanced pancreatic cancer and is associated with a median overall survival that approximates earlier stages of disease. (Surgery 2017;160:XXX-XXX.)

BACKGROUND Sedentary behavior and obesity are major risk factors for cardiovascular disease. Regular physical activity has independent protective effects on the cardiovascular system, but the mechanisms responsible remain elusive. Recent studies suggest that the protein peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) participates in the response to exercise training. We hypothesized that the arterioles of athletes maintain dilation to flow despite combined inhibition of multiple vasodilators, but loss of PGC-1α renders these vessels susceptible to inhibition of a single vasodilator pathway. In addition, arterioles from overweight and obese individuals will display an an exercise-like phenotype when PGC-1α is activated. METHODS Isolated arterioles from exercise-trained (ET) and from mildly overweight or obese subjects (body mass index >25) were cannulated, and changes in lumen diameter in response to graded increases in flow were recorded in the absence and presence of compounds that inhibit various endothelium-dependent vasodilators. RESULTS Microvessels of ET subjects displayed robust dilation that could not be inhibited through targeting the combination of nitric oxide, prostaglandins, and hydrogen peroxide, but were inhibited via interference with membrane hyperpolarization. Loss of PGC-1α (siRNA) in the microcirculation of ET subjects eliminates this vasodilatory robustness rendering vessels susceptible to blockade of H2O2 alone. Pharmacological activation of PGC-1α with alpha-lipoic acid in isolated microvessels from sedentary, overweight, and obese subjects increases arteriolar resistance to vasodilator blockade and protects against acute increases in intraluminal pressure. CONCLUSIONS These findings suggest that the microvascular adaptations to exercise training, and the exercise-induced protection against acute vascular stress in overweight/obese subjects, are mediated by PGC-1α.

Selective screening for pancreatic cancer (PC) has been proposed. We describe the establishment of a comprehensive multidisciplinary screening program using 3.0 T MRI. Criteria for screening included the presence of PC in: ≥ 2 first degree relatives (FDR), 1 FDR and 1 s degree relative (SDR), ≥ 3 any degree relatives (ADR), or any known hereditary cancer syndrome with increased PC risk. Imaging with 3.0 T MRI was performed routinely and endoscopic ultrasound was used selectively. Screening was completed in 75 patients (pts). Hereditary cancer syndromes were present in 42 (56%) of the 75 pts: BRCA2 (18), ATM (8), BRCA1 (6), CDKN2A (4), PALB2 (3), Lynch (2), and Peutz-Jeghers (1). A family history of PC was present in ≥ 2 FDR in 12 (16%) pts, 1 FDR and 1 SDR in 5 (7) pts, and ≥ 3 ADR in 16 (21%) pts. Of the 65 pts who received screening MRI, 28 (43%) pts had pancreatic cystic lesions identified, including 1 (1%) patient in whom a cholangiocarcinoma was diagnosed as well. No patient underwent surgical resection. Using a 3.0 T MRI to screen patients at high risk for developing PC identified radiographic abnormalities in 43% of patients, which were stable on subsequent surveillance. Specific guidelines for the frequency of surveillance and indications for surgery remain areas of active investigation as the global experience with high risk screening continues to mature.

Background It is difficult to successfully deliver multimodality therapy to patients with operable pancreatic cancer. Data on the natural history of such efforts are necessary for physicians to guide shared decision-making with patients and families. We report the survival of consecutive patients with borderline resectable pancreatic cancer who received neoadjuvant therapy before surgery. Methods Data regarding demographics, neoadjuvant therapy, surgery, pathology, and survival duration were abstracted on consecutive patients with borderline resectable pancreatic cancer diagnosed between 2009 and 2017 and not treated on available clinical trials. Borderline resectable pancreatic cancer was defined based on ≥1 of the following: local tumor anatomy, pretreatment serum carbohydrate antigen 19-9 >2,000 U/mL, and the presence of radiographic lesions indeterminate for metastases. Results Neoadjuvant therapy was delivered to 185 patients with borderline resectable pancreatic cancer who were not enrolled in competing clinical trials; 13 (7%) patients received chemoradiation, 12 (7%) received chemotherapy, and 160 (86%) received both. Of the 185 patients, 115 (62%) completed all intended neoadjuvant therapy and surgery; 81 (70%) of 115 underwent pancreaticoduodenectomy; and vascular reconstruction was performed in 51 (44%). A margin negative resection was achieved in 111 (97%) of 115 patients, and 83 (72%) were node negative. Median overall survival for all 185 patients was 20 months; 31 months for the 115 patients who completed all neoadjuvant therapy and surgery as compared to 13 months for the 70 patients who were not resected ( P 0001). Conclusion After neoadjuvant therapy, surgical resection was performed in 62% of patients with borderline resectable pancreatic cancer. Those who normalized preoperative serum carbohydrate antigen 19-9 and had node negative pathology achieved the longest survival. To further improve median survival for all patients, we are incorporating adaptive approaches to neoadjuvant therapy sequencing based on objective assessments of response.

A hallmark of cancer cells is the deregulated uptake of glucose in an effort to sustain the biosynthetic demands of rapid cellular proliferation. This metabolic process was first described by German physiologist Otto Warburg in the 1920s. In the seminal study, Warburg et al. observed a significant increase in glucose consumption and lactic acid production by cancer cells as compared to normal (non-cancerous) cells, despite aerobic conditions, suggesting an anomalous energy metabolism. Subsequent investigators have corroborated this clinical observation and concluded that cancer cells have the ability to reprogram their energy metabolism such that they rely primarily on glucose catabolism for cellular energy production. In contrast, the energy pathway favored by normal tissue cells under aerobic conditions is the coupling of glycolysis with mitochondrial oxidative phosphorylation, as it yields an approximately 18-fold increase in energy production in comparison to glycolysis alone. However, cancer cells are able to compensate by upregulating glucose transporters (GLUT) on the cell membrane, namely, GLUT1, resulting in an increased uptake of glucose into cells.

Among patients with localized pancreatic cancer (PC), the benefit of adjuvant therapy after neoadjuvant therapy and surgery is unknown. Patients with localized PC who completed all intended neoadjuvant therapy and surgery were categorized based on the receipt of adjuvant therapy and by pathologic lymph node status (LN−/LN+). Data was available from 234 consecutive patients, 121 (52%) with resectable and 113 (48%) with borderline resectable PC. Of the 234 patients, 92 (39%) were LN+ and 142 (61%) were LN−. The median overall survival (OS) for the 234 patients was 39 months, 42.3 months for patients who received any adjuvant therapy and 34.1 months for those who did not (p = 0.29). Of the 92 LN+ patients, the median OS with and without adjuvant therapy was 29.5 and 23.2 months, respectively (p = 0.02). Of the142 LN− patients, the median OS was 45 months with or without adjuvant therapy (p = 0.86). In an adjusted hazard model, additional adjuvant therapy had a significant protective effect among LN+ patients (HR 0.39; 95% CI 0.21–0.70; p = 0.002) but not in LN− patients (HR 0.89; 95% CI 0.53–1.52; p = 0.68). Among patients with localized PC who received neoadjuvant therapy and surgery, the benefit of adjuvant therapy was limited to those with node-positive disease.

The incidence of periampullary tumors is increasing. Pancreatic cancer estimated to become the second leading cause of cancer related deaths by 2020. Similar to many other solid organ tumors, the management of pancreatic cancer requires a multidisciplinary team approach and the sequencing of oncologic therapies has significant impact on quality of life, treatment toxicity, and survival. This chapter will review pancreatic cancer staging and provide a framework to guide discussions regarding neoadjuvant versus adjuvant therapy for pancreatic cancer. In addition, the management of tumors of the ampulla Vatar will be contrasted with the management of pancreatic cancer.

e15766 Background: The role of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in the staging of pancreatic cancer (PC) has not been well defined. We evaluated the prognostic value of FDG-PET imaging in patients with localized PC enrolled in a prospective trial of personalized molecular-directed neoadjuvant therapy. Methods: Pretreatment FDG-PET was classified as high or low based on a standardized uptake value (SUV) cutpoint of 7.2 (population median). Carbohydrate antigen 19-9 (CA19-9) was measured after the completion of neoadjuvant therapy (preoperative) and classified as normal (≤35 U/mL) or elevated. Results: Pretreatment FDG-PET imaging was performed on 100 consecutive patients; SUV was high in 50 and low in 50. Preoperative CA19-9 values were available in 99 of 100 patients; 54 (55%) were elevated and 45 (45%) were normal. Of the 100 patients, 81 completed neoadjuvant therapy and surgery, and 19 were not resected. Among the 81 resected patients, SUV was high in 37 (46%) and low in 44 (54%); preoperative CA19-9 was elevated in 40 (49%) and normal in 41 (51%). The median overall survival (OS) for all patients was 39 months; 45 months for who completed all intended neoadjuvant therapy and surgery and 9 months for patients who were not resected. The median OS for patients with normal CA19-9/low SUV, normal CA19-9/high SUV, elevated CA19-9/low SUV, and elevated CA19-9/high SUV were not reached, 35, 24, and 18 months, respectively (p = 0.0001). Conclusions: Pretreatment FDG-PET avidity and preoperative CA19-9 are important prognostic markers and may be used to estimate the anticipated benefit of surgery; information of immediate clinical significance for both treatment sequencing and the application of surgery to patients who are frequently of advanced age or high-risk.

Photoepilation, utilizing lasers and noncoherent light sources, is designed to irradiate as much of the follicular unit as possible, with melanin as the target chromophore. Wavelength absorption should generate energy sufficient to heat and destroy the hair follicle, while preserving the surrounding tissue. When performing photoepilation on African-American skin (Fitzpatrick skin types IV-VI) a greater risk of potential epidermal adverse events, such as dyspigmentation, blistering, crusting, edema, and subsequent scarring, is possible. To reduce epidermal melanin absorption of energy longer wavelengths are considered safer for use on Fitzpatrick skin types IV to VI. This article reviews and compares the reported incidences of adverse events in African-American skin, utilizing lasers and noncoherent light sources for assisted hair removal.