Background The objective of this study was to identify trends in the diagnosis and treatment of cystic neoplasms of the pancreas using a retrospective review of patients from a surgical database at ...an academic referral center during a 33-year period. Methods Patient characteristics, including demographics, pathology, and survival, were analyzed over 5 time periods between 1978 and 2011. Results A total of 851 consecutive patients underwent resection for a cystic neoplasm of the pancreas during a 33-year period. Sixty-five percent of patients were female, and mean age was 60 years. The most common pathologic diagnoses were intraductal papillary mucinous neoplasm (38%), mucinous cystic neoplasm (23%), serous cystadenoma (16%), and cystic neuroendocrine neoplasm (7%). There was a stepwise increase in the number of resections across time periods (67 between 1978 and 1989; 376 between 2005 and 2011), with a parallel increase in the proportion of incidentally discovered lesions (22% to 50%). Diagnosis of intraductal papillary mucinous neoplasm was very uncommon in the first 2 time periods (before the first recognition of intraductal papillary mucinous neoplasm as a distinct entity) but predominated in the last 2 (41% and 49%), and cystic neuroendocrine neoplasms, which constituted 3% of the cystic neoplasms in the first time-period, now comprise more than 8% of pancreatic cystic neoplasms. The proportion of malignant neoplasms decreased over time (41% between 1978 and 1989; 12% between 2005 and 2011), reflecting probably the earlier diagnosis and treatment of premalignant neoplasms. Although operative mortality was minimal (4/849, 0.5%), the postoperative complication rate was 38%. Overall 5-year survival for all mucinous lesions was 87%. Conclusion Cystic neoplasms of the pancreas are being diagnosed and treated with increasing frequency. At present, most are incidentally discovered intraductal papillary mucinous neoplasms.
Background Since Allen O. Whipple published his seminal paper in 1935, the procedure that bears his name has been performed widely throughout the world and is now a common operation in major medical ...centers. The goal of this study was to investigate the evolution of pancreatoduodenectomy at the Massachusetts General Hospital (MGH). Methods We sought to identify all pancreatoduodenectomies performed at the MGH since 1935. Cases were obtained from a computerized database, hospital medical records, and the MGH historical archive. Demographics, diagnosis, intraoperative variables and short-term surgical outcomes were recorded. Results The first pancreatoduodenectomy at the MGH was carried out in 1941; since then, 2,050 Whipple procedures have been performed. Pancreatic ductal adenocarcinoma was the most frequent indication (36%). Pylorus preservation has been the most important variation in technique, accounting for 45% of Whipple procedures in the 1980s; observation of frequent delayed gastric emptying after this procedure led to decline in its use. Pancreatic fistula was the most frequent complication (13%). Operative blood replacement and reoperation rates have decreased markedly over time; the most frequent indication for reoperation was intra-abdominal bleeding. Mortality has decreased from 45% to 0.8%, with sepsis and hypovolemic shock being the most frequent causes of death. Mean duration of hospital stay has decreased from >30 to 9.5 days, along with an increasing readmission rate (currently 19%). Conclusion The Whipple procedure in the 21st century is a well-established operation. Improvements in operative technique and perioperative care have contributed in making it a safe operation that continues evolving.
Patient-derived xenograft (PDX) tumors are powerful tools to study cancer biology. However, the ability of PDX tumors to model the biological and histological diversity of pancreatic ductal ...adenocarcinoma (PDAC) is not well known. In this study, we subcutaneously implanted 133 primary and metastatic PDAC tumors into immunodeficient mice. Fifty-seven tumors were successfully engrafted and even after extensive passaging, the histology of poorly-, moderately-, and well-differentiated tumors was maintained in the PDX models. Moreover, the fibroblast and collagen contents in the stroma of patient tumors were recapitulated in the corresponding PDX models. Analysis of the clinicopathological features of patients revealed xenograft tumor engraftment was associated with lymphovascular invasion (P = 0.001) and worse recurrence-free (median, 7 vs. 16 months, log-rank P = 0.047) and overall survival (median, 13 vs. 21 months, log-rank P = 0.038). Among successful engraftments, median time of growth required for reimplantation into new mice was 151 days. Reflective of the inherent biological diversity between PDX tumors with rapid (<151 days) and slow growth, differences in their growth were maintained during extensive passaging. Rapid growth was additionally associated with lymph node metastasis (P = 0.022). The association of lymphovascular invasion and lymph node metastasis with PDX formation and rapid growth may reflect an underlying biological mechanism that allows these tumors to adapt and grow in a new environment. While the ability of PDX tumors to mimic the cellular and non-cellular features of the parental tumor stroma provides a valuable model to study the interaction of PDAC cells with the tumor microenvironment, the association of successful engraftment with adverse clinicopathological features suggests PDX models over represent more aggressive forms of this disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The question of whether dedicated progenitor cells exist in adult vertebrate pancreas remains controversial. Centroacinar cells and terminal duct (CA/TD) cells lie at the junction between peripheral ...acinar cells and the adjacent ductal epithelium, and are frequently included among cell types proposed as candidate pancreatic progenitors. However these cells have not previously been isolated in a manner that allows formal assessment of their progenitor capacities. We have found that a subset of adult CA/TD cells are characterized by high levels of ALDH1 enzymatic activity, related to high-level expression of both Aldh1a1 and Aldh1a7. This allows their isolation by FACS using a fluorogenic ALDH1 substrate. FACS-isolated CA/TD cells are relatively depleted of transcripts associated with differentiated pancreatic cell types. In contrast, they are markedly enriched for transcripts encoding Sca1, Sdf1, c-Met, Nestin, and Sox9, markers previously associated with progenitor populations in embryonic pancreas and other tissues. FACS-sorted CA/TD cells are uniquely able to form self-renewing "pancreatospheres" in suspension culture, even when plated at clonal density. These spheres display a capacity for spontaneous endocrine and exocrine differentiation, as well as glucose-responsive insulin secretion. In addition, when injected into cultured embryonic dorsal pancreatic buds, these adult cells display a unique capacity to contribute to both the embryonic endocrine and exocrine lineages. Finally, these cells demonstrate dramatic expansion in the setting of chronic epithelial injury. These findings suggest that CA/TD cells are indeed capable of progenitor function and may contribute to the maintenance of tissue homeostasis in adult mouse pancreas.
The objective of our retrospective institutional experience is to report the overall response rate, R0 resection rate, progression‐free survival, and safety/toxicity of neoadjuvant FOLFIRINOX ...(5‐fluorouracil 5‐FU, oxaliplatin, irinotecan, and leucovorin) and chemoradiation in patients with locally advanced pancreatic cancer (LAPC). Patients with LAPC treated with FOLFIRINOX were identified via the Massachusetts General Hospital Cancer Center pharmacy database. Demographic information, clinical characteristics, and safety/tolerability data were compiled. Formal radiographic review was performed to determine overall response rates (ORRs). Twenty‐two patients with LAPC began treatment with FOLFIRINOX between July 2010 and February 2012. The ORR was 27.3%, and the median progression‐free survival was 11.7 months. Five of 22 patients were able to undergo R0 resections following neoadjuvant FOLFIRINOX and chemoradiation. Three of the five patients have experienced distant recurrence within 5 months. Thirty‐two percent of patients required at least one emergency department visit or hospitalization while being treated with FOLFIRINOX. FOLFIRINOX possesses substantial activity in patients with LAPC. The use of FOLFIRINOX was associated with conversion to resectability in >20% of patients. However, the recurrences following R0 resection in three of five patients and the toxicities observed with the use of this regimen raise important questions about how to best treat patients with LAPC.
This retrospective institutional experience from the Massachusetts General Hospital Cancer Center reports the overall response rate, R0 resection rate, progression‐free survival, and safety/toxicity of neoadjuvant FOLFIRINOX and chemoradiation in patients with locally advanced pancreatic cancer. FOLFIRINOX demonstrated substantial activity in patients with LAPC, although recurrences after resection and toxicities raise important questions about how to best treat these patients.
Hedgehog signalling-an essential pathway during embryonic pancreatic development, the misregulation of which has been implicated in several forms of cancer-may also be an important mediator in human ...pancreatic carcinoma. Here we report that sonic hedgehog, a secreted hedgehog ligand, is abnormally expressed in pancreatic adenocarcinoma and its precursor lesions: pancreatic intraepithelial neoplasia (PanIN). Pancreata of Pdx-Shh mice (in which Shh is misexpressed in the pancreatic endoderm) develop abnormal tubular structures, a phenocopy of human PanIN-1 and -2. Moreover, these PanIN-like lesions also contain mutations in K-ras and overexpress HER-2/neu, which are genetic mutations found early in the progression of human pancreatic cancer. Furthermore, hedgehog signalling remains active in cell lines established from primary and metastatic pancreatic adenocarcinomas. Notably, inhibition of hedgehog signalling by cyclopamine induced apoptosis and blocked proliferation in a subset of the pancreatic cancer cell lines both in vitro and in vivo. These data suggest that this pathway may have an early and critical role in the genesis of this cancer, and that maintenance of hedgehog signalling is important for aberrant proliferation and tumorigenesis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
MINIAn international survey of high-volume pancreas cancer surgeons revealed wide variations in management preferences, attitudes regarding contraindications to surgery, and the propensity to offer ...exploration. When presented with 6 hypothetical clinical vignettes using details from real patients that have received R0 resection, only 14% to 53% of participating surgeons were willing to offer exploration following neoadjuvant therapy.
OBJECTIVE:The aim of this study was to investigate surgeon preferences for the management of patients with locally advanced pancreatic cancer (LAPC).
BACKGROUND:Select patients with LAPC may become candidates for curative resection following neoadjuvant therapy, and recent reports of survival are encouraging. Yet the optimal management approach remains unclear.
METHODS:An extensive electronic survey was systematically distributed by email to an international cohort of pancreas surgeons. Data collected included practice characteristics, management preferences, attitudes regarding contraindications to surgery, and 6 clinical vignettes of patients that ultimately received a margin negative resection (with detailed videos of post-neoadjuvant imaging) to assess propensity for surgical exploration if resection status is not known.
RESULTS:A total of 153 eligible responses were received from 4 continents. Median duration of practice is 12 years (interquartile range 6–20) and 77% work in a university setting. Most surgeons (86%) are considered high volume (>10 resections/yr), 33% offer a minimally-invasive approach, and 50% offer arterial resections in select patients. Most (72%) always recommend neoadjuvant chemotherapy, and 65% prefer FOLFIRINOX. Preferences for the duration of chemotherapy varied widely39% prefer ≥2 months, 43% prefer ≥4 months, and 11% prefer ≥6 months. Forty-one percent frequently recommend neoadjuvant radiotherapy, and 53% prefer 5 to 6 weeks of chemoradiation. The proportion of surgeons favoring exploration following neoadjuvant varied extensively across 5 vignettes of LAPC, from 14% to 53%. In a vignette of oligometastatic liver metastases, 31% would offer exploration if a favorable therapy response is observed.
CONCLUSIONS:In an international cohort of pancreas surgeons, there is substantial variation in management preferences, perceived contraindications to surgery, and the propensity to consider exploration in LAPC. These results emphasize the importance of a robust and nuanced multidisciplinary discussion for each patient, and suggest an evolving concept of “resectability.”
Background Pancreatic ductal adenocarcinoma represents 90% of pancreatic cancers and is an important cause of cancer death in the United States. Operative resection remains as the only treatment ...providing prolonged survival, but even after a curative resection, 5-year survival rates are low. Our aim was to identify the prognostic factors for long-term survival after resection of pancreatic ductal adenocarcinoma related to patients, treatments, and tumor biology. Methods Retrospective review identified 959 patients who underwent resection of their pancreatic adenocarcinoma between February 1985 and December 2010, of whom 499 were resected before November 2006 and represent the cohort we describe in this study. Patient, tumor, and treatment-related variables were assessed for their associations with 5- and 10-year overall survival. Results Of the 499 patients, 49% were female and median age was 65 years. The majority of patients had stage IIb disease (60%). Actual 5-year survival after resection of pancreatic adenocarcinoma was 19% (95/499), and actual 10-year survival was 10% (33/329). Significant clinicopathologic factors predicting 5- and 10-year survival were negative margins and negative nodal status. Interestingly, 41% (39/95) of long-term survivors had positive nodes and 24% (23/95) had positive margins. Conclusion Pancreatic ductal adenocarcinoma demonstrates a very heterogeneous biology, but patients with negative resection margins and node negative cancers are more likely to survive 5 years after resection. However, our series demonstrates that the biology of the cancer rather than simple pathologic factors determine a patient's prognosis.
Different prognostic factors stratify patients with pancreatic adenocarcinoma. The purpose of this study was to determine whether preoperative CA19-9 levels can predict stage of disease or survival ...and whether a change in preoperative to postoperative CA19-9 or the postoperative CA19-9 predicts overall survival.
Four hundred twenty-four consecutive patients with pancreatic adenocarcinoma underwent resection between January 1, 1985 and January 1, 2004. Of the patients with a bilirubin less than 2 mg/dL, 176 had preoperative CA19-9 values, and 111 had pre- and postoperative CA19-9 values. Survival was measured from the first postoperative CA19-9 level measured (median, 39 days) until death or last follow-up. A multivariate failure time model was fit using clinical, operative, pathologic, and adjuvant treatment characteristics, and a categorization was defined by the values and changes in CA19-9 before and after surgery.
Of the 176 patients, 128 (73%) had T3 lesions, and 99 (56%) had N1 disease; 138 patients (78%) underwent pancreaticoduodenectomy. Median preoperative CA19-9 levels were lower in N0 patients compared with patients with positive nodes (nine v 164 U/mL, respectively; nonparametric P = .06) and in T1/T2 patients versus T3 patients (41 v 162 U/mL, respectively; P = .03). Median follow-up time (n = 111) was 1.8 years (range, 1 to 12.9 years), with overall actuarial 1-, 3-, and 5-year survival rates of 70%, 36%, and 30%, respectively. Significant predictors of survival on multivariate analysis included a decrease in CA19-9 (P = .0005), negative lymph nodes (P = .001), lower T stage (P = .0008), and postoperative CA19-9 less than 200 U/mL (P = .0007).
In patients with pancreatic adenocarcinoma, preoperative CA19-9 correlates with stage of disease. Both a postoperative decrease in CA19-9 and a postoperative CA19-9 value of less than 200 U/mL are strong independent predictors of survival, even after adjusting for stage. CA19-9 levels should be included in a patient's perioperative care and should be considered for prognostic nomograms.
Metastatic Tumors in the Pancreas in the Modern Era Konstantinidis, Ioannis T., MD; Dursun, Abdulmetin, MD; Zheng, Hui, PhD ...
Journal of the American College of Surgeons,
12/2010, Letnik:
211, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Background Tumors metastasizing to the pancreas are rare, and published series are limited by few patients treated for extended periods of time. Renal cell cancer (RCC) is the most common primary ...tumor metastasizing to the pancreas. Our aim was to describe the clinicopathologic characteristics and patient outcomes in a modern series of patients who underwent metastasectomy, with an emphasis on RCC. Study Design Retrospective review of all pancreatic resections between January 1993 and October 2009. Results We identified 40 patients with a median age of 62 years; 55% were female. Patients most commonly presented with abdominal pain (47.5%). Operations performed included 10 pancreaticoduodenectomies, 1 middle, 23 distal, 3 total pancreatectomies, and 3 enucleations. Primary cancers were RCC (n = 20), ovarian (n = 6), sarcoma (n = 3), colon (n = 3), melanoma (n = 2), and others (n = 6). Median survival for all patients after metastasectomy was 4.4 years. Median survival after metastasectomy for RCC was 8.7 years, and the 5-year actuarial survival was 61%. For RCCs, pancreas was the first site of an extrarenal recurrence in 85% and was synchronous with the primary in 5% of patients. There was no survival difference if the time interval to metastasis was shorter than the median (8.7 years), if tumor nodules were multiple or bigger than the median (3 cm), or if the pancreas was not the first site of metastases. Conclusions An aggressive approach to lesions metastatic to the pancreas is often warranted if the patient can be rendered free of disease. Although patients with RCC can experience long-term survival after metastasectomy, survival is less favorable for other primary tumors.
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