Charles J. Yeo

DPC4, A Candidate Tumor Suppressor Gene at Human Chromosome 18q21.1

About 90 percent of human pancreatic carcinomas show allelic loss at chromosome 18q. To identify candidate tumor suppressor genes on 18q, a panel of pancreatic carcinomas were analyzed for convergent sites of homozygous deletion. Twenty-five of 84 tumors had homozygous deletions at 18q21.1, a site that excludes DCC (a candidate suppressor gene for colorectal cancer) and includes DPC4, a gene similar in sequence to a Drosophila melanogaster gene (Mad) implicated in a transforming growth factor-β (TGF-β)-like signaling pathway. Potentially inactivating mutations in DPC4 were identified in six of 27 pancreatic carcinomas that did not have homozygous deletions at 18q21.1. These results identify DPC4 as a candidate tumor suppressor gene whose inactivation may play a role in pancreatic and possibly other human cancers.

Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes.

OBJECTIVE The authors reviewed the pathology, complications, and outcomes in a consecutive group of 650 patients undergoing pancreaticoduodenectomy in the 1990s. SUMMARY BACKGROUND DATA Pancreaticoduodenectomy has been used increasingly in recent years to resect a variety of malignant and benign diseases of the pancreas and periampullary region. METHODS Between January 1990 and July 1996, inclusive, 650 patients underwent pancreaticoduodenal resection at The Johns Hopkins Hospital. Data were recorded prospectively on all patients. All pathology specimens were reviewed and categorized. Statistical analyses were performed using both univariate and multivariate models. RESULTS The patients had a mean age of 63 +/- 12.8 years, with 54% male and 91% white. The number of resections per year rose from 60 in 1990 to 161 in 1995. Pathologic examination results showed pancreatic cancer (n = 282; 43%), ampullary cancer (n = 70; 11%), distal common bile duct cancer (n = 65; 10%), duodenal cancer (n = 26; 4%), chronic pancreatitis (n = 71; 11%), neuroendocrine tumor (n = 31; 5%), periampullary adenoma (n = 21; 3%), cystadenocarcinoma (n = 14; 2%), cystadenoma (n = 25; 4%), and other (n = 45; 7%). The surgical procedure involved pylorus preservation in 82%, partial pancreatectomy in 95%, and portal or superior mesenteric venous resection in 4%. Pancreatic-enteric reconstruction, when appropriate, was via pancreaticojejunostomy in 71% and pancreaticogastrostomy in 29%. The median intraoperative blood loss was 625 mL, median units of red cells transfused was zero, and the median operative time was 7 hours. During this period, 190 consecutive pancreaticoduodenectomies were performed without a mortality. Nine deaths occurred in-hospital or within 30 days of operation (1.4% operative mortality). The postoperative complication rate was 41%, with the most common complications being early delayed gastric emptying (19%), pancreatic fistula (14%), and wound infection (10%). Twenty-three patients required reoperation in the immediate postoperative period (3.5%), most commonly for bleeding, abscess, or dehiscence. The median postoperative length of stay was 13 days. A multivariate analysis of the 443 patients with periampullary adenocarcinoma indicated that the most powerful independent predictors favoring long-term survival included a pathologic diagnosis of duodenal adenocarcinoma, tumor diameter <3 cm, negative resection margins, absence of lymph node metastases, well-differentiated histology, and no reoperation. CONCLUSIONS This single institution, high-volume experience indicates that pancreaticoduodenectomy can be performed safely for a variety of malignant and benign disorders of the pancreas and periampullary region. Overall survival is determined largely by the pathology within the resection specimen.

Resected adenocarcinoma of the pancreas— 616 patients: Results, outcomes, and prognostic indicators

This large-volume, single-institution review examines factors influencing long-term survival after resection in patients with adenocarcinoma of the head, neck, uncinate process, body, or tail of the pancreas. Between January 1984 and July 1999 inclusive, 616 patients with adenocarcinoma of the pancreas underwent surgical resection. A retrospective analysis of a prospectively collected database was performed. Both univariate and multivariate models were used to determine the factors influencing survival. Of the 616 patients, 526 (85%) underwent pancreaticoduodenectomy for adenocarcinoma of the head, neck, or uncinate process of the pancreas, 52 (9%) underwent distal pancreatectomy for adenocarcinoma of the body or tail, and 38 (6%) underwent total pancreatectomy for adenocarcinoma extensively involving the gland. The mean age of the patients was 64.3 years, with 54% being male and 91% being white. The overall perioperative mortality rate was 2.3%, whereas the incidence of postoperative complications was 30%. The median postoperative length of stay was 11 days. The mean tumor diameter was 3.2 cm, with 72 % of patients having positive lymph nodes, 30% having positive resection margins, and 36% having poorly differentiated tumors. Patients undergoing distal pancreatectomy for left-sided lesions had larger tumors (4.7 vs. 3.1 cm, P <0.0001), but fewer node-positive resections (59% vs. 73%, P = 0.03) and fewer poorly differentiated tumors (29% vs. 36%, P<0.001), as compared to those undergoing pancreaticoduodenectomy for right-sided lesions. The overall survival of the entire cohort was 63% at 1 year and 17% at 5 years, with a median survival of 17 months. For right-sided lesions the 1- and 5-year survival rates were 64% and 17%, respectively, compared to 50% and 15% for left-sided lesions. Factors shown to have favorable independent prognostic significance by multivariate analysis were negative resection margins (hazard ratio [HR] = 0.64, confidence interval [CI] = 0.50 to 0.82, P = 0.0004), tumor diameter less than 3 cm (HR = 0.72, CI = 0.57 to 0.90, P = 0.004), estimated blood loss less than 750 ml (HR = 0.75, CI = 0.58 to 0.96, P = 0.02), well/moderate tumor differentiation (HR = 0.71, CI = 0.56 to 0.90, P = 0.005), and postoperative chemoradiation (HR = 0.50, CI = 0.39 to 0.64, P } < 0.0001). Tumor location in head, neck, or uncinate process approached significance in the final multivariate model (HR = 0.60, CI = 0.35 to 1.0, P = 0.06). Pancreatic resection remains the only hope for long-term survival in patients with adenocarcinoma of the pancreas. Completeness of resection and tumor characteristics including tumor size and degree of differentiation are important independent prognostic indicators. Adjuvant chemoradiation is a strong predictor of outcome and likely decreases the independent significance of tumor location and nodal status.

Trends in long-term survival following liver resection for hepatic colorectal metastases

ObjectiveTo examine trends in outcomes of patients undergoing resection at a single tertiary care referral center over a 16-year period. Summary Background DataHepatic resection is considered the treatment of choice in selected patients with colorectal metastasis confined to the liver. Although a variety of retrospective studies have demonstrated improvements in short-term outcomes in recent years, changes in long-term survival over time are less well-established. MethodsData from 226 consecutive patients undergoing potentially curative liver resection for colorectal metastases between 1984 and 1999 were analyzed. Actuarial survival rates related to prognostic determinants were analyzed using the log-rank test. ResultsThe median survival for the entire cohort was 46 months, with 5- and 10-year survival rates of 40% and 26% respectively. Ninety-three patients operated on between 1984 and 1992 were found to have an overall survival of 31% at 5 years, compared to 58% for the 133 patients operated on during the more recent period (1993–1999). Both overall and disease-free survival were significantly better in the recent time period compared with the earlier period on both univariate and multivariate analyses. Other independent factors associated with improved survival included number of metastatic tumors ≤ 3, negative resection margin, and CEA < 100. Comparisons were made between time periods for a variety of patient, tumor and treatment-related factors. Among all parameters studied, only resection type (anatomical versus nonanatomical), use of intraoperative ultrasonography, and perioperative chemotherapy administration differed between the early and recent time periods. ConclusionsLong-term survival following liver resection for colorectal metastases has improved significantly in recent years at our institution. Although the reasons for this survival trend are not clear, contributing factors may include the use of newer preoperative and intraoperative imaging, increased use of chemotherapy, and salvage surgical therapy.

Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma

The MTS1 gene on chromosome 9p21 encodes the p16 inhibitor of cyclinD/Cdk-4 complexes, and is deleted or mutated in a variety of tumour types. We found allelic deletions of 9p21–p22 in 85% of pancreatic adenocarcinomas. Analysis of MTS1 in pancreatic carcinomas (27 xenografts and 10 cell lines) showed homozygous deletions in 15 (41%) and sequence changes in 14 (38%). These included eight point mutations (four nonsense, two missense and two splice site mutations) and six deletions/ insertions, all accompanied by loss of the wild-type allele. Sequencing of MTS1 from primary tumours confirmed the mutations. Coexistent inactivations of both MTS1 and p53 was common and suggests that abnormal regulation of cyclin-dependent kinases may play an important role in the biology of pancreatic carcinoma.

1423 pancreaticoduodenectomies for pancreatic cancer: A single-institution experience

Pancreaticoduodenectomy (PD) with the possible addition of neoadjuvant or adjuvant therapy is the standard of care in the United States for adenocarcinoma originating in the pancreatic head, neck, and uncinate process. We reviewed 1423 patients who underwent a PD for a malignancy originating in the pancreas at our institution between 1970 and 2006. We examined 1175 PDs for ductal adenocarcinomas in greater detail. Eighteen different histological types of pancreatic cancer were identified; the most common diagnoses included ductal adenocarcinoma, neuroendocrine carcinoma, and IPMN with invasive cancer. Patients with ductal adenocarcinoma were analyzed in detail. The median age was 66 years, with patients in the present decade significantly older (68 years), on average, than patients in the three prior decades (e.g., 60 years in 1970, P=0.02). The median tumor diameter was 3 cm; 42% of the resections had positive margins and 78% had positive lymph nodes. The perioperative morbidity was 38%. The median postoperative stay declined over time, from 16 days in the 1980s to 8 days in the 2000s (P<0.001). The perioperative mortality declined from 30% in the 1970s to 1% in the 2000s (P<0.001). The median survival for all patients with ductal adenocarcinoma was 18 months (1-year survival =65 %, 2-year survival =37%, 5-year survival =18%). In a Cox proportional hazards model, pathological factors having a significant impact on survival included tumor diameter, resection margin status, lymph node status, and histologic grade. This is the largest single-institution experience with PD for pancreatic cancer. Patients who have cancers with favorable pathological features have a statistically significant improved long-term survival.

Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis

Reactive oxygen species (ROS) are mutagenic and may thereby promote cancer. Normally, ROS levels are tightly controlled by an inducible antioxidant program that responds to cellular stressors and is predominantly regulated by the transcription factor Nrf2 (also known as Nfe2l2) and its repressor protein Keap1 (refs 2–5). In contrast to the acute physiological regulation of Nrf2, in neoplasia there is evidence for increased basal activation of Nrf2. Indeed, somatic mutations that disrupt the Nrf2–Keap1 interaction to stabilize Nrf2 and increase the constitutive transcription of Nrf2 target genes were recently identified, indicating that enhanced ROS detoxification and additional Nrf2 functions may in fact be pro-tumorigenic. Here, we investigated ROS metabolism in primary murine cells following the expression of endogenous oncogenic alleles of Kras, Braf and Myc, and found that ROS are actively suppressed by these oncogenes. K-RasG12D, B-RafV619E and MycERT2 each increased the transcription of Nrf2 to stably elevate the basal Nrf2 antioxidant program and thereby lower intracellular ROS and confer a more reduced intracellular environment. Oncogene-directed increased expression of Nrf2 is a new mechanism for the activation of the Nrf2 antioxidant program, and is evident in primary cells and tissues of mice expressing K-RasG12D and B-RafV619E, and in human pancreatic cancer. Furthermore, genetic targeting of the Nrf2 pathway impairs K-RasG12D-induced proliferation and tumorigenesis in vivo. Thus, the Nrf2 antioxidant and cellular detoxification program represents a previously unappreciated mediator of oncogenesis.

Pancreaticoduodenectomy for cancer of the head of the pancreas: 201 patients

ObjectiveThis single-institution study examined the outcome after pancreaticoduodenectomy in patients with adenocarcinoma of the head of the pancreas. Summary of Background DataIn recent years, pancreaticoduodenectomy for adenocarcinoma of the head of the pancreas has been associated with decreased morbidity and mortality and, in some centers, 5-year survival rates in excess of 20%. MethodsTwo hundred one patients with pathologically verified adenocarcinoma of the head of the pancreas undergoing pancreaticoduodenectomy at The Johns Hopkins Hospital between 1970 and 1994 were analyzed (the last 100 resections were performed between March 1991 and April 1994). This is the largest single-institution experience reported to date. ResultsThe overall postoperative in-hospital mortality rate was 5%, but has been 0.7% for the last 149 patients. The actuarial 5-year survival for all 201 patients was 21%, with a median survival of 15.5 months. There were 11 5-year survivors. Patients resected with negative margins (curative resections: n = 143) had an actuarial 5-year survival rate of 26%, with a median survival of 18 months, whereas those with positive margins (palliative resections: n = 58) fared significantly worse, with an actuarial 5-year survival rate of 8% and a median survival of 10 months (p < 0.0001). Survival has improved significantly from decade to decade (p < 0.002), with the 3-year actuarial survival of 14% in the 1970s, 21% in the 1980s, and 36% in the 1990s. Factors significantly favoring long-term survival by univariate analyses included tumor diameter < 3 cm, negative nodal status, diploid tumor DNA content, tumor S phase fraction < 18%, pylorus-preserving resection, <800 mL intraoperative blood loss, <2 units of blood transfused, negative resection margins, and use of postoperative adjuvant chemotherapy and radiation therapy. Multivariate analyses indicated the strongest predictors of long-term survival were diploid tumor DNA content, tumor diameter < 3 cm, negative nodal status, negative resection margins, and decade of resection.

Intraductal Papillary Mucinous Neoplasms of the Pancreas: An Updated Experience

Objective:To update the authors’ experience with intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. Background Data:IPMNs are intraductal mucin-producing cystic neoplasms of the pancreas with clear malignant potential. Since the authors’ 2001 report, the number of IPMNs resected at our institution has more than doubled, providing an opportunity to define the clinical features of this distinct neoplasm. Methods:All patients undergoing pancreatic resection for an IPMN at the Johns Hopkins Hospital between January 1987 and March 2003 were evaluated. Noninvasive IPMNs were classified as “adenoma,” “borderline,” or “carcinoma-in situ” (CIS) depending on the degree of dysplasia within the specimen. Invasive cancers were classified as tubular, colloid, mixed, or anaplastic types. Pathology was retrospectively reviewed to identify main-duct or branch-duct origin of the tumors. Long-term overall survival for patients having IPMNs with invasive cancer was compared with those patients having IPMNs without an invasive component. Results:Between January 1987 and March 2003, inclusive, 136 pancreatic resections were performed for patients with IPMNs, with 78 resections performed since January 2001. The mean age of the patients was 66.8 ± 1.1 years, with 57% being male and 89% white. Pancreaticoduodenectomy was performed in 71% of patients, total pancreatectomy in 15%, distal pancreatectomy in 12%, and central pancreatic resection in 2%. IPMNs without evidence of invasive cancer were identified in 62% (n = 84) of patients (17% adenoma, 28% borderline, or 55% CIS). The remaining 38% (n = 52) of patients had IPMNs with associated invasive cancer (60% tubular, 27% colloid, 7% mixed, and 6% anaplastic). The mean age of patients with IPMN adenoma was 63.2 years, 66.7 years for those with borderline/CIS IPMNs, and 68.1 years for those with invasive cancer (P = 0.08, adenomas vs. invasive cancer). In those patients with invasive cancers, 15% had invasive cancer at the final surgical margin, 23% had IPMN without invasive cancer at the margin, and 54% had lymph node metastases. Residual IPMN was identified at the neck or uncinate margin in 24% of patients with noninvasive IPMNs. The overall 5-year survival for patients having IPMNs without invasive cancer was 77% (several deaths secondary to metachronous invasive cancer), compared with 43% in those patients with an invasive component (P < 0.0001). There were no differences in survival when comparing adenomas, borderline neoplasms, and CIS. Similarly, there were no statistically significant differences in survival when comparing branch-duct, main-duct, and combined variants; however, the branch-duct variants were more often noninvasive. For those patients with invasive IPMNs, 2-year survival was 40% when margins were positive for invasive cancer or for IPMN without invasive cancer, and 60% when margins were tumor-free (P = 0.15). Those patients with colloid carcinomas (n = 14) had improved survival compared with those with tubular carcinomas (n = 31), with 5-year survival rates of 83% and 24%, respectively. IPMN recurrences and deaths from cancer occurred in patients with both invasive and noninvasive IPMNs at initial resection. Conclusions:IPMNs continue to be recognized with increasing frequency. Five-year survival for those patients following resection of IPMNs with invasive cancer (43%) is improved compared with those patients with resected pancreatic ductal adenocarcinoma in the absence of IPMN (averages 15%–25%). Survival following resection of IPMNs without invasive cancer (regardless of degree of dyplasia) is good, but recurrent disease in the residual pancreas suggests that long-term surveillance is critical. Based on the age at resection data, there appears to be a 5-year lag time from IPMN adenoma (63.2 years) to invasive cancer (68.1 years).

Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma, part 2: randomized controlled trial evaluating survival, morbidity, and mortality.

ObjectiveTo evaluate, in a prospective, randomized single-institution trial, the end points of operative morbidity, operative mortality, and survival in patients undergoing standard versus radical (extended) pancreaticoduodenectomy. Summary Background DataNumerous retrospective reports and a few prospective randomized trials have suggested that the performance of an extended lymphadenectomy in association with a pancreaticoduodenal resection may improve survival for patients with pancreatic and other periampullary adenocarcinomas. MethodsBetween April 1996 and June 2001, 299 patients with periampullary adenocarcinoma were enrolled in a prospective, randomized single-institution trial. After intraoperative verification (by frozen section) of margin-negative resected periampullary adenocarcinoma, patients were randomized to either a standard pancreaticoduodenectomy (removing only the peripancreatic lymph nodes en bloc with the specimen) or a radical (extended) pancreaticoduodenectomy (standard resection plus distal gastrectomy and retroperitoneal lymphadenectomy). All pathology specimens were reviewed, fully categorized, and staged. The postoperative morbidity, mortality, and survival data were analyzed. ResultsOf the 299 patients randomized, 5 (1.7%) were subsequently excluded because their final pathology failed to reveal periampullary adenocarcinoma, leaving 294 patients for analysis (146 standard vs. 148 radical). The two groups were statistically similar with regard to age (median 67 years) and gender (54% male). All the patients in the radical group underwent distal gastric resection, while 86% of the patients in the standard group underwent pylorus preservation (P < .0001). The mean operative time in the radical group was 6.4 hours, compared to 5.9 hours in the standard group (P = .002). There were no significant differences between the two groups with respect to intraoperative blood loss, transfusion requirements (median zero units), location of primary tumor (57% pancreatic, 22% ampullary, 17% distal bile duct, 3% duodenal), mean tumor size (2.6 cm), positive lymph node status (74%), or positive margin status on final permanent section (10%). The mean total number of lymph nodes resected was significantly higher in the radical group. Of the 148 patients in the radical group, only 15% (n = 22) had metastatic adenocarcinoma in the resected retroperitoneal lymph nodes, and none had retroperitoneal nodes as the only site of lymph node involvement. One patient in the radical group with negative pancreaticoduodenectomy specimen lymph nodes had a micrometastasis to one perigastric lymph node. There were six perioperative deaths (4%) in the standard group versus three perioperative deaths (2%) in the radical group (P = NS). The overall complication rates were 29% for the standard group versus 43% for the radical group (P = .01), with patients in the radical group having significantly higher rates of early delayed gastric emptying and pancreatic fistula and a significantly longer mean postoperative stay. With a mean patient follow-up of 24 months, there were no significant differences in 1-, 3-, or 5-year and median survival when comparing the standard and radical groups. ConclusionsRadical (extended) pancreaticoduodenectomy can be performed with similar mortality but some increased morbidity compared to standard pancreaticoduodenectomy. The data to date fail to indicate that a survival benefit is derived from the addition of a distal gastrectomy and retroperitoneal lymphadenectomy to a pylorus-preserving pancreaticoduodenectomy.