Exome sequencing identifies nonsegregating nonsense ATM and PALB2 variants in familial pancreatic cancer.

We sequenced 11 germline exomes from five families with familial pancreatic cancer (FPC). One proband had a germline nonsense variant in ATM with somatic loss of the variant allele. Another proband had a nonsense variant in PALB2 with somatic loss of the variant allele. Both variants were absent in a relative with FPC. These findings question the causal mechanisms of ATM and PALB2 in these families and highlight challenges in identifying the causes of familial cancer syndromes using exome sequencing.

Identification of germline genomic copy number variation in familial pancreatic cancer.

Adenocarcinoma of the pancreas is a significant cause of cancer mortality, and up to 10 % of cases appear to be familial. Heritable genomic copy number variants (CNVs) can modulate gene expression and predispose to disease. Here, we identify candidate predisposition genes for familial pancreatic cancer (FPC) by analyzing germline losses or gains present in one or more high-risk patients and absent in a large control group. A total of 120 FPC cases and 1,194 controls were genotyped on the Affymetrix 500K array, and 36 cases and 2,357 controls were genotyped on the Affymetrix 6.0 array. Detection of CNVs was performed by multiple computational algorithms and partially validated by quantitative PCR. We found no significant difference in the germline CNV profiles of cases and controls. A total of 93 non-redundant FPC-specific CNVs (53 losses and 40 gains) were identified in 50 cases, each CNV present in a single individual. FPC-specific CNVs overlapped the coding region of 88 RefSeq genes. Several of these genes have been reported to be differentially expressed and/or affected by copy number alterations in pancreatic adenocarcinoma. Further investigation in high-risk subjects may elucidate the role of one or more of these genes in genetic predisposition to pancreatic cancer.

Screening for pancreatic cancer in a high-risk cohort: an eight-year experience.

BACKGROUND: Pancreatic adenocarcinoma is the fourth leading cause of cancer death. METHODS: A prospective cohort study was undertaken between 2003 and 2011 at a tertiary care centre in Toronto, Canada. Two hundred and sixty-two subjects were enrolled based on an elevated estimated lifetime risk for pancreatic cancer due to known genetic mutations and/or cancer family history. Subjects underwent annual magnetic resonance imaging, followed by additional investigations if abnormal findings were detected. Evidence of malignancy or suspicious macroscopic abnormalities prompted referral for surgical intervention. RESULTS: Average length of follow-up was 4.2 years, during which 84/262 (32%) subjects demonstrated pancreatic abnormalities. Three participants developed pancreatic adenocarcinoma (one 1.5-cm tumor was resected but recurred, while the other two subjects developed metastatic cancer), and a fourth participant developed a pancreatic neuroendocrine tumor that was resected. Fifteen subjects had radiologic evidence of branch-duct intraductal papillary mucinous neoplasms, of which two underwent surgical resection. Sixty-five subjects had simple pancreatic cysts that have remained stable. CONCLUSION: Magnetic resonance imaging can detect small pancreatic tumors and cystic lesions, but further improvement in sensitivity is needed. An understanding of the natural history of pre-invasive lesions in members of high-risk families is necessary for developing a more effective screening program.

Management of pancreatic adenocarcinoma in Ontario, Canada: a population-based study using novel case ascertainment.

BACKGROUND: Pancreatic adenocarcinoma (PA) is largely incurable, although recent progress has been made in the safety of surgery for PA and in adjuvant and palliative chemotherapy. The purpose of this study was to describe the management of PA in Ontario, Canada. METHODS: The Pathology Information Management System (PIMS), which uses electronic pathology reporting (E-path), was used to rapidly identify and recruit patients based on a pathologic diagnosis of PA between 2003 and 2006. Patients were mailed questionnaires for additional data. RESULTS: The patient participation rate was 26% (351 of 1325). Nonresponders were more likely to be older than 70 years (43% v. 28%, p < 0.001) and to have received treatment in nonacademic centres (53% v. 34%, p < 0.001). Fifty-four percent of responders underwent a potentially curative operation, and most (77%) were 70 years or younger (p = 0.03). Completed resections were documented in 83% of patients who underwent exploratory surgery with curative intent; 17% of patients had unresectable and/or metastatic disease at laparotomy. Of the completed resections, 24% were performed in nonacademic centres with a 32% positive margin rate; 76% were performed in academic centres with a 29% positive margin rate (p = 0.84). Resections with curative intent were less frequently aborted in academic centres (10% v. 33%, p < 0.001). Of the patients who responded to our questionnaire, 43% received chemotherapy and 7% participated in clinical trials. CONCLUSION: Despite using PIMS and E-path, the response rate for this study was low (< 30%). Nonresponders were older and more commonly treated in nonacademic centres. Patients undergoing surgery in academic centres had higher resection rates. The rate of adjuvant and palliative chemotherapy was stage-dependent and low.

Oncologic outcome in patients with ulcerative colitis associated with dyplasia or cancer who underwent stapled or handsewn ileal pouch-anal anastomosis.

PURPOSE: Ulcerative colitis is a risk factor for colorectal cancer. Restorative proctocolectomy with ileal pouch-anal anastomosis is a standard surgical management of patients with ulcerative colitis who have cancer or dysplasia, but the oncologic risk of stapled anastomosis vs mucosectomy with handsewn anastomosis is debated. We compare the risk of new cancer or recurrence in the pouch or rectal cuff in patients with ulcerative colitis undergoing stapled anastomosis vs mucosectomy with handsewn anastomosis. METHODS: This study was performed as a retrospective analysis of the clinical database at a single center, Mount Sinai Hospital, Toronto, Canada. The patients with ulcerative colitis associated with colorectal dysplasia or cancer who underwent ileal pouch-anal anastomosis between 1981 and 2009 were evaluated. The development of dysplasia or cancer at ileoanal anastomosis or in the pelvic pouch was assessed. RESULTS: Eighty-one patients underwent stapled (n = 59) or handsewn (n = 22) ileal pouch-anal anastomosis; 52 had evidence of dysplasia and 29 had colorectal cancer (24 colon; 5 rectum) at the time of surgery. Median follow-up was 76.1 months. Two of 10 (20%) patients with handsewn anastomosis and 0% patients with stapled anastomosis developed metastatic cancer. One patient with a 33-year history of colitis, a previously resected right-sided colon cancer, and subsequent high-grade dysplasia in the rectum underwent a handsewn pelvic pouch and developed an unresectable adenocarcinoma at the cuff 4 years later. A second patient with a 10-year history of colitis underwent handsewn pelvic pouch and developed dysplasia in the pouch 8 years after surgery. Nine patients were dead at last follow-up (11%). Of those patients, both colorectal cancer-related deaths were in patients with handsewn anastomoses. Differences in overall 5-year survival between the groups did not reach statistical significance. This study was limited by the sample size in subgroups and the few outcome events. CONCLUSIONS: Performing a stapled ileal pelvic anal anastomosis does not appear to be inferior to mucosectomy and handsewn anastomosis in oncologic outcome, and it seems appropriate in patients with ulcerative colitis associated with coexisting dysplasia or cancer.

Germline BRCA1 mutations predispose to pancreatic adenocarcinoma.

Although the association of germline BRCA2 mutations with pancreatic adenocarcinoma is well established, the role of BRCA1 mutations is less clear. We hypothesized that the loss of heterozygosity at the BRCA1 locus occurs in pancreatic cancers of germline BRCA1 mutation carriers, acting as a "second-hit" event contributing to pancreatic tumorigenesis. Seven germline BRCA1 mutation carriers with pancreatic adenocarcinoma and nine patients with sporadic pancreatic cancer were identified from clinic- and population-based registries. DNA was extracted from paraffin-embedded tumor and nontumor samples. Three polymorphic microsatellite markers for the BRCA1 gene, and an internal control marker on chromosome 16p, were selected to test for the loss of heterozygosity. Tumor DNA demonstrating loss of heterozygosity in BRCA1 mutation carriers was sequenced to identify the retained allele. The loss of heterozygosity rate for the control marker was 20%, an expected baseline frequency. Loss of heterozygosity at the BRCA1 locus was 5/7 (71%) in BRCA1 mutation carriers; tumor DNA was available for sequencing in 4/5 cases, and three demonstrated loss of the wild-type allele. Only 1/9 (11%) sporadic cases demonstrated loss of heterozygosity at the BRCA1 locus. Loss of heterozygosity occurs frequently in pancreatic cancers of germline BRCA1 mutation carriers, with loss of the wild-type allele, and infrequently in sporadic cancer cases. Therefore, BRCA1 germline mutations likely predispose to the development of pancreatic cancer, and individuals with these mutations may be considered for pancreatic cancer-screening programs.

Hereditary colorectal cancer syndromes: familial adenomatous polyposis and lynch syndrome.

Familial colorectal cancer (CRC) accounts for 10% to 20% of all cases of CRC. Two major autosomal dominant forms of heritable CRC are familial adenomatous polyposis (FAP) and Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer). Along with the risk for CRC, both syndromes are associated with elevated risk for other tumors. Improved understanding of the genetic basis of these diseases has not only facilitated the identification and screening of at-risk individuals and the development of prophylactic or early-stage intervention strategies but also provided better insight into sporadic CRC. This article reviews the clinical and genetic characteristics of FAP and Lynch syndrome, recommended screening and surveillance practices, and appropriate surgical and nonsurgical interventions.

Recurrent pyogenic cholangitis with hepatolithiasis--the role of surgical therapy in North America.

PURPOSE: To determine role of surgical intervention for Recurrent Pyogenic Cholangitis with hepatolithiasis at a North American hepatobiliary center. METHODS: Retrospective analysis of 42 patients presenting between 1986 and 2005. RESULTS: Mean age is 54.3 years (24-87). Twenty-seven patients (64%) underwent surgery, after unsuccessful endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous intervention in 19/27 patients. Surgical procedures were: 10 common bile duct explorations with choledochojejunostomy and a Hutson loop and 17 hepatectomies (10 with, 7 without Hutson loop). Liver resection was indicated for lobar atrophy or stones confined to single lobe. Operative mortality was zero; complication rates for hepatectomy and common bile duct exploration were comparable (35% vs. 30%). Median follow-up was 24 months (3-228). Of 21 patients with Hutson loops, only seven (33%) needed subsequent loop utilization, with three failures. At last follow-up, 4/27 (15%) surgical patients had stone-related symptoms requiring percutaneous intervention, compared to 4/11 (36%) surviving nonoperative patients. Cholangiocarcinoma was identified in 5/42 (12%) patients; four were unresectable and one was an incidental in-situ carcinoma in a resected specimen. CONCLUSION: Surgery is a valuable part of multidisciplinary management of recurrent pyogenic cholangitis with hepatolithiasis. Hepatectomy is a useful option for selected cases. Hutson loops are useful in some cases for managing stone recurrence. Cholangiocarcinoma risk is elevated in this disease.

Results of an aggressive approach to resection of locally recurrent rectal cancer.

BACKGROUND: The value of resection for locally recurrent rectal cancer (LRRC) remains controversial. We analyzed outcomes of an aggressive approach to resection of LRRC. METHODS: We conducted a retrospective chart review of 52 consecutive patients who underwent resection of LRRC from September 1997 through August 2005. Overall and disease-free survival (OS, DFS) curves were constructed by the Kaplan-Meier method, and compared by log-rank analysis. Median follow-up time was 29 months (range 3-72). RESULTS: Thirty-one patients (60%) were male. Median age was 60 years (range 36-88). Forty-six of the 52 patients were resected with curative intent, while 6 had known distant metastases at the time of resection. All 52 patients underwent grossly complete resection of local disease, and 41 (79%) had microscopically clear resection margins. An en bloc sacrectomy was performed in 28 (54%) patients. Postoperative mortality was nil; significant complications developed in 42% of patients. The complication rate was higher in patients with sacrectomy than without (50 vs. 33%, P = 0.017, Chi square). For the entire cohort of 52 patients, median OS and DFS were 40 and 24 months, respectively. Survival was equivalent in patients with and without sacrectomy. In the 46 patients who had resection with curative intent, 4-year OS was 48%. Median OS in the six patients with distant metastases at the time of resection was 21 months. OS was predicted by the presence of metastases (P = 0.01), and margin status (P < 0.0001). DFS was predicted by margin status (P = 0.0001). CONCLUSIONS: In this series of patients who underwent resection of LRRC, microscopic margin status was the most significant predictor of OS and DFS. Requirement for en bloc sacrectomy was not associated with inferior survival. Carefully selected patients with distant metastases may benefit from resection of LRRC.

Surgical resection of hepatic and pulmonary metastases from colorectal carcinoma.

BACKGROUND: Patients with hepatic and pulmonary metastases from colorectal cancer (CRC) may benefit from aggressive surgical therapy. We examined the longterm outcomes of patients who underwent both lung and liver resections for colorectal metastases over a 10-year period. STUDY DESIGN: Four hundred twenty-three hepatectomies were performed for metastatic CRC between 1992 and 2002 at two university-affiliated hospitals. Patients who underwent both lung and liver resections for metastatic CRC were studied. Demographic, perioperative, and survival data were evaluated by retrospective chart review. Disease-free survival (DFS) and overall survival (OS) were evaluated by Kaplan-Meier analysis and survival curves were compared using the log-rank test. RESULTS: Thirty-nine patients underwent both lung and liver resections for metastatic CRC. Eleven patients (28%) underwent staged liver and lung metastasectomy from synchronously identified metastases. Twenty-eight patients (72%) underwent sequential metastasectomy because of recurrent disease. The median disease-free and overall survivals after initial metastasectomy were 19.8 and 87 months, respectively. Serial metastasectomy was common in this patient population. The mean number of metastasectomies performed was 2.6 per patient (range 1 to 4). There was no difference in overall survival for patients with synchronous versus metachronous presentation of liver and lung metastases (p=0.45). The site of first recurrence after initial metastasectomy was, most commonly, the lung (n=19, 49%), followed by the liver (n=8, 21%). Nineteen patients (49%) underwent subsequent resections for recurrences. Seven patients (18%) underwent 2 or more liver resections for recurrent disease, and 12 (31%) underwent multiple lung resections. CONCLUSIONS: An aggressive multidisciplinary surgical approach should be undertaken for recurrent CRC metastases. In selected patients, serial metastasectomy for recurrent metastatic disease is safe and results in excellent longterm survival after CRC resection.

Remission of hormone-refractory prostate cancer attributed to Essiac.

Essiac is a popular complementary and alternative medicine (CAM) that is utilized by many cancer patients in North America. Much anecdotal reporting exists about its cancer-fighting qualities, but so far no clinical trials have been preformed to validate those claims. We describe here the case of a 64-year-old man whose hormone-refractory prostate cancer responded well to Essiac tea.