Predictors of failure after pancreaticoduodenectomy for ampullary carcinoma

BACKGROUND: Complete resection offers the only potential cure for ampullary carcinoma. We analyzed factors that contribute to treatment failure and survival in patients who underwent pancreaticoduodenectomy for ampullary carcinoma. STUDY DESIGN: We retrospectively reviewed all patients who underwent pancreaticoduodenectomy between August 1994 and August 2003 for ampullary carcinoma. Demographic, clinical, and pathologic data were collected. Chi-square analysis was used for categorical data and the t-test was used for continuous variables. Kaplan-Meier analyses were compared using the log-rank test to examine patient survival. RESULTS: Forty-three patients (24 men) aged 63.7 +/- 11.4 years (standard deviation) were followed for a mean of 23.9 months (median 660 days, range 18 to 2,249 days). Jaundice (n = 33) and weight loss (n = 13) were the most common presenting symptoms. Stage (p < 0.01) and degree of differentiation (p < 0.029) were significant predictors of failure by univariate analysis. But only stage (p < 0.04) was a significant predictor by multivariate analysis. Further analysis revealed that nodal status (p < 0.001), but not tumor grade, was a significant predictor of treatment failure. Neither demographic nor clinical variables were significant predictors. Five-year overall and disease-free survival rates were 67.4% and 51.4%, respectively. Both metastases and disease recurrence had significant impact on patient survival. CONCLUSIONS: Tumor stage is associated with treatment failure after pancreaticoduodenectomy for ampullary carcinoma and may identify candidates for adjuvant therapy. Because an aggressive surgical approach can be adopted safely with the best chance for cure, we recommend that pancreaticoduodenectomy be offered to all patients with ampullary tumors when malignancy or dysplasia is in question.     

Pathological features of colorectal carcinomas in MYH-associated polyposis

Aims:  MYH is a DNA glycosylase in the base excision repair pathway. Germ-line biallelic mutations in the MYH gene are associated with the development of multiple colorectal adenomas and colorectal carcinoma (CRC). A slightly increased risk of CRC is suggested in monoallelic MYH mutation carriers. The aim was to characterize the histopathological features of carcinomas from biallelics and monoallelics.
Methods and results:  Clinicopathological features of 57 colorectal carcinomas from 50 patients identified in familial CRC registries were recorded. These included 16 cancers from 14 MYH biallelics; 25 cancers from 22 MYH monoallelics; and 16 cancers from 14 controls. Carcinomas in biallelics demonstrated tubular, papillary or cribriform patterns as the predominant histological subtype, and main histological groups differed according to mutation status ( P  = 0.0053). All biallelic cancers were low grade, with high-grade tumours more common in monoallelics and controls ( P  = 0.002). Synchronous polyps were observed in 75% of biallelics, 33% of monoallelics and 43% of controls ( P  = 0.035). Serrated carcinoma was the predominant type in 12% (3/25) of the monoallelics but in none of the biallelics or controls. MYH immunohistochemistry failed to distinguish between groups.
Conclusions:  Neither pathological features nor immunohistochemistry could predict the MYH mutation status of CRCs in this study.     

Long-term survival after hepatic cryosurgery versus surgical resection for metastatic colorectal carcinoma: a critical review of the literature

Objective

To critically assess the evidence for long-term survival after hepatic resection and hepatic cryosurgery for metastatic colorectal cancer. The purpose of this review is to determine if a randomized controlled trial comparing these two treatment modalities is justified.

Data sources

A review of the medical literature from 1973 to 1995 using the MEDLINE and CAN-CERLIT databases. References were also retrieved from the bibliographies of identified articles and from experts in the field of hepatobiliary and pancreatic surgery.

Study selection

One hundred and seventy-eight studies were reviewed. Studies presenting original data on the results of hepatic resection or cryotherapy for colorectal liver metastases were selected. Studies were excluded if they did not present survival data longer than 2 years. Studies pertaining to resection for fewer than 60 patients with colorectal metastases to the liver were excluded.

Data extraction

Data forms were designed before studies were examined in detail. All studies that met the inclusion and exclusion criteria were reviewed and the identified data extracted and tabulated.

Data synthesis

No controlled studies were identified, only case series. Four reports on hepatic cryosurgery and 9 on hepatic resection met the study criteria. The cryosurgery studies were methodologically poor; the resection studies were larger and more methodologically sound. The median follow-up for cryosurgery ranged from 12 to 28.8 months, that for resection 21 to 69 months. There is clear evidence that hepatic cryosurgery has a role in the management of selected patients with colorectal metastases to the liver. However, valid conclusions cannot be made about the 5-year survival rate. The results of the studies on hepatic resection in patients with colorectal metastases to the liver have greater validity and consistency, with 5-year survival rates of 20% to 40%.

Conclusions

Although hepatic cryosurgery offers some unequivocal and other potential advantages over surgical resection for colorectal metastases to the liver, the published data do not support its use in patients with resectable disease outside a clinical trial, and do not yet justify a randomized trial. A study that collects prospective data on 2 groups of patients (resectable v. unresectable) who differ only in the anatomic location of their metastases within the liver is needed.     

Comprehensive characterization of a Canadian cohort of von Hippel-Lindau disease patients

Von Hippel-Lindau disease (VHL) is a heritable condition caused by pathogenic variants in VHL and is characterized by benign and malignant lesions in the central nervous system (CNS) and abdominal viscera. Due to its variable expressivity, existing efforts to collate VHL patient data do not adequately capture all VHL manifestations. We developed a comprehensive and standardized VHL database in the web-based application, REDCap, that thoroughly captures all VHL manifestation data. As an initial trial, information from 86 VHL patients from the University Health Network/Hospital for Sick Children was populated into the database. Analysis of this cohort showed missense variants occurring with the greatest frequency, with all variants localizing to the α- or β-domains of VHL. The most prevalent manifestations were central nervous system (CNS), renal, and retinal neoplasms, which were associated with frameshift variants and large deletions. We observed greater age-related penetrance for CNS hemangioblastomas with truncating variants compared to missense, while the reverse was true for pheochromocytomas. We demonstrate the utility of a comprehensive VHL database, which supports the standardized collection of clinical and genetic data specific to this patient population. Importantly, we expect that its web-based design will facilitate broader international collaboration and lead to a better understanding of VHL.     

Promoter methylation of Wnt5a is associated with microsatellite instability and BRAF V600E mutation in two large populations of colorectal cancer patients

Background:

In colorectal cancer (CRC), tumour microsatellite instability (MSI) status and CpG island methylator phenotype (CIMP) status are indicators of patient outcome, but the molecular events that give rise to these outcomes remain largely unknown. Wnt5a is a critical regulator of non-canonical Wnt activity and promoter hypermethylation of this gene has emerging prognostic roles in CRC; however the frequency and prognostic significance of this epigenetic event have not been explored in the context of colorectal tumour subtype. Consequently, we investigated the frequency and prognostic significance of Wnt5a methylation in a large cohort of MSI-stratified CRCs.

Methods:

Methylation was quantified in a large cohort of 1232 colorectal carcinomas from two clinically distinct populations from Canada. Associations were examined between methylation status and clinicopathlogical features, including tumour MSI status, BRAF V600E mutation, and patient survival.

Results:

In Ontario, Wnt5a methylation was strongly associated with MSI tumours after adjustment for age, sex, and tumour location (odds ratio (OR)=4.2, 95% confidence interval (CI)=2.4–7.4, P<10⁻⁶) and with BRAF V600E mutation, a marker of CIMP (OR=12.3, 95% CI=6.9–21.7, P<10⁻¹⁷), but was not associated with patient survival. Concordant results were obtained in Newfoundland.

Conclusion:

Methylation of Wnt5a is associated with distinct tumour subtypes, strengthening the evidence of an epigenetic-mediated Wnt bias in CRC.     

Body mass index in early adulthood and colorectal cancer risk for carriers and non-carriers of germline mutations in DNA mismatch repair genes

Background:

Carriers of germline mutations in DNA mismatch repair (MMR) genes have a high risk of colorectal cancer (CRC), but the modifiers of this risk are not well established. We estimated an association between body mass index (BMI) in early adulthood and subsequent risk of CRC for carriers and, as a comparison, estimated the association for non-carriers.

Methods:

A weighted Cox regression was used to analyse height and weight at 20 years reported by 1324 carriers of MMR gene mutations (500 MLH1, 648 MSH2, 117 MSH6 and 59 PMS2) and 1219 non-carriers from the Colon Cancer Family Registry.

Results:

During 122 304 person-years of observation, we observed diagnoses of CRC for 659 carriers (50%) and 36 non-carriers (3%). For carriers, the risk of CRC increased by 30% for each 5 kg m^–2 increment in BMI in early adulthood (hazard ratio, HR: 1.30; 95% confidence interval, CI: 1.08–1.58; P=0.01), and increased by 64% for non-carriers (HR: 1.64; 95% CI: 1.02–2.64; P=0.04) after adjusting for sex, country, cigarette smoking and alcohol drinking (and the MMR gene that was mutated in carriers). The difference in HRs for carriers and non-carriers was not statistically significant (P=0.50). For MLH1 and PMS2 (MutLα heterodimer) mutation carriers combined, the corresponding increase was 36% (HR: 1.36; 95% CI: 1.05–1.76; P=0.02). For MSH2 and MSH6 (MutSα heterodimer) mutation carriers combined, the HR was 1.26 (95% CI: 0.96–1.65; P=0.09). There was no significant difference between the HRs for MutLα and MutSα heterodimer carriers (P=0.56).

Conclusion:

Body mass index in early adulthood is positively associated with risk of CRC for MMR gene mutation carriers and non-carriers.     

Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer

Cancer risks for a person who has inherited a MUTYH mutation from only one parent (monoallelic mutation carrier) are uncertain. Using the Colon Cancer Family Registry and Newfoundland Familial Colon Cancer Registry, we identified 2,179 first- and second-degree relatives of 144 incident colorectal cancer (CRC) cases who were monoallelic or biallelic mutation carriers ascertained by sampling population complete cancer registries in the United States, Canada and Australia. Using Cox regression weighted to adjust for sampling on family history, we estimated that the country-, age- and sex-specific standardized incidence ratios (SIRs) for monoallelic mutation carriers, compared to the general population, were: 2.04 (95% confidence interval, CI 1.56-2.70; p < 0.001) for CRC, 3.24 (95%CI 2.18-4.98; p < 0.001) for gastric cancer, 3.09 (95%CI 1.07-12.25; p = 0.07) for liver cancer and 2.33 (95%CI 1.18-5.08; p = 0.02) for endometrial cancer. Age-specific cumulative risks to age 70 years, estimated using the SIRs and US population incidences, were: for CRC, 6% (95%CI 5-8%) for men and 4% (95%CI 3-6%) for women; for gastric cancer, 2% (95%CI 1-3%) for men and 0.7% (95%CI 0.5-1%) for women; for liver cancer, 1% (95%CI 0.3-3%) for men and 0.3% (95%CI 0.1-1%) for women and for endometrial cancer, 4% (95%CI 2-8%). There was no evidence of increased risks for cancers of the brain, pancreas, kidney, lung, breast or prostate. Monoallelic MUTYH mutation carriers with a family history of CRC, such as those identified from screening multiple-case CRC families, are at increased risk of colorectal, gastric, endometrial and possibly liver cancers.