Lucy Helyer

Aldehyde Dehydrogenase Activity of Breast Cancer Stem Cells Is Primarily Due To Isoform ALDH1A3 and Its Expression Is Predictive of Metastasis

Cancer stem cells (CSCs) are proposed to initiate cancer and propagate metastasis. Breast CSCs identified by aldehyde dehydrogenase (ALDH) activity are highly tumorigenic in xenograft models. However, in patient breast tumor immunohistological studies, where CSCs are identified by expression of ALDH isoform ALDH1A1, CSC prevalence is not correlative with metastasis, raising some doubt as to the role of CSCs in cancer. We characterized the expression of all 19 ALDH isoforms in patient breast tumor CSCs and breast cancer cell lines by total genome microarray expression analysis, immunofluorescence protein expression studies, and quantitative polymerase chain reaction. These studies revealed that ALDH activity of patient breast tumor CSCs and cell lines correlates best with expression of another isoform, ALDH1A3, not ALDH1A1. We performed shRNA knockdown experiments of the various ALDH isoforms and found that only ALDH1A3 knockdown uniformly reduced ALDH activity of breast cancer cells. Immunohistological studies with fixed patient breast tumor samples revealed that ALDH1A3 expression in patient breast tumors correlates significantly with tumor grade, metastasis, and cancer stage. Our results, therefore, identify ALDH1A3 as a novel CSC marker with potential clinical prognostic applicability, and demonstrate a clear correlation between CSC prevalence and the development of metastatic breast cancer. STEM CELLS 2011;29:32–45

A meta-analysis of D1 versus D2 lymph node dissection

BackgroundSurgery is the only curative treatment for patients with gastric cancer. However, the extent of lymph node dissection is still debated. Therefore, with the publication of newer trial results, we conducted an updated meta-analysis of D1 versus D2 randomized controlled trials comparing outcomes.MethodsSystematic searches were conducted using Medline, Embase, and the Cochrane Central Register of Controlled Trials from January 1, 1985, to December 31, 2010. Meta-analyses were performed using RevMan v5 software. Both short- and long-term outcomes were analyzed. Subgroup analyses of T stage and spleen/pancreas resection versus preservation were performed.ResultsOutcomes of 5 randomized trials involving 1642 patients (845 D1, 797 D2) enrolled from 1982 to 2005 were included. Despite the addition of the more recent trials, overall hospital mortality and reoperation rates were still higher in D2 cases. Subgroup analysis of recent trials and spleen/pancreas preservation revealed no significant difference in hospital mortality between groups. Five-year overall survival was similar between D1 versus D2 trials. Sub-analysis by tumor depth and spleen/pancreas preservation detected trends for improved survival with D2 lymphadenectomy in T3/T4 patients and those with spleen/pancreas preservation.ConclusionEarlier trials show that D2 dissections have higher operative mortality, while recent trials have similar rates. A trend of improved survival exists among D2 patients who did not undergo resection of the spleen or pancreas, as well as for patients with T3/T4 cancers.

A systematic review of the accuracy and utility of peritoneal cytology in patients with gastric cancer

BackgroundThere is lack of uniformity in the utilization of peritoneal cytology in gastric cancer management. The identification of intraperitoneal free cancer cells (IFCCs) is believed to confer poor prognosis. However, while some of these patients are palliated, others may undergo more aggressive therapies. In this review, we aimed to identify and synthesize findings on the use of peritoneal cytology in predicting peritoneal recurrence and overall survival in curative gastric cancer patients.MethodsElectronic literature searches were conducted using Medline, EMBASE, and the Cochrane Central Register of Controlled Trials from January 1, 1998 to December 31, 2009. We determined the accuracy, sensitivity, and specificity of peritoneal cytology in predicting peritoneal recurrence based on four techniques—conventional cytology, immunoassay, immunohistochemistry, and reverse transcriptase-polymerase chain reaction. Recurrence rates and overall survival rates for curative patients were determined, based on positivity or negativity for IFCCs.ResultsTwenty-eight articles were included. All four techniques showed wide variations in accuracy, sensitivity, and specificity in predicting peritoneal recurrence. Recurrence rates for patients positive for IFCCs ranged from 11.1 to 100%, while those negative for IFCCs had recurrence rates of 0–51%. Overall survival was significantly reduced for patients with positive IFCCs. Short follow-up periods and possible duplication of results may limit result interpretation.ConclusionThe presence of IFCCs appears to increase the risk of peritoneal recurrence and is associated with worse overall survival in gastric cancer patients. Further incorporation of peritoneal cytology in clinical decision-making in gastric cancer depends on the development of a consistently accurate and rapid IFCC detection method.

A systematic review of the accuracy and indications for diagnostic laparoscopy prior to curative-intent resection of gastric cancer

BackgroundDespite improved preoperative imaging techniques, patients with incurable or unresectable gastric cancer are still subjected to non-therapeutic laparotomy. Diagnostic laparoscopy (DL) has been advocated by some to be essential in decision-making in gastric cancer. We aimed to identify and synthesize findings on the value of DL for patients with gastric cancer, in this era of improved preoperative imaging.MethodsElectronic literature searches were conducted using Medline, EMBASE, and the Cochrane Central Register of Controlled Trials from January 1, 1998 to December 31, 2009. We calculated the change in management and avoidance of laparotomy based on the addition of DL and laparoscopic ultrasound (LUS). The accuracy, agreement (kappa), sensitivity, and specificity of DL in assessing tumor extent, nodal involvement, and the presence of metastases with respect to the gold standard (pathology) were also calculated.ResultsTwenty-one articles were included. DL showed moderate to substantial agreement with final pathology for T stage, but only fair agreement for N stage. For M staging, DL had an overall accuracy, sensitivity, and specificity ranging from 85–98.9%, 64.3–94%, and 80–100%, respectively. The use of DL altered treatment in 8.5–59.6% of cases, avoiding laparotomy in 8.5–43.8% of cases. LUS provided additional benefit in 5.8–7.2% of cases.ConclusionsDespite evolving preoperative imaging techniques, diagnostic laparoscopy continues to be of substantial value in staging patients with gastric cancer and in avoiding unnecessary laparotomy. The current data support DL for all patients with advanced gastric cancer.

A systematic review of surgery for non-curative gastric cancer

BackgroundMost gastric cancer patients present with advanced stage disease precluding curative surgical treatment. These patients may be considered for palliative resection or bypass in the presence of major symptoms; however, the utility of surgery for non-curative, asymptomatic advanced disease is debated and the appropriate treatment strategy unclear.PurposeTo evaluate the non-curative surgical literature to better understand the limitations and benefits of non-curative surgery for advanced gastric cancer.MethodsA literature search for non-curative surgical interventions in gastric cancer was conducted using MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials databases from 1 January 1985 to 1 December 2009. All abstracts were independently rated for relevance by a minimum of two reviewers. Outcomes of interest were procedure-related morbidity, mortality, and survival.ResultsFifty-nine articles were included; the majority were retrospective, single institution case series. Definitions describing the treatment intent for gastrectomy were incomplete in most studies. Only five were truly performed with relief of symptoms as the primary indication for surgery, while the majority were considered non-curative or not otherwise specified. High rates of procedure-related morbidity and mortality were demonstrated for all surgeries across the majority of studies and treatment-intent categories. Median and 1-year survival were poor, and values ranged widely within surgical approaches and across studies.ConclusionsA lack of transparent documentation of disease burden and symptoms limits the surgical literature in non-curative gastric cancer. Improved survival is not evident for all patients receiving non-curative gastrectomy. Further prospective research is required to determine the optimal intervention for palliative gastric cancer patients.

Systematic review of the predictors of positive margins in gastric cancer surgery and the effect on survival

BackgroundComplete resection is the only definitive treatment available for gastric cancer. Factors associated with positive margins and their survival effects have been the subject of many studies, but the appropriate management for these patients is still debated. The objective of this review is to examine positive margins after gastric cancer resections by exploring predictive factors, impact on survival, and optimal strategies for re-resection.MethodsA systematic electronic literature search was conducted using Medline and EMBASE from January 1, 1998, to December 31, 2009. Studies on gastric or gastroesophageal junction adenocarcinoma that either investigated the predictors for positive margin or employed multivariate methods to analyze the survival effects of positive margins were selected.ResultsTwenty-two studies incorporating 19355 patients were included in this review. Positive margins were associated with larger tumor size, deeper wall penetration, more extensive gastric involvement, greater nodal involvement, higher stage, diffuse histology, higher Borrmann type, lymphatic vessel involvement, and total gastrectomy. Patient survival was independently associated with margin status, and this survival effect was more prominent in early cancers in most studies that performed subgroup analyses.ConclusionsThe probability of acquiring positive margins is highly dependent on the biology and the extent of the tumor. There is a significant negative effect on survival, which is more prominent in cancers at early stages, making re-resection or a second operation important. Patients with more advanced disease can be offered more extensive surgery to remove disease, but this should be balanced against the risks of more extensive resections.

How many lymph nodes should be assessed in patients with gastric cancer? A systematic review

BackgroundNodal status is one of the most important prognostic factors in gastric adenocarcinoma (GC). As such, it is important to assess an appropriate number of lymph nodes (LNs) in order to accurately stage patients. However, the number of LNs assessed in each GC case varies, and in many cases the number examined per gastric specimen is less than current recommendations.PurposeWe aimed to identify and synthesize findings from all articles evaluating the association of clinicopathological features and long-term outcomes with the number of LNs assessed among GC patients.MethodsSystematic electronic literature searches were conducted using Medline, Embase, and the Cochrane Central Register of Controlled Trials from 1998 to 2009.ResultsTwenty-five articles were included in this review. Extensive resection, increased tumor size, and greater TNM staging were all associated with a greater number of LNs assessed. The disease-free survival was longer and recurrence rate was lower in patients with more LNs assessed. Overall survival, as well as survival by TNM and clinical stage, was improved among patients with an increased number of LNs assessed, but much of this appears to be due to stage migration, with the effect more pronounced in more advanced disease.ConclusionMore LNs assessed resulted in less stage migration and possibly better long-term outcomes. Although current guidelines suggest 16 LNs to be assessed, especially in advanced GC, a higher number of LNs should be assessed.

A systematic review of the indications for genetic testing and prophylactic gastrectomy among patients with hereditary diffuse gastric cancer.

BackgroundHereditary diffuse gastric cancer (HDGC) is a familial cancer syndrome specifically associated with germline mutations to the E-cadherin (CDH1) gene. HDGC is characterized by autosomal dominance and high penetrance and a high cumulative risk for advanced gastric cancer. Our purpose in this study was to identify and synthesize findings from all articles on: (1) current recommendations for CDH1 screening and prophylactic gastrectomy; (2) CDH1 testing results in HDGC patients; and (3) prophylactic gastrectomy results in HDGC patients.MethodsSystematic electronic literature searches were conducted using Medline, Embase, and the Cochrane Central Register of Controlled Trials from 1985 to 2009.ResultsSeventy articles were included in this review. Among patients with a positive family history of gastric cancer, 1085 were screened from 454 families, and 38.4% tested positive. Mutation-positive families also had a considerable family history of breast and colon cancer. Of the 322 patients screened for CDH1 mutations by current HDGC screening criteria, 29.2% tested positive. Among the 76.8% of patients who underwent prophylactic gastrectomy following positive CDH1 test results, 87.0% had positive final histopathology results and 64.6% had signet ring cells identified. Some of the patients with negative final histopathology results had opted to undergo prophylactic gastrectomy prior to CDH1 testing, and were ultimately found to be negative for CDH1 mutations.ConclusionCDH1 mutation testing in families with a history of gastric cancer and prophylactic gastrectomy in mutation-positive patients are recommended for the management of HDGC.

Optimal management of gastric cancer: results from an international RAND/UCLA expert panel.

Objective:Defining processes of care, which are appropriate and necessary for management of gastric cancer (GC), is an important step toward improving outcomes. Methods:Using a RAND/UCLA Appropriateness Method, an international multidisciplinary expert panel created 22 statements reflecting optimal management. All statements were scored for appropriateness and necessity. Results:The following tenets were scored appropriate and necessary: (1) preoperative staging by computed tomography of abdomen/pelvis; (2) positron-emission tomographic scans not routinely indicated; (3) consideration for adjuvant therapy; (4) further clinical trials; (5) multidisciplinary decision making; (6) sufficient support at hospitals; (7) assessment of 16 or more lymph nodes (LNs); (8) in metastatic disease, surgery only for palliation of major symptoms; (9) surgeons experienced in GC management; (10) and surgeons experienced in both GC management and advanced laparoscopic surgery for laparoscopic resection. The following were scored appropriate, but of indeterminate necessity: (1) diagnostic laparoscopy before treatment; (2) a multidisciplinary approach to linitis plastica; (3) genetic assessment for diffuse GC and family history, or age less than 45 years; (4) endoscopic removal of select T1aN0 lesions; (5) D2 LN dissection in curative intent cases; (6) D1 LN dissection for early GC or patients with comorbidities; (7) frozen section analysis of margins; (8) nonemergent cases performed in a hospital with a volume of more than 15 resections per year; and (9) by a surgeon with more than 6 resection per year. Conclusions:The expert panel has created 22 statements for the perioperative management of GC patients, to provide guidance to clinicians and improve the care received by patients.

Management of gastric cancer in Ontario.

To describe the processes of care for gastric cancer in Ontario and identify areas in which care and possibly survival can be improved.