ALDH1A3 promotes invasion and metastasis in triple-negative breast cancer by regulating the plasminogen activation pathway.

Aldehyde dehydrogenase 1A3 (ALDH1A3) is a cancer stem cell marker that promotes metastasis. Triple-negative breast cancer (TNBC) progression has been linked to ALDH1A3-induced gene expression changes. To investigate the mechanism of ALDH1A3-mediated breast cancer metastasis, we assessed the effect of ALDH1A3 on the expression of proteases and the regulators of proteases that degrade the extracellular matrix, a process that is essential for invasion and metastasis. This revealed that ALDH1A3 regulates the plasminogen activation pathway; it increased the levels and activity of tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA). This resulted in a corresponding increase in the activity of serine protease plasmin, the enzymatic product of tPA and uPA. The ALDH1A3 product all-trans-retinoic acid similarly increased tPA and plasmin activity. The increased invasion of TNBC cells by ALDH1A3 was plasminogen-dependent. In patient tumours, ALDH1A3 and tPA are co-expressed and their combined expression correlated with the TNBC subtype, high tumour grade and recurrent metastatic disease. Knockdown of tPA in TNBC cells inhibited plasmin generation and lymph node metastasis. These results identify the ALDH1A3-tPA-plasmin axis as a key contributor to breast cancer progression.

Case Report: Combined Intra-Lesional IL-2 and Topical Imiquimod Safely and Effectively Clears Multi-Focal, High Grade Cutaneous Squamous Cell Cancer in a Combined Liver and Kidney Transplant Patient.

Cutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer worldwide, with ever increasing incidence and mortality. While most patients can be treated successfully with surgical excision, cryotherapy, or radiation therapy, there exist a subset of patients with aggressive cSCC who lack adequate therapies. Among these patients are solid organ transplant recipients who due to their immunosuppression, develop cSCC at a dramatically increased rate compared to the normal population. The enhanced ability of the tumor to effectively undergo immune escape in these patients leads to more aggressive tumors with a propensity to recur and metastasize. Herein, we present a case of aggressive, multi-focal cSCC in a double organ transplant recipient to frame our discussion and current understanding of the immunobiology of cSCC. We consider factors that contribute to the significantly increased incidence of cSCC in the context of immunosuppression in this patient population. Finally, we briefly review current literature describing experience with localized therapies for cSCC and present a strong argument and rationale for consideration of an IL-2 based intra-lesional treatment strategy for cSCC, particularly in this immunosuppressed patient population.

Prognostic factors in metastatic gastric cancer: results of a population-based, retrospective cohort study in Ontario.

BACKGROUND: Stage IV gastric cancer is lethal, and little population-based research on prognostic factors has been performed in low-incidence countries. Therefore, we investigated the consistency of the associations of patient, disease and healthcare system factors identified in previous population-based research to understand their generalizability to other low-incidence populations. METHODS: A population-based, retrospective cohort study of patients diagnosed with Stage IV gastric cancer in Ontario between 1 April 2005 and 31 March 2008 was performed. Kaplan-Meier methodology and the log-rank test were used for bivariate analysis. Multivariate Cox proportional hazard regression was performed. Hazard ratios (HRs) and 95% confidence intervals (CIs) are presented. RESULTS: On multivariate analysis, patient, disease and healthcare system factors were independent predictors of survival. Increasing age per 10 years (HR 1.07; 95% CI 1.02-1.10), a tumor located in the gastroesophageal junction (HR 1.09; 95% CI 0.94-1.27) or middle of the stomach (HR 1.14; 95% CI 0.97-1.35), presence of carcinomatosis (HR 1.61; 95% CI 1.42-1.83) and a larger burden of metastatic disease (2-3 sites of metastatic disease: HR 1.17; 95% CI 1.03-1.32; ≥ 4 sites: HR 1.69; 95% CI 1.30-2.20) were associated with worse prognosis. Female gender, receipt of surgery, chemotherapy and radiotherapy and treatment from a high-volume, gastric cancer specialist were all associated with significantly better prognosis. In addition, there was evidence of significant geographic variation in survival. CONCLUSION: This study provides supporting evidence for patient, disease and healthcare system prognostic factors in metastatic gastric cancer. Future work investigating the role of emerging molecular and biologic information will need to take these established prognostic factors into consideration.

Processes of care in the multidisciplinary treatment of gastric cancer: results of a RAND/UCLA expert panel.

IMPORTANCE: There is growing interest in reducing the variations and deficiencies in the multidisciplinary management of gastric cancer. OBJECTIVE: To define optimal treatment strategies for gastric adenocarcinoma (GC). DESIGN, SETTING, AND PARTICIPANTS: RAND/UCLA Appropriateness Method involving a multidisciplinary expert panel of 16 physicians from 6 countries. INTERVENTIONS: Gastrectomy, perioperative chemotherapy, adjuvant chemoradiation, surveillance endoscopy, and best supportive care. MAIN OUTCOMES AND MEASURES: Panelists scored 416 scenarios regarding treatment scenarios for appropriateness from 1 (highly inappropriate) to 9 (highly appropriate). Median appropriateness scores from 1 to 3 were considered inappropriate; 4 to 6, uncertain; and 7 to 9, appropriate. Agreement was reached when 12 of 16 panelists scored the scenario similarly. Appropriate scenarios agreed on were subsequently scored for necessity. RESULTS: For patients with T1N0 disease, surgery alone was considered appropriate, while there was no agreement over surgery alone for patients T2N0 disease. Perioperative chemotherapy was appropriate for patients who had T1-2N2-3 or T3-4 GC without major symptoms. Adjuvant chemoradiotherapy was classified as appropriate for T1-2N1-3 or T3-4 proximal GC and necessary for T1-2N2-3 or T3-4 distal GC. There was no agreement regarding surveillance imaging and endoscopy following gastrectomy. Surveillance endoscopy was deemed to be appropriate after endoscopic resection. For patients with metastatic GC, surgical resection was considered inappropriate for those with no major symptoms, unless the disease was limited to positive cytology alone, in which case there was disagreement. CONCLUSIONS AND RELEVANCE: Patients with GC being treated with curative intent should be considered for multimodal treatment. For patients with incurable disease, surgical interventions should be considered only for the management of major bleeding or obstruction.

Surgical management of gastric perforation in the setting of gastric cancer.

BACKGROUND: Gastric perforation is a rare presentation of gastric cancer and is thought to be a predictor of advanced disease and, thus, poor prognosis. Guidelines do not exist for the optimal management strategy. We aimed to identify, review, and summarize the literature pertaining to perforation in the setting of gastric cancer. METHODS: A qualitative, systematic review of the literature was performed from January 1, 1985, to January 1, 2010. Searches of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were performed using search terms related to gastric cancer surgery. Abstracts were examined by two independent reviewers and a standardized data collection tool was used to extract relevant data points. Summary tables were created. RESULTS: Nine articles were included. Perforation was reported to occur in fewer than 5% of gastric cancer patients. Preoperative diagnosis of a gastric cancer was rated and occurred in 14-57% of patients in the papers reviewed. Mortality rates for emergency gastrectomy ranged from 0 to 50% and for simple closure procedures the rates ranged from 8 to 100%. Patients able to receive an R0 gastrectomy demonstrated better long-term survival (median 75 months, 50% 5-year) compared with patients who had simple closure procedures. CONCLUSIONS: Gastric cancer patients presenting with a gastric perforation demonstrate improved overall survival with an R0 resection; however, implementation of this management technique is complicated by infrequent preoperative gastric cancer diagnosis, and inability to perform an oncologic resection due to patient instability and intra-abdominal contamination.

Effective palliation and quality of life outcomes in studies of surgery for advanced, non-curative gastric cancer: a systematic review.

BACKGROUND: Relief of symptoms should be the primary focus of palliative treatment as defined by the World Health Organization. Evaluating the effectiveness of palliative interventions should incorporate this goal and include quality of life (QOL) outcome assessments. A systematic review of the surgical gastric cancer literature was performed to summarize the effectiveness of palliative surgical interventions in addressing QOL. METHODS: An electronic literature search of EMBASE, Medline, and the Cochrane Database of Controlled Trials was performed from January 1, 1985 to December 1, 2009. English language abstracts and articles were reviewed independently by two reviewers. A systematic approach to data abstraction and presentation was followed. RESULTS: No articles were identified as reporting true QOL outcomes using reliable, validated QOL instruments in surgically managed, advanced gastric cancer patients. Nine articles were identified as reporting outcomes measuring effectiveness of palliation. Commonly reported pre-procedure symptoms were weight loss, abdominal pain, vomiting, obstruction, and bleeding. Time to oral intake was reported in 5 of 9 studies, ranging from a mean of 2.9 days (laparoscopic gastrojejunostomy) to 8 days (surgical bypass). Length of postoperative inpatient stay ranged from a mean of 7 days (gastrojejunostomy) to 28 days (surgical bypass). Other measures of effective palliation included measures of clinical success, hospital re-admission rates, and post-procedure analgesic intake. CONCLUSION: A paucity of literature exists regarding the QOL of surgically managed gastric cancer patients. Prospectively designed studies using credible QOL measures are necessary to better inform the treatment decision-making process for these patients.

A systematic review of surgery for non-curative gastric cancer.

BACKGROUND: Most 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. PURPOSE: To evaluate the non-curative surgical literature to better understand the limitations and benefits of non-curative surgery for advanced gastric cancer. METHODS: A 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. RESULTS: Fifty-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. CONCLUSIONS: A 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.

Management of gastric cancer in Ontario.

OBJECTIVE: To describe the processes of care for gastric cancer in Ontario and identify areas in which care and possibly survival can be improved. SUMMARY BACKGROUND DATA: Survival in North America is poor for patients with gastric cancer, with stage-matched survival markedly worse than is seen in Asian and European series. Few Western studies have examined processes of care associated with gastric cancer. METHODS: We identified all cases of gastric cancer in Ontario, Canada from April 1, 2000 to March 31, 2005, and describe the demographics of patients, staging of the cancer, treatment, and survival. RESULTS: In this series of 3,666 patients, 81% of cases had a CT scan performed prior to resection and 90% of cases received an upper endoscopy. We found that 55% of patients were treated palliatively and only 1,645 patients underwent a curative-intent resection. Among patients who did not receive a resection over 50% of the cases appeared to have had a diagnostic laparoscopy rather than a laparotomy. Survival was related to the type of resection performed, likely reflecting the extent of disease. Higher institution volume and age were related to improved survival for curative-intent cases. CONCLUSION: In this population-based analysis, we found evidence of under-utilization of pre-operative radiology and endoscopy. Many patients were treated palliatively, reflecting presentation of the cancer at an advanced stage. For curative patients, survival was associated with age, surgical type, and resection in a higher volume institution.

Obesity is a risk factor for developing postoperative lymphedema in breast cancer patients.

Lymphedema (LE) is a well-known postoperative complication after axillary node dissection (ALND). Although, sentinel lymph node dissection (SLND) involves more focused surgery and less disruption of the axilla, early reports show up to 13% of patients experience some symptoms of LE. The purpose of this study was to determine predictors of arm LE in our patients under going SLND with or without an ALND. One hundred and thirty-seven breast cancer patients were treated at a comprehensive cancer center. Prospective measurement of arm volume was carried every 6 months from date of diagnosis. This data base was retrospectively reviewed for tumor stage, treatment, and subjective complaints of LE. Objective LE was defined as a change greater than 200 mL compared with the control arm. Univariate and multivariate analyses were performed. Arm volume changes were measured over 24 months (median follow-up 20 months) in 137 women: 82 stage I, 48 stage II, and 5 stage III; median age 56 years. Breast-conserving surgery was performed in 133 patients. All patients underwent SLND for axillary staging and for 52 patients this was the only axillary staging procedure. All node-positive patients (31) and 54 node-negative patients under went an immediate completion ALND, the latter as part of a study protocol. At 24 months, 16 (11.6%) patients were found to have objective LE (>200 mL increase). Patient age, tumor size, number of nodes harvested, or adjuvant chemotherapy was not found to be predictive of LE by univariate analysis. The risk of developing postoperative LE was primarily and significantly related to the patients' BMI (p = 0.003). Multivariate analysis revealed patients with a BMI >30 (obese) had an odds ratio of 2.93 (95% CI 1.03-8.31) compared with those with a BMI of <25 of having LE. Symptomatic LE (SLE), as defined by patient complaints was recorded in six of the above 16 patients, no SLE was recorded in patients without objective signs of edema. Univariate subgroup analysis compared the symptomatic to the nonsymptomatic patients and revealed the median number of nodes removed was higher in the symptomatic patients (17 verses 9, p = 0.045); however, these patients had a lower BMI (p = 0.0012). The mean change in arm volume was not significantly different between the groups. SLE occurs in one third of patients with objective arm swelling and most likely is multi-factorial in etiology. Although patients undergoing SLN were recorded as having objective LE, none reported SLE. The development of LE within 2 years of surgery is associated with the patient's BMI and this should be considered in preoperative counseling.

Surgeons' knowledge of quality indicators for gastric cancer surgery.

BACKGROUND: Gastric cancer survival in the West is inferior to that achieved in Asian centers. While differences in tumor biology may play a role, poor quality surgery likely contributes to understaging. We hypothesize that the majority of surgeons performing gastric cancer surgery in North America are unaware of the recommended standards. METHODS: Using the Ontario College of Physicians and Surgeons registry, surgeons who potentially included gastric cancer surgery in their scope of practice were identified. A questionnaire was mailed to 559; of those, 206 surgeons reported managing gastric cancer. Results were evaluated by chi(2) and logistic regression; P < 0.05 was considered significant. RESULTS: Eighty-six percent of respondents were male and 53% practiced in an urban nonacademic setting. Forty percent reported operating on two to five cases of gastric cancer per year, and 42% on fewer than two cases per year. One-third of surgeons identified 4 cm or less to be the desired gross proximal margin. Half used frozen section to evaluate margin status. Twenty percent of surgeons were unsure of the number of lymph nodes (LN) needed to accurately stage gastric cancer, and the median number reported by the remainder was 10 (range, 0-30). Only 16 of 206 identified both a proximal margin of 5 cm or less and 15 or more LN as desired targets. Those performing more than five gastric resections per year were more likely to report a D2 resection (P = 0.008). CONCLUSION: The majority of surgeons operating on gastric cancer in Ontario did not identify recommended quality indicators of gastric cancer surgery. A continuing medical education program should be designed to address this knowledge gap to improve the quality of surgery and patient outcomes.

Surgery as a bridge to palliative chemotherapy in patients with malignant bowel obstruction from colorectal cancer.

BACKGROUND: Malignant bowel obstruction (MBO) is a feature of the clinical course of 10-28% of colorectal cancer (CRC) patients and is associated with a poor prognosis. Recent advancements in palliative chemotherapy regimens have prolonged survival in patients with stage IV CRC. Few reports exist that describe outcomes in patients who have had surgery for MBO and subsequent chemotherapy as part of their treatment. The objective of this study was to review surgical outcomes in patients with MBO for CRC and to evaluate the extent to which surgery can serve as a bridge to palliative chemotherapy. METHODS: Patients who presented with MBO and had surgical treatment were identified from a prospectively kept database at a single tertiary care center between 09/99 and 08/04. Charts were retrospectively reviewed and clinical and outcomes data were abstracted. RESULTS: Forty-seven patients were identified who had surgery as part of the treatment for MBO from CRC. Operations included resections, bypasses and stoma creation. Overall, 80% of patients were able to tolerate solid food post-operatively and return home. The median survival for the entire cohort was 3.5 months. Seven patients died within 30 days of surgery. Of the remainder, 24 patients were palliated with surgery alone and 16 patients ultimately received palliative chemotherapy. Survival in the final cohort was significantly prolonged (P < 0.001). CONCLUSION: Surgery can adequately palliate a substantial proportion of patients with MBO from CRC with acceptable morbidity and mortality. In addition, in a subset of patients it can facilitate palliative chemotherapy that is associated with improved overall survival.

The use of complementary and alternative medicines among patients with locally advanced breast cancer--a descriptive study.

BACKGROUND: Complementary and alternative medicine (CAM) use is common among cancer patients. This paper reviews the use of CAM in a series of patients with locally advanced breast cancer (LABC). METHODS: Women with LABC attending a specialist clinic at a single Canadian cancer centre were identified and approached. Participants completed a self-administered survey regarding CAM usage, beliefs associated with CAM usage, views of their risks of developing recurrent cancer and of dying of breast cancer. Responses were scored and compared between CAM users and non-users. RESULTS: Thirty-six patients were approached, 32 completed the questionnaire (response rate 89%). Forty-seven percent of LABC patients were identified as CAM users. CAM users were more likely to be younger, married, in a higher socioeconomic class and of Asian ethnicity than non-users. CAM users were likely to use multiple modalities simultaneously (median 4) with vitamins being the most popular (60%). Motivation for CAM therapy was described as, "assisting their body to heal" (75%), to 'boost the immune system' (56%) and to "give a feeling of control with respect to their treatment" (56%). CAM therapy was used concurrently with conventional treatment in 88% of cases, however, 12% of patients felt that CAM could replace their conventional therapy. Psychological evaluation suggests CAM users perceived their risk of dying of breast cancer was similar to that of the non-Cam group (33% vs. 35%), however the CAM group had less severe anxiety and depression. CONCLUSION: The motivation, objectives and benefits of CAM therapy in a selected population of women with LABC are similar to those reported for women diagnosed with early stage breast cancer. CAM users display less anxiety and depression and are less likely to believe they will die of their breast cancer. However the actual benefit to overall and disease free survival has yet to be demonstrated, as well as the possible interactions with conventional therapy. Consequently more research is needed in this ever-growing field.