Activation of the SDF1/CXCR4 pathway retards muscle atrophy during cancer cachexia.

Cancer cachexia is a life-threatening syndrome that affects most patients with advanced cancers and causes severe body weight loss, with rapid depletion of skeletal muscle. No treatment is available. We analyzed microarray data sets to identify a subset of genes whose expression is specifically altered in cachectic muscles of Yoshida hepatoma-bearing rodents but not in those with diabetes, disuse, uremia or fasting. Ingenuity Pathways Analysis indicated that three genes belonging to the C-X-C motif chemokine receptor 4 (CXCR4) pathway were downregulated only in muscles atrophying because of cancer: stromal cell-derived factor 1 (SDF1), adenylate cyclase 7 (ADCY7), and p21 protein-activated kinase 1 (PAK1). Notably, we found that, in the Rectus Abdominis muscle of cancer patients, the expression of SDF1 and CXCR4 was inversely correlated with that of two ubiquitin ligases induced in muscle wasting, atrogin-1 and MuRF1, suggesting a possible clinical relevance of this pathway. The expression of all main SDF1 isoforms (α, ß, γ) also declined in Tibialis Anterior muscle from cachectic mice bearing murine colon adenocarcinoma or human renal cancer and drugs with anticachexia properties restored their expression. Overexpressing genes of this pathway (that is, SDF1 or CXCR4) in cachectic muscles increased the fiber area by 20%, protecting them from wasting. Similarly, atrophying myotubes treated with either SDF1α or SDF1ß had greater total protein content, resulting from reduced degradation of overall long-lived proteins. However, inhibiting CXCR4 signaling with the antagonist AMD3100 did not affect protein homeostasis in atrophying myotubes, whereas normal myotubes treated with AMD3100 showed time- and dose-dependent reductions in diameter, until a plateau, and lower total protein content. This further confirms the involvement of a saturable pathway (that is, CXCR4). Overall, these findings support the idea that activating the CXCR4 pathway in muscle suppresses the deleterious wasting associated with cancer.

Consensus statement: the 16th Annual Western Canadian Gastrointestinal Cancer Consensus Conference; Saskatoon, Saskatchewan; September 5-6, 2014.

The 16th annual Western Canadian Gastrointestinal Cancer Consensus Conference was held in Saskatoon, Saskatchewan, September 4-5, 2014. The Consensus Conference is an interactive, multidisciplinary event attended by health care professionals from across western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba) involved in the care of gastrointestinal cancer. Surgical, medical, and radiation oncologists; pathologists; radiologists; and allied health care professionals participated in presentation and discussion sessions for the purposes of developing the recommendations presented here. This consensus statement addresses current issues in the management of colorectal cancer.

Surgical process improvement tools: defining quality gaps and priority areas in gastrointestinal cancer surgery.

BACKGROUND: Surgery is a cornerstone of cancer treatment, but significant differences in the quality of surgery have been reported. Surgical process improvement tools (spits) modify the processes of care as a means to quality improvement (qi). We were interested in developing spits in the area of gastrointestinal (gi) cancer surgery. We report the recommendations of an expert panel held to define quality gaps and establish priority areas that would benefit from spits. METHODS: The present study used the knowledge-to-action cycle was as a framework. Canadian experts in qi and in gi cancer surgery were assembled in a nominal group workshop. Participants evaluated the merits of spits, described gaps in current knowledge, and identified and ranked processes of care that would benefit from qi. A qualitative analysis of the workshop deliberations using modified grounded theory methods identified major themes. RESULTS: The expert panel consisted of 22 participants. Experts confirmed that spits were an important strategy for qi. The top-rated spits included clinical pathways, electronic information technology, and patient safety tools. The preferred settings for use of spits included preoperative and intraoperative settings and multidisciplinary contexts. Outcomes of interest were cancer-related outcomes, process, and the technical quality of surgery measures. CONCLUSIONS: Surgical process improvement tools were confirmed as an important strategy. Expert panel recommendations will be used to guide future research efforts for spits in gi cancer surgery.

Sarcopenia is associated with postoperative infection and delayed recovery from colorectal cancer resection surgery.

BACKGROUND: Skeletal muscle depletion (sarcopenia) predicts morbidity and mortality in the elderly and cancer patients. METHODS: We tested whether sarcopenia predicts primary colorectal cancer resection outcomes in stage II-IV patients (n=234). Sarcopenia was assessed using preoperative computed tomography images. Administrative hospitalisation data encompassing the index surgical admission, direct transfers for inpatient rehabilitation care and hospital re-admissions within 30 days was searched for International Classification of Disease (ICD)-10 codes for postoperative infections and inpatient rehabilitation care and used to calculate length of stay (LOS). RESULTS: Overall, 38.9% were sarcopenic; 16.7% had an infection and 9.0% had inpatient rehabilitation care. Length of stay was longer for sarcopenic patients overall (15.9 ± 14.2 days vs 12.3 ± 9.8 days, P=0.038) and especially in those ≥ 65 years (20.2 ± 16.9 days vs 13.1 ± 8.3 days, P=0.008). Infection risk was greater for sarcopenic patients overall (23.7% vs 12.5%; P=0.025), and especially those ≥ 65 years (29.6% vs 8.8%, P=0.005). Most (90%) inpatient rehabilitation care was in patients ≥ 65 years. Inpatient rehabilitation was more common in sarcopenic patients overall (14.3% vs 5.6%; P=0.024) and those ≥ 65 years (24.1% vs 10.7%, P=0.06). In a multivariate model in patients ≥ 65 years, sarcopenia was an independent predictor of both infection (odds ratio (OR) 4.6, (95% confidence interval (CI) 1.5, 13.9) P<0.01) and rehabilitation care (OR 3.1 (95% CI 1.04, 9.4) P<0.04). CONCLUSION: Sarcopenia predicts postoperative infections, inpatient rehabilitation care and consequently a longer LOS.

Umbilical hernia repair in the presence of cirrhosis and ascites: results of a survey and review of the literature.

PURPOSE: Umbilical hernias are common in cirrhotics, yet, their management poses several challenges. The objective of this paper was to evaluate the indications, selection criteria, and technical aspects of umbilical hernia repair in patients with cirrhosis and ascites. METHODS: An extensive review of the literature since 1980 was performed. A survey was also conducted to obtain expert consensus to supplement any available conclusions from the literature. RESULTS: Nineteen surgeons (45%) responded to the survey. For asymptomatic hernias, all would consider hernia repair in Child's A cirrhosis, but not in more advanced disease, whereas the vast majority would consider the repair of complicated hernias. This seems to reflect the respondents' higher estimates of morbidity and mortality with more advanced liver disease. However, because the recent literature demonstrates much lower morbidity and mortality than in the past, many authors now advocate early elective repair. In addition, uncontrolled ascites appear to be strongly predictive of hernia recurrence (relative risk [RR] 8.5; 95% confidence interval [CI] 2.7-26.9). CONCLUSIONS: While acknowledging the limitations of this study, it appears that the early repair of umbilical hernias in patients with cirrhosis and ascites is safer than it was in the past and can be considered for selected patients. This may avoid increased morbidity and mortality associated with urgent repair later on. The control of ascites is critical to a successful outcome. Urgent repair of umbilical hernia in cirrhotic patients is indicated when complications develop.

Opening the black box of cancer surgery quality: WebSMR and the Alberta experience.

A web-based synoptic operative report, the WebSMR (Surgical Medical Record), was developed to define and improve the quality of cancer surgery. Surgeons accurately record the essential steps of an operation including important decision-making in an analyzable format. Outcomes can be reviewed with provincial aggregates for quality improvement and maintenance of certification. Future synoptic pathology and follow-up templates will open the "black box" of surgical processes to define quality indicators for the improvement of cancer outcomes.

Meta-analysis of pancreaticojejunostomy versus pancreaticogastrostomy reconstruction after pancreaticoduodenectomy.

BACKGROUND: Pancreaticoduodenectomy is the primary treatment for periampullary cancer. Associated morbidity is high and often related to pancreatic anastomotic failure. This paper compares rates of pancreatic fistula, morbidity and mortality after pancreaticoduodenectomy in patients having reconstruction by pancreaticogastrostomy with those in patients having reconstruction by pancreaticojejunostomy. METHODS: A meta-analysis was performed of all large cohort and randomized controlled trials carried out since 1990. RESULTS: Eleven articles were identified for inclusion: one prospective randomized trial, two non-randomized prospective trials and eight observational cohort studies. The meta-analysis revealed a higher rate of pancreatic fistula associated with pancreaticojejunostomy reconstruction (relative risk (RR) 2.62 (95 per cent confidence interval (c.i.) 1.91 to 3.60)). A higher overall morbidity rate was also demonstrated in this group (RR 1.43 (95 per cent c.i. 1.26 to 1.61)), as was a higher mortality rate (RR 2.51 (95 per cent c.i. 1.61 to 3.91)). CONCLUSION: Current literature suggests that the safer means of pancreatic reconstruction after pancreaticoduodenectomy is pancreaticogastrostomy, but much of the evidence comes from observational cohort study data.

Massive hemorrhage and infarction complicating focal nodular hyperplasia of the liver.

BACKGROUND: Spontaneous infarction or hemorrhage of focal nodular hyperplasia (FNH) has rarely been reported in the literature. CASE OUTLINE: A 43-year-old woman presented with upper abdominal pain and anemia. CT scan showed an enormous perihepatic hematoma. Trisegmentectomy successfully dealt with the problem. CONCLUSION: Although conservative management of FNH is often adopted, this case illustrates that these lesions can undergo massive bleeding.

IL-2 during in vitro priming promotes subsequent engraftment and successful adoptive tumor immunotherapy by persistent memory phenotypic CD8(+) T cells.

Adoptive T cell tumor immunotherapy potentially consists of two protective components by the transferred effector cells, the immediate immune response and the subsequent development of memory T cells. The extent by which adoptively transferred CD8(+) CTL are destined to become memory T cells is ambiguous as most studies focus on the acute effects on tumor shortly following adoptive transfer. In this study we show that a substantial fraction of the input CTL develop into memory cells that reject a s.c. tumor challenge. The use of exogenous IL-2 or a combination of IL-2 and IL-4, but not solely IL-4, during the ex vivo culture for the CTL inoculation was necessary for efficient development of CD8(+) memory T cells. Thus, an important component of adoptive immunotherapy using CTL is the production of CD8(+) Ag-specific memory cells which is primarily favored by IL-2 receptor signaling during ex vivo generation of the effector CTL.

Management of hilar bile duct carcinoma.

BACKGROUND/AIMS: Hilar cholangiocarcinoma is a rare tumor with a dismal prognosis. Because proximal bile duct cancers are uncommon, outcomes related to various therapeutic interventions are not well defined. METHODOLOGY: Between 1985 and 1997, 55 patients with bile duct cancers involving the proximal third of the extrahepatic bile ducts were seen. The management of patients with resectable and unresectable disease was retrospectively reviewed. All but four patients were followed until the time of death. RESULTS: Forty patients underwent laparotomy following preoperative assessment of extent of disease and 19 patients (35%) ultimately underwent resection with curative intent. Survival was significantly longer in patients who underwent resection (2-year survival 47% vs. 18%; P = 0.027). Of those patients whose disease was resected, 11 patients received adjuvant radiotherapy. Survival for this group was not significantly different from that seen in patients who did not receive adjuvant radiotherapy. Similarly, in patients with unresectable disease, administration of radiotherapy was not associated with an improved outcome. CONCLUSIONS: Locoregional extent of disease is the greatest problem in cases of proximal bile duct cancers. Resection provides the best hope for long-term survival, but new adjuvant strategies are needed.

Diminished benefit from resection of cancer of the head of the pancreas in patients of advanced age.

BACKGROUND AND OBJECTIVES: The incidence of pancreatic cancer is increasing, and an increasing proportion of these patients is older than 65 years. The benefits of resection in the geriatric population, in whom major comorbidity is more likely, are poorly defined. The authors sought to determine the relative benefits of resection of cancer of the head of the pancreas in different age groups, with particular emphasis on the geriatric population. METHODS: Between 1983 and 1995, 273 patients presented to the University of Miami for evaluation of noncystic epithelial cancer of the head of the pancreas. Resection was performed in 104 patients, and these patients are the subject of this retrospective review. Mean length of follow-up for surviving patients was 37 +/- 24 months. Outcomes were compared in patients < 65 years old (group 1, n = 38), 65-74 years old (group 2, n = 47), and > 74 years old (group 3, n = 19). RESULTS: Total pancreatectomy was performed in 12 patients and pancreaticoduodenectomy was performed in 92 patients. The overall complication rate was similar in all groups, but major morbidity was highest in group 3 (P = 0.05). Median survival for patients in group 2 was 25.1 months. Survival was significantly shorter in patients from groups 1 and 3 (median survivals 12.4 months and 11.4 months, respectively; P = 0.02). Following control for Hispanic ethnicity, which was also a significant prognostic factor on univariate analysis, only the oldest age group had a significantly shorter survival than the other two groups. Age > 74 years and Hispanic ethnicity remained significant after multivariate analysis. CONCLUSIONS: Long-term survival after resection is truncated in older patients. This finding and the observation that the major complication rate is higher in the older subgroup emphasize the need to evaluate critically whether older patients should be submitted to radical resection.

Influence of Hispanic ethnicity on outcome after resection of carcinoma of the head of the pancreas.

BACKGROUND: Poor outcomes in Hispanic patients have been reported for tumors at a number of sites. The authors sought to determine whether a similar phenomenon occurs in Hispanics after the resection of solid epithelial tumors of the head of the pancreas. METHODS: Between 1983-1995, 273 patients with noncystic epithelial carcinoma of the head of the pancreas were evaluated. Resection was accomplished in 104 patients (38%); these patients were the focus of the current retrospective review. Of the patients who underwent resection, 26 (25%) were Hispanic and 78 (75%) were non-Hispanic. RESULTS: Although Hispanic patients tended to present at a significantly younger age and their serum bilirubin level was significantly higher, no other differences in clinical characteristics were observed. After resection, Hispanic patients had a median survival of only 11.4 months, whereas the non-Hispanic group had a median survival of 21.7 months (P = 0.009). Hispanic ethnicity, as well as age > 74 years and jaundice at the time of presentation also were found to be significant prognostic factors on multivariate analysis. Hispanic patients did not present with more advanced disease and no delays in assessment by a physician or in proceeding to surgery were observed. Furthermore, the rate of resection was the same in Hispanic patients and non-Hispanic patients. Long-term survival after palliative bypass was similarly worse in the Hispanic subgroup. CONCLUSIONS: Hispanic patients treated at the study center appeared to have a diminished survival after resection of a tumor of the head of the pancreas. No treatment-related factors were identified that could explain this discrepancy in outcome.

Reversal of CD8+ T cell ignorance and induction of anti-tumor immunity by peptide-pulsed APC.

In the present report, we have studied the potential of naive and activated effector CD8(+) T cells to function as anti-tumor T cells to a solid tumor using OVA-specific T cells from TCR-transgenic OT-I mice. Adoptive transfer of naive OT-I T cells into tumor-bearing syngeneic mice did not inhibit tumor cell growth. The adoptively transferred OT-I T cells did not proliferate in lymphoid tissue of tumor-bearing mice and were not anergized by the tumor. In contrast, adoptive transfer of preactivated OT-I CTL inhibited tumor growth in a dose-dependent manner, indicating that E.G7 was susceptible to immune effector cells. Importantly, naive OT-I T cells proliferated and elicited an anti-tumor response if they were adoptively transferred into normal or CD4-deficient mice that were then vaccinated with GM-CSF-induced bone marrow-derived OVA-pulsed APC. Collectively, these data indicate that even though naive tumor-specific T cells are present at a relatively high fraction they remain ignorant of the tumor and demonstrate that a CD8-mediated anti-tumor response can be induced by Ag-pulsed APC without CD4 T cell help.

A subcutaneous or subfascial jejunostomy is beneficial in the surgical management of extrahepatic bile duct cancers.

BACKGROUND: Extrahepatic bile duct cancers are rare tumors with a dismal prognosis. Even after a resection, obstructive cholestasis and other biliary complications are the rule. To facilitate retrograde access to the biliary tree for treatment of such biliary complications, a modified Roux-en-Y hepaticojejunostomy is constructed such that the afferent limb is brought up as a subcutaneous or subfascial jejunostomy (SJ). The safety and utility of construction of an SJ was evaluated in patients with extrahepatic cholangiocarcinoma. METHODS: From 1985 to 1997, 24 patients with extrahepatic bile duct cancers received an SJ as part of their management. Demographic data, operative data, tumor characteristics, and postoperative courses were retrospectively reviewed. All but 3 patients were followed to the time of death. RESULTS: The average age of the patients was 62 +/- 9 years. The tumor was resected in 17 patients. Major complications occurred in 5 patients (21%). There was 1 operative death (4%). None of the complications could be attributed to construction of the SJ, although 1 patient had a soft tissue infection at the site of the percutaneous access of the SJ. Frequent dilatations of biliary strictures were required in 5 patients, and 1 patient eventually required insertion of an internal biliary stent. These procedures could all be accomplished through the SJ. CONCLUSIONS: The SJ is a technically simple and safe addition to the management of resectable and unresectable extrahepatic bile duct cancers, particularly proximal lesions. The procedure facilitates brachytherapy if indicated, and it allows convenient management of postoperative biliary complications, including recurrent strictures.

Extent of resection in the management of duodenal adenocarcinoma.

BACKGROUND: It has been postulated that segmental duodenal resection (SR) is not an adequate operation for patients with adenocarcinoma of the duodenum and that pancreaticoduodenectomy (PD) is the procedure of choice, regardless of the tumor site. However, data from previous studies do not clearly support this position. METHODS: We reviewed the records of 63 patients treated for duodenal adenocarcinoma from 1979 through 1998. Perioperative outcome, patient survival, and extent of lymphadenectomy were compared in patients who underwent PD and SR. RESULTS: The overall morbidity for PD and SR was 27% and 18%, respectively (not significant [NS]). Patients who underwent SR had a 5-year survival of 60% versus 30% for patients who underwent PD (NS). Lymph node status was a prognostic factor for survival (P = 0.014). The mean number of lymph nodes in the specimens was 9.9 +/- 2.1 for PD and 8.3 +/- 4.4 for SR (NS). CONCLUSIONS: Segmental duodenal resection for patients with duodenal adenocarcinoma is associated with acceptable postoperative morbidity and long-term survival. The procedure is especially well suited for distal duodenal tumors. Clearance of lymph nodes and outcome are comparable to PD.

Radical resection of periampullary tumors in the elderly: evaluation of long-term results.

Increasingly, patients of advanced age are coming for evaluation of periampullary tumors. Although several studies have demonstrated the safety of resecting periampullary tumors in older patients, few long-term survival data have been reported. Between 1983 and 1992 various periampullary masses were resected in 70 patients over age 65 (range 65-87 years). Total pancreatectomy was performed in 11 patients, and 59 patients underwent pancreaticoduodenectomy. The mean duration of hospitalization was 17 +/- 15 days. Major complications occurred in 27 patients (39%), and operative mortality rate was 8.5%. Overall median survival was 24 months; and 5-year survival was 25%. Perioperative outcome was compared in patients aged 65 to 74 years and in patients > or =75 years old. The older age group required longer periods in the surgical intensive care unit postoperatively, but the long-term survival was similar in the two age groups. Radical resection with the intent to cure periampullary tumors is safe in selected patients of advanced age, and long-term survival is in the range of expected survival for younger patients with the same tumors.

Expression of receptors for estrogen and progesterone in malignant colonic mucosa as a prognostic factor for patient survival.

BACKGROUND AND OBJECTIVES: Estrogen receptors (ER) and progesterone receptors (PR) have been detected in both normal and malignant colonic mucosa, but the prognostic value of this observation is unknown. We aimed to define the prognostic significance of the presence of ER and PR in malignant cells from colorectal adenocarcinoma specimens. METHODS: An immunohistochemical assay for ER and PR was performed on paraffinized sections from 65 colorectal adenocarcinoma specimens. Survival curves were analyzed to define the prognostic implications of ER and PR. RESULTS: Twenty nine (45%) tumors tested receptor positive (32% for ER and 23% for PR). Tumors of advanced stage were more likely to express receptors than early stage tumors (56% vs. 32%; P = 0.01). Median survival of patients with neoplasms expressing PR was 30 months. For patients whose tumors did not express any receptors, median survival had not been reached at the time of follow-up (P = 0.04). Similarly, patients with tumors expressing both receptors had significantly reduced survival (median survival = 20 months; P = 0.003). CONCLUSIONS: Expression of receptors for sex steroids correlates with advanced stage disease. Expression of PR by the tumor cells is associated with a shorter patient survival. The results suggest that sex steroids may play a role in carcinogenesis and tumor progression.

Day-care laparoscopic appendectomies.

OBJECTIVE: To demonstrate the safety of laparoscopic appendectomy in a day-care setting and to compare patients selected for laparoscopic versus open appendectomy. DESIGN: A retrospective, nonrandomized study. SETTING: A community hospital in a small town in British Columbia. PATIENTS: Ninety-four consecutive patients with a clinical diagnosis of acute appendicitis. INTERVENTIONS: Each patient underwent laparoscopic or open appendectomy as selected by the operating surgeon. OUTCOME MEASURES: Duration of operation and of hospital stay, morbidity and mortality. RESULTS: The average operating time was 32 minutes for open appendectomy and 36 minutes for laparoscopic appendectomy. Two (4%) of the 52 patients who had a laparoscopic appendectomy had significant complications; 1 of them required reoperation for intra-abdominal abscess. Thirty-nine (75%) of the laparoscopic appendectomies were done as day-care procedures. The average length of stay for the remaining patients was 2.1 days. The overall complication rate for patients who underwent open appendectomy was 20%. The average length of stay for these patients was 3.2 days; no patient was discharged within 24 hours. CONCLUSIONS: Laparoscopic appendectomy can be safely performed as a day-care procedure, even for selected patients with gangrenous or perforated appendices. Patients typically selected for open appendectomy include children and those with more advanced infection.

Increased thymidylate synthase gene expression in liver metastases from colorectal carcinoma: implications for chemotherapeutic options and survival.

OBJECTIVES: To determine the association of intratumoral thymidylate synthase (TS) gene expression with resistance to fluoropyrimidines and to study the association of TS gene expression with outcome in patients with liver metastases from colorectal cancer. METHODS: Intratumoral TS gene expression was measured by reverse transcriptase and polymerase chain reaction in 33 patients with liver metastases from colorectal carcinoma. Fifteen patients underwent resection, and 18 were treated with chemotherapy only. Patients with high levels of TS gene expression were compared to those with low levels of TS gene expression. RESULTS: All patients with a high level of TS gene expression were nonresponders to fluoropyrimidine chemotherapy. Median survival in patients with unresectable disease was shorter in those who had high levels of TS gene expression (7 months vs 15 months, P = 0.02). After hepatic resection, median disease-free interval was shorter in patients with high levels of TS gene expression (5 months vs 18 months; P = 0.004). Similarly, survival was shorter after resection in those with high TS gene expression (17 months vs 43 months, P = 0.0002). DISCUSSION: Increased TS gene expression is associated with a poor outcome in patients with liver metastases from colorectal carcinoma, whether resected or treated by chemotherapy only. This is related in part to reduced responsiveness to chemotherapeutic agents, but it also reflects inherently more aggressive behavior of metastases.

Metastasectomy as a cytoreductive strategy for treatment of isolated pulmonary and hepatic metastases from breast cancer.

The authors sought to examine the utility of resection in conjunction with adjuvant chemotherapy for treatment of metastases from breast cancer isolated to the liver or lungs. Limitations of regional therapy were examined and potential agents for systemic therapy were reviewed. As resection of metastases is a controversial therapeutic approach, no clinical trials are available for review. Rather, evidence for a potential role for surgery rests on retrospective studies of small series of patients. Technical advances have rendered resection of liver and lung metastases safe. Long-term results as reported by other investigators support the role of metastasectomy in selected patients. The site of failure following ablation of liver metastases is usually in the liver. Following resection of lung metastases, nonpulmonary and disseminated recurrences are most common. Adjuvant therapy with docetaxel or any other agent or combination with significant activity against visceral metastases might potentiate long-term results.