Citations

Abstract Abstract #106 Breast cancer has been proposed as a stem cell-derived disorder based on studies identifying cancer stem cells (CSCs) in breast tumors and established cell lines. These self-renewing CSCs are thought to be responsible for breast cancer formation, progression and recurrence; therefore, a deeper understanding of the signaling pathways regulating CSC survival will benefit development of novel therapeutic strategies. Notch signaling, which is known to be dysregulated in breast cancer and has been implicated in mammary stem cell self-renewal, can be effectively blocked by gamma-secretase inhibitors (GSIs). While GSIs are currently in clinical trials for breast cancer, it is unclear how these compounds will affect CSCs or if CSCs from different breast cancer phenotypes (estrogen receptor-alpha (ER)-positive and negative) will be differentially affected. Here, we demonstrate stem-like cells derived from the T47D breast cancer cell line show elevated levels of Notch signaling, with an ER-negative subclone (T47D-C42) having higher intrinsic levels of Notch activity compared to an ER-positive subclone (T47D-A18). Blockade of Notch signaling with three structurally distinct GSIs reduced the number of stem-like cells, and completely abolished secondary mammosphere formation, which is a measure of stem cell self-renewal. Importantly, this effect was irreversible with MRK-003, but not with the two other GSIs. Moreover, our results suggest that the ER-negative cell line was more sensitive to the GSIs compared to the ER-positive line. This is consistent with our recent report that loss of estrogen signals results in Notch activation. These novel findings support a role for Notch signaling in CSC self-renewal and proliferation, and they suggest Notch inhibition may have clinical benefits in targeting CSCs. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 106.

Abstract Abstract #1005 Background: Several models for the prediction of non-sentinel lymph node metastasis (+NSLN) in sentinel lymph node positive (+SLN) breast cancer patients have been published. Multiple variables have been shown to be important in prediction of +NSLN. To this date, models that utilize 7-8 variables have been significantly more discriminatory than models using only 2-3 variables. In this study, we evaluate the performance of the newly created Stanford online calculator (SOC) to predict the likelihood of +NSLN. The SOC uses 3 variables: primary tumor size, sentinel lymph node metastasis size, and presence/absence of lymphovascular invasion.
 Methods: From 1997-2004, 465 breast cancer patients with clinically negative axillae were found to have a +SLN and underwent completion axillary lymph node dissection (ALND) at the Mayo Clinic. Using the SOC the probability of having +NSLN was determined for each patient. Complete variable data was available for 464 patients which make up the cohort reported here. A receiver-operating characteristic (ROC) curve was created and the area-under-the-curve (AUC) was calculated. Mean probabilities of patients with and without +NSLN were compared. Additionally, patients with a low Stanford probability were examined to determine the model's accuracy in discriminating patients who could potentially be spared ALND. These results were compared to the results of the Mayo Clinic and Memorial Sloan Kettering Cancer Center (MSKCC) nomograms which have been previously applied to this same cohort of patients.
 Results: The AUC of the Stanford model was 0.72 (95% CI 0.67-0.77). The mean Stanford probabilities for patients with and without NSLN disease were 0.75 (range 0.06 to 1.0) and 0.50 (range 0.05 to 1.0), respectively (p < 0.0001). Examining patients with a Stanford probability <= 10%, we found that 47 patients met this criterion; 6 had +NSLN and 41 did not, for a false negative (FN) prediction rate of 13%. There was only 1 patient with Stanford probability <= 5%, and this patient did not have +NSLN. The AUC of the MSKCC and Mayo nomograms in this same patient population was 0.74 and 0.77, respectively. The AUCs did not differ significantly (p = 0.13) among the 3 models.
 
 Conclusion: Despite using only three variables, the Stanford nomogram appears to perform as well as, but not better than the MSKCC and Mayo nomograms in our patient cohort. Further validation in other patient populations is needed prior to widespread utilization of this nomogram. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1005.

In 2008, the Institute for Clinical Systems Improvement (ICSI) in Minnesota implemented a model of collaborative care management (CCM) for treatment of depression in primary care. This resulted in significant improvements on both clinical response and remission over usual care, although an increase in utilization metrics has been observed. Mental health comorbidities have previously been significantly associated with an increased likelihood of not responding to initial treatment. This retrospective study hypothesized that patients with mental health comorbidities are more likely to be associated with patients who were readmitted into CCM with recurrent depression. A total of 145 patients who had completed CCM were studied; of these, 32 were diagnosed with recurrent depression and were readmitted to CCM, and 113 were in remission for at least 4 months. There were no statistically significant demographic differences between the 2 groups. The initial screening GAD-7 score for anxiety was significantly increased in the readmission group (12.81 vs 9.20, P = .001) as was the average length of treatment from initial diagnosis to remission (168.09 vs 120.99 days, P = .002). All other initial screening tests were not different between the groups. When controlling for the independent variables by multiple logistic regression, the odds ratio for GAD-7 was 1.1156 (CI = 1.0.192 to 1.2212, P = .0177) and for days of treatment in CCM was 1.0123 (CI = 1.0041 to 1.0206, P = .0033). Patients who are readmitted to CCM for recurrent depression have a statistically increased risk of associated anxiety and a longer treatment course than those who have remained in remission for at least 4 months.

In patients with congenitally corrected transposition of the great arteries, the main concern has been the long-term performance of the morphologic right ventricle in association with tricuspid valve regurgitation when it remains as the systemic ventricle. Deterioration in ventricular function can occur slowly over many years, even without associated cardiac anomalies or previous surgical interventions. This review summarizes the authors' experience and provides a thorough review of the literature addressing the management of the failing systemic right ventricle as well as the tricuspid valve regurgitation with congenitally corrected transposition. This includes different surgical options, the authors' preferred management algorithm, and the late outcome.

ObjectiveThe harvest of some microvascular free flaps for head and neck reconstruction entails tedious and time‐consuming dissection of multiple perforating vessels and/or muscular attachments. The objective of this study is to investigate the use of ultrasonic shears as a means to decrease operative time and increase surgical efficiency in the harvest of microvascular free flaps.Study DesignProspective cohort study.SettingTertiary referral center.Subjects and MethodsA prospective study of all people undergoing fibula (FFF) or anterolateral thigh (ALT) free flap reconstruction of head and neck defects was conducted from October 1, 2005, through December 30, 2009.ResultsThere were 69 FFF and 39 ALT free flaps performed by a single surgeon during the study period. Ultrasonic shears were used in 53 (76.8%) FFF and 26 (80.6%) ALT free flaps, whereas traditional dissection techniques were used in 16 (23.2%) FFF and 13 (19.4%) ALT free flaps. The use of ultrasonic shears significantly decreased the harvest time of FFF and ALT free flaps an average of 14.5 and 16.3 minutes, respectively. The average cost savings associated with the use of ultrasonic shears was $492 for FFF and $543 for ALT free flaps compared to traditional dissections techniques. Similar rates of complications were observed when ultrasonic shears were used compared to traditional techniques.ConclusionsThe use of ultrasonic shears in the harvest of microvascular free flaps decreases operative time, leading to significantly decreased costs without an increased risk of complications compared to traditional dissection techniques.

Abstract The study goal was to characterize older chronic lymphocytic leukemia (CLL) patients and to evaluate outcomes in those patients who initiated infused therapy. Patients 66 years of age and older in the Surveillance, Epidemiology, and End Results (SEER) program with a CLL diagnosis were matched to their Medicare Part A and Part B claims for long-term follow-up. Treatment patterns, survival after initiation of infused therapy, and both hematologic and hospitalization outcomes were assessed. There were 6433 CLL patients identified, and 2040 received infused therapy. Treated patients were categorized as receiving rituximab monotherapy (16%), rituximab plus chemotherapy (14%), and chemotherapy alone (70%) based on the initial 60 days after infusion. Rituximab plus chemotherapy compared with chemotherapy alone was associated with a 25% lower risk of overall mortality (95% confidence interval, 9%-38%). Restricting to patients age 70 years and older did not change the risk reduction for rituximab plus chemotherapy. Hematologic interventions were more common with rituximab plus chemotherapy compared with chemotherapy alone, but there was no difference in all-cause hospitalizations. These analyses, based on observational data, suggest that the benefits of initial therapy with rituximab in a heterogeneous group of older CLL patients are comparable with those demonstrated in younger patients.

All patients undergoing bowel resection experience postoperative ileus, a transient cessation of bowel motility that prevents effective transit of intestinal contents or tolerance of oral intake, to varying degrees. An anesthesiologist plays a critical role, not only in the initiation of surgical anesthesia, but also with the selection and transition to effective postoperative analgesia regimens. Attempts to reduce the duration of postoperative ileus have prompted the study of various preoperative, perioperative, and postoperative regimens to facilitate gastrointestinal recovery. These include modifiable variables such as epidural anesthesia and analgesia, opioid-sparing anesthesia and analgesia, fluid restriction, colloid versus crystalloid combinations, prokinetic drugs, and use of the new peripherally acting mu-opioid receptor (PAM-OR) antagonists. Review and appropriate adaptation of these multiple modifiable interventions by anesthesiologists and their surgical colleagues will facilitate implementation of a best-practice management routine for bowel resection procedures that will benefit the patient and the healthcare system.

Purpose Cumulative sensory neurotoxicity (sNT) is the dose-limiting toxicity of oxaliplatin, which commonly leads to early discontinuation of oxaliplatin-based therapy in the palliative and adjuvant settings. In a nonrandomized, retrospective study, intravenous (IV) calcium/magnesium (Ca/Mg) was associated with reduced oxaliplatin-induced sNT. Methods Patients with colon cancer undergoing adjuvant therapy with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) were randomly assigned to Ca/Mg (1g calcium gluconate plus 1g magnesium sulfate pre- and post-oxaliplatin) or placebo, in a double-blinded manner. The primary end point was the percentage of patients with grade 2 or greater sNT at any time during or after oxaliplatin-based therapy by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version 3) criteria. An oxaliplatin-specific sNT scale and patient questionnaires were also used to assess sNT. After 104 of 300 planned patients were enrolled, the study was closed. This was due to preliminary reports from another trial that suggested that Ca/Mg decreased treatment efficacy; these data were subsequently found to be incorrect. Results Overall, 102 patients were available for analysis. Ca/Mg decreased the incidence of chronic, cumulative, grade 2 or greater sNT, as measured by NCI CTCAE (P = .038) and also by the oxaliplatin-specific sNT scale (P = .018). In addition, acute muscle spasms associated with oxaliplatin were significantly reduced (P = .01) No effect on acute, cold-induced sNT was found. No substantial differences in adverse effects were noted between Ca/Mg and placebo. Conclusion Despite early termination and decreased statistical power, this study supports IV Ca/Mg as an effective neuroprotectant against oxaliplatin-induced cumulative sNT in adjuvant colon cancer.

PurposeLenalidomide is an oral immunomodulatory drug with multiple effects on the immune system and tumor cell microenvironment leading to inhibition of malignant cell growth. Based on encouraging reports of lenalidomide in relapsed and refractory chronic lymphocytic leukemia (CLL), we investigated the first-line use of single-agent lenalidomide in CLL.Patients and MethodsUsing a starting dose of lenalidomide 10 mg/d for 21 days of a 28-day cycle and weekly 5-mg dose escalations to a target of 25 mg, we encountered severe toxicities (tumor lysis, fatal sepsis) in the first two patients enrolled. The study was halted and the protocol amended to a more conservative regimen: starting dose of lenalidomide 2.5 mg with monthly escalations to a target dose of 10 mg, and extended tumor lysis prophylaxis and monitoring. Gene expression profiles from patient samples before and after 7 days of lenalidomide were performed.ResultsTwenty-five patients were enrolled on the amended protocol. No further tumor lysis events were reported. Tumor flare was common (88%) but mild. Grade 3 to 4 neutropenia occurred in 72% of patients, with only five episodes of febrile neutropenia. The overall response rate was 56% (no complete responses). Although rapid peripheral lymphocyte reductions were observed, rebound lymphocytoses during the week off-therapy were common. Lenalidomide-induced molecular changes enriched for cytoskeletal and immune-related genes were identified.ConclusionLenalidomide is clinically active as first-line CLL therapy and is well-tolerated if a conservative approach with slow dose escalation is used. A lenalidomide-induced molecular signature provides insights into its immunomodulatory mechanisms of action in CLL.