Tumor-specific efficacy of transforming growth factor-beta RI inhibition in Eker rats.

PURPOSE: Transforming growth factor beta (TGF-beta), which generally stimulates the growth of mesenchymally derived cells but inhibits the growth of epithelial cells, has been proposed as a possible target for cancer therapy. However, concerns have been raised that whereas inhibition of TGF-beta signaling could be efficacious for lesions in which TGF-beta promotes tumor development and/or progression, systemic pharmacologic blockade of this signaling pathway could also promote the growth of epithelial lesions. EXPERIMENTAL DESIGN: We examined the effect of a TGF-beta inhibitor on mesenchymal (leiomyoma) and epithelial (renal cell carcinoma) tumors in Eker rats, which are genetically predisposed to develop these tumors with a high frequency. RESULTS: Blockade of TGF-beta signaling with the ALK5/type I TGF-beta R kinase inhibitor, SB-525334, was efficacious for uterine leiomyoma; significantly decreasing tumor incidence and multiplicity, and reducing the size of these mesenchymal tumors. However, SB-525334 was also mitogenic and antiapoptotic for epithelial cells in the kidney and exacerbated the growth of epithelial lesions present in the kidneys of these animals. CONCLUSION: Although pharmacologic inhibition of TGF-beta signaling with SB-525334 may be efficacious for mesenchymal tumors, inhibition of this signaling pathway seems to promote the development of epithelial tumors.     

Impact of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial on Clinical Management of the Axilla in Older Breast Cancer Patients: A SEER-Medicare Analysis

Background

American College of Surgeons Oncology Group (ACOSOG) Z0011 demonstrated that eligible breast cancer patients with positive sentinel lymph nodes (SLN) could be spared an axillary lymph node dissection (ALND) without sacrificing survival or local control. Although heralded as a “practice-changing trial,” some argue that the stringent inclusion criteria limit the trial’s clinical significance. The objective was to assess the potential impact of ACOSOG Z0011 on axillary surgical management of Medicare patients and examine current practice patterns.

Methods

Medicare beneficiaries aged ≥66 years with nonmetastatic invasive breast cancer diagnosed from 2001 to 2007 were identified from the Surveillance, Epidemiology and End Results-Medicare database (n = 59,431). Eligibility for ACOSOG Z0011 was determined: SLN mapping, tumor <5 cm, no neoadjuvant treatment, breast conservation; number of positive nodes was determined. Actual surgical axillary management for eligible patients was assessed.

Results

Twelve percent (6,942/59,431) underwent SLN mapping and were node positive. Overall, 2,637 patients (4.4 % (2,637/59,431) of the total cohort, but 38 % (2,637/6,942) of patients with SLN mapping and positive nodes) met inclusion criteria for ACOSOG Z0011, had 1 or 2 positive lymph nodes, and could have been spared an ALND. Of these 2,637 patients, 46 % received a completion ALND and 54 % received only SLN biopsy.

Conclusions

Widespread implementation of ACOSOG Z0011 trial results could potentially spare 38 % of older breast cancer patients who undergo SLN mapping with positive lymph nodes an ALND. However, 54 % of these patients are already managed with SLN biopsy alone, lessening the impact of this trial on clinical practice in older breast cancer patients.     

Characterization and Treatment of Local Recurrence Following Breast Conservation for Ductal Carcinoma In Situ

Purpose

The optimal treatment strategy for ductal carcinoma in situ (DCIS) continues to evolve and should consider the consequences of initial treatment on the likelihood, type, and treatment of recurrences.

Methods

We conducted a retrospective cohort study using two data sources of patients who experienced a recurrence (DCIS or invasive cancer) following breast-conserving surgery (BCS) for index DCIS: patients with an index DCIS diagnosed from 1997 to 2008 at the academic institutions of the National Comprehensive Cancer Network (NCCN; N = 88) and patients with an index DCIS diagnosed from 1990 to 2001 at community-based integrated healthcare delivery sites of the Health Maintenance Organization Cancer Research Network (CRN) (N = 182).

Results

Just under half of local recurrences in both cohorts were invasive cancer. While 40 % of patients in both cohorts underwent mastectomy alone at recurrence, treatment of the remaining patients varied. In the earlier CRN cohort, most other patients underwent repeat BCS (39 %) with only 18 % receiving mastectomy with reconstruction, whereas only 16 % had repeat BCS and 44 % had mastectomy with reconstruction in the NCCN cohort. Compared with patients not treated with radiation, those who received radiation for index DCIS were less likely to undergo repeat BCS (NCCN: 6.6 vs. 37 %, p = 0.001; CRN: 20 vs. 48 %, p = 0.0004) and more likely to experience surgical complications after treatment of recurrence (NCCN: 15 vs. 4 %, p = 0.17; CRN: 40 vs. 25 %, p = 0.09).

Conclusion

We found that treatment of recurrences after BCS and subsequent complications may be affected by the use of radiotherapy for the index DCIS. Initial treatment of DCIS may have long-term implications that should be considered.     

Hilar neuropeptide Y interneuron loss in the aged rat hippocampal formation

Neuropeptide Y-immunoreactive (NPY-I) interneurons in the dentate gyrus are vulnerable to various insults, including septohippocampal cholinergic deafferentation. The present study examined whether a loss of NPY-I neurons occurs during aging, when the functional integrity of the septohippocampal pathway is thought to be compromised. Sets of male Long Evans rats (consisting of young and aged rats, with and without spatial learning impairments assessed by the Morris water maze) were examined. Light microscopic analysis revealed that hilar NPY-I neuronal number in matched dorsal sections was significantly decreased in aged compared to young rats. Ultrastructural analysis disclosed that the microenvironment (the types of processes apposed to the plasmalemmal surface) of NPY-I neurons also differed significantly between young and aged rats. In particular, a subgroup of NPY-I neurons, distinguished by a higher percentage of unmyelinated axon coverage of the plasmalemmal surface, was present in young, but not aged, rats. Neither the number nor the microenvironment of NPY-I neurons significantly differed between aged animals that were impaired versus unimpaired in spatial learning performance. To our knowledge these findings represent the first report of an age-associated decline in the number of a specific, neurochemically identified neuronal subpopulation within the hippocampal formation. Additionally, they closely parallel observations in 192 IgG-saporin-lesioned animals, suggesting that a distinct subgroup of NPY-I interneurons is particularly dependent on the viability of septohippocampal cholinergic innervation for its survival. Since neuronal loss was not correlated with performance, this alteration by itself does not appear to be sufficient to produce learning impairment.     

Interference in a homogeneous assay for low-density lipoprotein cholesterol by lipoprotein X.

BACKGROUND: Homogeneous assays for cholesterol in low-density lipoprotein (LDL) are currently in wide use for guideline-based diagnosis and monitoring of dyslipaemic or coronary conditions. In some sera from patients with impaired liver function, we measured implausibly low LDL concentrations using a sugar compound-based assay [LDL-cholesterol (LDL-C), Roche Diagnostics]. We investigated whether an interfering factor, possibly associated with cholestasis, is consistently responsible for this disturbance. METHODS: We compared results of the LDL-C assay in samples with implausible (n=158) and plausible (n=65) LDL concentrations with those of another assay based on two selective detergents (LDLD, Beckman Coulter) and with sequential density ultracentrifugation. We measured total bilirubin, triglycerides, bile acids and lipoprotein X (Lp X) concentrations in samples with the described disturbance and examined the effect of bile salt addition to normal samples. RESULTS: The LDL-C assay was negatively biased compared to the LDLD assay (bias -0.63 mmol/L) and sequential density ultracentrifugation (bias -0.85 mmol/L) in samples with an implausible lipoprotein profile, but showed good method agreement in all other samples. The bile acid concentration did not correlate with the LDL bias, and addition of bile acids showed no interference with the LDL-C assay. The Lp X concentration correlated with the bias between the LDL-C and LDLD assays (R=0.66, p<0.0001); there was no interference with the LDLD assay, even at high Lp X concentrations. CONCLUSIONS: We conclude that the LDL-C assay is subject to interference by Lp X and can provide grossly negatively biased results in cholestatic conditions. In such patients, LDL measurement with an assay based on a different method should be performed.     

The ACGME competencies in the operating room

BACKGROUND: In 1999, the ACGME introduced the 6 competencies that have become the basis for resident education. Since the operating room (OR) has traditionally been the major focus for resident teaching in surgery, we performed an observational study to determine whether it is an appropriate setting for the teaching and/or assessment of the competencies. METHODS: A 3-person team observed 11 operations and recorded all teaching events. Observers then determined whether each event involved the teaching of a competency by faculty or demonstration of a competency by residents. Frequency counts, mean times, and ranges were calculated for each competency taught and demonstrated. RESULTS: The Patient Care competency was both the most commonly taught and demonstrated. Faculty spent an average of 33% of operative time instructing in patient care, and residents demonstrated it 65% of the time. The Interpersonal/Communication Skills (4%) and Practice-Based Learning/Improvement (4%) competencies were also occasionally demonstrated by residents. The remaining competencies were addressed less frequently. CONCLUSIONS: OR teaching was primarily devoted to the Patient Care competency. The OR was also an appropriate setting for evaluating resident performance in this area. New approaches to OR teaching or educational efforts in other settings such as the clinic are necessary for teaching and assessing the remaining competencies.