Cell adhesion molecules have been implicated as key organizers of synaptic structures, but there is still a need to determine how these molecules facilitate neurotransmitter receptor recruitment to ...developing synapses. Here, we identify erythrocyte protein band 4.1-like 3 (protein 4.1B) as an intracellular effector molecule of Synaptic Cell Adhesion Molecule 1 (SynCAM1) that is sufficient to recruit NMDA-type receptors (NMDARs) to SynCAM1 adhesion sites in COS7 cells. Protein 4.1B in conjunction with SynCAM1 also increased the frequency of NMDAR-mediated mEPSCs and area of presynaptic contact in an HEK293 cell/ neuron co-culture assay. Studies in cultured hippocampal neurons reveal that manipulation of protein 4.1B expression levels specifically affects NMDAR-mediated activity and localization. Finally, further experimentation in COS7 cells show that SynCAM1 may also interact with protein 4.1N to specifically effect AMPA type receptor (AMPAR) recruitment. Thus, SynCAM1 may recruit both AMPARs and NMDARs by independent mechanisms during synapse formation.
Six Holstein cows were used in a complete block design to examine effects of period of lactation and somatotropin (bST) administration on concentrations of insulin, insulin-like growth factors ...(IGF-I, IGF-II), IGF-binding protein 2 (IGFBP-2). During late lactation, the dry period and the subsequent early lactation, cows received injections of NaHCO3 buffer for 5 d and bST for 7 d. Cows were in positive energy and protein balances during late lactation and the dry period and in slight negative balances during early lactation. Basal insulin concentrations were highest in late lactation (170 pmol/L), whereas bST concentrations were higher in early lactation (0.6 microgram/L). Insulin was increased by BST in the dry period (255 pmol/L) and late lactation (149 pmol/L) but not in early lactation (14 pmol/L), probably because of greater availability of glucose during positive nutrient balance. Basal IGF-I was lowest in early lactation (63.6 MA) but was increased by bST during all periods. The IGF-I response to bST administration was lower during early lactation (74.1 microgram/L) compared with late lactation (123.6 microgram/L) arid dry period (146.0 microgram/L). The IGF-I concentrations were not affected by period of lactation of bST administration but IGF-II tended to be higher during bST administration when cows were dry. Concentration of IGFBP-2 was higher during early lactation when cows were in negative nutrient balance (479.5 microgram/L) than during the dry period (289.2 microgram/L) arid was decreased with bST. These data support a role of insulin and IGF in regulation of milk production. Availability of nutrients may be involved in regulating these hormones, particularly during bST treatment
The present study evaluated the outcome of salvage treatment for women with local or local-regional recurrence after initial breast conservation treatment with radiation for mammographically detected ...ductal carcinoma
in situ (DCIS; intraductal carcinoma) of the breast. The study cohort consisted of 90 women with local only first failure (
n
=
85) or local-regional only first failure (
n
=
5). The histology at the time of recurrence was invasive carcinoma for 53 patients (59%), non-invasive carcinoma for 34 patients (38%), angiosarcoma for one patient (1%), and unknown for two patients (2%). The median follow-up after salvage treatment was 5.5 years (mean
=
5.8 years; range
=
0.2–14.2 years). The 10-year rates of overall survival, cause-specific survival, and freedom from distant metastases after salvage treatment were 83%, 95%, and 91%, respectively. Adverse prognostic factors for the development of subsequent distant metastases after salvage treatment were invasive histology of the local recurrence and pathologically positive axillary lymph nodes. These results demonstrate that local and local-regional recurrences can be salvaged with high rates of survival and freedom from distant metastases. Close follow-up after initial breast conservation treatment with radiation is warranted for the early detection of potentially salvageable local and local-regional recurrences.
Whole-breast irradiation after breast-conserving surgery for patients with early-stage breast cancer decreases ipsilateral breast-tumour recurrence (IBTR), yielding comparable results to mastectomy. ...It is unknown whether accelerated partial breast irradiation (APBI) to only the tumour-bearing quadrant, which shortens treatment duration, is equally effective. In our trial, we investigated whether APBI provides equivalent local tumour control after lumpectomy compared with whole-breast irradiation.
We did this randomised, phase 3, equivalence trial (NSABP B-39/RTOG 0413) in 154 clinical centres in the USA, Canada, Ireland, and Israel. Adult women (>18 years) with early-stage (0, I, or II; no evidence of distant metastases, but up to three axillary nodes could be positive) breast cancer (tumour size ≤3 cm; including all histologies and multifocal breast cancers), who had had lumpectomy with negative (ie, no detectable cancer cells) surgical margins, were randomly assigned (1:1) using a biased-coin-based minimisation algorithm to receive either whole-breast irradiation (whole-breast irradiation group) or APBI (APBI group). Whole-breast irradiation was delivered in 25 daily fractions of 50 Gy over 5 weeks, with or without a supplemental boost to the tumour bed, and APBI was delivered as 34 Gy of brachytherapy or 38·5 Gy of external bream radiation therapy in 10 fractions, over 5 treatment days within an 8-day period. Randomisation was stratified by disease stage, menopausal status, hormone-receptor status, and intention to receive chemotherapy. Patients, investigators, and statisticians could not be masked to treatment allocation. The primary outcome of invasive and non-invasive IBTR as a first recurrence was analysed in the intention-to-treat population, excluding those patients who were lost to follow-up, with an equivalency test on the basis of a 50% margin increase in the hazard ratio (90% CI for the observed HR between 0·667 and 1·5 for equivalence) and a Cox proportional hazard model. Survival was assessed by intention to treat, and sensitivity analyses were done in the per-protocol population. This trial is registered with ClinicalTrials.gov, NCT00103181.
Between March 21, 2005, and April 16, 2013, 4216 women were enrolled. 2109 were assigned to the whole-breast irradiation group and 2107 were assigned to the APBI group. 70 patients from the whole-breast irradiation group and 14 from the APBI group withdrew consent or were lost to follow-up at this stage, so 2039 and 2093 patients respectively were available for survival analysis. Further, three and four patients respectively were lost to clinical follow-up (ie, survival status was assessed by phone but no physical examination was done), leaving 2036 patients in the whole-breast irradiation group and 2089 in the APBI group evaluable for the primary outcome. At a median follow-up of 10·2 years (IQR 7·5–11·5), 90 (4%) of 2089 women eligible for the primary outcome in the APBI group and 71 (3%) of 2036 women in the whole-breast irradiation group had an IBTR (HR 1·22, 90% CI 0·94–1·58). The 10-year cumulative incidence of IBTR was 4·6% (95% CI 3·7–5·7) in the APBI group versus 3·9% (3·1–5·0) in the whole-breast irradiation group. 44 (2%) of 2039 patients in the whole-breast irradiation group and 49 (2%) of 2093 patients in the APBI group died from recurring breast cancer. There were no treatment-related deaths. Second cancers and treatment-related toxicities were similar between the two groups. 2020 patients in the whole-breast irradiation group and 2089 in APBI group had available data on adverse events. The highest toxicity grade reported was: grade 1 in 845 (40%), grade 2 in 921 (44%), and grade 3 in 201 (10%) patients in the APBI group, compared with grade 1 in 626 (31%), grade 2 in 1193 (59%), and grade 3 in 143 (7%) in the whole-breast irradiation group.
APBI did not meet the criteria for equivalence to whole-breast irradiation in controlling IBTR for breast-conserving therapy. Our trial had broad eligibility criteria, leading to a large, heterogeneous pool of patients and sufficient power to detect treatment equivalence, but was not designed to test equivalence in patient subgroups or outcomes from different APBI techniques. For patients with early-stage breast cancer, our findings support whole-breast irradiation following lumpectomy; however, with an absolute difference of less than 1% in the 10-year cumulative incidence of IBTR, APBI might be an acceptable alternative for some women.
National Cancer Institute, US Department of Health and Human Services.
The optimal means of combining breast-conserving surgery, radiation therapy, and chemotherapy for the treatment of patients with early-stage, node-positive breast cancer is not known. We reviewed the ...results in 295 patients treated at the Joint Center for Radiation Therapy and affiliated institutions from 1976 to 1985. All patients had positive axillary nodes on dissection, had no gross residual disease in the breast or axilla after surgery, and received breast irradiation (with or without nodal irradiation) and three or more cycles of a cyclophosphamide, methotrexate, and fluorouracil (CMF)-based or doxorubicin-containing regimen. Median follow-up in patients without any failure was 78 months. Breast failure rates were assessed in relation to the sequencing of radiotherapy and chemotherapy. The different sequences were not randomly assigned, and the characteristics of the sequence groups differed. The actuarial 5-year breast failure rate was 4% in 99 patients receiving radiotherapy before chemotherapy; 8% in 54 patients sequentially receiving some chemotherapy, then radiotherapy without concurrent chemotherapy, then further chemotherapy; and 6% in 116 patients receiving concurrent chemotherapy and radiotherapy. However, the failure rate was 41% in 26 patients who received all chemotherapy before radiotherapy. The crude incidences of local failure within 4 years of treatment in these groups were 3%, 2%, 4%, and 15%, respectively (P = .065 for all four groups not being the same). The actuarial 5-year local failure rate was 5% for 252 patients irradiated within 16 weeks after surgery compared with 35% for 34 patients irradiated more than 16 weeks after surgery. The 4-year crude incidences were 4% and 12% for the two groups, respectively (P = .06). These results suggest that delaying the initiation of radiotherapy may result in an increased likelihood of local failure. Formal randomized controlled trials will be needed to confirm these results and to improve the integration of these treatment modalities.
To assess women's preferences regarding the trade-off between the risks and benefits of treatment with radiation therapy (RT) after breast-conserving surgery (BCS) for ductal carcinoma-in-situ ...(DCIS).
Utilities were obtained from 120 patients and 210 nonpatients for eight relevant health states using standard gambles.
Differences in utilities obtained from patient and nonpatient participants between health states were relatively similar. Reduction in the likelihood of local recurrence associated with RT did not result in higher utilities. Utilities for noninvasive recurrence were only lower after initial treatment with RT. Patient and nonpatient participants had the lowest utilities for invasive local recurrence, regardless of initial treatment or manner of salvage therapy. When comparing patient and nonpatient utilities directly, patients had higher utility for being without recurrence after initial RT and lower utility for invasive recurrence salvaged by mastectomy after initial BCS alone. None of the clinical or sociodemographic factors examined explained more than 5% of the variability in the patients' or nonpatients' utilities or their differences.
The principal benefit associated with adding RT to BCS for DCIS seems to be its ability to reduce invasive recurrences.
Objectives: To assess the serum and lower respiratory tract tobramycin concentrations (CT) produced by a single dose of tobramycin for inhalation delivered by a nebulizer and a compressor in patients ...with cystic fibrosis (CF) 6 months to 6 years of age. Study design: We performed a dose escalation study of serum CT measured before and 0.5, 1, 2, and 4 hours after a single dose of inhaled tobramycin, either 180 mg (10 patients) or 300 mg (19 patients). In a separate group of 12 patients, epithelial lining fluid (ELF) CT was measured by bronchoalveolar lavage 30 to 45 minutes after a 300-mg dose. Results: A 180-mg dose of inhaled tobramycin produced a mean peak serum CT of 0.5 μg/mL (SD 0.4; range, <0.2 to 1.4 μg/mL). A 300-mg dose produced a mean peak serum CT of 0.6 μg/mL (SD 0.5; range, <0.2 to 1.2 μg/mL). These peak values are well below the accepted maximum trough concentration with parenteral dosing (2 μg/mL). The target ELF CT was 20 μg/mL, 10-fold greater than the minimal inhibitory concentration for most Pseudomonas aeruginosa isolates from very young patients with CF (2 μg/mL). Mean ELF CT was 90 μg/mL (SD 54; range, 16 to 204 μg/mL) and exceeded the target concentration in 11 patients. Conclusion: In patients with CF ages 6 months to 6 years, a single 300-mg dose of inhaled tobramycin appears to produce safe peak serum concentrations and drug concentrations in the bactericidal range in the lower respiratory tract. (J Pediatr 2001;139:572-7)
To systematically evaluate four different techniques of radiation therapy (RT) used to treat non–small-cell lung cancer and to determine their efficacy in meeting multiple normal-tissue constraints ...while maximizing tumor coverage and achieving dose escalation.
Treatment planning was performed for 18 patients with Stage I to IIIB inoperable non–small-cell lung cancer using four different RT techniques to treat the primary lung tumor ± the hilar/mediastinal lymph nodes: (
1) Intensity-modulated radiation therapy (IMRT), (
2) Optimized three-dimensional conformal RT (3D-CRT) using multiple beam angles, (
3) Limited 3D-CRT using only 2 to 3 beams, and (
4) Traditional RT using elective nodal irradiation (ENI) to treat the mediastinum. All patients underwent virtual simulation, including a CT scan and
18fluorodeoxyglucose positron emission tomography scan, fused to the CT to create a composite tumor volume. For IMRT and 3D-CRT, the target included the primary tumor and regional nodes either ≥1.0 cm in short-axis dimension on CT or with increased uptake on PET. For ENI, the target included the primary tumor plus the ipsilateral hilum and mediastinum from the inferior head of the clavicle to at least 5.0 cm below the carina. The goal was to deliver 70 Gy to ≥99% of the planning target volume (PTV) in 35 daily fractions (46 Gy to electively treated mediastinum) while meeting multiple normal-tissue dose constraints. Heterogeneity correction was applied to all dose calculations (maximum allowable heterogeneity within PTV 30%). Pulmonary and esophageal constraints were as follows: lung
V
20 ≤25%, mean lung dose ≤15 Gy, esophagus
V
50 ≤25%, mean esophageal dose ≤25 Gy. At the completion of all planning, the four techniques were contrasted for their ability to achieve the set dose constraints and deliver tumoricidal RT doses.
Requiring a minimum dose of 70 Gy within the PTV, we found that IMRT was associated with a greater degree of heterogeneity within the target and, correspondingly, higher mean doses and tumor control probabilities (TCPs), 7%–8% greater than 3D-CRT and 14%–16% greater than ENI. Comparing the treatment techniques in this manner, we found only minor differences between 3D-CRT and IMRT, but clearly greater risks of pulmonary and esophageal toxicity with ENI. The mean lung
V
20 was 36% with ENI vs. 23%–25% with the three other techniques, whereas the average mean lung dose was approximately 21.5 Gy (ENI) vs. 15.5 Gy (others). Similarly, the mean esophagus
V
50 was doubled with ENI, to 34% rather than 15%–18%. To account for differences in heterogeneity, we also compared the techniques giving each plan a tumor control probability equivalent to that of the optimized 3D-CRT plan delivering 70 Gy. Using this method, IMRT and 3D-CRT offered similar results in node-negative cases (mean lung and esophageal normal-tissue complication probability NTCP of approximately 10% and 2%–7%, respectively), but ENI was distinctly worse (mean NTCPs of 29% and 20%). In node-positive cases, however, IMRT reduced the lung
V
20 and mean dose by approximately 15% and lung NTCP by 30%, compared to 3D-CRT. Compared to ENI, the reductions were 50% and >100%. Again, for node-positive cases, especially where the gross tumor volume was close to the esophagus, IMRT reduced the mean esophagus
V
50 by 40% (vs. 3D-CRT) to 145% (vs. ENI). The esophageal NTCP was at least doubled converting from IMRT to 3D-CRT and tripled converting from IMRT to ENI. Finally, the total number of fractions for each plan was increased or decreased until all outlined normal-tissue constraints were reached/satisfied. While meeting all constraints, IMRT or 3D-CRT increased the deliverable dose in node-negative patients by >200% over ENI. In node-positive patients, IMRT increased the deliverable dose 25%–30% over 3D-CRT and 130%–140% over ENI. The use of 3D-CRT without IMRT increased the deliverable RT dose >80% over ENI. Using a limited number of 3D-CRT beams decreased the lung
V
20, mean dose, and NTCP in node-positive patients.
The use of 3D-CRT, particularly with only 3 to 4 beam angles, has the ability to reduce normal-tissue toxicity, but has limited potential for dose escalation beyond the current standard in node-positive patients. IMRT is of limited additional value (compared to 3D-CRT) in node-negative cases, but is beneficial in node-positive cases and in cases with target volumes close to the esophagus. When meeting all normal-tissue constraints in node-positive patients, IMRT can deliver RT doses 25%–30% greater than 3D-CRT and 130%–140% greater than ENI. Whereas the possibility of dose escalation is severely limited with ENI, the potential for pulmonary and esophageal toxicity is clearly increased.
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