The value of image-guided intensity-modulated radiotherapy in challenging clinical settings.

OBJECTIVE: To illustrate the wider potential scope of image-guided intensity-modulated radiotherapy (IG-IMRT), outside of the "standard" indications for IMRT. METHODS: Nine challenging clinical cases were selected. All were treated with radical intent, although it was accepted that in several of the cases the probability of cure was low. IMRT alone was not adequate owing to the close proximity of the target to organs at risk, the risk of geographical miss, or the need to tighten planning margins, making image-guided radiotherapy an essential integral part of the treatment. Discrepancies between the initial planning scan and the daily on-treatment megavoltage CT were recorded for each case. The three-dimensional displacement was compared with the margin used to create the planning target volume (PTV). RESULTS: All but one patient achieved local control. Three patients developed metastatic disease but benefited from good local palliation; two have since died. A further patient died of an unrelated condition. Four patients are alive and well. Toxicity was low in all cases. Without daily image guidance, the PTV margin would have been insufficient to ensure complete coverage in 49% of fractions. It was inadequate by >3 mm in 19% of fractions, and by >5 mm in 9%. CONCLUSION: IG-IMRT ensures accurate dose delivery to treat the target and avoid critical structures, acting as daily quality assurance for the delivery of complex IMRT plans. These patients could not have been adequately treated without image guidance. ADVANCES IN KNOWLEDGE: IG-IMRT can offer improved outcomes in less common clinical situations, where conventional techniques would provide suboptimal treatment.

A randomised study evaluating the use of pyridoxine to avoid capecitabine dose modifications.

BACKGROUND: Pyridoxine is frequently used to treat capecitabine-induced hand-foot syndrome (HFS), although the evidence of benefit is lacking. We performed a randomised placebo-controlled trial to determine whether pyridoxine could avoid the need for capecitabine dose modifications and improve outcomes. METHODS: A total of 106 patients planned for palliative single-agent capecitabine (53 in each arm, 65%/35% colorectal/breast cancer) were randomised to receive either concomitant pyridoxine (50 mg po) or matching placebo three times daily. RESULTS: Compared with placebo, pyridoxine use was associated with an increased rate of avoiding capecitabine dose modifications (37% vs 23%, relative risk 0.59, 95% CI 0.29, 1.20, P=0.15) and fewer grade 3/4 HFS-related adverse events (9% vs 17%, odds ratio 0.51, 95% CI 0.15-1.6, P=0.26). Use of pyridoxine did not improve response rate or progression-free survival. CONCLUSION: Pyridoxine may reduce the need for capecitabine dose modifications and the incidence of severe HFS, but does not impact on antitumour effect.

The Cambridge Breast Intensity-modulated Radiotherapy Trial: patient- and treatment-related factors that influence late toxicity.

AIMS: The effect of patient- and treatment-related factors in the development of late normal tissue toxicity after radiotherapy is not yet fully established. The aim of this study was to elucidate the relative importance of such factors in the development of late toxicity after breast-conserving surgery and adjuvant breast radiotherapy. MATERIALS AND METHODS: Patient- and treatment-related factors were analysed in 1014 patients who had received adjuvant radiotherapy to the breast in the Cambridge Breast Intensity-modulated Radiotherapy (IMRT) Trial. Late toxicity data were collected using photographic and clinical assessments and patient-reported questionnaires at 2 years after radiotherapy. RESULTS: On multivariate analysis, a larger breast volume was statistically significantly associated with the development of breast shrinkage assessed by serial photographs (odds ratio per litre increase in breast volume = 1.98, 95% confidence interval 1.41, 2.78; P < 0.0005), telangiectasia (odds ratio = 3.94, 95% confidence interval 2.49, 6.24; P < 0.0005), breast oedema (odds ratio = 3.65, 95% confidence interval 2.54, 5.24; P < 0.0005) and pigmentation (odds ratio = 1.75, 95% confidence interval 1.21, 2.51; P = 0.003). Current smokers had an increased risk of developing pigmentation (odds ratio = 2.09, 95% confidence interval 1.23, 3.54; P = 0.006). Patients with a moderate or poor post-surgical cosmesis had a greatly increased risk of moderate or poor overall cosmesis (odds ratio = 38.19; 95% confidence interval 21.9, 66.7; P < 0.0005). Postoperative infection requiring antibiotics was associated with increased risk of telangiectasia (odds ratio = 3.39, 95% confidence interval 1.94, 5.91; P < 0.0005) and breast oversensitivity (odds ratio = 1.78, 95% confidence interval 1.27, 2.49; P = 0.001). CONCLUSIONS: In this study, the greatest risk factors for the development of late toxicity 2 years after breast-conserving surgery and adjuvant radiotherapy were larger breast volume, baseline pre-radiotherapy surgical cosmesis, postoperative infection and possibly smoking. These factors seem to be more important than relatively small differences in dose inhomogeneity and the addition of boost radiotherapy at 2 years after the completion of radiotherapy. The modification of potentially preventable risk factors, such as postoperative infection and smoking, may limit the development of late toxicity after breast radiotherapy.

Selective internal radiation therapy with 90Y-SIR-Spheres microspheres for non-resectable colorectal metastases in the liver.

Almost half the patients with colorectal cancer will develop liver metastasis at some stage during their disease. Potentially curative surgical resection is possible in some of these patients. In those patients unsuitable for surgery, treatment with systemic chemotherapy and external radiation therapy is relatively ineffective. Many studies have described the successful use of selective internal radiation therapy (SIRT) with 90Y-SIR-Spheres microspheres in patients with inoperable liver metastasis. The authors report on a patient who has been in complete remission for 1 year after treatment with SIRT.

Titanium clip placement to allow accurate tumour bed localisation following breast conserving surgery: audit on behalf of the IMPORT Trial Management Group.

INTRODUCTION: Accurate tumour bed (TB) localisation is a key requirement for the UK IMPORT (Intensity Modulated Partial Organ Radiotherapy) trial. We audited the value of titanium clips for TB localisation following breast conserving surgery (BCS) in breast radiotherapy (RT) planning. PATIENTS AND METHODS: At surgery, paired clips were positioned around the TB as follows: 1. Medial, lateral, superior and inferior: half-way between skin and fascia; 2. Posterior: at the pectoral fascia; 3. Anterior: close to the suture line. Thirty consecutive patients with clips inserted were audited at the time of RT planning. Audit standards were set as follows: (i) 5/6 pairs of clips identified on RT planning computed tomography (CT) scan - 100%; (ii) possible clip migration: <10%; (iii) TB localisation improved with clips: >50%. Inter- and intra-observer variability in clinician outlining of the TB was studied in a subset of 12 randomly selected patients to see if this impacted on positioning of radiotherapy field borders. RESULTS: Five or six pairs of clips were identified in all 30 cases. The TB could be successfully identified using CT seroma alone in only 8/30 (27%) patients. Clips were essential for the TB localisation of the other 22/30 (73%) patients. There was no evidence of clip migration. TB localisation led to modified RT field borders in 18/30 (60%) patients. Five of these patients had highly visible seromas, so the addition of clips modified field borders in 13/30 (43%) patients. Both inter- and intra-observer variability was reasonable and did not impact on positioning of radiotherapy field borders. CONCLUSION: Titanium clips provide an accurate and reliable method of TB localisation following BCS. We anticipate that the audit results will lead to clips being adopted as best practice by the Association of Breast Surgeons (ABS) at BASO (British Association of Surgical Oncology).

Anti-perforin antibody treatment ameliorates experimental crescentic glomerulonephritis in WKY rats.

The depletion of CD8+ cells has been shown to prevent the initiation and progression of antiglomerular basement membrane (GBM) crescentic glomerulonephritis (GN) in Wistar-Kyoto (WKY) rats. In this study, we asked whether CD8+ cells produce their effects by perforin/granzyme-mediated or by Fas ligand (FasL)-mediated pathways. The glomerular mRNA expression of perforin and granzyme B corresponded with the number of CD8+ cells, whereas that of granzyme A, Fas, and FasL did not. The enhanced mRNA level of perforin and granzyme B was not evident in CD8+-depleted rats. The number of apoptotic cells in the glomeruli was significantly increased at day 3. Perforin mRNA was found in cells infiltrating the glomerulus by in situ hybridization and by using dual-staining immunohistochemistry perforin protein was found in glomerular CD8+ cells. We found that perforin was readily visualized at the inner surface of the glomerular capillaries by immunoelectron microscopy. Based on these results, we treated animals with a perforin antibody in vivo and found that it significantly reduced the amount of proteinuria, frequency of crescentic glomeruli, and the number of glomerular monocytes and macrophages, although the number of glomerular CD8+ cells was not changed. Our results suggest that CD8+ cells play a role in glomerular injury as effector cells in part through a perforin/granzyme-mediated pathway in the anti-GBM WKY rat model of crescentic GN.

Effects of grazing residues or feeding corn from a corn rootworm-protected hybrid (MON 863) compared with reference hybrids on animal performance and carcass characteristics.

One grazing and two feeding experiments were conducted to compare the feeding value of corn residue or corn grain from a genetically enhanced corn hybrid (corn rootworm-protected; event MON 863) with nontransgenic, commercially available, reference hybrids. In Exp. 1, two 13.7-ha fields, containing corn residues from either a genetically enhanced corn root-worm-protected hybrid (MON 863), or a near-isogenic, nontransgenic control hybrid (CON) were divided into four equal-sized paddocks. Sixty-four steer calves (262 +/- 15 kg) were stratified by BW and assigned randomly to paddock to achieve a stocking rate of 0.43 ha/steer for 60 d, with eight steers per paddock and 32 steers per hybrid. A protein supplement was fed at 0.45 kg/steer daily (DM basis) to ensure protein intake did not limit performance. Steer ADG did not differ (P = 0.30) between steers grazing the MON 863 (0.39 kg/d) and CON (0.34 kg/d) corn residues for 60 d. The four treatments for the feeding experiments (Exp. 2 and 3) included two separate reference hybrids, the near-isogenic control hybrid (CON), and the genetically enhanced hybrid (MON 863) resulting in two preplanned comparisons of CON vs. MON 863, and MON 863 vs. the average of the reference hybrids (REF). In Exp. 2, 200 crossbred yearling steers (365 +/- 19 kg) were fed in 20 pens, with five pens per corn hybrid. In Exp. 3, 196 crossbred yearling steers (457 +/- 33 kg) were fed in 28 pens, with seven pens per corn hybrid. In Exp. 2, DMI and G:F did not differ (P > 0.10) between MON 863 and CON; however, steers fed MON 863 had a greater (P = 0.04) ADG than steers fed CON. Gain efficiency was greater (P = 0.05) for MON 863 cattle than for REF cattle in Exp. 2, but other performance measurements (DMI and ADG) did not differ (P > 0.10) between MON 863 and REF. No differences (P > 0.10) were observed for performance (DMI, ADG, and G:F) between MON 863 and CON or MON 863 and REF in Exp. 3. In terms of carcass characteristics, no differences (P > 0.10) were observed between MON 863 and CON, as well as MON 863 and REF, for marbling score, LM area, or 12th rib fat thickness in both Exp. 2 and 3. Overall, performance was not negatively affected in the corn residue grazing or feedlot experiments, suggesting the corn rootworm-protected hybrid (event MON 863) is similar to conventional, nontransgenic corn grain and residues when utilized by beef cattle.

Reduction of radiotherapy-induced late complications in early breast cancer: the role of intensity-modulated radiation therapy and partial breast irradiation. Part II--Radiotherapy strategies to reduce radiation-induced late effects.

Radiotherapy after conservation surgery has been proven to decrease local relapse and death from breast cancer, and is now firmly established in the management of early breast carcinoma. Currently, the challenge is to optimise the therapeutic ratio by minimising treatment-related morbidity, while maintaining or improving local control and survival. The second part of this review examines the role of two approaches: intensity-modulated radiation therapy (IMRT) and partial breast irradiation, as means of improving the therapeutic ratio. Discussion of IMRT includes both inverse- and forward-planned methods: the breast usually requires minimal modulation to improve dose homogeneity, and therefore lends itself to simpler forward-planned IMRT techniques; whereas inverse-planned IMRT may be useful in selected cases. There are many dosimetry studies reporting the superiority of IMRT over conventional breast radiotherapy, but there is still a paucity of clinical data regarding patient benefit from these techniques. A critical literature review of clinical partial breast radiotherapy studies focuses on the influence of irradiated breast volume, dose and fractionation, and patient selection on normal tissue side-effects and local control. Clinical reports of partial breast irradiation show several encouraging, but some concerning results about local recurrence rates. Therefore, mature results from randomised trials comparing partial breast irradiation with whole-breast radiotherapy are required. Accurate localisation of the tumour bed and application of appropriate clinical target volumes and planning target volumes are discussed in detail, as these concepts are fundamental for partial breast irradiation.

Reduction of radiotherapy-induced late complications in early breast cancer: the role of intensity-modulated radiation therapy and partial breast irradiation. Part I--normal tissue complications.

Radiotherapy after conservation surgery has been proven to decrease local relapse and death from breast cancer, and is now firmly established in the management of early breast carcinoma. Currently, the challenge is to minimise the morbidity caused by this treatment without losing its efficacy. This review will be divided into two parts, with Part I focusing on the radiation factors contributing to late normal tissue complications after radiotherapy for early breast cancer. Three major normal tissue side-effects will be discussed: cosmetic outcome, cardiac complications and pulmonary side-effects.

Effect of organic matter addition to the pen surface and pen cleaning frequency on nitrogen mass balance in open feedlots.

Three finishing trials were conducted to determine the effects of dietary manipulation and management on N losses from open feedlots. In each experiment, 96 steers were assigned randomly to 12 nutrient balance pens. In Trial 1, calves were fed for 180 d during the winter/spring months; in Trial 2, yearlings were fed for 132 d in the summer. In Trials 1 and 2, N losses from pens were compared directly by adding OM to the pen surface or indirectly by feeding digestible ingredients designed to increase OM excretion. The dietary treatment (BRAN) included 30% corn bran (DM basis) replacing dry-rolled corn. Pens where OM was directly added received sawdust applications (SAWDUST) at a rate to match OM excretion from the BRAN diet. These two treatments were compared with a conventional, 75% dry-rolled corn diet (CON). Because CON and SAWDUST diets were identical, performance for both treatments was similar during Trials 1 and 2. The BRAN diet decreased (P < 0.10) gain efficiency during Trials 1 and 2 by 9.5% relative to CON. Fecal N excretion was greater (P < 0.01) for calves and yearlings when BRAN was fed compared with CON. Adding OM to the pen surface increased (P < 0.01) the amount of N in manure removed from pens and reduced (P < 0.10) N losses in Trial 1. Nitrogen losses were not significantly different among treatments in Trial 2. In Trial 3, calves were fed for 166 d during the winter/spring months. A 2 x 2 factorial design was used to evaluate pen cleaning frequency and diets similar to CON and BRAN. Pens were either cleaned monthly or once at the end of the feeding period. Daily DMI was greater (P = 0.01) and ADG was lower (P < 0.01) when cattle were fed BRAN compared with CON. Responses from all three trials indicate a negative effect of BRAN on gain efficiency. Dietary treatment and cleaning frequency interacted for N balance in the feedlot. Nitrogen losses decreased and manure N increased (P < 0.10) for cattle fed BRAN compared with CON when pens were cleaned monthly. Feeding BRAN did not affect total manure N, but resulted in higher N losses when pens were cleaned only once. For all trials, BRAN increased the amount of N remaining in composted manure. Adding OM to pen surfaces and/or cleaning pens more frequently may decrease N losses from open feedlot pens and from compost, although responses seem influenced by ambient temperature or season.

A novel continuous infusional 5-fluorouracil-based chemotherapy regimen compared with conventional chemotherapy in the neo-adjuvant treatment of early breast cancer: 5 year results of the TOPIC trial.

BACKGROUND: To compare the efficacy of continuous infusional 5-fluorouracil (5-FU)-based chemotherapy against conventional bolus chemotherapy in the preoperative treatment of patients with large operable early breast cancer. PATIENTS AND METHODS: Four hundred and twenty-six women with histologically proven 3 cm invasive early breast cancer were randomised to receive pre-operative infusional 5-FU 200 mg/m(2) by daily 24 h continuous infusion via a Hickman line for 18 weeks with epirubicin 60 mg/m(2) intravenous (i.v.) bolus on day 1 and cisplatin 60 mg/m(2) i.v. bolus on day 1, both repeating 3-weekly (infusional ECisF), or conventional bolus doxorubicin 60 mg/m(2) i.v. on day 1 and cyclophosphamide 600 mg/m(2) i.v. on day 1, both repeating 3-weekly (AC), both schedules for six courses. Patients subsequently had local therapy (surgery or radiotherapy or both) and tamoxifen 20 mg orally daily as appropriate. RESULTS: The 5 year results for AC and infusional ECisF, respectively, were as follows: overall response, 75% and 77%; complete clinical remission, 31% and 34%; pathological complete remission (pathCR), 16% for both; and pathCR with residual ductal carcinoma in situ (DCIS), 25% and 24%. Mastectomy rates were 37% and 34%, respectively. Five-year overall survival was 74% for AC and 82% for infusional ECisF (hazard ratio 0.76, 95% confidence interval 0.51-1.13; P = 0.18). Both treatments were well tolerated. Grade III/IV lethargy, vomiting, alopecia and plantar-palmar erythema were significantly greater for infusional ECisF; grade III/IV leucopenia was significantly greater for AC. CONCLUSIONS: Preoperative continuous infusional 5-FU-based chemotherapy is no more active than conventional AC for early breast cancer; with a median 5 year follow-up, the infusion-based schedule shows a non-significant trend towards improved survival.

A radiotherapy technique to improve dose homogeneity around bone prostheses.

Purpose. Following limb conserving surgery for bone or soft tissue sarcoma, patients may require post-operative radiotherapy to minimise the risk of local recurrence. In such circumstances the metal prosthesis reduces the dose in its shadow by approximately 10% when using opposed fields. We describe a technique to boost the underdosed area to overcome this problem.Patients or subjects. Seven sequential patients presenting between 1995 and 2001 had their treatment individualised because they had metal prosthesis in the treatment volume.Methods. To improve the target dose homogeneity we used a custom-made keyhole cutout to boost the area in the shadow of the prosthesis. The degree of attenuation caused by the metal prosthesis was estimated and a boost dose calculated. Exit thermoluminescent dosimetry (TLD) was used to confirm the estimates made.Results and discussion. Variation between patients was seen, demonstrating the need for exit TLD to individualise the treatment plan. The use of a boost field provides a method to overcome under-dosage in the shadow of a metal prosthesis. It improves dose homogeneity throughout the target volume and ensures adequate dose intensity around the prosthesis, the site most at risk of local recurrence.

Undegradable intake protein supplementation of compensating spring-born steers and summer-born steers during summer grazing.

Three trials were conducted to determine the effects of previous winter gain (Trials 1 and 3) and age of calf (Trials 1 and 2) on response to undegradable intake protein (UIP) supplementation during summer grazing. In Trial 1, 48 spring-born steers (243 kg) were used in a 4 x 2 factorial arrangement. Steers were wintered at four rates of gain: 0.65 (FAST), 0.24 (SLOW), 0.38 (S/F), and 0.38 (F/S) kg/d. The intermediate rates of gain (S/F and F/S) were created by switching steers from slow to fast or fast to slow midway through the wintering period. Following winter treatments, steers were assigned to one of two summer treatments: supplemented (S) or nonsupplemented (NS). In Trial 2, 32 summer-born steers were wintered at an ADG of 0.25 kg/d and allotted to the same summer treatments as Trial 1. The supplement was formulated to supply 200 g/d of UIP. Steers from both trials grazed upland Sandhills range from May to September 1998. In Trial 3, 49 spring-born steers (228 kg) were used in a 2 x 7 factorial arrangement of treatments. Steers were wintered at two rates of gain, 0.71 (FAST) and 0.24 kg/d (SLOW) and then assigned randomly to one of six levels of UIP supplementation or an energy control. Protein supplements were formulated to deliver 75, 112.5, 150, 187.5, 225, or 262.5 g/d of UIP. Sources of UIP for all trials were treated soybean meal and feather meal. In Trial 1, there were no (P > 0.05) winter by summer treatment interactions, and UIP supplementation increased (P = 0.0001) pasture gains over NS steers. In Trial 2, supplementation increased (P = 0.001) pasture ADG of summer-born steers by 0.15 kg/d compared with NS steers. In Trial 3, a winter gain by UIP supplementation interaction was observed (P = 0.09). Gain of FAST steers responded quadratically (P = 0.09) across UIP levels, with the maximum gain occurring at the 150 g/d UIP level. The SLOW steers responded linearly (P = 0.02) to increasing UIP levels; however, the response was negative. Levels of UIP above 150 g/d reduced steers gains; therefore, the data were reanalyzed excluding these levels. These new analyses showed that FAST steers responded linearly (P = 0.08; 0.2 kg/d) to increasing UIP, whereas the SLOW steers had no response to UIP. In Trials 1 and 3, SLOW steers experienced compensatory gain and had higher gains overall. We concluded that previous winter gain affected the response to UIP supplementation with the FAST winter gain group having a greater response.

Relationship between psychological well-being and lung health status in patients with bronchiectasis.

Patients with bronchiectasis often complain of abnormal tiredness, difficulty in concentrating or low spirits. This study was carried out to examine levels of anxiety and depression in bronchiectasis and their relationship with other measures of lung health. One hundred and eleven patients with bronchiectasis determined by high-resolution computed tomography (CT) scan were studied using a range of physiological and psychological outcome measures. Patients completed anxiety and depression, health status (quality of life), fatigue and dypnoea questionnaires. Lung function was measured and exercise capacity was assessed using a shuttle walk test. Anxiety and depression scores formed a continuum. Moderate-severe anxiety was more frequent than equivalent levels of depression (17 vs 9% of patients). Anxiety and depression scores were associated with perceived health status (r=0.33 and 0.55). Neither anxiety nor depression was associated with the extent of bronchiectasis on CT scan. Depression was correlated with breathlessness and exercise performance (r=0.33 and 0.40), but anxiety was not. The correlation between depression and exercise performance was not simply due to the influence of somatic items in the depression questionnaire. We conclude that anxiety and depression are quite common in bronchiectasis in that 34% of patients had elevated scores for anxiety depression or both. The non-somatic components of depression were linked to dyspnoea and exercise performance, but anxiety was only related to perceived health. Therefore, treatment aimed at reducing symptoms and improving exercise capacity will not reduce levels of anxiety which need alternative therapy.

Effect of corn processing on starch digestion and bacterial crude protein flow in finishing cattle.

Six ruminally and duodenally cannulated yearling steers (523 kg) were used in a replicated 3 x 3 Latin square design experiment to study the effects of corn processing on nutrient digestion, bacterial CP production, and ruminal fermentation. Dietary treatments consisted of 90% concentrate diets that were based on dry-rolled (DRC), high-moisture (HMC), or steam-flaked (SFC) corn. Each diet contained 2.0% urea (DM basis) as the sole source of supplemental nitrogen. Each period lasted 17 d, with d 1 through 14 for diet adaptation and d 15 through 17 for fecal, duodenal, and ruminal sampling. Dry matter and OM intakes were similar for DRC and SFC but were approximately 15% higher (P < 0.05) for HMC. True ruminal OM digestibilities were 18 and 10% greater (P < 0.05) for HMC than for DRC or SFC, respectively. Ruminal starch digestibilities were similar between HMC and SFC and were approximately 19% greater (P < 0.05) than DRC. Postruminal OM digestibility was similar among treatments; however, postruminal starch digestibility was 15% greater (P < 0.05) for SFC than for DRC or HMC, which were similar. Total-tract DM and OM digestibilities were similar between HMC and SFC and were 4% greater (P < 0.05) than DRC. Likewise, total-tract starch digestibilities were similar between HMC and SFC and were 3% greater (P < 0.05) than DRC. Bacterial CP flow to the duodenum was 29% greater (P < 0.05) for HMC than for DRC or SFC, which were similar. Bacterial N efficiencies were similar among treatments. Based on bacterial CP flow from the rumen, we estimate that dietary DIP requirements are approximately 12% higher for HMC-based diets than for DRC or SFC-based diets, which were similar.

A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival.

The role of DNA methylation and of the maintenance DNA methyltransferase Dnmt1 in the epigenetic regulation of developmental stage- and cell lineage-specific gene expression in vivo is uncertain. This is addressed here through the generation of mice in which Dnmt1 was inactivated by Cre/loxP-mediated deletion at sequential stages of T cell development. Deletion of Dnmt1 in early double-negative thymocytes led to impaired survival of TCRalphabeta(+) cells and the generation of atypical CD8(+)TCRgammadelta(+) cells. Deletion of Dnmt1 in double-positive thymocytes impaired activation-induced proliferation but differentially enhanced cytokine mRNA expression by naive peripheral T cells. We conclude that Dnmt1 and DNA methylation are required for the proper expression of certain genes that define fate and determine function in T cells.

Early pulmonary infection, inflammation, and clinical outcomes in infants with cystic fibrosis.

A thorough understanding of the early natural history of cystic fibrosis (CF) lung disease is critical for the development of effective interventions in the youngest patients. We assessed the evolution of pulmonary infection, inflammation, and clinical course among 40 infants over a 2-year period through annual bronchoalveolar lavage (BAL) for culture and measurements of pro- and anti-inflammatory cytokines, semiannual infant pulmonary function testing, and quarterly clinical evaluations. Both the prevalence of CF pathogens and their density in BAL fluid increased with age. Infants had neutrophilic lower airway inflammation and elevated IL-8 concentrations independent of whether CF pathogens were recovered. Total leukocyte and neutrophil densities and IL-8 concentrations increased with density of CF pathogens in BAL fluid, whether the isolated organism was P. aeruginosa or another pathogen. IL-10 concentrations were similar in CF subjects and non-CF historical controls. Infants generally had suboptimal growth (low weight and height percentiles) and obstructive lung disease (decreased expiratory flows and air trapping). Subjects from whom CF pathogens were isolated at > 10(5) cfu/mL had the worst air trapping and lowest Brasfield chest X-ray scores. Our findings provide a foundation for future studies of early intervention in CF lung disease, including antimicrobial and anti-inflammatory therapy.

Role of cyclin kinase inhibitor p21 in systemic autoimmunity.

The cyclin kinase inhibitor protein p21 affects multiple processes relevant to the immune system, including cell cycle progression, replicative senescence, hemopoietic stem cell quiescence, and apoptosis. Therefore, malfunction of this protein may be a contributor to the pathogenesis of systemic autoimmunity. Here, we report that mixed background p21-deficient 129/Sv x C57BL/6 mice showed increased in vitro and in vivo T cell cycling and activation, moderate hypergammaglobulinemia and, at low penetrance, anti-chromatin autoantibodies. Homeostatic anti-self MHC/peptide ligand-induced proliferation of p21-deficient T cells was also enhanced. However, lymphoid organ enlargement was very mild, presumably due to increased apoptosis of the rapidly dividing cells. Moreover, the older p21-deficient mice had kidney pathology representing a similar, but slightly more advanced, state than that seen in the control mice. The timing and severity of the above serologic, cellular, and histologic manifestations in p21-deficient mice were unaffected by gender. Thus, p21 deficiency significantly enhances T cell activation and homeostatic proliferation, and can induce mild autoimmune manifestations at a low incidence without gender bias, but does not in itself generate the full spectrum of lupus-like disease.

Complete resolution of metastatic breast cancer by withdrawal of hormone replacement therapy.

We report the case history of a patient with a known history of locally recurrent breast cancer, who developed metastatic disease while taking hormone replacement therapy (HRT). She underwent complete radiographic resolution of disease with no treatment other than cessation of the HRT.