Factors Associated with Late Local Radiation Toxicity after Post-Operative Breast Irradiation.

Purpose: To assess determinants associated with late local radiation toxicity in patients treated for breast cancer. Methods: A systematic review was performed. All studies reporting ≥2 variables associated with late local radiation toxicity after treatment with postoperative whole breast irradiation were included. Cohort studies, randomized controlled trials, and cross-sectional studies were eligible designs. Study characteristics and definitions of determinants and outcome measures were extracted. If possible, the measure of association was extracted. Results: Twenty-one studies were included in this review. Six out of seven studies focused on the association between radiotherapy (boost) dose or irradiated breast volume and late radiation toxicity found significant results. Tumor bed boost was associated with late radiation toxicity, fibrosis, and/or edema in six out of twelve studies. Lower age was associated with late breast toxicity in one study, while in another study, higher age was significantly associated with breast fibrosis. Also, no association between age and late radiation toxicity was found in eight out of twelve studies. Similar inconsistent results were found in the association between late radiation toxicity and other patient-related factors (i.e., breast size, diabetes mellitus) and surgical and systemic treatment-related factors (i.e., complications after surgery, chemotherapy, and time between surgery and radiotherapy). Conclusion: In modern 3D radiotherapy, radiotherapy (boost) dose and volume are-like in 2D radiotherapy-associated with late local radiation toxicity, such as breast fibrosis and edema. Treatment de-escalation, for example, partial breast irradiation in selected patients might be important to decrease late local toxicity without compromising locoregional control and survival.

Patient-reported cosmetic satisfaction and the long-term association with quality of life in irradiated breast cancer patients.

PURPOSE: To evaluate patient-reported cosmetic satisfaction in women treated with radiation therapy for breast cancer and to determine the association between dissatisfaction and quality of life (QoL) and depression. METHODS: Within the prospective UMBRELLA breast cancer cohort, all patients ≥ 1 year after breast conserving treatment or mastectomy with immediate reconstruction were selected. Self-reported cosmetic satisfaction was measured on a 5-point Likert scale. QoL, social functioning, and emotional functioning were measured using EORTC QLQ-C30 and BR23 at 1, 2, and 3 years after inclusion. Mixed model analysis was performed to assess the difference in different domains of QoL between patients with good versus poor self-reported cosmetic satisfaction over time after adjustment for potential confounders. Depression scores were collected by means of the HADS-NL questionnaire. Chi-square test or Fisher's exact test was used to assess the difference in proportions of HADS score ≥ 8, indicating increased depression risk, between satisfied and dissatisfied patients. RESULTS: 808 patients were selected for analysis. Respectively one, two, and three years after surgery, 8% (63/808), 7% (45/626), and 8% (31/409) of patients were dissatisfied with their cosmetic outcome. Poor patient-reported cosmetic satisfaction was independently associated with impaired QoL, body image, and lower emotional and social functioning. Scores ≥ 8 on the HADS depression subscale were significantly more common in dissatisfied patients. CONCLUSIONS: Dissatisfaction with cosmetic outcome was low after breast cancer surgery followed by radiation therapy during 3 years follow-up. Knowing the association between dissatisfaction with cosmetic outcome and QoL and depression could help to improve the preoperative counseling of breast cancer patients.

Delay in weight bearing in surgically treated tibial shaft fractures is associated with impaired healing: a cohort analysis of 166 tibial fractures.

BACKGROUND: The relation between timing of weight bearing after a fracture and the healing outcome is yet to be established, thereby limiting the implementation of a possibly beneficial effect for our patients. The current study was undertaken to determine the effect of timing of weight bearing after a surgically treated tibial shaft fracture. MATERIALS AND METHODS: Surgically treated diaphyseal tibial fractures were retrospectively studied between 2007 and 2015. The timing of initial weight bearing (IWB) was analysed as a predictor for impaired healing in a multivariate regression. RESULTS: Totally, 166 diaphyseal tibial fractures were included, 86 cases with impaired healing and 80 with normal healing. The mean age was 38.7 years (range 16-89). The mean time until IWB was significantly shorter in the normal fracture healing group (2.6 vs 7.4 weeks, p < 0.001). Correlation analysis yielded four possible confounders: infection requiring surgical intervention, fracture type, fasciotomy and open fractures. Logistic regression identified IWB as an independent predictor for impaired healing with an odds ratio of 1.13 per week delay (95% CI 1.03-1.25). CONCLUSIONS: Delay in initial weight bearing is independently associated with impaired fracture healing in surgically treated tibial shaft fractures. Unlike other factors such as fracture type or soft tissue condition, early resumption of weight bearing can be influenced by the treating physician and this factor therefore has a direct clinical relevance. This study indicates that early resumption of weight bearing should be the treatment goal in fracture fixation. LEVEL OF EVIDENCE: 3b.

Hyperbaric oxygen therapy for local late radiation toxicity in breast cancer patients: A systematic review.

PURPOSE: This systematic review aims to provide an overview of the literature on the effect of hyperbaric oxygen therapy (HBOT) on symptoms of local late radiation toxicity (LRT) in patients treated for breast cancer. METHODS: A systematic search was performed in September 2021. All studies with a sample size of ≥10 patients reporting the effect of HBOT for symptoms of LRT after radiotherapy of the breast and/or chest wall were included. The ROBINS-I tool was used for critical appraisal of methodological quality. The toxicity outcomes pain, fibrosis, lymphedema, necrosis/skin problems, arm and shoulder mobility, and breast and arm symptoms were evaluated. RESULTS: Nine studies concerning a total of 1308 patients were included in this review. Except for one study, sample sizes were small. Most studies had inadequate methodology with a substantial risk of bias. Post-HBOT, a significant reduction of pain was observed in 4/5 studies, of fibrosis in 1/2 studies, and of lymphedema of the breast and/or arm in 4/7 studies. Skin problems of the breast were significantly reduced in 1/2 studies, arm- and shoulder mobility significantly improved in 2/2 studies, and breast- and arm symptoms were significantly reduced in one study. CONCLUSION: This systematic review indicates that HBOT might be useful for reducing symptoms of LRT in breast cancer patients, however evidence is limited. A randomized controlled trial in a larger cohort of patients including a combination of patient- and clinician-reported outcome measures would be valuable to assess the effect of HBOT on symptoms of LRT.

Patient-Reported Symptoms of Late Toxicity in Patients With Breast Cancer Treated With Hypofractionated Radiation Therapy and the Association With Quality of Life.

PURPOSE: Our purpose was to assess the prevalence of patient-reported symptoms of local late toxicity in patients with irradiated breast cancer and determine the association between late toxicity and quality of life. METHODS: Within the prospective Utrecht cohort for Multiple BReast cancer intErvention studies and Long-term evaluation cohort, a survey on self-reported late toxicity was sent to all patients with breast cancer with ≥12 months interval since radiation therapy treated with curative intent. Patients were treated with hypofractionated radiation therapy of 40 Gy/15 fractions or 42.5 Gy/16 fractions, with or without a simultaneous integrated boost. Symptoms of late toxicity were evaluated on a 4-point Likert scale. Late toxicity was defined as moderate-severe breast or chest wall pain combined with at least 1 other mild-severe late toxicity symptom, that is, breast or arm/hand lymphedema, firmness of the breast, or impaired arm movement. Physical, role, and social functioning were measured before, during, and after the late toxicity survey using the European Organization for Research and Treatment of Cancer Quality of Life Core questionnaire-C30 and compared with a Dutch normative population. RESULTS: In the study, 1613/2248 patients (72%) were included. Of those, 16% (n = 265) reported late toxicity. The median time interval between radiation therapy and survey was 38 months (interquartile range, 21-55). Moderate/severe firmness of the breast, chest wall pain, and breast pain were reported by, respectively, 18% (n = 295), 14% (n = 225), and 10% (n = 140) of all patients. Physical, role, and social functioning were below the clinical threshold (ie, clinically relevant impairment) in 13% to 52% of patients with late toxicity and 2% to 26% of patients without late toxicity. Patients with late toxicity significantly more often received analgesics, physiotherapy, and lymphedema therapy compared with patients without late toxicity. CONCLUSIONS: This study provided insight into the prevalence of patient-reported late toxicity after hypofractionated radiation therapy and the influence of late toxicity on quality of life after breast cancer. These results may help health care professionals to inform their patients about long-term effects of breast cancer treatment including hypofractionated radiation therapy.

Assessing the effect of hyperbaric oxygen therapy in breast cancer patients with late radiation toxicity (HONEY trial): a trial protocol using a trial within a cohort design.

BACKGROUND: Breast cancer treatment with radiotherapy can induce late radiation toxicity, characterized by pain, fibrosis, edema, impaired arm mobility, and poor cosmetic outcome. Hyperbaric oxygen therapy (HBOT) has been proposed as treatment for late radiation toxicity; however, high-level evidence of effectiveness is lacking. As HBOT is standard treatment and reimbursed by insurers, performing classic randomized controlled trials is difficult. The "Hyperbaric OxygeN therapy on brEast cancer patients with late radiation toxicity" (HONEY) trial aims to evaluate the effectiveness of HBOT on late radiation toxicity in breast cancer patients using the trial within cohorts (TwiCs) design. METHODS: The HONEY trial will be conducted within the Utrecht cohort for Multiple BREast cancer intervention studies and Long-term evaluation (UMBRELLA). Within UMBRELLA, breast cancer patients referred for radiotherapy to the University Medical Centre Utrecht are eligible for inclusion. Patients consent to collection of clinical data and patient-reported outcomes and provide broad consent for randomization into future intervention studies. Patients who meet the HONEY in- and exclusion criteria (participation ≥ 12 months in UMBRELLA, moderate/severe breast or chest wall pain, completed primary breast cancer treatment except hormonal treatment, no prior treatment with HBOT, no contraindications for HBOT, no clinical signs of metastatic or recurrent disease) will be randomized to HBOT or control group on a 2:1 ratio (n = 120). Patients in the control group will not be informed about participation in the trial. Patients in the intervention arm will undergo 30-40 HBOT treatment sessions in a high pressure chamber (2.4 atmospheres absolute) where they inhale 100% oxygen through a mask. Cohort outcome measures (i.e., physical outcomes, quality of life, fatigue, and cosmetic satisfaction) of the HBOT group will be compared to the control group at 3 months follow-up. DISCUSSION: This pragmatic trial within the UMBELLA cohort was designed to evaluate the effectiveness of HBOT on late radiation toxicity in breast cancer patients using the TwiCs design. Use of the TwiCs design is expected to address issues encountered in classic randomized controlled trials, such as contamination (i.e., HBOT in the control group) and disappointment bias, and generate information about acceptability of HBOT. TRIAL REGISTRATION: ClinicalTrials.gov. NCT04193722 . Registered on 10 December 2019.

Higher reconstruction failure and less patient-reported satisfaction after post mastectomy radiotherapy with immediate implant-based breast reconstruction compared to immediate autologous breast reconstruction.

PURPOSE: To improve shared decision making, clinical- and patient-reported outcomes between immediate implant-based and autologous breast reconstruction followed by postmastectomy radiotherapy (PMRT) were compared. METHODS: All women with in situ and/or invasive breast cancer who underwent skin sparing mastectomy with immediate breast reconstruction (IBR) (autologous- or implant based, one- or two staged) followed by PMRT in the Utrecht region between 2012 and 2016 were selected from the Netherlands Cancer Registry, of which 112 (59%) agreed to participate. The primary outcome was reconstruction failure after the start of radiotherapy, and secondary outcomes were patient-reported outcomes measured with BREAST-Q. RESULTS: 109 patients underwent skin-sparing mastectomy, of which 29 (27%) underwent immediate autologous reconstruction and 80 (73%) received immediate implant-based reconstruction. After PMRT, reconstruction failure occurred in 17 patients (21%) with implant-based reconstruction, while no failure was seen in the autologous group (p = 0.04). Mean patient-reported 'Satisfaction with Breasts' (50.9 vs. 63.7, p = 0.001) and 'Sexual Well-being' (46.0 vs. 55.5, p = 0.037) were lower after implant-based reconstruction compared to autologous reconstruction. Thirteen patients with autologous flaps underwent surgical cosmetic corrections compared to ten patients in the implant group (45 vs. 13%, p = 0.001). IBR and PMRT in this study resulted in a high rate of severe capsular contraction in implant-based reconstruction (16.9%) and fibrosis in autologous reconstruction (13.8%). CONCLUSIONS: Patients treated with PMRT and one or two stage immediate implant-based reconstruction were at greater risk of developing reconstruction failure and were less satisfied when compared to one or two stage immediate autologous reconstruction. Since fairly high complication rates in both reconstruction methods after PMRT are observed, it raises the question whether immediate breast reconstruction should be considered at all when PMRT is indicated. Patients considering or potential candidates for IBR should be informed about the consequences of PMRT and especially when opting for autologous reconstruction one should possibly perform reconstruction in a secondary setting.

The Non-Union Scoring System: an interobserver reliability study.

PURPOSE: The Non-Union Scoring System (NUSS) aims to classify non-unions according to their severity and relate them to four treatment categories. The main purpose of this study was to evaluate the reliability of the NUSS. In addition we assessed its clinical validity. METHODS: Forty-four Patients with a tibia non-union between 2005 and 2015 were included in this study. Data from all included patients were scored independently by three observers according to the NUSS criteria. The interobserver agreement was evaluated using the intraclass correlation coefficient (ICC). The interobserver agreement of the Weber-Cech system was assessed using Fleiss' kappa. Finally, the clinical validity of the NUSS was analysed by comparing outcomes of the actual treatment groups to the proposed treatment groups following from the NUSS scores. RESULTS: Forty-four patients were included. The comparison of NUSS scores between observers showed substantial agreement [ICC; 0.78 (0.67-0.86)]. The comparison of the Weber-Cech classification between observers showed only fair agreement [Fleiss κ; 0.30 (0.17-0.42)]. The χ2 test for the treatment groups according to the NUSS and the treatments at index procedure showed an independent relation (χ2 = 5.794, 6 degrees of freedom, p: 0.447). In contrast, the proposed treatment strategy corresponds well to the definitive treatment (χ2 = 29.963, 9 degrees of freedom, p < 0.001). CONCLUSION: We conclude that the NUSS is both a reliable and valid system to classify non-unions.

Changes in resident rat peritoneal macrophage eicosanoid release, induced by altering the buffer K+/Na+ ratio, are Ca2+ dependent.

Altering the buffer K+/Na+ ratio ([K+]o/[Na+]o) resulted in a biphasic change in the basal release of prostaglandin E2, 6-ketoprostaglandin F1 alpha (the stable breakdown product of prostaglandin I2) and thromboxane B2 (the stable metabolite of thromboxane A2), from resident rat peritoneal macrophages. Changing the [K+]o (at the expense of [Na+]o) from 15 mM to 0 mM or 75 mM (combined concentration of [K+]o and [Na+]o was maintained at 150 mM) resulted in a stimulation of 6-ketoprostaglandin F1 alpha and thromboxane B2 release. Prostaglandin E2 synthesis was also stimulated when the [K+]o was decreased from 15 mM to 0 mM. When the [K+]o was increased to 45 mM, prostaglandin E2 formation was inhibited but returned to values observed at 15 mM K+ when the [K+]o was further increased to 75 mM. Prostaglandin E2 synthesis at 75 mM K+ was still only 40% of that measured in the absence of K+, however. When cells were incubated in a Ca2+-free medium (+EDTA) eicosanoid release was drastically reduced and the changes in arachidonic acid metabolite release observed on changing the buffer [K+]o/[Na+]o were abolished. Total release of radiolabel ([14C]arachidonic acid and its radiolabelled metabolites) from macrophages prelabelled with [14C]arachidonic acid followed the same pattern as basal eicosanoid release, suggesting that changing [K+]o influenced phospholipase A2 activity, and hence, substrate availability. At all [K+]o values, from 0 mM to 75 mM, cicletanide reduced the release of radioactivity from macrophages prelabelled with [14C]arachidonic acid (by about 15%). In the presence of [K+]o, cicletanide had a stimulatory effect on the metabolism of the free fatty acid which masked the decrease in eicosanoid release expected due to inhibition of arachidonic acid release from phospholipid. In the presence of 5 mM K+, cicletanide inhibited the basal release but enhanced the arachidonic acid-stimulated synthesis of eicosanoids from resident macrophages in a dose-related fashion, confirming the dual action of the drug, i.e., the inhibitory effect on arachidonic acid release and the stimulation of arachidonic acid metabolism. The possible in vivo significance of these results is discussed.

Crystallization and preliminary X-ray study of a lipase from Pseudomonas glumae.

Lipase from Pseudomonas glumae has been purified and crystallized in two forms, using the hanging drop method of vapour diffusion at 4 degrees C and 15 degrees C. Both forms grew at pH 9.0 from 0.1 M-Tris buffer in the presence of 10% (v/v) acetone. Form 1 was crystallized from 27 to 29% polyethylene glycol in the presence of less than 0.5% (v/v) n-dodecyl-beta-D-glucopyranoside. Form 2 was grown from 17 to 19% ammonium sulphate in the presence of 1% n-octyl-beta-D-glucopyranoside. Form 1 is orthorhombic with space group P2(1)2(1)2(1), and cell dimensions of a = 158.1 A, b = 158.6 A, c = 63.4 A, Form 2 is tetragonal with space group P4(1)2(1)2 (or P4(3)2(1)2) and cell dimensions of a = 89.3 A, c = 180.4 A. Form 1 probably has four molecules per asymmetric unit and diffracts to at least 2.5 A. Form 2 has two molecules per asymmetric unit and diffracts to at least 3.0 A.

Enhanced prostaglandin E2 and thromboxane B2 release from resident peritoneal macrophages isolated from morphine-dependent rats.

Resident peritoneal macrophages from morphine-addicted rats (4 days) released more prostaglandin (PG) E2 and thromboxane (Tx) B2, but not 6-keto-PGF1 alpha, than cells from control animals. This effect, which was due to an enhancement of endogenous AA turnover, was not related to any changes in cAMP synthesis or lysosomal enzyme secretion. [D-Ala2]-Met-enkephalin had no effect on eicosanoid release in vitro. Both morphine and PGE2 have been shown to depress macrophage functions. We suggest that morphine-stimulated macrophage PGE2 synthesis, and the consequent inhibition of phagocytosis, could contribute to the decreased resistance to infections associated with opiate addiction.

Donor heart endothelial cells as targets for graft infiltrating lymphocytes after clinical cardiac transplantation.

The in vitro cytotoxic reactivity of allograft infiltrating cells cultured from endomyocardial biopsies was tested against endothelial cells (EC) isolated from the own donor heart. EC derived from pieces of atrium were found to be proper targets for graft infiltrating cytotoxic T cells from four patients. The specificity of this cytotoxicity was further analysed by cold target inhibition studies and blocking with anti-CD3, anti-CD4 or anti-CD8 monoclonal antibodies. The experiments revealed that, besides a clearly HLA directed recognition, a more heterogeneous, multispecific response can be found, which might be partially explained by the activity of EC specific T cell clones. We conclude that this system provides a valuable approach to investigate the reactivity of graft infiltrating cells against EC in relation to the clinical course of the transplantation.

Differential regulation of the cyclooxygenase pathway in starch elicited rat peritoneal macrophages by prostaglandin E2, U-44069, a stable endoperoxide analogue and dibutyryl-cyclic AMP.

The basal and carrageenin-stimulated release of thromboxane (TX) B2, the stable product of TXA2, 6-ketoPGF1 alpha, the stable breakdown product of prostacyclin (PGI2) and prostaglandin (PG) E2 from 24 h starch elicited rat peritoneal macrophages was inhibited by dibutyryl-cyclic AMP (db-cAMP). PGE2 also inhibited the release of TXA2 and 6-keto-PGF1 alpha whereas the stable endoperoxide analogue, U-44069, stimulated PGE2 and 6-keto PGF1 alpha release but inhibited TXB2 release. The effects of all three mediators tested were related to an increase of Mø intracellular cAMP content.

Linoleic and dihomo-gamma-linolenic acids modulate granuloma growth and granuloma macrophage eicosanoid release.

We have already demonstrated that arachidonic acid (AA) inhibits carrageenin-induced granuloma growth in vivo and that this effect is related to an increase in prostaglandin E2 formation. As prostaglandin E1 has been shown to be more effective in inhibiting granuloma growth than prostaglandin E2 we investigated the effect of linoleic acid (LA) (18:2 omega 6) and dihomo-gamma-linolenic acid (DHGLA) (20:3 omega 6), potential precursors of prostaglandin E1, in this model. LA and DHGLA inhibited the development of carrageenin-induced granulomas in the rat when injected locally. Both fatty acids (FA) stimulated the release of prostaglandin (PG) E1 from granuloma macrophages (M phi) in vitro, DHGLA being most effective. LA had little effect on the release of PGE2, 6 keto PGF1 alpha, the stable product of prostacyclin (PGI2) or thromboxane (Tx) B2, the stable metabolite of TxA2. DHGLA had no effect on the release of 6 keto PGF1 alpha, but inhibited PGE2 and, to a lesser extent, TxB2 synthesis.

The relationship between sickness absence from work and pattern of cigarette smoking.

In four worksites of 1248 employees, 907 were found who had worked for the employer for 12 months or more and had had a preemployment medical examination. Nonsmokers were absent from work for sickness reasons less often than smokers (3.1 hours per month compared with 3.6 for women, 3.5 compared with 3.9 for men). Among smokers who reported the amount smoked heavier smokers claimed more sickness absence than less heavy smokers. Smokers reporting one pack or more per day had twice the sickness absence of smokers who smoked half a pack or less per day. The results support other studies which show higher relative risk for sickness absence among smokers than among nonsmokers.

Quasifree pi0 and pi- electroproduction on 4He in the Delta-resonance region.

The reactions 4He(e, e' p3He)pi- and 4He(e, e' p3He)pi0 were studied simultaneously, and for the first time, in a large kinematical domain including the Delta-resonance region. This was achieved by detecting the recoiling 3He and 3H nuclei instead of the emitted pions. The dependences of the cross section on the recoil momentum p(rec), the invariant mass WpiN, and the direction thetapi,q' and phipi,q' of the produced pion, are globally well described by the results of (quasifree) distorted-wave impulse approximation calculations. However, in the Delta-resonance region there are clear discrepancies, which point to medium modifications of the Delta in 4He.

Copper modulation of macrophage cyclooxygenase metabolite synthesis.

The effect of copper on the release of cyclooxygenase metabolites from starch elicited, rat, peritoneal macrophages was investigated. Copper sulphate, in the range 10(-6)-10(-5) M, inhibited the formation of prostaglandin (PG) E2 and thromboxane (Tx) B2, the stable metabolite of TxA2, in a dose dependent manner but had no effect on the production of 6-keto-PGF1 alpha, the stable product of prostacyclin. At higher concentrations (5 x 10(-5) and 10(-4) M) the synthesis of all three metabolites of arachidonic acid (AA) was stimulated as was the release of radioactivity from macrophages prelabelled with 14C AA. Copper had no effect on the metabolism of exogenous AA however. At 10(-4) M copper also stimulated secretion of the lysosomal enzyme, beta-glucuronidase (GUR). Copper nitrate (10(-4) M), but not zinc sulphate, also stimulated eicosanoid formation and lysosomal enzyme release. Our results are consistent with the idea that copper stimulates eicosanoid formation via an effect on PL activity.

Prognostic implications of glial fibrillary acidic protein containing cell types in oligodendrogliomas.

In oligodendroglial tumors the intermediate filament glial fibrillary acidic protein (GFAP) may be expressed by cells with the morphologic characteristics of typical oligodendrocytes (gliofibrillary oligodendrocytes [GFOC]) and by miniature forms of gemistocytes (minigemistocytes) as well. These latter cell types have been regarded as transitional cells that represent intermediate forms between an oligodendroglial and an astrocytic phenotype. Furthermore, in oligodendrogliomas GFAP may be expressed by intermingled classic large gemistocytes, which are not considered transitional cells. In a retrospective study of 111 oligodendrogliomas, the presence of the various GFAP-positive cell types was correlated with the survival rates of the patients. Therefore, GFAP expression was visualized with the use of an indirect conjugated peroxidase method. The survival times of the patients were recorded and statistical comparisons were made. The percentage of GFAP-positive tumor cells is increased in oligodendrogliomas of 28 patients who underwent a second biopsy (all these patients had been treated with radiation therapy as well). It was found that neither the presence of GFOC nor that of minigemistocytes is predictive of the survival. In contrast, patients with classic gemistocytes had survival lengths approximately twice as short as those of patients who did not have these cells in their tumors. No clear correlation was found between tumor grading or any of the individual histopathologic features with the presence of the various GFAP-positive cell types. The ominous sign of the presence of gemistocytes in oligodendrogliomas confirms some earlier reports about the prognostic significance of this cell type in astrocytomas.