Automated Test for Monthly Quality Assurance of Optical Surface Imaging Dynamic Localization Accuracy.

The American Association of Physicists in Medicine (AAPM) recently published the report of Task Group (TG) 302, which provides recommendations on acceptance, commissioning, and ongoing routine quality assurance (QA) for surface-guided radiation therapy (SGRT) systems. One of the recommended monthly QA tests is a dynamic localization accuracy test. This work aimed to develop an automated procedure for monthly SGRT dynamic localization QA. An anthropomorphic head phantom was rigidly attached to the 6-dof couch of a TrueBeam linac. TrueBeam Developer Mode was used to take an MV image of the phantom at the starting position, then automatically drive the couch through a series of translations and rotations, taking an MV image after each translation. The Identify SGRT system monitored the motion of the phantom surface from the starting position. Translations assessed on MV images were compared to translations reported in trajectory log files and Identify log files. Rotations were compared between trajectory log files and Identify log files. Three experiments were conducted. None of the translations or rotations from any experiment exceeded the tolerance values for stereotactic ablative body radiation therapy (SABR) recommended by AAPM TG-142. Maximum deviations from the expected translation values from MV imaging, trajectory log files, and Identify log files were -0.94mm, -0.11mm, and -0.78mm, respectively. Maximum deviations from the expected rotation values from trajectory log files and Identify log files were 0.01 and -0.2 degrees, respectively. The proposed method is a simple automated way to complete monthly dynamic localization QA of SGRT systems.

Pre-emptive pharmacogenomics implementation among polypharmacy patients 65 years old and older: a clinical pilot.

Aim: Pre-emptive testing of pharmacogenomic (PGx) variations has potential to improve medication safety and effectiveness; however, testing is not routine. Given the newfound payor coverage of multigene testing and the potential value of testing within aging patients, it is imperative to test local PGx testing capabilities, report results to patients and providers, and determine the value of testing. Materials & methods: We designed a randomized clinical pilot of a pre-emptive PGx testing process using the electronic health record compared with usual care among an aging primary care population. Results & conclusion: The impact of the program on prescribing patterns, healthcare utilization and costs of care will be evaluated. We hypothesize that implementation of a pre-emptive multigene PGx panel is feasible among elderly, polypharmacy, primary care patients, measured by the number of enrolled patients with PGx results entered in the medical record. Health system wide PGx implementation, including capacity needed to integrate these valuable results, is also described.

Medication use and comorbidities in an increasingly younger osteoarthritis population: an 18-year retrospective open-cohort study.

OBJECTIVES: As understanding of the pathogenesis and treatment strategies for osteoarthritis (OA) evolves, it is important to understand how patient factors are also changing. Our goal was to examine demographics and known risk factors of patients with OA over time. DESIGN: Open-cohort retrospective study using electronic health records. SETTING: Large US integrated health system with 7 hospitals, 2.6 million outpatient clinic visits and 97 300 hospital admissions annually in a mostly rural geographic region. PARTICIPANTS: Adult patients with at least two encounters and a diagnosis of OA or OA-relevant surgery between 2001 and 2018. Because of geographic region, over 96% of participants were white/Caucasian. INTERVENTIONS: None. PRIMARY AND SECONDARY OUTCOME MEASURES: Descriptive statistics were used to examine age, sex, body mass index (BMI), Charlson Comorbidity Index, major comorbidities and OA-relevant prescribing over time. RESULTS: We identified 290 897 patients with OA. Prevalence of OA increased significantly from 6.7% to 33.5% and incidence increased 37% (from 3772 to 5142 new cases per 100 000 patients per year) (p<0.0001). Percentage of females declined from 65.3% to 60.8%, and percentage of patients with OA in the youngest age bracket (18-45 years) increased significantly (6.2% to 22.7%, p<0.0001). The percentage of patients with OA with BMI ≥30 remained above 50% over the time period. Patients had low comorbidity overall, but anxiety, depression and gastro-oesophageal reflux disease showed the largest increases in prevalence. Opioid use (tramadol and non-tramadol) showed peaks followed by declines, while most other medications increased slightly in use or remained steady. CONCLUSIONS: We observe increasing OA prevalence and a greater proportion of younger patients over time. With better understanding of how characteristics of patients with OA are changing over time, we can develop better approaches for managing disease burden in the future.

ERK1/2-RSK regulation of oestrogen homeostasis.

The molecular mechanisms regulating oestrogen homeostasis have been primarily studied in the mammary gland, which is the focus of this review. In the non-pregnant adult, the mammary gland undergoes repeated cycles of proliferation and apoptosis in response to the fluctuating levels of oestrogen that occur during the reproductive stage. Oestrogen actions are mediated through the steroid hormone receptors, oestrogen receptor α and ß and through a G-protein coupled receptor. In the mammary gland, ERα is of particular importance and thus will be highlighted. Mechanisms regulating oestrogen-induced responses through ERα are necessary to maintain homeostasis given that the signalling pathways that are activated in response to ERα-mediated transcription can also induce transformation. ERK1/2 and its downstream effector, p90 ribosomal S6 kinase (RSK), control homeostasis in the mammary gland by limiting oestrogen-mediated ERα responsiveness. ERK1/2 drives degradation coupled ERα-mediated transcription, whereas RSK2 acts as a negative regulator of ERK1/2 activity to limit oestrogen responsiveness. Moreover, RSK2 acts as a positive regulator of translation. Thus, RSK2 provides both positive and negative signals to maintain oestrogen responsiveness. In addition to transmitting signals through tyrosine kinase receptors, ERK1/2-RSK engages with hedgehog signalling to maintain oestrogen levels and with the HIPPO pathway to regulate ERα-mediated transcription. Additionally, ERK1/2-RSK controls the progenitor populations within the mammary gland to maintain the ERα-positive population. RSK2 is involved in increased breast cancer risk in individuals taking oral contraceptives and in parity-induced protection against breast cancer. RSK2 and ERα may also co-operate in diseases in tissues outside of the mammary gland.

Therapeutic targeting of p90 ribosomal S6 kinase.

The Serine/Threonine protein kinase family, p90 ribosomal S6 kinases (RSK) are downstream effectors of extracellular signal regulated kinase 1/2 (ERK1/2) and are activated in response to tyrosine kinase receptor or G-protein coupled receptor signaling. RSK contains two distinct kinase domains, an N-terminal kinase (NTKD) and a C-terminal kinase (CTKD). The sole function of the CTKD is to aid in the activation of the NTKD, which is responsible for substrate phosphorylation. RSK regulates various homeostatic processes including those involved in transcription, translation and ribosome biogenesis, proliferation and survival, cytoskeleton, nutrient sensing, excitation and inflammation. RSK also acts as a major negative regulator of ERK1/2 signaling. RSK is associated with numerous cancers and has been primarily studied in the context of transformation and metastasis. The development of specific RSK inhibitors as cancer therapeutics has lagged behind that of other members of the mitogen-activated protein kinase signaling pathway. Importantly, a pan-RSK inhibitor, PMD-026, is currently in phase I/1b clinical trials for metastatic breast cancer. However, there are four members of the RSK family, which have overlapping and distinct functions that can vary in a tissue specific manner. Thus, a problem for transitioning a RSK inhibitor to the clinic may be the necessity to develop isoform specific inhibitors, which will be challenging as the NTKDs are very similar to each other. CTKD inhibitors have limited use as therapeutics as they are not able to inhibit the activity of the NTKD but could be used in the development of proteolysis-targeting chimeras.

Identifying requirements for RSK2 specific inhibitors.

Identifying isoform-specific inhibitors for closely related kinase family members remains a substantial challenge. The necessity for achieving this specificity is exemplified by the RSK family, downstream effectors of ERK1/2, which have divergent physiological effects. The natural product, SL0101, a flavonoid glycoside, binds specifically to RSK1/2 through a binding pocket generated by an extensive conformational rearrangement within the RSK N-terminal kinase domain (NTKD). In modelling experiments a single amino acid that is divergent in RSK3/4 most likely prevents the required conformational rearrangement necessary for SL0101 binding. Kinetic analysis of RSK2 association with SL0101 and its derivatives identified that regions outside of the NTKD contribute to stable inhibitor binding. An analogue with an n-propyl-carbamate at the 4" position on the rhamnose moiety was identified that forms a highly stable inhibitor complex with RSK2 but not with RSK1. These results identify a SL0101 modification that will aid the identification of RSK2 specific inhibitors.

FACS protocol for direct comparison of cell populations isolated from mice.

A FACS protocol is described that eliminates isolation and staining artifacts to allow accurate comparison between cell populations isolated from organs obtained from disparate mouse groups. This protocol was validated by characterizing the estrogen receptor positive cells within the mammary gland of transgenic mice with different genotypes at different stages of the estrous cycle. We include protocols necessary to batch stage animals within the cycle to proceed directly to FACS, which provides optimal RNA yields for RNA-seq. For complete details on the use and execution of this protocol, please refer to Ludwik et al. (2020).

The Use of Absorbable Mesh in Implant-Based Breast Reconstruction: A 7-Year Review.

BACKGROUND: Breast reconstruction is most frequently performed using implants or expanders. Adjunctive materials such as acellular dermal matrix and synthetic meshes are used to support the implant or expander. A paucity of large studies exist on the use of synthetic mesh for breast reconstruction. METHODS: A retrospective chart review of all patients over the past 7 years who had implant reconstruction with synthetic absorbable mesh at the Massachusetts General Hospital was performed. Data were collected on demographic and surgical outcomes. Statistical analysis was performed. RESULTS: A total of 227 patients (376 mastectomies) were treated with direct-to-implant subpectoral reconstruction with absorbable mesh from 2011 to 2017. The infection rate was 2.1 percent. The rate of capsular contracture was 4.8 percent. Patients who had radiation therapy either preoperatively or postoperatively had a higher rate of complications, including capsular contracture. Cost savings for using mesh instead of acellular dermal matrix surpassed $1.2 million. CONCLUSION: Synthetic absorbable mesh is a safe alternative to acellular dermal matrix in prosthetic breast reconstruction and provides stable results along with significant cost savings. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Factors Associated With HIV Testing Among Atlanta's Homeless Youth.

Homeless youth experience increased risk of contracting HIV, making HIV testing imperative in this population. We analyzed factors associated with HIV testing among homeless youth in Atlanta, Georgia using data from the 2015 Atlanta Youth Count and Needs Assessment. The analysis included 693 homeless youth aged 14-25 years, of whom 88.4% reported ever being tested for HIV, and 74.6% reported being tested within the previous year. Prevalence of ever testing for HIV was significantly higher among youth who reported risk factors for HIV (sexually active, transactional sex, or ever having an STI). Higher prevalence of testing within the last year was significantly associated with experiencing physical abuse or transactional sex. However, reporting ≥ 4 sexual partners or not using condoms were not associated with higher testing. Although testing prevalence among homeless youth was high, homeless youth engaging in certain high risk behaviors could benefit from further promotion of HIV testing.

Synthesis and Biological Evaluation of 4'-Substituted Kaempfer-3-ols.

The synthesis of two series of five kaempfer-3-ols was described. The first set all have a C-3 hydroxyl group and the second has a carboxymethoxy ether at the C-3 position. Both series have variable substitution at the C-4' position (i.e., OH, Cl, F, H, OMe). Both kaempferols and carboxymethoxy ethers were evaluated for their ability to inhibit ribosomal s6 kinase (RSK) activity and cancer cell proliferation.

Migraine Surgery: An All or Nothing Phenomenon? Prospective Evaluation of Surgical Outcomes.

OBJECTIVE: A detailed analysis of outcomes after migraine surgery suggests an anatomic etiology of pain, such as peripheral nerve compression, in select patients. BACKGROUND: Historically, surgeons have not played a role in the treatment of migraine. However, a subgroup of patients with extracranial anatomic triggers appear to benefit from surgical intervention. Traditionally, the determination of success or failure of migraine surgery is based on whether there is greater or less than 50% improvement of the migraine headache index (MHI) after surgery. However, in this study, patients either did not respond to treatment (≤5%) or improved completely (≥80%). Detailed analysis is provided of this surprising finding. METHODS: Subjects completed a prospective migraine questionnaire preoperatively as well as at 3 and 12 months postoperatively. RESULTS: All variables improved significantly from baseline. Interestingly, in 83% of patients, the MHI improved either ≥80% or ≤5%, suggesting a more binary distribution. Only 17% of indices fell in the intermediate (5% to 80%) range. Moreover, 69% of patients had ≥80% improvement resulting in a mean improvement of 96% in this group. The remaining 14% had ≤5% improvement, with an average improvement of 0%. CONCLUSION: Migraine surgery remains controversial. Traditional conservative therapy targets the central theory of migraine propagation. This study again prospectively demonstrates the efficacy of surgical trigger site deactivation in migraine patients. Patients either failed to improve or improved after surgery, with few intermediate outcomes. The binary distribution of data lends further support to an anatomic etiology of pain, that is, peripheral nerve compression, in select patients.

Genetic identification of familial hypercholesterolemia within a single U.S. health care system.

Familial hypercholesterolemia (FH) remains underdiagnosed despite widespread cholesterol screening. Exome sequencing and electronic health record (EHR) data of 50,726 individuals were used to assess the prevalence and clinical impact of FH-associated genomic variants in the Geisinger Health System. The estimated FH prevalence was 1:256 in unselected participants and 1:118 in participants ascertained via the cardiac catheterization laboratory. FH variant carriers had significantly increased risk of coronary artery disease. Only 24% of carriers met EHR-based presequencing criteria for probable or definite FH diagnosis. Active statin use was identified in 58% of carriers; 46% of statin-treated carriers had a low-density lipoprotein cholesterol level below 100 mg/dl. Thus, we find that genomic screening can prompt the diagnosis of FH patients, most of whom are receiving inadequate lipid-lowering therapy.

Rhinoplasty Education Using a Standardized Patient Encounter.

BACKGROUND: Comprehensive aesthetic surgery training continues to be a challenge for residency programs. Our residency program developed a rhinoplasty-based objective structured clinical examination (OSCE) based upon validated methods as part of the residency education curriculum. We report our experience with the rhinoplasty-based OSCE and offer guidance to its incorporation within residency programs. METHODS: The encounter involved resident evaluation and operative planning for a standardized patient desiring a rhinoplasty procedure. Validated OSCE methods currently used at our medical school were implemented. Residents were evaluated on appropriate history taking, physical examination, and explanation to the patient of treatment options. Examination results were evaluated using analysis of variance (statistical significance P<0.05). RESULTS: Twelve residents completed the rhinoplasty OSCE. Medical knowledge assessment showed increasing performance with clinical year, 50% versus 84% for postgraduate year 3 and 6, respectively (P<0.005). Systems-based practice scores showed that all residents incorrectly submitted forms for billing and operative scheduling. All residents confirmed that the OSCE realistically represents an actual patient encounter. All faculty confirmed the utility of evaluating resident performance during the OSCE as a useful assessment tool for determining the Next Accreditation System Milestone level. CONCLUSIONS: Aesthetic surgery training for residents will require innovative methods for education. Our examination showed a program-educational weakness in billing/coding, an area that will be improved upon by topic-specific lectures. A thoroughly developed OSCE can provide a realistic educational opportunity to improve residents' performance on the nonoperative aspects of rhinoplasty and should be considered as an adjunct to resident education.

Clinical Significance of Internal Mammary Lymph Node Biopsy during Microsurgical Breast Reconstruction: Review of 264 Cases.

BACKGROUND: Despite the knowledge of alternate lymphatic draining patterns of the breast, routine evaluation of the internal mammary lymph node basin is still not considered standard of care. The advent of microsurgical breast reconstruction using the internal mammary vessels as recipients, however, has allowed sampling of internal mammary lymph nodes with technical ease, thus revisiting their role in breast cancer management. In the present study, the authors reviewed their experience with this practice. METHODS: A retrospective analysis of patients who underwent internal mammary lymph node biopsy at the time of autologous breast reconstruction using the internal mammary vessels between 2004 and 2012 was performed. Parameters of interest included patient age, timing of reconstruction (immediate versus delayed), disease stage, and pathologic findings of internal mammary lymph nodes. RESULTS: A total of 264 autologous breast reconstructions using the internal mammary vessels were performed in 204 patients with a median age of 44.5 years. The majority of reconstructions were immediate [n = 211 (79.9 percent)]. Seventy-two percent of patients had either stage I [72 patients (35.3 percent)] or stage II disease [75 patients (36.8 percent)]. Six patients were found to have internal mammary lymph node metastasis. Stage migration and alteration in adjuvant therapy occurred in all patients. CONCLUSION: Internal mammary lymph node sampling at the time of autologous breast reconstruction using the internal mammary system should become routine practice, as the morbidity associated with internal mammary lymph node harvest is low and the impact in cases of nodal involvement is quite substantial. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Cleft Lip Standardized Patient Examinations: The Role in Plastic Surgery Resident Education.

BACKGROUND: Our institution has incorporated the use of objective structured clinical examinations (OSCE) in our residency curriculum. The OSCE provides trainee education and evaluation while addressing the six Accreditation Council for Graduate Medical Education (ACGME) core competencies required within training programs. We report our program's experience with the first cleft OSCE ever conducted. METHODS: A validated method for administration of OSCEs currently used at our medical school was utilized for residents in postgraduate years (PGYs) 3 through 6. The video-recorded patient encounter involved a 1-month-old newborn with a unilateral cleft lip and palate and used standardized patient actors as parents. A post-encounter written exam assessed medical knowledge. A questionnaire regarding the utility of the exercise was administered to residents after the OSCE. Results were evaluated using analysis of variance (P < .05). RESULTS: There was a positive correlation with increasing level of training in terms of medical knowledge (P < .04). Residents in PGY-3 and PGY-4 demonstrated lower understanding of the surgical markings and details of the lip repair compared with those in PGY-5 and PGY-6 (P < .03). All residents performed similarly on evaluation of the remaining ACGME core competencies. All residents agreed that this was a realistic and useful encounter. CONCLUSION: Results of our cleft OSCE demonstrate that medical knowledge regarding the evaluation, management, and surgical repair of patients is less in midlevel residents. All residents expressed an interest in earlier exposure to pediatric patients in the training period. Although a cleft OSCE does not replace clinical rotations, it is a valuable adjunct to training and evaluation of trainees, particularly for junior residents.

Temporal trends in lipid screening and therapy among youth from 2002 to 2012.

BACKGROUND: Pediatric lipid management recommendations have evolved from selective screening to universal screening to identify and target therapy for genetic dyslipidemias. Data on the success of the selective screening guidelines for lipid testing, dyslipidemia detection, and lipid management are conflicting. OBJECTIVE: To determine temporal trends in lipid testing, dyslipidemia categories and pharmacotherapy in a cohort of 653,642 individual youth aged 2 to 20 years from 2002 to 2012. METHODS: Summary data on lipid test results, lipid-lowering medicine (LLM) dispensings, and International Classification of Diseases, Ninth Revision diagnoses were compiled from the virtual data warehouses of 5 sites in the Cardiovascular Research Network. Temporal trends were determined using linear regression. RESULTS: Among the average 255,160 ± 25,506 children enrolled each year, lipid testing declined from 16% in 2002 to 11% in 2012 (P < .001 for trend). Among the entire population, the proportion newly detected each year with low-density lipoprotein cholesterol >190 mg/dL, a value commonly used to define familial hypercholesterolemia, increased over time from 0.03% to 0.06% (P = .03 for trend). There was no significant change over time in the proportion of the yearly population initiated on LLM or statins specifically (0.045 ± 0.009%, P = .59 [LLM] and 0.028 ± 0.006%, P = .25 [statin]). CONCLUSIONS: Although lipid testing declined during 2002 to 2012, the detection of familial hypercholesterolemia-level low-density lipoprotein cholesterol increased. Despite this increased detection, pharmacotherapy did not increase over time. These findings highlight the need to enhance lipid screening and management strategies in high-risk youth.

Facelift combined with simultaneous fractional laser resurfacing: Outcomes and complications.

BACKGROUND: The combination of simultaneous surgical rhytidectomy with ablative resurfacing has been a controversial procedure due to the concern of postoperative wound healing. Traditional ablative resurfacing lasers are believed to have higher rates of complications, leading to delayed healing and skin flap loss when combined with face rhytidectomy surgeries. With the development of fractionated ablative laser therapy, there has been increased interest in combining these two procedures. The objective of this study is to evaluate the clinical outcomes of patients undergoing simultaneous full-face rhytidectomy in combination with fractionated ablative skin resurfacing. METHODS: A retrospective chart analysis was performed for all patients who had a combined procedure of facelift and ablative fractional laser resurfacing from 2008 to 2013 by the senior author (SKS). Postoperative recovery and complications were recorded. The surgical technique used for performing the facelift was an extended supraplatysmal dissection with SMAS plication. Fraxel Re:Pair 10,600-nm fractional carbon dioxide laser was used to perform an ablative resurfacing including the elevated skin flaps. RESULTS: A total of 86 patients were included. Average age was 60.01 years (range of 45-78 years). Longest follow up was five years. The average size of the elevated skin flaps was 100 cm(2). Average skin type was a Fitzpatrick type 2. All patients had complete re-epithelialization by one week after their procedure. Four patients (4.6%) experienced acne outbreaks. Four patients (4.6%) had facial erythema that persisted greater than two weeks. Of these four patients, all resolved by five weeks postoperatively. There was no delayed wound healing or skin flap loss observed. CONCLUSION: Our results indicate that simultaneous rhytidectomy with fractionated ablative laser resurfacing does not cause an increase in wound healing or skin loss. Due to improved patient outcomes with combining these procedures, we believe that this can be increasingly offered as a safe combination.

Quality of life and patient satisfaction after microsurgical abdominal flap versus staged expander/implant breast reconstruction: a critical study of unilateral immediate breast reconstruction using patient-reported outcomes instrument BREAST-Q.

Staged expander-implant breast reconstruction (EIBR) and microsurgical abdominal flap breast reconstruction (MAFBR) are the most common modes of breast reconstruction (BR) in the United States. Whether the mode of breast reconstruction has an impact on patient quality of life (QoL) and satisfaction remains a question. A retrospective study was conducted identifying a population of 119 patients who underwent unilateral immediate BR. Only patients who were eligible for either EIBR or MAFBR based on preoperative characteristics were included in the study. The following parameters were retrieved: demographics, mode of reconstruction, cancer, recovery, QoL, and patient satisfaction. The latter two parameters were determined using the BREAST-Q BR module questionnaire. Two-way analysis of variance with mode of reconstruction and occurrence of complication as independent variables was used to determine the effect on patient satisfaction and QoL. The association between mode of reconstruction and patient response with each item of the QoL and satisfaction survey domains was analyzed. The overall response rate was 62.2 %. Non-respondents and respondents did not significantly differ in demographics, surgery type, cancer staging, adjuvant therapy, and complication rate. Age and BMI were significantly higher in MAFBR, while level of education was higher in EIBR. MAFBR had higher scores in psychosocial and sexual wellbeing, satisfaction with outcome, breast, information, and plastic surgeon when compared with patients who underwent EIBR. For patients eligible for both MAFBR and EIBR, MAFBR is associated with higher levels of satisfaction and QoL. Comprehensive pre-operative information of pros and cons of both modes of BR is crucial for patients to make a well-informed decision, thus, resulting in higher levels of satisfaction.

Outcome analysis of expander/implant versus microsurgical abdominal flap breast reconstruction: a critical study of 254 cases.

BACKGROUND: Expander-implant breast reconstruction (EIBR) and microsurgical abdominal flap breast reconstruction (MAFBR) are currently the two most frequent breast reconstruction techniques performed in the United States. The aim of this study was to compare outcomes between EIBR and MAFBR in order to help future breast cancer patients to be more knowledgeable and better informed in choosing their optimal reconstruction option. METHODS: Medical records of 795 patients who underwent breast reconstruction at Stanford Hospital from 2007 to 2011 were reviewed. We found 254 patients to be candidates for both MAFBR and EIBR preoperatively and included them in the study. Patients demographics, postoperative clinic visits, length of hospital stay, postoperative complications, and follow-up time were compared. Logistic regression analysis was used to determine risk factors for major complications. RESULTS: MAFBR patients had 8.7 clinic visits postoperatively, while 14.6 visits were needed for EIBR patients. Length of hospital stay was 4.8 ± 1.32 days for MAFBR and 2.1 ± 0.9 days for EIBR. Complication occurred in 21.3 % of MAFBR versus 37.4 % for EIBR patients. Follow-up duration was 24.7 ± 17.2 months for EIBR and 30.1 ± 18.5 months for MAFBR. On multivariate analysis, EIBR and a body mass index of ≥30 kg/m(2) were the only significant predictors of major complication. CONCLUSIONS: For patients eligible for both options, MAFBR has a lower incidence of major complications and fewer postoperative visits, but it has a longer initial hospital stay compared to EIBR. Patients should be informed of not only short-term but also long-term possible risks and benefits in order to make an informed decision.

Responses to ionizing radiation mediated by inflammatory mechanisms.

Since the early years of the twentieth century, the biological consequences of exposure to ionizing radiation have been attributed solely to mutational DNA damage or cell death induced in irradiated cells at the time of exposure. However, numerous observations have been at variance with this dogma. In the 1950s, attention was drawn to abscopal effects in areas of the body not directly irradiated. In the 1960s reports began appearing that plasma factors induced by irradiation could affect unirradiated cells, and since 1990 a growing literature has documented an increased rate of DNA damage in the progeny of irradiated cells many cell generations after the initial exposure (radiation-induced genomic instability) and responses in non-irradiated cells neighbouring irradiated cells (radiation-induced bystander effects). All these studies have in common the induction of effects not in directly irradiated cells but in unirradiated cells as a consequence of intercellular signalling. Recently, it has become clear that all the various effects demonstrated in vivo may reflect an ongoing inflammatory response to the initial radiation-induced injury that, in a genotype-dependent manner, has the potential to contribute primary and/or ongoing damage displaced in time and/or space from the initial insult. Importantly, there is direct evidence that non-steroidal anti-inflammatory drug treatment reduces such damage in vivo. These new findings highlight the importance of tissue responses and indicate additional mechanisms of radiation action, including the likelihood that radiation effects are not restricted to the initiation stage of neoplastic diseases, but may also contribute to tumour promotion and progression. The various developments in understanding the responses to radiation exposures have implications not only for radiation pathology but also for therapeutic interventions.