The Clinical Frailty Scale for Risk Stratification in Patients With Fibrotic Interstitial Lung Disease.

BACKGROUND: Previous studies have shown the importance of frailty in patients with fibrotic interstitial lung disease (ILD). RESEARCH QUESTION: Is the Clinical Frailty Scale (CFS) a valid tool to improve risk stratification in patients with fibrotic ILD? STUDY DESIGN AND METHODS: Patients with fibrotic ILD were included from the prospective multicenter Canadian Registry for Pulmonary Fibrosis. The CFS was assessed using available information from initial ILD clinic visits. Patients were stratified into fit (CFS score 1-3), vulnerable (CFS score 4), and frail (CFS score 5-9) subgroups. Cox proportional hazards and logistic regression models with mixed effects were used to estimate time to death or lung transplantation. A derivation and validation cohort was used to establish prognostic performance. Trajectories of functional tests were compared using joint models. RESULTS: Of the 1,587 patients with fibrotic ILD, 858 (54%) were fit, 400 (25%) were vulnerable, and 329 (21%) were frail. Frailty was a risk factor for early mortality (hazard ratio, 5.58; 95% CI, 3.64-5.76, P < .001) in the entire cohort, in individual ILD diagnoses, and after adjustment for potential confounders. Adding frailty to established risk prediction parameters improved the prognostic performance in derivation and validation cohorts. Patients in the frail subgroup had larger annual declines in FVC % predicted than patients in the fit subgroup (-2.32; 95% CI, -3.39 to -1.17 vs -1.55; 95% CI, -2.04 to -1.15, respectively; P = .02). INTERPRETATION: The simple and practical CFS is associated with pulmonary and physical function decline in patients with fibrotic ILD and provides additional prognostic accuracy in clinical practice.

Lung imaging patterns in connective tissue disease-associated interstitial lung disease impact prognosis and immunosuppression response.

OBJECTIVES: Interstitial lung disease (ILD) in connective tissue diseases (CTD) have highly variable morphology. We aimed to identify imaging features and their impact on ILD progression, mortality and immunosuppression response. METHODS: Patients with CTD-ILD had high-resolution chest computed tomography (HRCT) reviewed by expert radiologists blinded to clinical data for overall imaging pattern (usual interstitial pneumonia [UIP]; non-specific interstitial pneumonia [NSIP]; organizing pneumonia [OP]; fibrotic hypersensitivity pneumonitis [fHP]; and other). Transplant-free survival and change in percent-predicted forced vital capacity (FVC) were compared using Cox and linear mixed effects models adjusted for age, sex, smoking, and baseline FVC. FVC decline after immunosuppression was compared with pre-treatment. RESULTS: Of 645 CTD-ILD patients, the frequent CTDs were systemic sclerosis (n = 215), rheumatoid arthritis (n = 127), and inflammatory myopathies (n = 100). NSIP was the most common pattern (54%), followed by UIP (20%), fHP (9%), and OP (5%). Compared with UIP, FVC decline was slower for NSIP (1.1%/year, 95%CI 0.2, 1.9) and OP (3.5%/year, 95%CI 2.0, 4.9), and mortality was lower for NSIP (HR 0.65, 95%CI 0.45, 0.93) and OP (HR 0.18, 95%CI 0.05, 0.57), but higher in fHP (HR 1.58, 95%CI 1.01, 2.40). The extent of fibrosis also predicted FVC decline and mortality. After immunosuppression, FVC decline was slower compared with pre-treatment in NSIP (by 2.1%/year, 95%CI 1.4, 2.8), with no change for UIP or fHP. CONCLUSION: Multiple radiologic patterns are possible in CTD-ILD, including a fHP pattern. NSIP and OP were associated with better outcomes and response to immunosuppression, while fHP had worse survival compared with UIP.

An Unusual Presentation of SCAD in a Young Male Soldier.

Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic cause of myocardial infarction and sudden cardiac death in young individuals without significant cardiovascular risk factors. The etiology of SCAD appears to be multifactorial and is often precipitated by physical and emotional stress superimposed on underlying arteriopathy, connective tissue disorders, systemic inflammatory disorders, genetic factors, and hormonal influences. There are no current societal guidelines to stratify young soldiers' risk of developing SCAD. Diagnosis typically requires invasive coronary artery angiography which is largely unavailable in stations with limited medical resources. Furthermore, young patients with SCAD often present with atypical cardiac symptoms, such as heartburn leading to the misdiagnosis of gastroesophageal reflux disease and a delay in diagnosis and management. We present a 21-year-old active duty male who was transferred from Okinawa, Japan to a tertiary military medical center for evaluation of hypercoagulable conditions after CT revealed non-obstructing portal venous thrombosis extending to right hepatic vein, splenic vein thrombosis with splenic infarct, and bilateral wedge-shaped renal infarct. Extensive work-up ultimately revealed mid-left anterior descending spiral dissection with transmural infarct of inferior, anteroseptal, and inferoseptal wall resulting in the formation of left ventricular thrombus, subsequently causing thromboembolism to multiple organs. This case demonstrates the ramifications of SCAD when diagnosis and management are delayed and serve as a poignant reminder for all providers to include SCAD in the differential diagnosis for young soldiers with atypical chest pain.

Early Discharge for Revision Total Knee and Hip Arthroplasty: Predictors of Success.

BACKGROUND: The rate of revision total joint arthroplasties is expected to increase drastically in the near future. Given the recent pandemic, there has been a general push toward early discharge. This study aimed to assess for predictors of early postoperative discharge after revision total knee arthroplasty (rTKA) and revision total hip arthroplasty (rTHA). METHODS: There were 77 rTKA and 129 rTHA collected between January 1, 2019 and December 31, 2021. Demographic data, comorbidities, a comorbidity index, the modified frailty index (mFI-5), and surgical history were collected. The Common Procedural Terminology codes for each case were assessed. Patients were grouped into 2 cohorts, early discharge (length of stay [LOS] <24 hours) and late discharge (LOS >24 hours). RESULTS: In the rTHA cohort, age >65 years, a history of cardiac or liver disease, an mFI-5 of >1, a comorbidity index of >2.7, a surgical time >122 minutes, and the need for a transfusion were predictors of prolonged LOS. Only the presence of a surgical time of >63 minutes or an mFI-5 >1 increased patient LOS in the rTKA cohort. In both rTHA and rTKA patients, periprosthetic joint infection resulted in a late discharge for all patients, mean 4.8 and 7.1 days, respectively. Dual component revision was performed in 70.5% of rTHA. Only 27.6% of rTKA were 2-component revisions or placements of an antibiotic spacer. CONCLUSIONS: Several patient and surgical factors preclude early discharge candidacy. For rTHA, an mFI-5 of >2/5, comorbidity index of >4, or a surgical time of >122 minutes is predictive of prolonged LOS. For rTKA, an mFI-5 of >2/5, Charlson Comorbidity Index of >5, or a surgical time of >63 minutes predicts prolonged LOS.

Adverse Events and Compliance Among Inflammatory Bowel Disease Patients Treated With Home- vs Office-Based Biologic Infusions.

BACKGROUND: Biologic medications are a common therapy for those with inflammatory bowel disease (IBD). There are limited data on the outcomes of home-based biologic infusions for patients with IBD. The aim of this study was to compare the safety and efficacy of biologic infusions for IBD patients who receive either home- or office-based administration. METHODS: Patients receiving infliximab or vedolizumab were analyzed retrospectively over a period of 152 weeks. Survival free of major adverse events including delayed infusion reaction, steroid initiation, drug discontinuation, or IBD-related emergency department visits, admission, and surgery were compared using a Kaplan-Meier curve. Individual adverse events, infusion-.related quality measures, and markers of patient adherence were analyzed. RESULTS: Adverse event-free survival was greater among those receiving home-based infusion (n = 154) compared with office-based infusion (n = 133). The office infusion cohort had higher rates of delayed infusion reactions (4 vs 0), IBD-related surgery (6 vs 0), and drug discontinuation (44 vs 35); this was a sicker cohort of patients compared with those in the home infusion group. Home infusion patients were less likely to receive correct weight-based dosing for infliximab (71.7% vs 89.3%), obtain labs for drug monitoring (53.2% vs 71.4%), and adhere to routine clinic visits (37.9% vs 58.1%). CONCLUSIONS: The home-based infusion of biologics for IBD appears safe with lower rates of major adverse events compared with office-based infusions. However, those receiving home infusion were less likely to receive correct weight-based dosing for infliximab and were poorly adherent to routine follow-up.

There are higher rates of adverse events among inflammatory bowel disease patients infused with biologics in the office rather than at home. The quality of care delivered and patient adherence to follow-up is reduced among those receiving home infusions.

Integration and Application of Radiologic Patterns From Clinical Practice Guidelines on Idiopathic Pulmonary Fibrosis and Fibrotic Hypersensitivity Pneumonitis.

BACKGROUND: Clinical practice guidelines separately describe radiologic patterns of usual interstitial pneumonia (UIP) and fibrotic hypersensitivity pneumonitis (fHP), without direction on whether or how to apply these approaches concurrently within a single patient. RESEARCH QUESTION: How can we integrate guideline-defined radiologic patterns to diagnose interstitial lung disease (ILD) and what are the pitfalls associated with described patterns that require reassessment in future guidelines? STUDY DESIGN AND METHODS: Patients from the Canadian Registry for Pulmonary Fibrosis underwent detailed reevaluation in standardized multidisciplinary discussion. CT scan features were quantified by chest radiologists masked to clinical data, and guideline-defined patterns were assigned. Clinical data then were provided to the radiologist and an ILD clinician, who jointly determined the leading diagnosis. RESULTS: Clinical-radiologic diagnosis in 1,593 patients was idiopathic pulmonary fibrosis (IPF) in 26%, fHP in 12%, connective tissue disease-associated ILD (CTD-ILD) in 34%, idiopathic pneumonia with autoimmune features in 12%, and unclassifiable ILD in 10%. Typical and probable UIP patterns corresponded to a diagnosis of IPF in 66% and 57% of patients, respectively. Typical fHP pattern corresponded to an fHP clinical diagnosis in 65% of patients, whereas compatible fHP was nonspecific and associated with CTD-ILD or IPAF in 48% of patients. No pattern ruled out CTD-ILD. Gas trapping affecting > 5% of lung parenchyma on expiratory imaging was an important feature broadly separating compatible and typical fHP from other patterns (sensitivity, 0.77; specificity, 0.91). INTERPRETATION: An integrated approach to guideline-defined UIP and fHP patterns is feasible and supports > 5% gas trapping as an important branch point. Typical or probable UIP and typical fHP patterns have moderate predictive values for a corresponding diagnosis of IPF and fHP, although occasionally confounded by CTD-ILD; compatible fHP is nonspecific.

Pembrolizumab Induced Calcitriol-Mediated Hypercalcemia.

PD-1/PD-L1 inhibitors such as pembrolizumab have radically improved the prognosis for many patients with advanced malignancies. Although revolutionary, its use can be complicated and limited by various immune-related adverse effects. Effective management depends on early recognition and prompt intervention. Herein, we describe a unique syndrome of hypercalcemia, with associated acute renal injury and hypoxic respiratory failure that was responsive to corticosteroids suggestive of immunotoxicity from pembrolizumab.

Interstitial Lung Disease in ANCA-Associated Vasculitis: Pathogenic Considerations and Impact for Patients' Outcomes.

PURPOSE OF REVIEW: This review provides an update on recent advances in the diagnosis, pathogenesis, clinical presentation, histopathological findings, and treatment approaches for antineutrophil cytoplasmic antibody (ANCA) vasculitis-associated interstitial lung disease (AAV-ILD) with a focus on literature published in the last 3 years. RECENT FINDINGS: Although there is no validated definition of AAV-ILD, which contributes to some of the heterogeneity seen in study results, there has been an increasing number of publications in recent years on this topic. Most patients with AAV-ILD have MPO-ANCA vasculitis, and this association appears to reduce their 5-year-survival to 60-66% (Sun et al. BMC Pulm Med 21(1), 2021, Maillet et al. J Autoimmun 106, 2020). Median age of diagnosis ranges from mid-60 s to mid-70 s (Ando et al. Respir Med 107(4), 2013), Kagiyama et al. BMJ Open Respir Res 2(1):1-9, 2015, Hozumi et al. Lung 194(2):235-42, 2016, Liu et al. Chest 156(4):715-23, 2019, Maillet et al. J Autoimmun 106, 2020, Wurmann et al. Sarcoidosis Vasc Diffuse Lung Dis 37(1):37-42, 2020, Watanabe et al. BMC Pulm Med 19(1), 2019). Computed tomography (CT) chest imaging for patients with AAV-ILD often shows a usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia (NSIP) pattern (12-58% and 13-61%, respectively) (Sun et al. BMC Pulm Med 21(1), 2021, Maillet et al. J Autoimmun 106, 2020, Wurmann et al. Sarcoidosis Vasc Diffuse Lung Dis 37(1):37-42, 2020, Watanabe et al. BMC Pulm Med 19(1), 2019, Baqir at al. Sarcoidosis Vasc Diffuse Lung Dis Off J WASOG 36(3):195-201, 2019). Additionally, lung biopsies typically do not demonstrate active inflammation, or capillaritis, questioning whether these patients should be treated with either immunotherapy or anti-fibrotic therapy, or both (Hozumi et al. Lung 194(2):235-42, 2016, Liu et al. Chest 156(4):715-23, 2019, Kitching at al. Nat Rev Dis Prim 6(1):71, 2020, Tanaka et al. Respir Med 106(12):1765-70, 2012). Besides immunosuppressive treatments, recent advances in anti-fibrotic therapy may offer patients with progressive AAV-ILD an alternative and/or more effective and individualized treatment option.

Characterizing Behaviors Associated with Enteric Pathogen Exposure among Infants in Rural Ecuador through Structured Observations.

The relative importance of environmental pathways that results in enteropathogen transmission may vary by context. However, measurement of contact events between individuals and the environment remains a challenge, especially for infants and young children who may use their mouth and hands to explore their environment. Using a mixed-method approach, we combined 1) semistructured observations to characterize key behaviors associated with enteric pathogen exposure and 2) structured observations using Livetrak, a customized software application, to quantify the frequency and duration of contacts events among infants in rural Ecuador. After developing and iteratively piloting the structured observation instrument, we loaded the final list of prompts onto a LiveTrak pallet to assess environmental exposures of 6-month infants (N = 19) enrolled in a prospective cohort study of diarrheal disease. Here we provide a detailed account of the lessons learned. For example, in our field site, 1) most mothers reported washing their hands after diaper changes (14/18, 77.8%); however only a third (4/11, 36.4%) were observed washing their hands; 2) the observers noted that animal ownership differed from observed animal exposure because animals owned by neighboring households were reported during the observation; and 3) using Livetrak, we found that infants frequently mouthed their hands (median = 1.9 episodes/hour, median duration: 1.6 min) and mouthed surroundings objects (1.8 episodes/hour, 1.9 min). Structured observations that track events in real time, can complement environmental sampling, quantitative survey data and qualitative interviews. Customizing these observations enabled us to quantify enteric exposures most relevant to our rural Ecuadorian context.

Survival after inpatient or outpatient pulmonary rehabilitation in patients with fibrotic interstitial lung disease: a multicentre retrospective cohort study.

BACKGROUND: The impact of pulmonary rehabilitation (PR) on survival in patients with fibrotic interstitial lung disease (ILD) is unknown. Given the challenges conducting a large randomised controlled trial, we aimed to determine whether improvement in 6-minute walk distance (6MWD) was associated with better survival. METHODS: This retrospective, international cohort study included patients with fibrotic ILD participating in either inpatient or outpatient PR at 12 sites in 5 countries. Multivariable models were used to estimate the association between change in 6MWD and time to death or lung transplantation accounting for clustering by centre and other confounders. RESULTS: 701 participants (445 men and 256 women) with fibrotic ILD were included. The mean±SD ages of the 196 inpatients and 505 outpatients were 70±11 and 69±12 years, respectively. Baseline/changes in 6MWD were 262±128/55±83 m for inpatients and 358±125/34±65 m for outpatients. Improvement in 6MWD during PR was associated with lower hazard rates for death or lung transplant on adjusted analysis for both inpatient (HR per 10 m 0.94, 95% CI 0.91 to 0.97, p<0.001) and outpatient PR (HR 0.97, 95% CI 0.95 to 1.00, p=0.042). Participation in ≥80% of planned outpatient PR sessions was associated with a 33% lower risk of death (95% CI 0.49% to 0.92%). CONCLUSIONS: Patients with fibrotic ILD who improved physical performance during PR had better survival compared with those who did not improve performance. Confirmation of these hypothesis-generating findings in a randomised controlled trial would be required to definitely change clinical practice, and would further support efforts to improve availability of PR for patients with fibrotic ILD.

Cervical Cancer Screening Coverage - China, 2018-2019.

What is already known about this topic?: The World Health Organization set a 2030 target of 70% cervical cancer screening coverage for women aged 35-45 years. Coverage stood at 37% in China in 2015. What is added by this report?: In 2018-2019, China's cervical cancer screening coverage reached 43.4% in women aged 35-44 years and 36.8% in women aged 35-64 years. Screening coverage was still lower in rural areas as well as central and western regions; large variations existed across provincial-level administrative divisions. What are the implications for public health practice?: National and local policy and financial support should be maintained for cervical cancer screening, along with more targeted health education and outreach efforts and strengthened accessibility of health services in the rural areas and central and western regions.

Cashew-Induced Oxalate Nephropathy: A Rare Cause of Acute Renal Failure.

We present a rare case of cashew-induced oxalate nephropathy in a 69 year old veteran male with history of type 2 diabetes mellitus, nephrolithiasis, and undiagnosed chronic kidney disease (CKD). Oxalate nephropathy is a rare cause of acute renal failure with poor prognosis. The various causes of oxalate nephropathy are categorized as primary or secondary hyperoxaluria. Primary hyperoxaluria is caused by genetic mutation in genes involved in the metabolism of glyoxylate. Secondary hyperoxaluria is caused by mal-absorptive state, excessive intake of oxalate-rich diet, inflammatory diseases, and medications such as orlistat and antibiotics. Diet-induced oxalate nephropathy is often identified after unexplained acute kidney injury in patients with underlying CKD. Definitive diagnosis requires renal biopsy as laboratory tests are non-specific. A simple dietary history in CKD patients during routine primary care visit may lead to early diagnosis and lead to prevention of acute renal failure and progression of renal disease.

Recognition of nonproline N-terminal residues by the Pro/N-degron pathway.

Eukaryotic N-degron pathways are proteolytic systems whose unifying feature is their ability to recognize proteins containing N-terminal (Nt) degradation signals called N-degrons, and to target these proteins for degradation by the 26S proteasome or autophagy. GID4, a subunit of the GID ubiquitin ligase, is the main recognition component of the proline (Pro)/N-degron pathway. GID4 targets proteins through their Nt-Pro residue or a Pro at position 2, in the presence of specific downstream sequence motifs. Here we show that human GID4 can also recognize hydrophobic Nt-residues other than Pro. One example is the sequence Nt-IGLW, bearing Nt-Ile. Nt-IGLW binds to wild-type human GID4 with a Kd of 16 µM, whereas the otherwise identical Nt-Pro-bearing sequence PGLW binds to GID4 more tightly, with a Kd of 1.9 µM. Despite this difference in affinities of GID4 for Nt-IGLW vs. Nt-PGLW, we found that the GID4-mediated Pro/N-degron pathway of the yeast Saccharomyces cerevisiae can target an Nt-IGLW-bearing protein for rapid degradation. We solved crystal structures of human GID4 bound to a peptide bearing Nt-Ile or Nt-Val. We also altered specific residues of human GID4 and measured the affinities of resulting mutant GID4s for Nt-IGLW and Nt-PGLW, thereby determining relative contributions of specific GID4 residues to the GID4-mediated recognition of Nt-Pro vs. Nt-residues other than Pro. These and related results advance the understanding of targeting by the Pro/N-degron pathway and greatly expand the substrate recognition range of the GID ubiquitin ligase in both human and yeast cells.

Evaluating the potential benefit of reduced planning target volume margins for low and intermediate risk patients with prostate cancer using real-time electromagnetic tracking.

PURPOSE: The aim of this study is to quantify and describe the feasibility, clinical outcomes, and patient-reported outcomes of reduced planning target volume (PTV) margins for prostate cancer treatment using real-time, continuous, intrafraction monitoring with implanted radiation frequency transponder beacons. METHODS AND MATERIALS: For this prospective, nonrandomized trial, the Calypso localization system was used for intrafraction target localization in 31 patients with a PTV margin reduced to 2 mm in all directions. A total of 1333 fractions were analyzed with respect to movement of the prostate, pauses and interruptions, and dosimetric data. Pre- and posttreatment quality-of-life scores were tracked at baseline, during treatment, and up to 24 months after treatment. RESULTS: The mean time of daily treatment was 10 minutes, with 96.1% of all treatments falling within a 20-minute treatment window standard. On average, beacon motion exceeded 3 mm during active treatment only 1.76% of the time. The average length of treatment interruption was 34.2 seconds, with an average of 1 interruption every 3.39 fractions. The displacement or excursion of the prostate was the greatest in the superior or inferior dimension (0.11 mm and 0.09 mm, respectively) and anterior or posterior dimension (0.07 mm and 0.13 mm, respectively), followed by the left or right dimension (0.05 mm and 0.06 mm, respectively). At 6 months, patients demonstrated a smaller change in Expanded Prostate Cancer Index Composite scores than the ProtecT comparator group (decreased short-term morbidity). However, in the Bowel and Urinary domains at 12 and 24 months, there was no significant difference. CONCLUSIONS: Our data confirm and support that the use of Calypso tracking with intensity modulated radiation therapy reliably provides minimal disruption to daily treatments and overall time of treatment, with the PTV only moving outside of a 3-mm margin < 2% of the time. The use of a 3-mm PTV margin provides adequate dosimetric coverage while minimizing genitourinary and gastrointestinal toxicity.

Effect of Mobile Health Interventions on the Secondary Prevention of Cardiovascular Disease: Systematic Review and Meta-analysis.

BACKGROUND: Despite the strong uptake of mobile health (mhealth) technology targeted at cardiovascular care, it is still unclear if this improves adherence to therapy and patient-related outcomes in those with established cardiovascular disease. METHODS: A systematic search of English and Chinese language studies was conducted to investigate the benefit of mhealth technology for the secondary prevention of cardiovascular disease. RESULTS: Twenty-seven studies with 5165 patients were included in the systematic review. Patients in the mhealth group showed increased adherence to medical therapy (odds ratio [OR], 4.51; P < 0.00001), as well as increased adherence to pharmacologic and nonpharmacologic therapy (OR, 3.86; P < 0.00001). Patients in the mhealth group showed the ability to meet recommended blood pressure targets (OR, 2.80; P < 0.001) with a trend toward the ability to meet exercise goals (OR, 2.55; P = 0.07), however, no significant difference in smoking cessation (OR, 1.42; P = 0.45) and the ability to meet lipid target levels (OR, 1.16; P = 0.29) was found. Patients in the mhealth group did not show a reduction in hospital readmission (OR, 0.93; P = 0.96), with a small number of studies showing a reduction in angina (OR, 0.23; P = 0.005), and a decrease in transient ischemic attack/stroke recurrence in those with cerebrovascular disease (OR, 0.18; P < 0.0001) and a trend toward lower observed mortality rate (OR, 0.19; P = 0.06). CONCLUSIONS: The mhealth group compared with the usual care group had increased adherence to medical therapy, ability to reach blood pressure targets, exercise goals, and showed less anxiety and increased awareness of diet and exercise. There was no difference in smoking cessation, ability to meet low-density lipoprotein cholesterol targets, and hospital readmission.

Development of a mobile phone-based intervention to improve adherence to secondary prevention of coronary heart disease in China.

Coronary heart disease (CHD) is a major disease burden globally and in China, but secondary prevention among CHD patients remains insufficient. Mobile health (mHealth) technology holds promise for improving secondary prevention but few previous studies included both provider-facing and patient-directed measures. We conducted a physician needs assessment survey (n = 59), physician interviews (n = 6), one focus group and a short cellphone message validation survey (n = 14) in Shanghai and Hainan, China. Based on these results, we developed a multifaceted mHealth intervention that includes: (1) a provider-facing bilingual mobile app guiding prescription of evidence-based medications for secondary prevention and (2) a patient-directed short messaging system automatically sending reminders to patients regarding medication adherence and lifestyle changes (4-5 messages per week for 12 weeks). This combined intervention has the potential to improve secondary prevention of CHD and to be adapted to other countries and healthcare conditions.

Deep inspiration breath hold with electromagnetic confirmation of chest wall position for adjuvant therapy of left-sided breast cancer: Technique and accuracy.

PURPOSE: With most patients now living long after their breast cancer diagnosis, minimizing long-term side effects of breast cancer treatment, such as reducing late cardiac and pulmonary side effects of radiation therapy (RT), is particularly important. It is now possible to use an electromagnetic tracking system to allow real-time tracking of chest wall (CW) position during the delivery of RT. Here, we report our experience using electromagnetic surface transponders as an added measure of CW position during deep inspiration breath hold (DIBH). METHODS AND MATERIALS: We conducted a single-institution institutional review board-approved retrospective review of 15 female left-sided breast cancer patients treated between July 2012 and June 2013 with conventional whole breast radiation. We compared daily port films with treatment planning digitally reconstructed radiographs to establish daily setup accuracy, then used Calypso tracings to compare the position of the CW during the daily port film with the position of the CW during that day's treatment to determine the reproducibility of the breath hold position. Finally, we created competing treatment plans not using DIBH and used a paired t test to compare mean heart (MH) and left anterior descending (LAD) coronary artery dose between the 2 techniques. RESULTS: Mean total error (inter- and intrafraction) was dominated by interfraction error and was greatest in the longitudinal direction with a mean of 2.13 mm and 2 standard deviations of 8.2 mm. DIBH significantly reduced MH and LAD dose versus free breathing plans (MH, 1.26 Gy vs 2.84 Gy, P ≤ .001; LAD, 5.49 Gy vs 18.15 Gy, P ≤ .001). CONCLUSIONS: This study demonstrates that DIBH with electromagnetic confirmation of CW position is feasible, and allows potential improvement in the accurate delivery of adjuvant RT therapy for breast cancer.

Capicua regulates cell proliferation downstream of the receptor tyrosine kinase/ras signaling pathway.

Signaling via the receptor tyrosine kinase (RTK)/Ras pathway promotes tissue growth during organismal development and is increased in many cancers [1]. It is still not understood precisely how this pathway promotes cell growth (mass accumulation). In addition, the RTK/Ras pathway also functions in cell survival, cell-fate specification, terminal differentiation, and progression through mitosis [2-7]. An important question is how the same canonical pathway can elicit strikingly different responses in different cell types. Here, we show that the HMG-box protein Capicua (Cic) restricts cell growth in Drosophila imaginal discs, and its levels are, in turn, downregulated by Ras signaling. Moreover, unlike normal cells, the growth of cic mutant cells is undiminished in the complete absence of a Ras signal. In addition to a general role in growth regulation, the importance of cic in regulating cell-fate determination downstream of Ras appears to vary from tissue to tissue. In the developing eye, the analysis of cic mutants shows that the functions of Ras in regulating growth and cell-fate determination are separable. Thus, the DNA-binding protein Cic is a key downstream component in the pathway by which Ras regulates growth in imaginal discs.

An overexpression screen in Drosophila for genes that restrict growth or cell-cycle progression in the developing eye.

We screened for genes that, when overexpressed in the proliferating cells of the eye imaginal disc, result in a reduction in the size of the adult eye. After crossing the collection of 2296 EP lines to the ey-GAL4 driver, we identified 46 lines, corresponding to insertions in 32 different loci, that elicited a small eye phenotype. These lines were classified further by testing for an effect in postmitotic cells using the sev-GAL4 driver, by testing for an effect in the wing using en-GAL4, and by testing for the ability of overexpression of cycE to rescue the small eye phenotype. EP lines identified in the screen encompass known regulators of eye development including hh and dpp, known genes that have not been studied previously with respect to eye development, as well as 19 novel ORFs. Lines with insertions near INCENP, elB, and CG11518 were characterized in more detail with respect to changes in growth, cell-cycle phasing, and doubling times that were elicited by overexpression. RNAi-induced phenotypes were also analyzed in SL2 cells. Thus overexpression screens can be combined with RNAi experiments to identify and characterize new regulators of growth and cell proliferation.