Control of Paneth cell function by HuR regulates gut mucosal growth by altering stem cell activity.

Rapid self-renewal of the intestinal epithelium requires the activity of intestinal stem cells (ISCs) that are intermingled with Paneth cells (PCs) at the crypt base. PCs provide multiple secreted and surface-bound niche signals and play an important role in the regulation of ISC proliferation. Here, we show that control of PC function by RNA-binding protein HuR via mitochondria affects intestinal mucosal growth by altering ISC activity. Targeted deletion of HuR in mice disrupted PC gene expression profiles, reduced PC-derived niche factors, and impaired ISC function, leading to inhibited renewal of the intestinal epithelium. Human intestinal mucosa from patients with critical surgical disorders exhibited decreased levels of tissue HuR and PC/ISC niche dysfunction, along with disrupted mucosal growth. HuR deletion led to mitochondrial impairment by decreasing the levels of several mitochondrial-associated proteins including prohibitin 1 (PHB1) in the intestinal epithelium, whereas HuR enhanced PHB1 expression by preventing microRNA-195 binding to the Phb1 mRNA. These results indicate that HuR is essential for maintaining the integrity of the PC/ISC niche and highlight a novel role for a defective PC/ISC niche in the pathogenesis of intestinal mucosa atrophy.

Choosing Wisely For Critical Care: The Next Five.

OBJECTIVES: To formulate new "Choosing Wisely" for Critical Care recommendations that identify best practices to avoid waste and promote value while providing critical care. DATA SOURCES: Semistructured narrative literature review and quantitative survey assessments. STUDY SELECTION: English language publications that examined critical care practices in relation to reducing cost or waste. DATA EXTRACTION: Practices assessed to add no value to critical care were grouped by category. Taskforce assessment, modified Delphi consensus building, and quantitative survey analysis identified eight novel recommendations to avoid wasteful critical care practices. These were submitted to the Society of Critical Care Medicine membership for evaluation and ranking. DATA SYNTHESIS: Results from the quantitative Society of Critical Care Medicine membership survey identified the top scoring five of eight recommendations. These five highest ranked recommendations established Society of Critical Care Medicine's Next Five "Choosing" Wisely for Critical Care practices. CONCLUSIONS: Five new recommendations to reduce waste and enhance value in the practice of critical care address invasive devices, proactive liberation from mechanical ventilation, antibiotic stewardship, early mobilization, and providing goal-concordant care. These recommendations supplement the initial critical care recommendations from the "Choosing Wisely" campaign.

Acute Care Surgery Model and Outcomes in Emergency General Surgery.

BACKGROUND: Annually, more than 2 million patients are admitted with emergency general surgery (EGS) conditions. Emergency general surgery cases comprise 11% of all general surgery operations, yet account for 47% of mortalities and 28% of complications. Using the statewide general surgery Michigan Surgical Quality Collaborative (MSQC) data, we previously confirmed that wide variations in EGS outcomes were unrelated to case volume/complexity. We assessed whether patient care model (PCM) affected EGS outcomes. STUDY DESIGN: There were 34 hospitals that provided data for PCM, resources, surgeon practice patterns, and comprehensive MSQC patient data from January 1, 2008 to December 31, 2016 (general surgery cases = 126,494; EGS cases = 39,023). Risk and reliability adjusted outcomes were determined using hierarchical multivariable logistic regression analysis with multiple clinical covariates and PCM. RESULTS: The general surgery service (GSS) model was more common (73%) than acute care surgery (ACS, 27%). Emergency general surgery 30-day mortality was 4.1% (intestinal resections 11.6%). The ACS model was associated with a reduction of 31% in mortality (odds ratio [OR] 0.69; 95% CI 0.52-0.92] for EGS cases, related to decreased mortality in the intestinal resection cohort (8.5% ACS vs 12% GSS, p < 0.0001). Morbidity in EGS was 17.4% (9.7% elective); highest (40%) in intestinal resection, and PCM did not affect morbidity. We identified specific variables for an optimal EGS risk adjustment model. CONCLUSIONS: This is the first multi-institutional study to identify that an ACS model is associated with a significant 31% mortality reduction in EGS using prospectively collected, clinically obtained, research-quality collaborative data. We identified that new risk adjustment models are necessary for EGS outcomes evaluations.

Safety and Tolerability of Intravenous Valproic Acid in Healthy Subjects: A Phase I Dose-Escalation Trial.

BACKGROUND: Valproic acid, a histone deacetylase inhibitor, has beneficial effects in the setting of cancer, neurologic diseases, and traumatic injuries. In animal models of traumatic injury, a single dose of valproic acid has been shown to reduce mortality. The purpose of this trial was to determine the maximum tolerated single dose of intravenous valproic acid in healthy humans. METHODS: A double-blinded, placebo-controlled, dose-escalation trial design was used to identify dose-limiting toxicities in healthy subjects who received a single dose of intravenous valproic acid. Patients were monitored for adverse events and data were collected for pharmacokinetic, pharmacodynamic, and safety profiling of valproic acid. RESULTS: Fifty-nine healthy subjects (mean 30 ± 12 years) were enrolled. Forty-four subjects received valproic acid in doses from 15 to 150 mg/kg. The most common adverse events were hypoacusis (n = 19), chills (n = 18), and headache (n = 16). The maximum tolerated dose was 140 mg/kg. Dose-limiting toxicities included headache and nausea lasting longer than 12 h. No drug-related abnormalities were seen in other safety measures including laboratory tests, hemodynamic parameters, cardiac rhythm monitoring, and cognitive testing. A two-compartment model was predictive of valproic acid concentration-time profiles, with a strong correlation (R 2 = 0.56) observed between the number of reported adverse events and the dose level. CONCLUSIONS: The maximum tolerated dose of intravenous valproic acid in healthy subjects is 140 mg/kg. This is significantly higher than the previously established maximum tolerated dose of 60-75 mg/kg. Next, the safety and tolerability of high-dose valproic acid will be tested in trauma patients in hemorrhagic shock. ClinicalTrials.gov Identifier: NCT01951560.

Pain management for blunt thoracic trauma: A joint practice management guideline from the Eastern Association for the Surgery of Trauma and Trauma Anesthesiology Society.

INTRODUCTION: Thoracic trauma is the second most prevalent nonintentional injury in the United States and is associated with significant morbidity. Analgesia for blunt thoracic trauma was first addressed by the Eastern Association for the Surgery of Trauma (EAST) with a practice management guideline published in 2005. Since that time, it was hypothesized that there have been advances in the analgesic management for blunt thoracic trauma. As a result, updated guidelines for this topic using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) framework recently adopted by EAST are presented. METHODS: Five systematic reviews were conducted using multiple databases. The search retrieved articles regarding analgesia for blunt thoracic trauma from January1967 to August 2015. Critical outcomes of interest were analgesia, postoperative pulmonary complications, changes in pulmonary function tests, need for endotracheal intubation, and mortality. Important outcomes of interest examined included hospital and intensive care unit length of stay. RESULTS: Seventy articles were identified. Of these, 28 articles were selected to construct the guidelines. The overall risk of bias for all studies was high. The majority of included studies examined epidural analgesia. Epidural analgesia was associated with lower short-term pain scores in most studies, but the quality and quantity of evidence were very low, and no firm evidence of benefit or harm was found when this modality was compared with other analgesic interventions. The quality of evidence for paravertebral block, intrapleural analgesia, multimodal analgesia, and intercostal nerve blocks was very low as assessed by GRADE. The limitations with the available literature precluded the formulation of strong recommendations by our panel. CONCLUSION: We propose two evidence-based recommendations regarding analgesia for patients with blunt thoracic trauma. The overall risk of bias for all studies was high. The limitations with the available literature precluded the formulation of strong recommendations by our panel. We conditionally recommend epidural analgesia and multimodal analgesia as options for patients with blunt thoracic trauma, but the overall quality of evidence supporting these modalities is low in trauma patients. These recommendations are based on very low-quality evidence but place a high value on patient preferences for analgesia. These recommendations are in contradistinction to the previously published Practice Management Guideline published by EAST.

Improvement in acute care surgery medical student education and clerkships: use of feedback and loop closure.

BACKGROUND: The unpredictable and sometimes chaotic environment present in acute care surgery services (trauma, burn, surgical critical care, and nontrauma emergency surgery) can cause high levels of anxiety and stress that could impact a medical students' experience during their third year of medical school surgical clerkship. This negative perception perhaps is a determinant influence in diverting talented students into other medical subspecialties. We sought out to objectively identify potential areas of improvement through direct feedback and implement programmatic changes to address these areas. We hypothesized that as the changes were made, students' perception of the rotation would improve. MATERIALS AND METHODS: Review of end of clerkship third year of medical school trauma burn surgery rotation evaluations and comments was performed for the 2010-2011 academic year. Trends in negative feedback were identified and categorized into five areas for improvement as follows: logistics, student expectations, communication, team integration, and feedback. A plan was designed and implemented for each category. Feedback on improvements to the rotation was monitored via surveys and during monthly end of rotation face-to-face student feedback sessions with the rotation faculty facilitator and surgery clerkship director. Data were compiled and reviewed. RESULTS: Perceptions of the rotation markedly improved within the first month of the changes and continued to improve over the study time frame (2011-2013) in all five categories. We also observed an increase in the number of students selecting a surgical residency in the National Resident Matching Program match from a low of 8% in 2009-2010 before any interventions to 25% after full implementation of the improvement measures in 2011-2012. CONCLUSIONS: A systematic approach using direct feedback from students to address service-specific issues improves perceptions of students on the educational value of a busy trauma-burn acute care surgery service and may have a positive influence on students considering surgical careers to pursue a surgical specialty.

Reduction in Venous Thromboembolism Events: Trauma Performance Improvement and Loop Closure Through Participation in a State-Wide Quality Collaborative.

BACKGROUND: The Michigan Trauma Quality Improvement Program (MTQIP) is a collaborative quality initiative sponsored by Blue Cross Blue Shield of Michigan and Blue Care Network (BCBSM/BCN). The MTQIP benchmark reports identified our trauma center as a high outlier for venous thromboembolism (VTE) episodes. This study outlines the performance improvement (PI) process used to reduce the rate of VTE using MTQIP infrastructure. STUDY DESIGN: Trauma patients admitted for > 24 hours, with an Injury Severity Score (ISS) ≥ 5, were included in this study. We performed a preliminary analysis examining prophylaxis drug type to VTE, adjusted by patient confounders and timing of first dose, using MTQIP data abstracted for our hospital. It showed that patients receiving enoxaparin had a VTE rate that was half that of those receiving unfractionated heparin (odds ratio 0.46, 95% CI 0.25 to 0.85). Guided by these results, we produced the following plan: consolidation to single VTE prophylaxis agent and dose, focused education of providers, initiation of VTE prophylaxis for all patients-with clear exception rules-and dose withholding minimization. Results were monitored using the MTQIP platform. RESULTS: After implementation of our focused PI plan, the VTE rate decreased from 6.2% (n = 36/year) to 2.6% (n = 14/year). Our trauma center returned to average performance status within MTQIP. CONCLUSIONS: Participation in MTQIP provided identification of trauma center outlier status for the outcome of VTE. Analysis of MTQIP data allowed creation of a local action plan. The MTQIP infrastructure supported execution and monitoring of the action plan consistent with loop-closure practices, as advocated by the American College of Surgeons Committee on Trauma, and a positive performance improvement result was achieved with VTE reduction.

An evidence-based approach to patient selection for emergency department thoracotomy: A practice management guideline from the Eastern Association for the Surgery of Trauma.

BACKGROUND: Within the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework, we performed a systematic review and developed evidence-based recommendations to answer the following PICO (Population, Intervention, Comparator, Outcomes) question: should patients who present pulseless after critical injuries (with and without signs of life after penetrating thoracic, extrathoracic, or blunt injuries) undergo emergency department thoracotomy (EDT) (vs. resuscitation without EDT) to improve survival and neurologically intact survival? METHODS: All patients who underwent EDT were included while those involving either prehospital resuscitative thoracotomy or operating room thoracotomy were excluded. Quantitative synthesis via meta-analysis was not possible because no comparison or control group (i.e., survival or neurologically intact survival data for similar patients who did not undergo EDT) was available for the PICO questions of interest. RESULTS: The 72 included studies provided 10,238 patients who underwent EDT. Patients presenting pulseless after penetrating thoracic injury had the most favorable EDT outcomes both with (survival, 182 [21.3%] of 853; neurologically intact survival, 53 [11.7%] of 454) and without (survival, 76 [8.3%] of 920; neurologically intact survival, 25 [3.9%] of 641) signs of life. In patients presenting pulseless after penetrating extrathoracic injury, EDT outcomes were more favorable with signs of life (survival, 25 [15.6%] of 160; neurologically intact survival, 14 [16.5%] of 85) than without (survival, 4 [2.9%] of 139; neurologically intact survival, 3 [5.0%] of 60). Outcomes after EDT in pulseless blunt injury patients were limited with signs of life (survival, 21 [4.6%] of 454; neurologically intact survival, 7 [2.4%] of 298) and dismal without signs of life (survival, 7 [0.7%] of 995; neurologically intact survival, 1 [0.1%] of 825). CONCLUSION: We strongly recommend that patients who present pulseless with signs of life after penetrating thoracic injury undergo EDT. We conditionally recommend EDT for patients who present pulseless and have absent signs of life after penetrating thoracic injury, present or absent signs of life after penetrating extrathoracic injury, or present signs of life after blunt injury. Lastly, we conditionally recommend against EDT for pulseless patients without signs of life after blunt injury. LEVEL OF EVIDENCE: Systematic review/guideline, level III.

Methylene blue for burn-induced vasoplegia: case report and review of literature.

We report the use of a single dose of methylene blue in a patient with burn-induced vasoplegia refractory to fluids, vasopressors, and steroids. Administration of methylene blue allowed for cessation of epinephrine infusion within 2 hours of administration, and reduction in excessive fluid resuscitation. The patient's clinical course continued for 2 months and was complicated by severe acute respiratory distress syndrome, pneumonia, septic shock, poor skin graft adherence, renal failure requiring continuous renal replacement therapy, cutaneous mucormycosis, and ultimately, withdrawal of care and death. Despite the eventual outcome, this is the longest reported survival following methylene blue administration for vasoplegia secondary to burn injury.

Clostridium difficile infection: update on diagnosis, epidemiology, and treatment strategies.

BACKGROUND: Clostridium difficile infection (CDI) has increased in incidence and severity over the past quarter century, and is now considered a major cause of healthcare-associated infections. METHODS: Review of the pertinent English-language medical literature. RESULTS: There has been a substantial change in the management of CDI. The emergence of the NAP1/BI/O27 strain in the early to mid-2000s has been associated with more severe forms of CDI. The pathophysiology, epidemiology, clinical manifestations and diagnosis, as well as new strategies for medical and surgical management are discussed in this review. CONCLUSIONS: Clostridium difficile infection can range from benign diarrhea to severe disease associated with substantial morbidity and mortality. Treatment modalities vary based on disease severity and timing of onset. The mainstay of medical treatment remains metronidazole and oral/rectal vancomycin. New management strategies are evolving, including adjunctive treatments such as monoclonal antibodies, vaccination, and fecal transplant. In patients with severe disease or clinical deterioration, early surgical consultation for total colectomy or loop ileostomy may be life-saving. Infection control measures are vital to mitigating the spread of CDI.

Emergent versus elective cholecystectomy: conversion rates and outcomes.

BACKGROUND: Laparoscopic cholecystectomy (LC) is the procedure of choice for treatment of cholelithiasis/cholecystitis. Conversion rates (CR) to open cholecystectomy (OC) have been reported previously as 5-15% in elective cases, and up to 25% in patients with acute cholecystitis. We examined the CR in a tertiary-care academic hospital and a statewide surgery quality collaborative, and to compare complications and outcomes in elective and emergency cholecystectomy. METHODS: Prospective data were obtained from: 1) Non-Trauma Emergency Surgery (NTE) database of all emergent cholecystectomies 1/1/2008-12/31/2009; and 2) Michigan Surgical Quality Collaborative (MSQC) database with a random sample of 20-30% of all operations performed 1/1/2005-12/31/2010, including both University of Michigan (UM) data and statewide data from 34 participating hospitals. Patient characteristics, CR, and outcomes were compared for emergent vs. elective cases. RESULTS: Non-trauma ES patients had a mean hospital length of stay (HLOS) of 4.9 d. Open cholecystectomy-HLOS was greater (4.0, LC; 7.9 laparoscopic converted to open cholecystectomy; 8.7, OC, p<0.0001); mortality was 0.35% and CR was 17.5%. In the UM-MSQC dataset, OC-HLOS was greater (6.8 OC vs. 4.6 LC, p<0.001); mortality was 0.65%; CR was 9.1% in elective cases and 14.9% in emergent cases. CR was almost two-fold higher [17.5% of all NTE cholecystectomies vs. 9.1% of UM-MSQC elective cholecystectomies (p=0.00078)]. The statewide MSQC cholecystectomy data showed significantly increased HLOS in emergent cholecystectomy patients (4.34 vs. 2.65 d; p<0.0001). Morbidity (8.8 vs. 3.7%) and mortality (2.6 vs. 0.5%) rates were also significantly higher in emergent vs. elective cholecystectomies (p<0.0001). CONCLUSION: In NTE patients requiring cholecystectomy, CR is almost two-fold higher but is lower than in reports published previously (25%). However, there is a wide variability in mortality and morbidity for emergency cholecystectomy in both unadjusted and risk-adjusted analyses. Further studies are required to determine modifiable risk factors to improve outcomes in emergency cholecystectomy.

Mechanisms of cardiac and renal dysfunction in patients dying of sepsis.

RATIONALE: The mechanistic basis for cardiac and renal dysfunction in sepsis is unknown. In particular, the degree and type of cell death is undefined. OBJECTIVES: To evaluate the degree of sepsis-induced cardiomyocyte and renal tubular cell injury and death. METHODS: Light and electron microscopy and immunohistochemical staining for markers of cellular injury and stress, including connexin-43 and kidney-injury-molecule-1 (Kim-1), were used in this study. MEASUREMENTS AND MAIN RESULTS: Rapid postmortem cardiac and renal harvest was performed in 44 septic patients. Control hearts were obtained from 12 transplant and 13 brain-dead patients. Control kidneys were obtained from 20 trauma patients and eight patients with cancer. Immunohistochemistry demonstrated low levels of apoptotic cardiomyocytes (<1-2 cells per thousand) in septic and control subjects and revealed redistribution of connexin-43 to lateral membranes in sepsis (P < 0.020). Electron microscopy showed hydropic mitochondria only in septic specimens, whereas mitochondrial membrane injury and autophagolysosomes were present equally in control and septic specimens. Control kidneys appeared relatively normal by light microscopy; 3 of 20 specimens showed focal injury in approximately 1% of renal cortical tubules. Conversely, focal acute tubular injury was present in 78% of septic kidneys, occurring in 10.3 ± 9.5% and 32.3 ± 17.8% of corticomedullary-junction tubules by conventional light microscopy and Kim-1 immunostains, respectively (P < 0.01). Electron microscopy revealed increased tubular injury in sepsis, including hydropic mitochondria and increased autophagosomes. CONCLUSIONS: Cell death is rare in sepsis-induced cardiac dysfunction, but cardiomyocyte injury occurs. Renal tubular injury is common in sepsis but presents focally; most renal tubular cells appear normal. The degree of cell injury and death does not account for severity of sepsis-induced organ dysfunction.

Common complications in the critically ill patient.

Critically ill patients in intensive care units are subject to many complications associated with therapy. Many of these complications are health care-associated infections and are related to indwelling devices, including ventilator-associated pneumonia, central line-associated bloodstream infection, catheter-associated urinary tract infection; surgical site infection, venous thromboembolism, deep venous thrombosis, and pulmonary embolus are other common complications. All efforts should be undertaken to prevent these complications in surgical critical care, and national efforts are under way for each of these complications. In this article, epidemiology, risk factors, diagnosis, treatment, and prevention of these complications in critically ill patients are discussed.

Immunosuppression in patients who die of sepsis and multiple organ failure.

CONTEXT: Severe sepsis is typically characterized by initial cytokine-mediated hyperinflammation. Whether this hyperinflammatory phase is followed by immunosuppression is controversial. Animal studies suggest that multiple immune defects occur in sepsis, but data from humans remain conflicting. OBJECTIVES: To determine the association of sepsis with changes in host innate and adaptive immunity and to examine potential mechanisms for putative immunosuppression. DESIGN, SETTING, AND PARTICIPANTS: Rapid postmortem spleen and lung tissue harvest was performed at the bedsides of 40 patients who died in intensive care units (ICUs) of academic medical centers with active severe sepsis to characterize their immune status at the time of death (2009-2011). Control spleens (n = 29) were obtained from patients who were declared brain-dead or had emergent splenectomy due to trauma; control lungs (n = 20) were obtained from transplant donors or from lung cancer resections. MAIN OUTCOME MEASURES: Cytokine secretion assays and immunophenotyping of cell surface receptor-ligand expression profiles were performed to identify potential mechanisms of immune dysfunction. Immunohistochemical staining was performed to evaluate the loss of immune effector cells. RESULTS: The mean ages of patients with sepsis and controls were 71.7 (SD, 15.9) and 52.7 (SD, 15.0) years, respectively. The median number of ICU days for patients with sepsis was 8 (range, 1-195 days), while control patients were in ICUs for 4 or fewer days. The median duration of sepsis was 4 days (range, 1-40 days). Compared with controls, anti-CD3/anti-CD28-stimulated splenocytes from sepsis patients had significant reductions in cytokine secretion at 5 hours: tumor necrosis factor, 5361 (95% CI, 3327-7485) pg/mL vs 418 (95% CI, 98-738) pg/mL; interferon γ, 1374 (95% CI, 550-2197) pg/mL vs 37.5 (95% CI, -5 to 80) pg/mL; interleukin 6, 3691 (95% CI, 2313-5070) vs 365 (95% CI, 87-642) pg/mL; and interleukin 10, 633 (95% CI, -269 to 1534) vs 58 (95% CI, -39 to 156) pg/mL; (P < .001 for all). There were similar reductions in 5-hour lipopolysaccharide-stimulated cytokine secretion. Cytokine secretion in sepsis patients was generally less than 10% that in controls, independent of age, duration of sepsis, corticosteroid use, and nutritional status. Although differences existed between spleen and lung, flow cytometric analysis showed increased expression of selected inhibitory receptors and ligands and expansion of suppressor cell populations in both organs. Unique differences in cellular inhibitory molecule expression existed in immune cells isolated from lungs of sepsis patients vs cancer patients and vs transplant donors. Immunohistochemical staining showed extensive depletion of splenic CD4, CD8, and HLA-DR cells and expression of ligands for inhibitory receptors on lung epithelial cells. CONCLUSIONS: Patients who die in the ICU following sepsis compared with patients who die of nonsepsis etiologies have biochemical, flow cytometric, and immunohistochemical findings consistent with immunosuppression. Targeted immune-enhancing therapy may be a valid approach in selected patients with sepsis.

Measurement of chemoresistance markers in patients with stage III non-small cell lung cancer: a novel approach for patient selection.

BACKGROUND: The long-term survival of patients with stage III non-small cell lung cancer treated with a combination of chemotherapy and radiation is 10% to 20%. Survival could potentially be increased and toxicity limited if one could identify patients most likely to respond to a particular treatment regimen. This project prospectively evaluated a panel of potential immunohistochemical markers of chemoresistance in a population of patients with pathology-confirmed stage III non-small cell lung cancer in order to determine the prognostic value of each marker in relation to response to chemotherapy or survival. METHODS: Immunohistochemical staining was performed on histologically positive mediastinal nodal specimens obtained from 59 patients (mean age, 62 years; range, 41 to 79 years) without evidence of distant metastatic disease treated with navelbine-based chemotherapy and external beam radiation therapy between 1996 and 2001. Included were markers for apoptosis (p53, bcl-2), drug efflux/degradation (MDR, GST-pi), growth factors (EGFr, Her2-neu), and mismatch repair (hMLH1, hMSH2). After chemotherapy, patients underwent radiologic evaluation for response measured by standard criteria. RESULTS: After a median 41 months of follow-up (range, 17 to 55 months), 43 patients had recurrent disease and 38 of these patients were dead of cancer (median cancer-free survival of 10 months and overall survival of 18 months). Patients who demonstrated a complete or partial response (n = 38) had a significantly improved survival (p = 0.002) compared with those with stable or progressive cancer (n = 21). Multivariable Cox step-wise regression analysis of marker expression associated overexpression of p53 and low expression of hMSH2 with poor treatment response and cancer death. CONCLUSIONS: These preliminary data suggest that marker expression may allow the separation of patients into low- and high-risk groups with respect to survival after combined navelbine-based chemotherapy and XRT. This could represent a novel method of selecting patients for a particular treatment regimen if these data are reproduced in a larger prospective trial.