Commissioning an Anthropomorphic Spine and Lung Phantom for Remote Dose Verification of Institutions Participating in RTOG 0631

The RPC developed a new phantom to ensure comparable and consistent radiation administration in spinal radiosurgery clinical trials. This study assessed the phantom’s dosimetric and anatomic utility. The ‘spine phantom’ is a water filled thorax with anatomy encountered in spinal radiosurgery: target volume, vertebral column, spinal canal, esophagus, heart, and lungs. The dose to the target volume was measured with axial and sagittal planes of radiochromic film and thermoluminescent dosimeters (TLD). The dose distributions were measured with the radiochromic film calibrated to the absolute dose measured by the TLD. Four irradiations were administered: a four angle box plan, a seven angle conformal plan, a seven angle IMRT plan, and a nine angle IMRT plan (denoted as IMRT plan #1 and plan #2, respectively). In each plan, at least 95% of the defined tumor volume received 8 Gy. For each irradiation the planned and administered dose distributions were registered via pinpricks, and compared using point dose measurements, dose profiles, isodose distributions, and gamma analyses. Based on previous experience at the RPC, a gamma analysis was considering passing if greater than 95% of pixels passed the criteria of 5% dose difference and 3 mm distance-to-agreement. Each irradiation showed acceptable agreement in the qualitative assessments and exceeded the 95% passing rate at the 5% / 3 mm criteria, except IMRT plan #1, which was determined to have been poorly localized during treatment administration. The measured and planned dose distributions demonstrated acceptable agreement at the 5% / 3 mm criteria, and the spine phantom was determined to be a useful tool for the remote assessment of an institution’s treatment planning and dose delivery regimen.

Assessment of Collimator Jaw Optimization in Reducing Normal Tissue Irradiation with Intensity Modulated Radiation Therapy

Purpose: To evaluate normal tissue dose reduction in step-and-shoot intensity-modulated radiation therapy (IMRT) on the Varian 2100 platform by tracking the multileaf collimator (MLC) apertures with the accelerator jaws. Methods: Clinical radiation treatment plans for 10 thoracic, 3 pediatric and 3 head and neck patients were converted to plans with the jaws tracking each segment’s MLC apertures. Each segment was then renormalized to account for the change in collimator scatter to obtain target coverage within 1% of that in the original plan. The new plans were compared to the original plans in a commercial radiation treatment planning system (TPS). Reduction in normal tissue dose was evaluated in the new plan by using the parameters V5, V10, and V20 in the cumulative dose-volume histogram for the following structures: total lung minus GTV (gross target volume), heart, esophagus, spinal cord, liver, parotids, and brainstem. In order to validate the accuracy of our beam model, MLC transmission measurements were made and compared to those predicted by the TPS. Results: The greatest change between the original plan and new plan occurred at lower dose levels. The reduction in V20 was never more than 6.3% and was typically less than 1% for all patients. The reduction in V5 was 16.7% maximum and was typically less than 3% for all patients. The variation in normal tissue dose reduction was not predictable, and we found no clear parameters that indicated which patients would benefit most from jaw tracking. Our TPS model of MLC transmission agreed with measurements with absolute transmission differences of less than 0.1 % and thus uncertainties in the model did not contribute significantly to the uncertainty in the dose determination. Conclusion: The amount of dose reduction achieved by collimating the jaws around each MLC aperture in step-and-shoot IMRT does not appear to be clinically significant.

THE ROLE OF RECEPTOR TYROSINE KINASE AXL IN PANCREATIC DUCTAL ADENOCARCINOMA AND ITS REGULATION BY HEMATOPOIETIC PROGENITOR KINASE 1

Pancreatic ductal adenocarcinoma (PDA) is one of the most aggressive malignancies with less than 5% of five year survival rate. New molecular markers and new therapeutic targets are urgently needed for patients with PDA. Oncogenic receptor tyrosine kinase Axl has been reported to be overexpressed in many types of human malignancies, including diffuse glioma, melanoma, osteosarcoma, and carcinomas of lung, colon, prostate, breast, ovary, esophagus, stomach, and kidney. However, the expression and functions of Axl in PDA are unclear. We hypothesized that Axl contributes to the development and progression of PDA. We examined Axl expression in 54 human PDA samples and their paired benign pancreatic tissue by immunohistochemistry, we found that Axl was overexpressed in 70% of stage II PDAs, but only 22% of benign ducts (P=0.0001). Axl overexpression was associated with higher frequencies of distant metastasis and was an independent prognostic factor for both poor overall and recurrence-free survivals in patients with stage II PDA (p = 0.03 and 0.04). Axl silencing by shRNA in pancreatic cancer cell lines, panc-28 and Panc-1, decreased tumor cell migration and invasion and sensitized PDA cells to apoptosis stimuli such as γ-irradiation and serum starvation. In addition, we found that Axl-mediated Akt and NF-κB activation and up regulation of MMP2 were involved in the invasion, migration and survival of PDA cells. Thus, we demonstrate that Axl plays an important role in the development and progression of PDA. Targeting Axl signaling pathway may represent a new approach for the treatment of PDA. To understand the molecular mechanisms of Axl overexpression in PDA, we found that Axl expression was down-regulated by hematopoietic progenitor kinase 1 (HPK1), a newly identified tumor suppressor in PDA. HPK1 is lost in over 95% of PDAs. Restoration of HPK1 in PDA cells down-regulated Axl expression. HPK1-mediated Axl degradation was inhibited by leupeptin, baflomycin A1, and monensin, suggesting that HPK1-mediated Axl degradation was through endocytosis-lysosome pathway. HPK1 interacted with and phosphorylated dynamin, a critical component of endocytosis pathway. Overexpression of dominant negative form of dynamin blocked the HPK1-mediated Axl degradation. Therefore we concluded that HPK1-mediated Axl degradation was through endocytosis-lysosome pathway and loss of HPK1 expression may contribute to Axl overexpression in PDAs.

Implantation of Prophylactic Nonabsorbable Intraperitoneal Mesh in Patients With Peritonitis Is Safe and Feasible

BACKGROUND: Patients with peritonitis undergoing emergency laparotomy are at increased risk for postoperative open abdomen and incisional hernia. This study aimed to evaluate the outcome of prophylactic intraperitoneal mesh implantation compared with conventional abdominal wall closure in patients with peritonitis undergoing emergency laparotomy. METHOD: A matched case-control study was performed. To analyze a high-risk population for incisional hernia formation, only patients with at least two of the following risk factors were included: male sex, body mass index (BMI) >25 kg/m(2), malignant tumor, or previous abdominal incision. In 63 patients with peritonitis, a prophylactic nonabsorbable mesh was implanted intraperitoneally between 2005 and 2010. These patients were compared with 70 patients with the same risk factors and peritonitis undergoing emergency laparotomy over a 1-year period (2008) who underwent conventional abdominal closure without mesh implantation. RESULTS: Demographic parameters, including sex, age, BMI, grade of intraabdominal infection, and operating time were comparable in the two groups. Incidence of surgical site infections (SSIs) was not different between groups (61.9 vs. 60.3 %; p = 0.603). Enterocutaneous fistula occurred in three patients in the mesh group (4.8 %) and in two patients in the control group (2.9 %; p = 0.667). The incidence of incisional hernia was significantly lower in the mesh group (2/63 patients) than in the control group (20/70 patients) (3.2 vs. 28.6 %; p < 0.001). CONCLUSIONS: Prophylactic intraperitoneal mesh can be safely implanted in patients with peritonitis. It significantly reduces the incidence of incisional hernia. The incidences of SSI and enterocutaneous fistula formation were similar to those seen with conventional abdominal closure.

Transcriptional regulation of the mouse $\alpha$2(I) collagen gene

The mouse $\alpha$2(I) collagen gene is specifically expressed in a limited number of cell types in the body including fibroblasts and osteoblasts. We had previously shown that a promoter containing the sequences between $-$350 and +54 bp was expressed at low levels in a cell- and tissue-specific fashion in transgenic mice. Further studies suggested that the sequence between $-$315 and $-$284 bp could mediate cell- and tissue-specific expression of reporter genes in cell culture and in transgenic mice. We report here characterization of the proteins binding to this segment and propose a model for the cell-specific expression conferred by this sequence. In this study we also identified a strong enhancer for the mouse $\alpha$2(I) collagen gene located approximately 13.5 to 19.5 kb upstream of the transcriptional start site. This enhancer segment is characterized by the presence of three cell-specific hypersensitive sites and can drive high levels of cell-specific expression of a heterologous 220-bp mouse $\alpha$1(I) collagen promoter. In the course of this study, we identified a novel zinc finger transcription factor (designated murine epithelial zinc finger, mEZF) which was transiently expressed in the mesenchymal cells which give rise to the skeletal primordia and the metanephric kidney during the early stages of embryogenesis. In newborn mice, the mEZF gene is expressed at high levels in differentiated epithelial cells of the skin, oral mucosa, tongue, esophagus, stomach and colon. Chromosomal mapping suggested that the mEZF gene mapped to mouse Chromosome 4 and that the human homolog of mEZF would likely map to human Chromosome 9q31. This region of the human genome contains tumor suppressor genes for basal cell carcinomas of the skin as well as for squamous cell carcinomas of various organs. We cloned and characterized the human homolog of mEZF and mapped its chromosomal position as a first step in determining whether or not this gene plays a role in the development of these tumors. ^

Loss of β1-integrin-deficient cells during the development of endoderm-derived epithelia

Beta1-integrins (beta1) represent cell surface receptors which mediate cell-matrix and cell-cell interactions. Fässler and Meyer described chimeric mice containing transgenic cells that express the LacZ gene instead of the beta1 gene. They observed beta1-negative cells in all germ layers at embryonic day E 8.5. Later in development, using a glucose phosphate isomerase assay of homogenized tissue samples, high levels of transgenic cells were found in skeletal muscle and gut, low levels in lung, heart, and kidney and none in the liver and spleen (Fässler and Meyer 1995). In order to study which cell types require beta1 during development of the primitive gut including its derivatives, chimeric fetuses containing 15 to 25% transgenic cells were obtained at days E 14.5 and E 15.5. They were LacZ (beta-galactosidase) stained "en bloc" and cross-sectioned head to tail. In esophagus, trachea, lung, stomach, hindgut, and the future urinary bladder, we observed various mesoderm-derived beta1-negative cells (e.g. fibroblasts, chondrocytes, endothelial cells, and smooth muscle cells) but no beta1-negative epithelial cells. Since the epithelia of lung, esophagus, trachea, stomach, hindgut, and urinary bladder are derived from the endodermal gut tube, we hypothesize that beta1 is essential for the development and/or survival of the epithelia of the fore- and hindgut and its derivatives.

Swallowing Activity Assessed by Ambulatory Impedance-pH Monitoring Predicts Awake and Asleep Periods at Night

INTRODUCTION: Voluntary muscle activity, including swallowing, decreases during the night. The association between nocturnal awakenings and swallowing activity is under-researched with limited information on the frequency of swallows during awake and asleep periods. AIM: The aim of this study was to assess nocturnal swallowing activity and identify a cut-off predicting awake and asleep periods. METHODS: Patients undergoing impedance-pH monitoring as part of GERD work-up were asked to wear a wrist activity detecting device (Actigraph(®)) at night. Swallowing activity was quantified by analysing impedance changes in the proximal esophagus. Awake and asleep periods were determined using a validated scoring system (Sadeh algorithm). Receiver operating characteristics (ROC) analyses were performed to determine sensitivity, specificity and accuracy of swallowing frequency to identify awake and asleep periods. RESULTS: Data from 76 patients (28 male, 48 female; mean age 56 ± 15 years) were included in the analysis. The ROC analysis found that 0.33 sw/min (i.e. one swallow every 3 min) had the optimal sensitivity (78 %) and specificity (76 %) to differentiate awake from asleep periods. A swallowing frequency of 0.25 sw/min (i.e. one swallow every 4 min) was 93 % sensitive and 57 % specific to identify awake periods. A swallowing frequency of 1 sw/min was 20 % sensitive but 96 % specific in identifying awake periods. Impedance-pH monitoring detects differences in swallowing activity during awake and asleep periods. Swallowing frequency noticed during ambulatory impedance-pH monitoring can predict the state of consciousness during nocturnal periods

Trends and outcomes in the use of surgery and radiation for the treatment of locally advanced esophageal cancer: a propensity score adjusted analysis of the surveillance, epidemiology, and end results registry from 1998 to 2008

We examined outcomes and trends in surgery and radiation use for patients with locally advanced esophageal cancer, for whom optimal treatment isn't clear. Trends in surgery and radiation for patients with T1-T3N1M0 squamous cell or adenocarcinoma of the mid or distal esophagus in the Surveillance, Epidemiology, and End Results database from 1998 to 2008 were analyzed using generalized linear models including year as predictor; Surveillance, Epidemiology, and End Results doesn't record chemotherapy data. Local treatment was unimodal if patients had only surgery or radiation and bimodal if they had both. Five-year cancer-specific survival (CSS) and overall survival (OS) were analyzed using propensity-score adjusted Cox proportional-hazard models. Overall 5-year survival for the 3295 patients identified (mean age 65.1 years, standard deviation 11.0) was 18.9% (95% confidence interval: 17.3-20.7). Local treatment was bimodal for 1274 (38.7%) and unimodal for 2021 (61.3%) patients; 1325 (40.2%) had radiation alone and 696 (21.1%) underwent only surgery. The use of bimodal therapy (32.8-42.5%, P = 0.01) and radiation alone (29.3-44.5%, P < 0.001) increased significantly from 1998 to 2008. Bimodal therapy predicted improved CSS (hazard ratios [HR]: 0.68, P < 0.001) and OS (HR: 0.58, P < 0.001) compared with unimodal therapy. For the first 7 months (before survival curve crossing), CSS after radiation therapy alone was similar to surgery alone (HR: 0.86, P = 0.12) while OS was worse for surgery only (HR: 0.70, P = 0.001). However, worse CSS (HR: 1.43, P < 0.001) and OS (HR: 1.46, P < 0.001) after that initial timeframe were found for radiation therapy only. The use of radiation to treat locally advanced mid and distal esophageal cancers increased from 1998 to 2008. Survival was best when both surgery and radiation were used.

Treatment modalities for T1N0 esophageal cancers: a comparative analysis of local therapy versus surgical resection

BACKGROUND To investigate the role of nonsurgical treatment for early-stage esophageal cancer, we compared the outcomes of local therapy to esophagectomy, using a large, national database. METHODS Five-year cancer-specific and overall survival (OS) of patients, with T1N0M0 squamous cell or adenocarcinoma of the mid or distal esophagus treated with either surgery or local therapy, with ablative and/or excision techniques, in the Surveillance Epidemiology and End Results cancer registry from 1998 to 2008, were compared using the Kaplan-Meier approach, and multivariable and propensity-score adjusted Cox proportional hazard, and competing risk models. RESULTS Of 1458 patients with T1N0 esophageal cancer, 1204 (83%) had surgery and 254 (17%) had local therapy only. The use of local therapy increased significantly from 8.1% in 1998 to 24.1% in 2008 (p < 0.001). The 5-year OS after local excisional therapy and surgery was not significantly different (55.5% versus 64.1% respectively, p = 0.07), and 5-year cancer-specific survival (CSS) also did not differ (81.7% versus 75.8%, p = 0.10). However, after propensity-score adjustment, CSS was better for patients who underwent local therapy compared with those who underwent surgery (hazard ratio: 0.46, 95% confidence interval: 0.27-0.77, p = 0.003), whereas OS remained similar. CONCLUSION The use of local therapy for T1N0 esophageal cancers increased significantly from 1998 to 2008. Compared with those treated with esophagectomy, patients treated with local therapy had similar OS but improved CSS, indicating a higher chance of dying from other causes. Further studies are needed to confirm the oncologic efficacy of local therapy when used in patients whose lifespans are not limited by conditions other than esophageal cancer.

Voluntary ingestion of antiparasitic drugs emulsified in honey represents an alternative to gavage in mice

The oral route is the most frequently used method of drug intake in humans. Oral administration of drugs to laboratory animals such as mice typically is achieved through gavage, in which a feeding needle is introduced into the esophagus and the drug is delivered directly into the stomach. This method requires technical skill, is stressful for animals, and introduces risk of injury, pain and morbidity. Here we investigated another method of drug administration. The benzimidazole derivative albendazole was emulsified in commercially available honey and administered to mice by voluntary feeding or gavage. Mice that received albendazole by either gavage or honey ingestion had virtually identical levels of serum albendazole sulfoxide, indicating that uptake and metabolism of albendazole was similar for both administration techniques. In addition, dosing mice with the albendazole-honey mixture for 8 wk had antiparasitic activity comparable to earlier studies using gavage for drug administration. Compared with gavage, voluntary ingestion of a drug in honey is more rapid, less stressful to the animal, and less technically demanding for the administrator. Because of its low cost and ready availability, honey presents a viable vehicle for drug delivery.

Evaluation of an esophageal Doppler probe for the identification of experimental pseudo-electromechanical dissociation: a preliminary study

STUDY OBJECTIVE To determine the effectiveness of an esophageal doppler device to non-invasively detect experimental pseudo-electromechanical dissociation (pseudo-EMD). DESIGN Prospective, controlled, laboratory investigation using an asphyxial canine cardiac arrest model and a newly-developed esophageal flat-flow probe doppler unit. INTERVENTIONS Mongrel dogs (20) were instrumented for hemodynamic monitoring. The esophageal doppler probe was placed in the distal esophagus of each animal. Electromechanical dissociation (EMD) was induced by clamping the endotracheal tube. MEASUREMENTS AND MAIN RESULTS A period of pseudo-EMD was defined as the time where cardiac contractility was present, measured by a micromanometer tipped thoracic aortic catheter, without concurrent femoral pulses by palpation. The pseudo-EMD period could be produced consistently in all 20 animals. The characteristic doppler flow sounds were easily heard using the esophageal device in all animals. The time from endotracheal tube clamping until loss of femoral pulses was 622 +/- 96 s; until loss of radial artery doppler signals was 616 +/- 92 s; until loss of esophageal doppler signals was 728 +/- 88 s; and until loss of aortic fluctuations by thoracic aortic catheter was 728 +/- 82 s. The times to loss of esophageal doppler sounds and loss of aortic fluctuations were not significantly different. However, they were significantly longer than the time to loss of femoral pulses (P < 0.02). CONCLUSIONS The canine asphyxial EMD model can be used for short experimental studies of pseudo-EMD. Pseudo-EMD can be consistently and non-invasively detected with this esophageal doppler device. The device is as reliable as a micromanometer tipped aortic arch catheter in detecting pseudo-EMD. The doppler device could potentially be useful in improving recognition of near cardiac arrest in pre-hospital and emergency department settings. Further research on the utility of this device in other models of low-flow states should be performed.

Tumor budding in upper gastrointestinal carcinomas.

The basis of personalized medicine in oncology is the prediction of an individual's risk of relapse and death from disease. The presence of tumor budding (TB) at the tumor-host interface of gastrointestinal cancers has been recognized as a hallmark of unfavorable disease biology. TB is defined as the presence of dedifferentiated cells or small clusters of up to five cells at the tumor invasive front and can be observed in aggressive carcinomas of the esophagus, stomach, pancreas, ampulla, colon, and rectum. Presence of TB reproducibly correlates with advanced tumor stage, frequent lymphovascular invasion, nodal, and distant metastasis. The UICC has officially recognized TB as additional independent prognostic factor in cancers of the colon and rectum. Recent studies have also characterized TB as a promising prognostic indicator for clinical management of esophageal squamous cell carcinoma, adenocarcinoma of the gastro-esophageal junction, and gastric adenocarcinoma. However, several important issues have to be addressed for application in daily diagnostic practice: (1) validation of prognostic scoring systems for TB in large, multi-center studies, (2) consensus on the optimal assessment method, and (3) inter-observer reproducibility. This review provides a comprehensive analysis of TB in cancers of the upper gastrointestinal tract including critical appraisal of perspectives for further study.

The impact of neural invasion severity in gastrointestinal malignancies: a clinicopathological study.

OBJECTIVES Because neural invasion (NI) is still inconsistently reported and not well characterized within gastrointestinal malignancies (GIMs), our aim was to determine the exact prevalence and severity of NI and to elucidate the true impact of NI on patient's prognosis. BACKGROUND The union internationale contre le cancer (UICC) recently added NI as a novel parameter in the current TNM classification. However, there are only a few existing studies with specific focus on NI, so that the distinct role of NI in GIMs is still uncertain. MATERIALS AND METHODS NI was characterized in approximately 16,000 hematoxylin and eosin tissue sections from 2050 patients with adenocarcinoma of the esophagogastric junction (AEG)-I-III, squamous cell carcinoma (SCC) of the esophagus, gastric cancer (GC), colon cancer (CC), rectal cancer (RC), cholangiocellular cancer (CCC), hepatocellular cancer (HCC), and pancreatic cancer (PC). NI prevalence and severity was determined and related to patient's prognosis and survival. RESULTS NI prevalence largely varied between HCC/6%, CC/28%, RC/34%, AEG-I/36% and AEG-II/36%, SCC/37%, GC/38%, CCC/58%, and AEG-III/65% to PC/100%. NI severity score was uppermost in PC (24.9±1.9) and lowest in AEG-I (0.8±0.3). Multivariable analyses including age, sex, TNM stage, and grading revealed that the prevalence of NI was significantly associated with diminished survival in AEG-II/III, GC, and RC. However, increasing NI severity impaired survival in AEG-II/III and PC only. CONCLUSIONS NI prevalence and NI severity strongly vary within GIMs. Determination of NI severity in GIMs is a more precise tool than solely recording the presence of NI and revealed dismal prognostic impact on patients with AEG-II/III and PC. Evidently, NI is not a concomitant side feature in GIMs and, therefore, deserves special attention for improved patient stratification and individualized therapy after surgery.

Surgical treatments for esophageal cancers.

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the role of the nurse in preparation of esophageal resection (ER); the management of patients who develop high-grade dysplasia after having undergone Nissen fundoplication; the trajectory of care for the patient with esophageal cancer; the influence of the site of tumor in the choice of treatment; the best location for esophagogastrostomy; management of chylous leak after esophagectomy; the optimal approach to manage thoracic esophageal leak after esophagectomy; the choice for operational approach in surgery of cardioesophageal crossing; the advantages of robot esophagectomy; the place of open esophagectomy; the advantages of esophagectomy compared to definitive chemoradiotherapy; the pathologist report in the resected specimen; the best way to manage patients with unsuspected positive microscopic margin after ER; enhanced recovery after surgery for ER: expedited care protocols; and long-term quality of life in patients following esophagectomy.

Adenocarcinoma at the gastroesophageal junction.

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the clinical differences between carcinomas arising slightly above, slightly below, and within the gastroesophageal junction (GEJ); information provided by biopsies; information provided by resection specimens following neoadjuvant therapy; histologic differences existing between carcinomas arising slightly above, slightly below, and within the GEJ; differences provided by immunohistochemistry in these tumors; information given by endoscopic mucosal resection specimens; the role of esophageal pyloric gland adenomas as precursors of adenocarcinomas in the region of the cardia; the role of pancreatic metaplasia; Her2 immunoreactivity to make distinctions in the site of origin; and intestinal metaplasia limited to the cardia as a precursor of adenocarcinoma.