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Leading a seminar group for students of Infant Observation is a fascinating experience. A group of students gather, usually with substantial professional experience of working with children and fam...

Background Despite evidence that low osmolar radiocontrast media is not associated with acute kidney injury, it is important to evaluate this association in critically ill patients with normal kidney function. Methods This retrospective observational study included 7,333 adults with an ICU stay at a six-hospital health system in south Florida. Patients who received contrast were compared with unexposed control subjects prior to and following propensity score (PS) matching derived from baseline characteristics, admission diagnoses, comorbidities, and severity of illness. Acute kidney injury (AKI), defined as initial onset (stage I) or increased severity, was determined from serum creatinine levels according to Kidney Disease: Improving Global Outcomes guidelines. Results Based on 2,306 PS-matched pairs obtained from 2,557 patients who received IV contrast and 4,776 unexposed control subjects, the increase in AKI attributable to contrast was 1.3% (19.3% vs 18.0%; P = .273), and no association was found between contrast and the pattern of onset and recovery. Hospital mortality increased by 14.3% subsequent to AKI (18.0 vs 3.6; P Conclusions In critically ill adults with normal kidney function, low osmolar radiocontrast media did not substantively increase AKI. Rather than limiting the use of contrast in ICU patients, efforts to prevent AKI should focus on the susceptibility of patients with sepsis, diabetes complications, high Acute Physiology and Chronic Health Evaluation scores, and history of renal disease.

Background For patients undergoing breast cancer surgery, the pre- and post-operative periods can be characterised by feelings of fear, anxiety, and uncertainty. Telehealth offers an opportunity to provide perioperative support to surgical patients and overcome some of the barriers to accessing care. Aims In order to inform the development of a telehealth support model for women undergoing breast cancer surgery, this feasibility study explored: (a) access and preferences for telehealth; and (b) the proportion of participants who reported problems with unmet information and preparation needs related to surgery, post-operative pain, anxiety, and quality of life. Methods Women aged 18–85 years attending for a follow-up appointment within 2 months of undergoing surgery for breast cancer were asked to complete a baseline (T1) and 1-month follow-up (T2) survey. Surveys assessed telehealth access and preferences, preparatory information receipt and preparedness for surgery, and anxiety, pain, and quality of life. Results Fifty-three T1 (45% consent rate) and 50 T2 surveys were returned. One fifth of the sample (20%) travelled 50 km or more to access surgery. Most participants had access to a device suitable for telehealth (75%); however, only 15% indicated that they would have accepted a teleconsultation with their surgeon post-operatively if this had been offered. The most frequently reported unmet preparatory information needs were information about: how long it would take to recover from the surgery; how other patients had experienced similar surgery; and practical needs such as parking or transport. Approximately one third of the sample reported potentially clinically significant symptoms of anxiety, and less than one in ten women reported moderate levels of pain. Conclusions While the majority of women had access to a suitable device and internet connection for telehealth, less than one fifth would have accepted a home-based video-link teleconsultation with their surgeon post-operatively. A small proportion of the sample would have liked more information about aspects of surgery including about managing side effects and anxiety. The key findings in terms of teleconsultation preferences and information and preparation needs from this study will be incorporated into the telehealth support model being developed.

Background and Purpose— Failure to recanalize predicts mortality in acute ischemic stroke. In the North American Solitaire Acute Stroke registry, we investigated parameters associated with mortality in successfully recanalized patients. Methods— Logistic regression was used to evaluate baseline characteristics and recanalization parameters for association with 90-day mortality. A multivariable model was developed based on backward selection with retention criteria of P P ≤0.10), then refit to minimize the number of excluded cases (missing data). Results— Successfully recanalized patients had lower mortality (25.2% [59/234] versus 46.9% [38/81] P P =0.205). However, mortality was significantly higher in patients with symptomatic intracranial hemorrhage (72% [23/32] versus 26% [73/281]; P P P c index=0.72), proximal occlusion, initial National Institutes of Health Stroke Scale≥18, and use of rescue therapy remained significant independent predictors of 90-day mortality. Conclusions— Failure to recanalize and presence of symptomatic intracranial hemorrhage resulted in increased mortality. Despite successful recanalization, proximal occlusion, high National Institutes of Health Stroke Scale, and need for rescue therapy were predictors of mortality.

Prostate biopsy positivity after radiotherapy (RT) is a significant determinant of eventual biochemical failure. We mapped pre- and post-treatment tumor locations to determine if residual disease is location-dependent.There were 303 patients treated on a randomized hypofractionation trial. Of these, 125 underwent prostate biopsy 2-years post-RT. Biopsy cores were mapped to a sextant template, and 86 patients with both pre-/post-treatment systematic sextant biopsies were analyzed.The pretreatment distribution of positive biopsy cores was not significantly related to prostate region (base, mid, apex; p=0.723). Whereas all regions post-RT had reduced positive biopsies, the base was reduced to the greatest degree and the apex the least (p=0.045). In 38 patients who had a positive post-treatment biopsy, there was change in the rate of apical positivity before and after treatment (76 vs. 71%; p=0.774), while significant reductions were seen in the mid and base.In our experience, persistence of prostate tumor cells after RT increases going from the base to apex. MRI was used in planning and image guidance was performed daily during treatment, so geographic miss of the apex is unlikely. Nonetheless, the pattern observed suggests that attention to apex dosimetry is a priority.

In prior retrospective studies, we assessed a number of prostate tumor tissue biomarkers that were associated independently with the clinical outcome of men treated with radiotherapy (RT) ± androgen deprivation therapy (ADT). In this report, the associations of selected biomarkers with biochemical or clinical disease failure (BCDF) were prospectively evaluated in men with T1-T3 prostate cancer on a randomized hypofractionation trial.Biomarkers were analyzed in 263 of 303 men randomly assigned to standard vs moderate hypofractionation. Median follow-up was 65.9 months. Archival tissue was analyzed for Ki-67 (n = 231), MDM2 (n = 209), p16 (n = 195), Cox-2 (n = 126), p53 (n = 206), bcl2 (n = 223), bax (n = 210), and PKA (n = 160). The base model for multivariable Fine-Gray regression analysis included treatment assignment and risk groups. All statistical tests were two-sided.Each biomarker was tested one at a time relative to the base model and selected for inclusion in multivariable analysis. Ki-67 (hazard ratio [HR] = 2.31, 95% confidence interval [CI] = 1.19 to 4.48, P = .01) and bcl2bax (HR = 2.19, 95% CI = 1.08 to 4.46, P = .03) were statistically significantly related to higher BCDF and were independently statistically significant when considered jointly (Ki-67: HR = 2.26, 95% CI = 1.12 to 4.58, P = .02; bcl2bax: HR = 2.14, 95% CI = 1.03 to 4.41, P = .04). At 2.5 years postradiotherapy, the C-index of Ki-67 was 73.2%, while for the base model was only 46.2%; Ki-67 was the most statistically significant when tested without bcl2bax.In this prospective multiple biomarker analysis in men with prostate cancer treated with RT±ADT, both Ki-67 and bcl2bax were independently related to early BCDF; however, Ki-67 alone is indicated to be the most clinically meaningful by C-index analysis and is universally available.

Docetaxel and capecitabine combination is synergistic in preclinical models. We investigated the efficacy and toxicity of this combination as second-line chemotherapy in patients with metastatic pancreatic adenocarcinoma (mPC), pretreated with gemcitabine-based chemotherapy.Eligible patients were treated with capecitabine 800 mg/m(2) orally PO bid on days 1-14 in combination with intravenous docetaxel 30 mg/m(2) on days 1 and 8 of each 21-day cycle. The primary end point was overall response rate. Using a three-stage sequential design, two interim analyses for early stopping due to lack of efficacy were planned and conducted after 13 and 26 patients were accrued. Secondary end points included time to treatment failure, progression-free survival (PFS), overall survival (OS) and 50 % drop in CA19-9 levels.Forty-three patients were evaluable for toxicity and 42 evaluable for response, at a median age of 64 years. The majority of patients (74 %) had ECOG PS 0-1. Six patients (14 %) achieved a partial tumor response, and stable disease for ≥2 cycles was observed in 59 % of patients (n = 25). Thirty-five percent (n = 11/31) of patients had a ≥50 % decrease in CA19-9 levels. The median PFS was 3.7 months (95 % CI 2.1-4.3 months), and the median OS was 5.3 months (95 % CI 4.3-8.6 months). Treatment was generally well tolerated. Grade 3 toxicity and grade 4 toxicity were seen in 45 and 5 % of patients, respectively. One patient had a potential treatment-related mortality.The combination of capecitabine and docetaxel is active and well tolerated in mPC patients pretreated with gemcitabine-based therapy.

2555 Background: Given the activity of immune checkpoint inhibitors (ICI) in mismatch repair deficient tumors, we evaluated if homologous recombination repair deficiency associates with solid tumor response to ICI. Methods: We conducted a phase 2 trial (NCT03274661) of PEM in metastatic solid tumor patients progressing on standard of care and for whom PEM had no FDA approved indication. We evaluated a triple stain (FANCD2foci/DAPI/Ki67) immunofluorescence functional assay of the Fanconi Anemia pathway (FATSI) in treated patients’ archived tumors as a correlative biomarker. Patients with microsatellite unstable tumors were not eligible. The primary objective was objective response rate (iORR, CR+PR) by Immune Response Criteria, with the hypothesis that patients with FATSI negative tumors will have better clinical outcome. Secondary objectives were progression free survival (PFS), 6 months PFS and survival. PEM was given every 3 weeks and computed tomography scans were performed every 6 weeks. We utilized a two-stage phase II trial design to detect an iORR ≥ 20% in the whole population tested vs. the null hypothesis that the true iORR ≤5%. If ≥ 2 of the first 20 evaluable patients had an objective response the trial proceeded to full accrual of 39 evaluable patients. Outcomes were evaluated according to FATSI staining. Results: 42 patients (40 evaluable) (35F,7M; median age 62[36-83]) enrolled. Median # of prior regimens was 2[1-7]. Primary Dx included ovarian/fallopian (13), endometrial (10), colorectal (3), cervix (2), pancreatic(2), vaginal (2) and 1 each of various others. No unexpected toxicities occurred. Response evaluation showed 2 CR, 5 PR, 11 SD, 22 PD and 2 NE (iORR 18%). FATSI tumor analyses results are available in 34 patients; 25 FATSI positive, 9 negative. 2 PR, 8 SD, 14 PD, 1 NE occurred among the FATSI (+) (iORR 8%) and 2 CR, 2 PR, 2 SD, 3 PD among the FATSI (-) patients (iORR 44%). mPFS and 6m-PFS were 54 days and 12% (3/25) in FATSI (+), versus 248 days and 56% (5/9) in FATSI (-) patients; p = 0.017. Conclusions: PEM has meaningful antitumor activity in non MSI-high malignancies with no current FDA approved indications. Evaluation of FATSI as a biomarker supports a biomarker selected population approach. Clinical trial information: NCT03274661.

Purpose To determine if escalated radiation dose using hypofractionation significantly reduces biochemical and/or clinical disease failure (BCDF) in men treated primarily for prostate cancer. Patients and Methods Between June 2002 and May 2006, men with favorable- to high-risk prostate cancer were randomly allocated to receive 76 Gy in 38 fractions at 2.0 Gy per fraction (conventional fractionation intensity-modulated radiation therapy [CIMRT]) versus 70.2 Gy in 26 fractions at 2.7 Gy per fraction (hypofractionated IMRT [HIMRT]); the latter was estimated to be equivalent to 84.4 Gy in 2.0 Gy fractions. High-risk patients received long-term androgen deprivation therapy (ADT), and some intermediate-risk patients received short-term ADT. The primary end point was the cumulative incidence of BCDF. Secondarily, toxicity was assessed. Results There were 303 assessable patients with a median follow-up of 68.4 months. No significant differences were seen between the treatment arms in terms of the distribution of patients by clinicopathologic or treatment-related (ADT use and length) factors. The 5-year rates of BCDF were 21.4% (95% CI, 14.8% to 28.7%) for CIMRT and 23.3% (95% CI, 16.4% to 31.0%) for HIMRT (P = .745). There were no statistically significant differences in late toxicity between the arms; however, in subgroup analysis, patients with compromised urinary function before enrollment had significantly worse urinary function after HIMRT. Conclusion The hypofractionation regimen did not result in a significant reduction in BCDF; however, it is delivered in 2.5 fewer weeks. Men with compromised urinary function before treatment may not be ideal candidates for this approach.

Antigen containing, allogeneic cells secreting the genetically modified protein and peptide-chaperone gp96-Ig cross, prime and expand antigen specific CD8 T cells with therapeutic antitumor activity in mice. In a first in man phase I study, we now report the results of therapeutic vaccination of non-small cell lung cancer (NSCLC) patients with an established, allogeneic non-small cell lung adenocarcinoma cell line secreting gp96-Ig. Advanced NSCLC-patients stage IIIB or IV of any histological subtype were enrolled and treated with up to 36 vaccinations over the course of 18 weeks. Primary endpoint was safety, secondary endpoints tumor response and overall survival. Measurement of tumor antigen specific CD8 CTL responses is precluded by the lack of known NSCLC associated antigens. Therefore, we measured patient CD8 T cell-IFN-γ responses to allo-antigens of the vaccine cells as surrogate for tumor antigen specific CD8 CTL. In 7 of 18 treated patients tumor growth was stabilized, however none of the 18 patients had an objective tumor response by RECIST criteria. Of 15 patients evaluable for immune response, 11 responded to vaccination with more than twofold increase in CD8-IFN-γ frequency above baseline. These patients had a median survival time of 16.5 months. Four patients who had no CD8 response above base line had survival times from 2.1 to 6.7 months. Our data are consistent with the concept that generation of CD8 CTL by therapeutic vaccination may delay tumor growth and progression and mediate prolonged survival even in the absence of objective tumor responses. Further studies will be required to test this concept and promising result.

The open approach continues to be widely performed for ventral hernia repair, while the minimally invasive laparoscopic approach has grown adoption over the last decade. Recently, robotic operation was described as a new modality due to the ease for performing intracorporeal closure of the hernia defect. This study is one of the first multi-institutional case series evaluating robotic-assisted laparoscopic ventral hernia repairs, with the goal of describing robotic-assisted surgical techniques for ventral and incisional hernia repair and the outcomes in teaching and community hospital settings. Medical records of consecutive patients (including surgeon’s learning curve cases) who underwent ventral or incisional hernia repair utilizing the da Vinci Surgical System (Intuitive Surgical Inc, Sunnyvale CA) were retrospectively reviewed. Data collected included preoperative history and perioperative outcomes. Data for a total of 368 patients from four institutions involving five surgeons were analyzed. They were predominantly females (60.3 %), and the mean age was 51 years. The majority of the patients were obese or morbidly obese (47.8 and 20.9 %), and 83.2 % of the patients had a history of prior abdominal operation. Conversion rate was 0.8 %, and mean length of stay was 1 day. Total postoperative complications rate up to 30 days was 8.4 %, of which incidence of paralytic ileus was 2.4 %. This large case series of 368 patients demonstrates reproducibility of safety and performance associated with robotic-assisted ventral hernia repairs performed by five surgeons at four institutions. In addition, the results of short term perioperative outcomes for surgeons during their early experience for robotic-assisted cases are in the range of what is reported in the existing published data on laparoscopic and open ventral hernia repairs. Further comparative evidence initiatives are being pursued to determine the benefits of robotic-assisted technique and technology for long-term and patient-reported outcomes.

Objective To evaluate the feasibility of combining low-dose fractionated whole abdominal radiation (LDF-WAR) with weekly full-dose cisplatin (FD-CDDP) for patients with stage III/IV endometrial carcinoma. Methods Patients with optimally debulked stage III/IV carcinoma of the endometrium (without extra-abdominal disease) were eligible for the study. Postoperatively, patients received the institutional standard systemic chemotherapy and vaginal brachytherapy. Patients then underwent experimental six weekly cycles of FD-CDDP (40mg/m 2 , maximum 70mg IV) followed by LDF-WAR 6–8hours after initiation of chemotherapy. In a conservative design, 6 patients were accrued to two sequential cohorts of LDF-WAR, at 0.5Gy/fraction [Fx] (total 3Gy) and 0.75Gy/Fx (total 4.5Gy). Toxicities and laboratory studies were evaluated at each visit. Results Twelve patients were enrolled from January 2005 to June 2009 with median follow-up of 13.5months (range: 5–27months). Seventy-five percent of enrolled patients had uterine papillary serous histology. Eleven patients at least partially completed therapy (range: 2–6 cycles of FD-CDDP/LDF-WAR) with one additional patient opting out at the higher dose level. Combination therapy overall was well tolerated. Three patients in each cohort experienced grade 3 acute hematologic events with one recorded grade 4 toxicity in the second cohort. Of patients receiving any of the experimental treatment, five have experienced recurrences. Three of these patients were in cohort one and received 0.5Gy/Fx LDF-WAR. Conclusion Combination therapy with LDF-WAR as a novel chemopotentiator to FD-CDDP is a feasible adjuvant regimen in optimally debulked patients with stage III/IV endometrial carcinoma. Further investigation is warranted to determine treatment efficacy.

In patients with aggressive non-Hodgkin lymphomas (NHLs), T-cell lymphoma (TCL) confers a poor prognosis. Since rituximab has increased survival for patients with diffuse large B-cell lymphoma (DLBCL), we hypothesized that the difference in outcome by phenotype became more pronounced recently and evaluated these changes using the Surveillance, Epidemiology, and End Results (SEER) Program. Cases diagnosed in 1992-1997 (era 1) and 1998-2003 (era 2) were evaluated for outcomes according to immunophenotype and era. A total of 22,252 patients with DLBCL and 2222 with TCL were included. In both eras, patients with TCL were more likely to die from their disease than those with DLBCL. Death from NHL decreased significantly from era 1 to era 2 for all DLBCL patients grouped by age and stage but in none of the TCL groups. Improved outcomes for DLBCL after the introduction of rituximab-based therapies in 1997 have no counterpart in patients with TCL, pointing to the need for new therapies to treat TCL.

TPS3108Background: Recent studies have shown that patients with mismatch repair deficiency have an increased response rate to immune checkpoint inhibitors (ICI). This led to the tissue-agnostic FDA...

Introduction In 2003, consolidation docetaxel was a promising concept for unresectable stage IIIA/B nonsmall cell lung cancer (NSCLC). To test the hypothesis that chemoradiotherapy with carboplatin and irinotecan followed by consolidation docetaxel would be feasible and clinically active, we conducted a phase II study. Methods Thirty-two patients with unresectable stage IIIA/B NSCLC received irinotecan (30 mg/m 2 ) and carboplatin dosed to a target area under the concentration curve of 2, each administered weekly for 7 weeks. Concurrent radiotherapy was administered more than 7 weeks to a total dose of 63 Gy in 35 fractions. Consolidation docetaxel (75 mg/m 2 ) was administered every 3 weeks for 3 doses 4 weeks after chemoradiotherapy. The primary end point was objective response rate by RECIST. Results Complete responses occurred in 4 patients and partial responses occurred in 14, for an objective response rate of 56.3% (95% confidence interval [CI], 37.7-73.6%). Median progression-free survival was 6.5 months (95% CI, 4.6-13.5); median duration of survival was 14.8 months (95% CI, 6.9-27.3). The most common hematologic toxicity was leukopenia, which were grade 3 or 4 in 16 patients (50%). Radiation pneumonitis (grade ≥2) occurred in 13 of 31 treated patients (42%). Conclusions These findings suggested that concurrent chemoradiotherapy with carboplatin and irinotecan followed by consolidation docetaxel is clinically active based on median survival in patients with unresectable stage III NSCLC; however, the 42% incidence of clinical radiation pneumonitis was unexpected and warrants further investigation to determine the mechanism and preventive strategies.

Novel therapeutic approaches are needed in mantle cell lymphoma (MCL). We conducted a phase II study in MCL testing an intensive regimen, R-MACLO-IVAM-T, a modification of the NCI 89-C-41 protocol. Newly diagnosed patients were treated with rituximab, methotrexate, doxorubicin, cyclophosphamide, and vincristine (cycle 1) followed by rituximab, ifosfamide (and mesna), etoposide, and cytarabine (cycle 2). These two cycles were repeated once, and patients achieving complete response (CR) received maintenance thalidomide. Among the 22 patients enrolled, 21 completed two or more cycles and achieved a CR. Three patients relapsed, while 17 are alive and relapse-free after a median follow-up of 37 months (range 19-65 months). Two patients died: one from sepsis during cycle 1 and another at 38 months while in remission from MCL. The progression-free survival at 3 years was 78% (95% CI: 51-91%). These results compare favorably with previously reported outcomes suggesting that durable remissions can be achieved without myeloablative therapy.

Recently, the robotic single-site platform has been used to ameliorate the difficulties seen in single-incision laparoscopic surgery (SILC) while preserving the benefits of standard laparoscopic cholecystectomy. The purpose of this study is to describe the clinical outcomes of a large series of single-incision robotic cholecystectomy (SIRC). Medical records of consecutive patients who underwent SIRC were retrospectively reviewed. All procedures were performed by six surgeons at five different North American centers involved in the study. All patients included in the study underwent a cholecystectomy attempted through single site at the umbilicus, using the da Vinci® Surgical System (Intuitive Surgical Inc. Sunnyvale, CA). A total of 465 patients met study criteria. Median age was 48 years (range 18–89); 351 (75.5 %) were female and 304 (66.4 %) were overweight or obese. Except for gender, case characteristics differed significantly by surgeon/site. Previous abdominal surgery was reported for 226 (48.6 %) cases. SIRC was successfully completed in 455 (97.8 %) cases, and there were no conversions to open surgery. Median surgical time was 52 min with a decreasing trend after 55–85 cases. Male gender, obesity and diagnoses other than biliary dyskinesia were independent predictors of longer surgical times. The complication rate was 2.6 %. Our large, multicenter study demonstrates that robotic single-site cholecystectomy is safe and feasible in a wide range of patients.

This study examined the relation between arterial compliance of the lower extremities and aerobic capacity in patients with a broad spectrum of cardiovascular risk but without overt coronary heart disease (CHD). Local arterial compliance was noninvasively measured in the thigh and calf in 104 men and 99 women using air plethysmography. Subjects also underwent maximal exercise treadmill testing as a measure of aerobic capacity. In univariate analysis, age (r = -0.49, p0.001), systolic blood pressure at rest (r = -0.27, p0.001), pulse pressure (r = -0.39, p0.001), total cholesterol (r = -0.25, p0.001), triglycerides (r = -0.025, p0.001), non-high-density lipoprotein cholesterol (r = -0.23, p0.001), high-sensitivity C-reactive protein (r = -0.21, p = 0.002), and low-density lipoprotein cholesterol (r = -0.15, p = 0.03) all demonstrated a significant inverse association with treadmill time. Thigh and calf compliance demonstrated a significant positive association with treadmill time (r = 0.48, p0.001; r = 0.46, p0.001). In multivariate analysis, thigh compliance (p = 0.003), age (p0.001), gender (p = 0.005), and triglycerides (p = 0.017) were independent predictors of treadmill time. In conclusion, thigh compliance measured with a simple-to-use, fully automated device independently predicts aerobic fitness in patients with a wide range of cardiovascular risk but without CHD.

This paper is a description of work carried out by a teacher working as a participant observer with a group of five latency-aged children. An account of the progression of the group is described and the contribution of group work to the development of the latency child is discussed. The author has attempted to demonstrate the usefulness of observational skills to this sort of work.

To evaluate reliability, accuracy, and agreement of simple visual estimation (SVE) in determining the degree of peripheral arterial stenosis compared with calibrated measurements.In 2 sessions, 23 interventionists with a wide range of experience and subspecialty training reviewed 42 angiographic images of lower extremity and carotid arteries (21 iliofemoral arteries and 21 carotid arteries). An independent physician measured all lesions using manual calipers. Intrarater and interrater reliability were assessed by intraclass correlation. A ± 5% error was considered the threshold for accuracy, and weighted κ statistics were computed to assess agreement with respect to the degree of stenosis (50%, nonsignificant; 50%-80%, significant;80%, severe).Intrarater reliability of SVE was 0.99, and interrater reliability was 0.83. Accuracy varied from 52.8% for images of severe stenosis to 26.5% and 18.1% for significant and nonsignificant stenosis, respectively (P.001). Agreement between SVE and caliper with regard to degree of stenosis was good (weighted κ 0.56) overall with correct classification ranging from 92.6% for severe stenosis to 53.4% and 68.2% for significant and nonsignificant stenosis, respectively (P.001). Misclassification of nonsignificant and significant stenosis was more frequent for carotid arteries than for lower extremities.Despite high reliability, SVE of peripheral arterial stenosis has limited accuracy in determining the exact degree of stenosis. Although severe stenosis is readily identified by SVE, arterial stenosis of80% is frequently overestimated, especially for carotid arteries, and should be confirmed by caliper assessment.

BackgroundMechanical thrombectomy with stent-retrievers results in higher recanalization rates compared with previous devices. Despite successful recanalization rates (Thrombolysis in Cerebral Infarction (TICI) score ≥2b) of 70–83%, good outcomes by 90-day modified Rankin Scale (mRS) score ≤2 are achieved in only 40–55% of patients. We evaluated predictors of poor outcomes (mRS >2) despite successful recanalization (TICI ≥2b) in the North American Solitaire Stent Retriever Acute Stroke (NASA) registry.MethodsLogistic regression was used to evaluate baseline characteristics and recanalization outcomes for association with 90-day mRS score of 0–2 (good outcome) vs 3–6 (poor outcome). Univariate tests were carried out for all factors. A multivariable model was developed based on backwards selection from the factors with at least marginal significance (p≤0.10) on univariate analysis with the retention criterion set at p≤0.05. The model was refit to minimize the number of cases excluded because of missing covariate values; the c-statistic was a measure of predictive power.ResultsOf 354 patients, 256 (72.3%) were recanalized successfully. Based on 234 recanalized patients evaluated for 90-day mRS score, 116 (49.6%) had poor outcomes. Univariate analysis identified an increased risk of poor outcome for age ≥80 years, occlusion site of internal carotid artery (ICA)/basilar artery, National Institute of Health Stroke Scale (NIHSS) score ≥18, history of diabetes mellitus, TICI 2b, use of rescue therapy, not using a balloon-guided catheter or intravenous tissue plasminogen activator (IV t-PA), and >30 min to recanalization (p≤0.05). In multivariable analysis, age ≥80 years, occlusion site ICA/basilar, initial NIHSS score ≥18, diabetes, absence of IV t-PA, ≥3 passes, and use of rescue therapy were significant independent predictors of poor 90-day outcome in a model with good predictive power (c-index=0.80).ConclusionsAge, occlusion site, high NIHSS, diabetes, no IV t-PA, ≥3 passes, and use of rescue therapy are associated with poor 90-day outcome despite successful recanalization.

Cytochrome c and dATP/ATP induce oligomerization of Apaf-1 into two distinct apoptosome complexes: an approximately 700 kDa complex, which recruits and activates caspases-9, -3 and -7, and an approximately 1.4 MDa complex, which recruits and processes caspase-9, but does not efficiently activate effector caspases. While searching for potential inhibitors of the approximately 1.4 MDa apoptosome complex, we observed an approximately 30 kDa Apaf-1 immunoreactive fragment that was associated exclusively with the inactive complex. We subsequently determined that caspase-3 cleaved Apaf-1 within its CED-4 domain (SVTD(271) downward arrowS) in both dATP-activated lysates and apoptotic cells to form a prominent approximately 30 kDa (p30) N-terminal fragment. Purified recombinant Apaf-1 p30 fragment weakly inhibited dATP-dependent activation of caspase-3 in vitro. However, more importantly, prevention of endogenous formation of the p30 fragment did not stimulate latent effector caspase processing activity in the large complex. Similarly, the possibility that XIAP, an inhibitor of apoptosis protein (IAP), was responsible for the inactivity of the approximately 1.4 MDa complex was excluded as immunodepletion of this caspase inhibitor failed to relieve the inhibition. However, selective proteolytic digestion of the approximately 1.4 MDa and approximately 700 kDa complexes showed that Apaf-1 was present in conformationally distinct forms in these two complexes. Therefore, the inability of the approximately 1.4 MDa apoptosome complex to process effector caspases most likely results from inappropriately folded or oligomerized Apaf-1.

Apaf-1, by binding to and activating caspase-9, plays a critical role in apoptosis. Oligomerization of Apaf-1, in the presence of dATP and cytochrome c, is required for the activation of caspase-9 and produces a caspase activating apoptosome complex. Reconstitution studies with recombinant proteins have indicated that the size of this complex is very large in the order of ∼1.4 MDa. We now demonstrate that dATP activation of cell lysates results in the formation of two large Apaf-1-containing apoptosome complexes with M r values of ∼1.4 MDa and ∼700 kDa. Kinetic analysis demonstrates that in vitro the ∼700-kDa complex is produced more rapidly than the ∼1.4 MDa complex and exhibits a much greater ability to activate effector caspases. Significantly, in human tumor monocytic cells undergoing apoptosis after treatment with either etoposide orN-tosyl-l-phenylalanyl chloromethyl ketone (TPCK), the ∼700-kDa Apaf-1 containing apoptosome complex was predominately formed. This complex processed effector caspases. Thus, the ∼700-kDa complex appears to be the correctly formed and biologically active apoptosome complex, which is assembled during apoptosis.

The S10b (SUG2) ATPase cDNA has been cloned by reverse transcription-polymerase chain reaction/rapid amplification of cDNA ends from mRNA of intersegmental muscles of the tobacco horn moth (Manduca sexta). The S10b ATPase is a component of the 26 S proteasome, and its concentration and that of its mRNA increase dramatically during development in a manner similar to other ATPases of the 19 S regulator of the 26 S proteasome. The S10b and S6′ (TBP1) ATPases are also present in a complex of ∼220 kDa in intersegmental muscles. The 220-kDa complex markedly activates (2–10-fold) the 26 S proteasome, even when bound to anti-S10b antibodies immobilized on Sepharose, and increases in concentration ∼5-fold like the 26 S proteasome in the intersegmental muscles in preparation for the programmed death of the muscle cells. A similar activator complex is present in human brain and placenta. Free activator complexes cross-activate: the Manduca complex activates rat skeletal muscle 26 S proteasomes, and the placental complex activates Manduca 26 S proteasomes. The placental activator complex contains S10b and S6′, but not p27. This 220-kDa activator complex has been evolutionarily conserved between species from insect to man and may have a fundamental role in proteasome regulation.

Each 19S regulator of the 26S proteasome contains six ATPase subunits as well as many (>14) non-ATPase protein subunits. The ATPase subunits have been detected in other complexes which may regulate transcription and possibly other cellular processes. The S10b (yeast SUG2 or human p42) and the S6' (TBP1) ATPases have been found in an activator complex (modulator) prepared from bovine red cells. We have identified and partially characterised a similar activator from different human tissues (from soluble extracts of human brain, placenta and human embryonic kidney cells) and an insect: an activator is present in soluble extracts of abdominal intersegmental muscle from Manduca sexta. Activation is ATP and concentration dependent. There is no stimulation of human red cell-derived 20S proteasome by the Manduca activator ruling out 11S regulator in the preparations. Additionally, cross-species activation occurs: the Manduca activator increases the activity of rat skeletal muscle 26S proteasomes and the human placental activator similarly increases the activity of 26S proteasomes prepared from muscles from Manduca sexta. Finally, there is no evidence for other ATPases in the activator complex.

Purpose Magnetic resonance (MR) imaging and computed tomography (CT) are used almost exclusively in radiation therapy planning of glioblastoma multiforme (GBM), despite their well-recognized limitations. MR spectroscopic imaging (MRSI) can identify biochemical patterns associated with normal brain and tumor, predominantly by observation of choline (Cho) and N -acetylaspartate (NAA) distributions. In this study, volumetric 3-dimensional MRSI was used to map these compounds over a wide region of the brain and to evaluate metabolite-defined treatment targets (metabolic tumor volumes [MTV]). Methods and Materials Volumetric MRSI with effective voxel size of ∼1.0 mL and standard clinical MR images were obtained from 19 GBM patients. Gross tumor volumes and edema were manually outlined, and clinical target volumes (CTVs) receiving 46 and 60 Gy were defined (CTV 46 and CTV 60 , respectively). MTV Cho and MTV NAA were constructed based on volumes with high Cho and low NAA relative to values estimated from normal-appearing tissue. Results The MRSI coverage of the brain was between 70% and 76%. The MTV NAA were almost entirely contained within the edema, and the correlation between the 2 volumes was significant (r=0.68, P =.001). In contrast, a considerable fraction of MTV Cho was outside of the edema (median, 33%) and for some patients it was also outside of the CTV 46 and CTV 60 . These untreated volumes were greater than 10% for 7 patients (37%) in the study, and on average more than one-third (34.3%) of the MTV Cho for these patients were outside of CTV 60 . Conclusions This study demonstrates the potential usefulness of whole-brain MRSI for radiation therapy planning of GBM and revealed that areas of metabolically active tumor are not covered by standard RT volumes. The described integration of MTV into the RT system will pave the way to future clinical trials investigating outcomes in patients treated based on metabolic information.

Objective: The purpose of this study was to determine whether women with a family history of ovarian cancer are at reduced risk of ovarian cancer from the use of oral contraceptives and to compare their risk with that of women with no family history of ovarian cancer. Study Design: A population-based case-controlled study was conducted from May 1994 through July 1998 in which 767 women aged 20 to 69 years with a diagnosis of epithelial ovarian cancer were ascertained from 39 hospitals in 3 northeastern states. Personal interviews with the women and 1367 control subjects provided data that allowed us to estimate the relative risk of ovarian cancer in relation to a family history of cancer and total duration of oral contraception. Results: Among the 33 case patients and 24 control subjects with a first-degree family history of ovarian cancer, risk of ovarian cancer declined with increasing duration of oral contraception ( P =.01). Risk reduction from short-term use of oral contraceptives (≤48 months) did not differ significantly by family history (combined estimate of odds ratio, 0.72; 90% CI, 0.59%-0.87%). Risk reduction from long-term use of oral contraceptives (>48 months) was greater in women with a positive family history of ovarian cancer (odds ratio, 0.12) than in women with a negative family history of ovarian cancer (odds ratio, 0.51; test of interaction, P =.04; 692 case patients, 1279 control subjects). Conclusion: Four to 8 years of oral contraception may substantially reduce the risk of ovarian cancer by age 70 years in women with a family history of the disease, from approximately 4 women per 100 women who did not use oral contraceptives to only 2 women per 100 women who did use oral contraceptives. (Am J Obstet Gynecol 2002;186:8-14.)

Adoptive T-cell therapy holds great promise for the treatment of metastatic melanoma. However, prohibitive costs associated with current technology required for culture and expansion of tumor-reactive T-cells, the need for intense preconditioning regimens to induce lymphopenia, and the unpredictable anti-tumor effect of adoptively transferred T-cells remain significant impediments for its clinical implementation. Here we report a simplified combinatorial approach that involves short activation of CD8(+) T cells in the presence of IL-12 followed by adoptive transfer into tumor bearing animals after a single injection of cyclophosphamide. This approach resulted in complete eradication of B16 melanoma, and the establishment of long term immunological memory capable of fully protecting mice after a second B16 melanoma challenge. The activated donor cells were unique because they simultaneously exhibited traits for cytotoxic effector function, central memory-like, homing, and senescence. After tumor eradication and within three months after transfer, CD8+ cells exhibited a conventional memory CTL phenotype. Moreover, these memory CTLs acquired functional attributes characteristic of memory stem cells, including the ability to resist chemotherapy-induced toxicity. Our results suggest that short-term T-cell receptor signaling in the presence of IL-12 promotes promiscuous qualities in naïve CTL which - upon transfer into lymphopenic hosts- are sufficient to eradicate tumors and generate life-long tumor-specific memory.

miR-155, processed from the B-cell integration cluster (BIC), is one of the few well-studied microRNAs (miRNAs) and is involved in both innate immunity and tumorigenesis. BIC/miR-155 is induced by distinct signaling pathways, but little is known about the underlying mechanisms. We have identified two conserved potential interferon (IFN) regulatory factor (IRF)-binding/interferon-stimulated response element motifs in the Bic gene promoter. Two oncogenic IRFs, IRF4 and -7, in addition to some other members of the family, bind to and significantly transactivate the Bic promoter. Correspondingly, the endogenous levels of IRF4 and -7 are correlated with that of the BIC transcript in Epstein-Barr virus (EBV)-transformed cells. However, RNA interference studies have shown that depletion of IRF4, rather than of IRF7, dramatically decreases the endogenous level of BIC by up to 70% in EBV- or human T-cell leukemia virus type 1 (HTLV1)-transformed cell lines and results in apoptosis and reduction of proliferation rates that are restored by transient expression of miR-155. Moreover, the endogenous levels of the miR-155 target, SHIP1, are consistently elevated in EBV- and HTLV1-transformed cell lines stably expressing shIRF4. In contrast, transient expression of IRF4 decreases the SHIP1 level in EBV-negative B cells. Furthermore, the level of IRF4 mRNA is significantly correlated with that of BIC in adult T-cell lymphoma/leukemia (ATLL) tumors. These results show that IRF4 plays an important role in the regulation of BIC in the context of EBV and HTLV1 infection. Our findings have identified Bic as the first miRNA-encoding gene for IRFs and provide evidence for a novel molecular mechanism underlying the IRF/BIC pathway in viral oncogenesis.

To analyze a series of sentinel nodes (SNs) from patients with node-positive breast cancer to determine their diagnostic value, to delineate a working algorithm, and to assess the clinical value of our common practiceA prospectively collected database.Tertiary referral center.One hundred five patients with node-positive breast cancer who underwent SN biopsy.The diagnostic value of SNs by analyzing the sensitivity of processing the hottest, 2 hottest, hot and blue, or hot, blue, and suspicious SNs.Three hundred fifty-three axillary SNs were recorded in the database. An analysis of the 282 radioactive axillary nodes for which the 10-second count was recorded reveals that the most radioactive node was positive in 73 of 94 analyzable patients (77.7%). Consideration of the 2 most intense axillary nodes was sufficient to diagnose nodal disease in an additional 12 patients, representing a significant increase in sensitivity to 90.4% (P.001). Examination of all other radioactive nodes did not diagnose any additional cases. On the basis of all 105 patients, consideration of nonradioactive blue axillary nodes did not add significant diagnostic value relative to testing only radioactive nodes: sensitivity of 86.7% vs 88.6% (P = .50), whereas consideration of all hot, blue, and suspicious nodes improved sensitivity to 96.2% (P = .002).Processing of the 2 hottest nodes, along with suspicious but nonhot and nonblue nodes, is sufficient for initial axillary staging. Additional radioactive SNs should be processed only in the presence of nodal disease.

Background: We report results of a study assessing the use of a novel applicator to deliver low-doserate brachytherapy (LDR) to carcinoma of the uterine cervix. It offers the advantage of simultaneous loading of vaginal "tandem" and "ovoid-equivalent" sources and obviates the need for vaginal packing. Purpose: To test the hypothesis that the applicator could deliver, reproducibly, the prescribed dose without compromising the rate of loco-regional (LR) tumor control. End points: 1) doses delivered to Pt. A, rectum, bladder and vaginal surface (as defined by ICRU), 2) variability of such doses amongst the study patients, 3) rates of local control and adverse events. Methods and Materials: Twenty-five patients with histologically-proven carcinoma of the cervix were entered consecutively. The median duration of follow-up was 38 (7-48) months. Summary statistics were calculated for each end point. Incidence of vaginal stenosis, rectovaginal (RV) fistulae, and proctitis were all reported using NCI, CTCAE version 3.0 (December 2003). Cumulative incidence of local and distant failure as well as Kaplan-Meier estimates of recurrence-free and overall survival were calculated. Results: No patients received a total dose to point A outside the limit of 10% variability from the intended dose. A 10% limit above the maximal operator-defined rectal and bladder doses was not exceeded in any patient. LR control rate was 24 out of 25 (96%). Three study patients (12%) developed RV (recto-vaginal) fistulae. Conclusions: The data indicate that although this applicator delivers sufficient dose to Point A with excellent local control of disease, an unexpectedly high rate of RV fistulae was demonstrated that was due to several factors. Further investigations are needed to determine the optimal role of this novel application system for cervical cancer, such as for patients with "minimal" vaginal involvement. Categories: Obstetrics/Gynecology, Radiation Oncology

Abstract: The evaluation of the Victoria Police Department’s Community Police Station (Co.P.S.) Program measured the strategy’s success in controlling and preventing crime within the community. This article illustrates how the evaluation assessed the impacts of the Co.P.S. Program on its eight distinct objectives. The conceptual framework on which this evaluation was based is described, as well as the comprehensive and eclectic research designs. Four key perspectives were used to examine the impacts : crime rates, the citizenry, the Co.P.S. volunteers, and the Police Department personnel. Some findings are highlighted.

Immunohistochemistry for estrogen receptor may be used to distinguish metastatic breast cancers from adenocarcinomas of other sites, including those of the lung. The estrogen receptor exists as 2 subtypes, alpha and beta. Estrogen receptor alpha is the predominant subtype expressed by more than two-thirds of human breast cancers. Adenocarcinomas of lung origin may also express estrogen receptor, primarily the beta subtype. Human estrogen receptor alpha is highly homologous to estrogen receptor beta and consequently, antibodies used to detect estrogen receptor alpha in breast carcinomas may detect estrogen receptor beta in pulmonary adenocarcinomas. We investigated the immunohistochemical expression of estrogen receptor in proven primary lung adenocarcinomas using 3 anti-estrogen receptor alpha antibodies: mouse monoclonal 1D5, 6F11, and rabbit monoclonal SP1.Ninety-two pulmonary adenocarcinomas (53 women and 39 men) confirmed by clinical presentation and positive immunohistochemistry for thyroid transcription factor-1 (TTF-1) were included in this study. There were 19 incisional biopsies and 73 excisional specimens. Immunohistochemistry for estrogen receptor using antibodies 1D5, 6F11, and SP1 was performed on formalin-fixed, paraffin-embedded tissue following antigen retrieval. Any nuclear reactivity for estrogen receptor was considered a positive result.Focal positive nuclear reaction for estrogen receptor was detected in 7 (7.6%) cases of primary pulmonary adenocarcinoma using antibody 1D5, 13 (14.1%) using 6F11, and 25 (27.2%) using SP1. The differences in reactivity for estrogen receptor in pulmonary adenocarcinomas between SP1 and 1D5, and between SP1 and 6F11 were statistically significant (P0.001). Positive cases showed only a focal pattern of staining with each of the 3 antibodies. There was no significant difference in reactivity for estrogen receptor in pulmonary adenocarcinomas of men and women. Positive staining was highest in nonmucinous bronchioloalveolar adenocarcinomas for all of the antibodies, and for SP1, variation by histologic subtype was significant (P0.001).SP1 has a significantly higher detection rate for the expression of estrogen receptor in pulmonary adenocarcinomas when compared with either 1D5 or 6F11. Caution should therefore be exercised in the use of this antibody alone in distinguishing a metastatic breast from a primary pulmonary adenocarcinoma.

BACKGROUND: Bevacizumab in combination with carboplatin and paclitaxel improves overall response and survival in patients with advanced or recurrent nonsmall cell lung carcinoma. However, this drug is not recommended in patients with squamous cell carcinoma or neoplasms with a dominant squamous component. Therefore, identification of squamous cell differentiation has therapeutic implications. In many instances, cytology is the diagnostic tool of choice; however, routine cytomorphology is limited in classification of nonsmall cell carcinomas into squamous and nonsquamous subtypes. The aim of this study was to identify the value of p63 immunocytochemical analysis in this distinction. METHODS: Review of cytology records identified 51 consecutive pulmonary specimens (16 fine needle aspiration samples, 15 washes, 12 brushes, and 8 lavages) with the diagnosis of nonsmall cell lung carcinoma (9 carcinomas with squamous differentiation and 42 carcinomas without squamous differentiation). Histologically, they all proved to be nonsmall cell carcinomas, 26 with squamous differentiation and 25 without squamous differentiation. p63 immunocytochemical stain was performed on archival alcohol-fixed Papanicolaou-stained cytology slides using standard immunocytochemical methods. RESULTS: Twenty-three (88 %) of the 26 histologically proven squamous cell carcinomas were positive for p63 on cytologic smears. By using p63 immunocytochemistry, the authors detected 14 carcinomas with squamous differentiation not identified by cytomorphology. Smears from all histologically proven carcinomas with squamous differentiation were positive for p63. Sensitivity of cytology for the detection of nonsmall cell carcinoma of lung with squamous differentiation increased from 35% to 88% using p63 immunocytochemistry (P = .001; McNemar test). The squamous component in 4 carcinomas was detected only in cytologic and not in corresponding histologic samples when subsequent p63 immunostaining was performed. CONCLUSIONS: The authors concluded that p63 is a useful marker for the detection of nonsmall cell carcinomas of lung with squamous differentiation when used in cytologic pulmonary samples. p63 immunocytochemistry significantly increases the sensitivity for the identification of lung neoplasms with squamous differentiation from 35% to 88% (P = .001). Therefore, p63 immunocytochemistry may be used in pulmonary cytologic samples of nonsmall cell carcinomas to identify squamous differentiation and to improve therapeutic selection of patients with lung cancer. Cancer (Cancer Cytopathol) 2009. © 2009 American Cancer Society.

Aim: To gain an understanding of patients’ lived experience following photodynamic therapy (PDT) for the treatment of advanced cancer. Background: Existing literature on PDT tends to be predominantly grounded in basic science and mainly associated with the effect of PDT on the cancer rather than the individual’s experience. An appreciation of the impact on patients’ day-to-day life may enhance the support and advice offered to patients undergoing this treatment. Method: A Heideggerian hermeneutic phenomenological approach was used as the philosophical framework. Semi-structured interviews were conducted with a purposive sample of six participants. Thematic content analysis was adopted to analyse the data, which yielded six themes. Findings: Analysis of the data yielded six themes: the impact on day-to-day life; existential meaning; the physical effects of treatment; kaleidoscope of emotions; information gap; and family burden. Conclusion: PDT offers palliation of symptoms for some participants while offering hope of enhanced quality of life. Patients and their families have to be willing and well-informed of the need to comply with the guidance provided by healthcare professionals and information leaflets to avoid any photosensitive reaction. There is a need for education for healthcare professionals as PDT is not well recognized or understood as a treatment for advanced cancer.

Ninety-nine extended care residents were followed over a fourteen month period, in order to compare outcomes associated with relocation and renovations. One group of residents were temporarily moved to other facilities during renovations, two groups were moved internally, and a control group in a similar home experienced neither relocation nor renovations. The groups constituted naturally assembled collectives, but were similar in terms of age, sex, and length of admission. Significant differences were found between the groups, both two weeks and two months after moving. The residents who were moved externally showed a number of improvements; they had significantly higher ADL scores, improved auditory comprehension, decreased pain, fewer incidence reports and reduced doses of PRN medicines. The group of residents who showed the most negative changes were those who were moved inside the home at the outset of the renovations. These residents showed sharp increases in PRN medicine use, diminished ADL functioning, and increased symptoms of pain. While the groups differed two weeks and two months following the move, after 14 months, differences were no longer apparent. The findings highlighted the potential importance of comprehensive preparation, resident choice, and resident perceptions, in the face of multiple stresses.

4-1BB is a T-cell costimulatory receptor which binds its ligand 4-1BBL, resulting in prolonged T cell survival. We studied the antitumor effects of adoptively transferred tumor-specific T cells expanded ex vivo using tumors transduced with herpes simplex virus (HSV) amplicons expressing 4-1BBL as a direct source of antigen and costimulation. We constructed HSV amplicons encoding either the 4-1BBL (HSV.4-1BBL) or B7.1 (HSV.B7.1) costimulatory ligands. Lewis lung carcinoma cells expressing ovalbumin (LLC/OVA) were transduced with HSV.4-1BBL, HSV.B7.1, or control HSV amplicons and used to stimulate GFP+ OVA-specific CD8+ T cells (OT-1/GFP) ex vivo. Naive or ex vivo stimulated OT-1/GFP cells were adoptively transferred into LLC/OVA tumor-bearing mice. Higher percentages of OT-1/GFP cells were seen in the peripheral blood, spleen, and tumor bed of the HSV.4-1BBL–stimulated OT-1/GFP group compared with all other experimental groups. OT-1 cells identified within the tumor bed and draining lymph nodes of the HSV.4-1BBL–stimulated OT-1 group showed enhanced bromodeoxyuridine (BrdUrd) incorporation, suggesting ongoing expansion in vivo. Mice receiving HSV.4-1BBL–stimulated OT-1/GFP had significantly decreased tumor volumes compared with untreated mice (P < 0.001) or to mice receiving naive OT-1/GFP (P < 0.001). Transfer of HSV.B7.1-stimulated OT-1/GFP did not protect mice from tumor. Mice that received HSV.4-1BBL–stimulated OT-1/GFP exhibited increased cytolytic activity against LLC/OVA and higher percentages of Ly-6C+ OT-1/GFP in the spleen and tumor bed compared with controls. Tumor-specific T cells stimulated ex vivo using tumor transduced with HSV.4-1BBL expand in vivo following adoptive transfer, resulting in tumor eradication and the generation of tumor-specific CD44+Ly-6C+CD62L− effector memory T cells. [Cancer Res 2007;67(20):10027–37]

Background A phase II trial to evaluate neoadjuvant (NAD), surgery and adjuvant (AD) combination chemotherapy without radiation therapy (RT) for patients with esophageal adenocarcinoma staged with endoscopic ultrasound and CT as T3N1 was carried out. Methods Thirty-three eligible patients were enrolled. NAD therapy was administered in two 49-day cycles and included cisplatin, floxuridine, paclitaxel and leucovorin. Esophageal resection was performed followed by AD therapy. Results Thirty-three patients initiated NAD therapy; 10 experienced grade 3 and 4 toxicities, which included leucopenia, fatigue, nausea, diarrhea and stomatitis. Additionally, 16 patients experienced grade 1 and 2 hematologic and non-hematologic toxicities. Fifteen patients were down-staged, of whom five were T2, seven were T1, and three had nodal disease with no evidence of residual cancer in the esophageal bed. Fifteen patients remained T3, and two showed progressive disease. Thirty-two patients proceeded to surgery and 30 were resected. Although all resected patients were eligible for AD therapy, 15 did not receive it either because of patient refusal or surgeon recommendation. Fifteen patients received AD therapy: nine who had remained T3 and six who had down-staged. Three patients experienced grade 3 and 4 toxicities similar to those in NAD therapy. Six patients had grade 1 and 2 toxicities. Kaplan-Meier estimates of overall survival at 1, 3 and 5 years were 73% (95% CI: 58-88%), 52% (95% CI: 34-69%) and 29% (95% CI: 13-45%), respectively. Median survival was 42 months. Conclusion Deletion of RT may safely allow for more aggressive chemotherapy and increase chances of survival. The results need to be confirmed in a randomized phase II or larger phase III trial.

Considerable time and energy goes into the organisation of careers expos held each year in many parts of Australia. While in some centres these have been replaced by alternative forms of information-sharing on careers, in other places they have persisted either as the regular careers event of the year or run to complement a range of careers activities. In Darwin, alternatives have been considered yet there has been some reluctance to forego the annual event. To analyse the success of the 1996 Darwin Careers Expo, a survey of exhibitors, teachers and students was undertaken on behalf of the Careers Expo Planning Committee. Students completed the survey in a very positive way, and their cooperation warrants acknowledgment. Overall, the results affirm the benefits of the organisers’ and exhibiters’ efforts and provide some insights into ways of improving the next Expo.

The objective of this study was to determine the effect, if any, on survival of adjuvant 5-FU-based chemoradiotherapy following pancreaticoduodenectomy for pancreatic carcinoma. A systematic review of the published literature was undertaken. Survival estimates were derived from published reports. Five prospective studies (4 level I, 1 level II) with a total of 607 (229 surgery only; 378 surgery-adjuvant) patients followed for survival met selection criteria. Two-year survival ranged from 15%-37% in the surgery only group and 37%-43% in the surgery and adjuvant groups. The survival advantage (absolute difference) ranged from 3%-27% and no individual study achieved statistical significance (5%). Although clinical heterogeneity existed in surgery-alone control groups with regard to trial date, no statistical heterogeneity was detected (P = 0.459, chi2 test), allowing pooling of survival data. Using a fixed effects model, the summary estimate showed an absolute 2-year survival benefit with adjuvant therapy of 12% (95% CI, 3%-21%, P = 0.011). Trials after 1997 (n = 3) indicated a survival benefit of 8% to patients receiving adjuvant therapy (95% CI, -3-18%, P = 0.145). The result was not statistically significant, and there was no evidence of heterogeneity (P = 0.626, chi2 test). Summary estimates were unchanged when the analysis was performed with a random effects model. 5-FU based chemotherapy with radiotherapy given after resection imparts a small overall survival benefit of 2 years. The benefit of 5-FU-based adjuvant therapy, however, has declined in recent years, and its significance remains unproven in the context of current diagnostic and surgical practice.