Efficacy and Safety of Reirradiation with Stereotactic Body Radiation Therapy for Locally Recurrent Pancreatic Adenocarcinoma.

AIMS: The purpose of this study was to report on outcomes of a cohort of patients who were treated with reirradiation with stereotactic body radiation therapy (SBRT) for locally recurrent pancreatic adenocarcinoma. MATERIALS AND METHODS: Patients treated with SBRT reirradiation for locally recurrent pancreatic adenocarcinoma from December 2009 to April 2020 were included in the study. Descriptive statistics were used to record patient demographics, tumour and treatment characteristics. Kaplan-Meier analysis was used to evaluate overall survival, local progression-free survival (LPFS), distant metastasis-free survival and progression-free survival (PFS). RESULTS: In total, 27 patients were included in the study. The median follow-up time from local recurrence was 19.7 months (range 4.2-43.1 months). Most patients received five-fraction SBRT (26/27, 96%). The median overall survival after local recurrence treatment was 18.3 months (range 3.0-42.6 months), with 6-month, 1-year and 2-year overall survival rates of 88.5%, 73.1% and 33.6%. The median LPFS after local recurrence treatment was 16.2 months (range 2.3-33.6 months), with 6-month, 1-year and 2-year LPFS rates of 95.8%, 62.9% and 27.2%. Peri-SBRT chemotherapy improved LPFS (median 17.5 versus 8.5 months; P = 0.010) and overall survival (median 19.3 versus 5.5 months; P = 0.049). Tumours ≤ 3 cm in the greatest dimension showed better local control (median LPFS 19.2 versus 10.2 months; P = 0.130). There was one case (4%) of acute grade 3 pain and one case (4%) of late grade 3 gastrointestinal toxicity. CONCLUSIONS: Reirradiation with five-fraction SBRT is safe, but local control remains suboptimal. Patients with smaller tumours experienced improved outcomes, as did patients whose treatment plan included the administration of peri-SBRT chemotherapy.

Brachiocephalic artery haemorrhage during percutaneous tracheostomy.

Percutaneous tracheostomy was performed on a 69-year-old woman to facilitate weaning. Insertion of the size 7 tracheostomy tube resulted in profuse bleeding around the tracheostomy site. On inflation of the tracheostomy balloon, the bleeding stopped. Urgent computed tomography demonstrated the brachiocephalic artery was abnormally high and lying in an oblique fashion over the trachea, and the tracheostomy tube was displacing the trachea posteriorly. Surgical repair of the defect in the brachiocephalic artery was undertaken and a surgical tracheostomy was performed in theatre. This case raises important issues about the potential dangers of percutaneous tracheostomy in cases of abnormal anatomy. It also emphasises the importance of direct visualisation of the seeker needle using the endoscope. In cases where there is a suspicion of abnormal anatomy, it is safer to obtain preprocedural imaging or perform a surgical tracheostomy.

Prevalence of Trichomonas vaginalis and coinfection with Chlamydia trachomatis and Neisseria gonorrhoeae in the United States as determined by the Aptima Trichomonas vaginalis nucleic acid amplification assay.

Our aim was to determine Trichomonas vaginalis prevalence using the Aptima Trichomonas vaginalis assay (ATV; Gen-Probe) and the prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae coinfections in U.S. women undergoing screening for C. trachomatis/N. gonorrhoeae. Discarded urogenital samples from 7,593 women (18 to 89 years old) undergoing C. trachomatis/N. gonorrhoeae screening using the Aptima Combo 2 assay (Gen-Probe) in various clinical settings were tested with ATV. Overall, T. vaginalis, C. trachomatis, and N. gonorrhoeae prevalences were 8.7%, 6.7%, and 1.7%, respectively. T. vaginalis was more prevalent than C. trachomatis or N. gonorrhoeae in all age groups except the 18- to 19-year-old group. The highest T. vaginalis prevalence was in women ≥ 40 years old (>11%), while the highest C. trachomatis prevalence (9.2%) and N. gonorrhoeae prevalence (2.2%) were in women <30 years old. Coinfection prevalences were 1.3% for C. trachomatis/T. vaginalis, 0.61% for C. trachomatis/N. gonorrhoeae and N. gonorrhoeae/T. vaginalis, and 0.24% for C. trachomatis/N. gonorrhoeae/T. vaginalis and highest in women <30 years old. T. vaginalis prevalence differed by race/ethnicity, with the highest prevalence in black women (20.2%). T. vaginalis prevalence ranged from 5.4% in family planning clinics to 22.3% in jails. Multivariate analysis determined that ages of ≥ 40 years, black race, and patient locations were significantly associated with T. vaginalis infection. T. vaginalis is the most common sexually transmitted infection (STI) in women of >40 years, while C. trachomatis and N. gonorrhoeae prevalence is lowest in that age group. Higher T. vaginalis prevalence in women of >40 years is probably attributed to the reason for testing, i.e., symptomatic status versus routine screening in younger women. Coinfections were relatively low. High T. vaginalis prevalence in all age groups suggests that women screened for C. trachomatis/N. gonorrhoeae, whether asymptomatic or symptomatic, should be screened for T. vaginalis.

Pilocytic astrocytoma mimicking craniopharyngioma: a case series.

Although they are one of the most common brain tumours in childhood, pilocytic astrocytomas are rare in adulthood. We report a series of three pilocytic astrocytomas presenting as an intra/suprasellar mass in the fourth to sixth decades of life. All three radiologically mimicked the appearance of a craniopharyngioma, thus representing a potential radiological and diagnostic pitfall. In this series all three patients underwent successful operative management and have remained well throughout follow-up. The majority of information concerning pilocytic astrocytomas is derived from paediatric populations and so only limited and often conflicting data exist for pilocytic astrocytomas developing in adulthood. Decisions regarding treatment of pilocytic astrocytomas in adults must be made on a multidisciplinary, case-by-case basis.

Satisfaction with conduit harvest site scars in coronary bypass surgery.

INTRODUCTION: Scars from conduit harvesting are common in coronary artery bypass patients. As an outward manifestation of surgery, the scar is important in patient perception of operative success and quality of care received. The aim of this study was to determine patient satisfaction with scars from radial artery and saphenous vein harvests at a tertiary cardiothoracic centre. METHODS: We surveyed 62 patients attending follow-up appointment using the Patient Scar Assessment Questionnaire. This is a reliable and valid measure of a patient's perception of scarring. Data were analysed using ratings of scar attributes and features. We compared findings according to site and patient choice of scar site using the Mann-Whitney U test. RESULTS: Analysis of both global and summative ratings showed no overall statistical differences between arm and leg scars (p<0.05). However, patients given a choice gave significantly higher ratings of scar appearance on global ratings versus those given no choice. Patients also reported greater satisfaction with appearance than those given no choice on summative ratings (p<0.05). CONCLUSIONS: Patient choice of conduit site is an important determinant of the overall rating of scar appearance. Overall satisfaction is influenced by scar appearance. Clinicians should ensure, wherever possible, that they involve patients in conduit site selection.

A rare case of vomiting: fourth ventricular B-cell lymphoma.

We document the case of a 69-year-old man presenting with 6 weeks of intractable vomiting. Magnetic Resonance Imaging showed a homogenously enhancing mass in the caudal fourth ventricle. Surgical exploration and biopsy was performed and pathological examination demonstrated a high-grade B-cell lymphoma. The lesion was a primary tumour in an immuno-competent patient. Despite the increasing incidence of primary central nervous system lymphomas this is believed to be only the third ever case to have occurred at this rare site. We suggest that primary B-cell lymphoma should be considered with homogenous lesions of the fourth ventricle.

Comparison of the APTIMA CT and GC assays with the APTIMA combo 2 assay, the Abbott LCx assay, and direct fluorescent-antibody and culture assays for detection of Chlamydia trachomatis and Neisseria gonorrhoeae.

The Gen-Probe APTIMA Combo 2 (AC2) is a Food and Drug Administration-cleared nucleic acid amplification test (NAAT) for the detection of Chlamydia trachomatis and Neisseria gonorrhoeae from urine and urogenital swab specimens. The Centers for Disease Control and Prevention have recommended confirmation of positive NAAT results in low-prevalence populations. APTIMA CT (ACT) and APTIMA GC (AGC) are two discrete NAATs for C. trachomatis and N. gonorrhoeae detection that are suitable for confirming AC2-positive results because they target different nucleic acid sequences. Our objective was to determine if ACT and AGC could be used as confirmatory tests for AC2 and to correlate the APTIMA assays with culture, direct fluorescent-antibody (DFA), and LCx CT and GC assays. Urine and swab specimens (1,304) were initially tested with either culture, DFA, or LCx, followed by AC2. A subset (675) was then tested with ACT and AGC. There was absolute concordance between ACT-AGC and AC2. LCx did not detect 1 of 14 AC2-ACT- and 1 of 6 AC2-AGC-positive urine samples, and it yielded one C. trachomatis- and one N. gonorrhoeae-positive swab result that were not detected by AC2 and ACT-AGC. Culture failed to detect 5 of 20 AC2-ACT and 3 of 4 AC2-AGC positives, and DFA missed 4 of 4 AC2-ACT positives. Thus, ACT and AGC relative sensitivity compared to that of AC2 was 100%. All APTIMA assays detected more confirmed positive results than culture, DFA, and LCx. The performance of APTIMA assays was not altered by the use of various swab types and by long-term storage of specimens. All APTIMA assays are highly sensitive and rapid. ACT and AGC can be recommended for confirmation of positive results from other NAATs, such as AC2 and LCx.

TGF-beta signalling pathways in early Xenopus development.

Many different ligands of the TGF-beta superfamily signal in the early Xenopus embryo and are required for the specification and patterning of the three germ layers as well as for gastrulation. Recent advances in the field are helping us understand how ligand activity is regulated both spatially and temporally, the mechanism by which the signals are transduced to the nucleus and how essentially the same signalling pathway can activate completely different sets of genes in different regions of the embryo.

Loss of Smad4 function in pancreatic tumors: C-terminal truncation leads to decreased stability.

At early stages of tumorigenesis, the transforming growth factor-beta (TGF-beta) signaling pathway is thought to have tumor suppressor activity as a result of its ability to arrest the growth of epithelial cells. Smad4 plays a pivotal role in the TGF-beta signaling pathway and has been identified as a tumor suppressor, being mutated or deleted in approximately 50% of pancreatic carcinomas and 15% of colorectal cancers. A nonsense mutation generating a C-terminal truncation of 38 amino acids in the Smad4 protein has been identified in a pancreatic adenocarcinoma (Hahn, S. A., Schutte, M., Hoque, A. T., Moskaluk, C. A., da Costa, L. T., Rozenblum, E., Weinstein, C. L., Fischer, A., Yeo, C. J., Hruban, R. H., and Kern, S. E. (1996) Science 271, 350-353), and here we investigate the functional consequences of this mutation. We demonstrate that the C-terminal truncation prevents Smad4 homomeric complex formation and heteromeric complex formation with activated Smad2. Furthermore, the mutant protein is unable to be recruited to DNA by transcription factors and hence cannot form transcriptionally active DNA-binding complexes. These observations are supported by molecular modeling, which indicates that the truncation removes residues critical for homomeric and heteromeric Smad complex formation. We go on to show that the mutant Smad4 is highly unstable compared with wild type Smad4 and is rapidly degraded through the ubiquitin-proteasome pathway. Consistent with this, we demonstrate that the pancreatic adenocarcinoma harboring this mutated allele, in conjunction with loss of the other allele, expresses no Smad4 protein. Thus we conclude that these tumors completely lack Smad4 activity.

Xenopus Smad3 is specifically expressed in the chordoneural hinge, notochord and in the endocardium of the developing heart.

The Smads are intracellular signalling molecules that transduce signals from receptors for members of the TGF-beta superfamily to the nucleus. We have cloned the Xenopus orthologue of Smad3 (XSmad3). It is 94.6% identical to human Smad3 at the amino acid level. It is expressed as a maternal mRNA which disappears after stage 10.5, but reappears at the early tailbud stages. It is much less abundant than XSmad2 at the early developmental stages. From Stage 27 onwards XSmad3 is expressed with XSmad2 throughout the head region and in the somitic region. Strikingly however, XSmad3 alone is specifically expressed in the chordoneural hinge, the notochord and in the developing heart. Closer analysis reveals that XSmad3 is specifically expressed in the endocardium but not in the myocardium or pericardium. The chordoneural hinge staining persists at least until stage 40 whereas the staining in the endocardium peaks at approximately stage 32/33.

pp(macro)-->tt(macro)H: a discovery mode for the Higgs boson at the Fermilab Tevatron.

The production of a standard model Higgs boson in association with a top quark pair at the upcoming high luminosity run ( 15 fb(-1) integrated luminosity) of the Fermilab Tevatron ( square root of s = 2.0 TeV) is revisited. For Higgs masses below 140 GeV we demonstrate that the production cross section times branching ratio for H-->bb macro decays yields a significant number of events and that this mode is competitive with and complementary to the searches using pp(macro) -->WH,ZH associated production. For higher mass Higgs bosons the H-->W(+)W(-) decays are more difficult but have the potential to provide a few spectacular events.

Molecular diagnostic testing for infectious diseases using TMA technology.

Molecular diagnostic tests based on nucleic acid amplification technologies (NAATs) have become widely established in clinical microbiology laboratories in recent years. The acceptance of these tests has been driven by the development of more accurate and less labor-intensive commercial assay kits by diagnostic manufacturers. Infectious disease diagnostic assays using transcription-mediated amplification (TMA) NAAT have become increasingly popular in many clinical microbiology laboratories. Recent technology developments have improved the performance and simplified the use of the TMA assays. These new technologies have been applied to the development of multiplex TMA tests to improve the testing accuracy for organisms, such as Chlamydia trachomatis and Neisseria gonorrhoeae in clinical microbiology laboratories. TMA tests for HIV-1 and HCV have also led to improvements in blood bank testing which can improve the safety of the public blood supply.

Self-body split: issues of identity in physical recovery following a stroke.

PURPOSE: To explore the perceived life and identity changes described by individuals following a single stroke using a life narrative approach. METHOD: Individuals admitted to hospital with a stroke, no previous disability, returning home; took part in life narrative interviews in hospital, and six months and one year post-discharge. The Gross Motor subscale of the Rivermead Motor Assessment and Nottingham 10 point Activities of Daily Living Scale were completed. RESULTS: Eight stroke respondents (five male, three female; mean age 67 years (range 56-82). The one year mean motor score was 9 (range 7-11) and self-care score was 9 (range 7-10). All respondents described a fundamental change in their lives and identity. The main issue was a split between themselves and their body. In hospital their body appeared to become separate, precarious and perplexing. By one year the majority still found their body unreliable, and their physical ability influenced by the social setting. CONCLUSION: The new experience of a split between self and body appears to be the focus of life for at least a year. This study suggests that rehabilitation professionals should consider longer-term (although not necessarily intensive) physical activity programmes that address these psychological as well as neuromuscular changes.

Transforming growth factor beta-independent shuttling of Smad4 between the cytoplasm and nucleus.

Smad4 plays a pivotal role in all transforming growth factor beta (TGF-beta) signaling pathways. Here we describe six widely expressed alternatively spliced variants of human Smad4 with deletions of different exons in the linker, the region of Smad4 that separates the two well-conserved MH1 and MH2 domains. All these Smad4 variants form complexes with activated Smad2 and Smad3 and are incorporated into DNA-binding complexes with the transcription factor Fast-1, regardless of the amount of linker they contain. However, sequences encoded by exons 5 to 7 in the linker are essential for transcriptional activation. Most importantly, our observation that different Smad4 isoforms have different subcellular localizations has led us to the identification of a functional CRM1-dependent nuclear export signal in the Smad4 linker and a constitutively active nuclear localization signal in the N-terminal MH1 domain. In the absence of TGF-beta signaling, we conclude that Smad4 is rapidly and continuously shuttling between the nucleus and the cytoplasm, the distribution of Smad4 between the nucleus and the cytoplasm being dictated by the relative strengths of the nuclear import and export signals. We demonstrate that inhibition of CRM1-mediated nuclear export by treatment of cells with leptomycin B results in endogenous Smad4 accumulating very rapidly in the nucleus. Endogenous Smad2 and Smad3 are completely unaffected by leptomycin B treatment, indicating that the nucleocytoplasmic shuttling is specific for Smad4. We propose that, upon TGF-beta signaling, complex formation between Smad4 and activated Smad2 or -3 leads to nuclear accumulation of Smad4 through inhibition of its nuclear export. We demonstrate that after prolonged TGF-beta signaling Smad2 becomes dephosphorylated and Smad2 and Smad4 accumulate back in the cytoplasm.

Raf induces TGFbeta production while blocking its apoptotic but not invasive responses: a mechanism leading to increased malignancy in epithelial cells.

c-Raf-1 is a major effector of Ras proteins, responsible for activation of the ERK MAP kinase pathway and a critical regulator of both normal growth and oncogenic transformation. Using an inducible form of Raf in MDCK cells, we have shown that sustained activation of Raf alone is able to induce the transition from an epithelial to a mesenchymal phenotype. Raf promoted invasive growth in collagen gels, a characteristic of malignant cells; this was dependent on the operation of an autocrine loop involving TGFbeta, whose secretion was induced by Raf. TGFbeta induced growth inhibition and apoptosis in normal MDCK cells: Activation of Raf led to inhibition of the ability of TGFbeta to induce apoptosis but not growth retardation. ERK has been reported previously to inhibit TGFbeta signaling via phosphorylation of the linker region of Smads, which prevents their translocation to the nucleus. However, we found no evidence in this system that ERK can significantly influence the function of Smad2, Smad3, and Smad4 at the level of nuclear translocation, DNA binding, or transcriptional activation. Instead, strong activation of Raf caused a broad protection of these cells from various apoptotic stimuli, allowing them to respond to TGFbeta with increased invasiveness while avoiding cell death. The Raf-MAP kinase pathway thus synergizes with TGFbeta in promoting malignancy but does not directly impair TGFbeta-induced Smad signaling.

Medical students' attitudes toward pain and the use of opioid analgesics: implications for changing medical school curriculum.

BACKGROUND: Barriers to pain management include physicians' lack of knowledge and attitudes. Our aim was to investigate future physicians' knowledge and attitudes toward pain and the use of opioid analgesics. METHODS: We tested a medical school class during their freshman and senior years. Stepwise regression analysis was used to identify the personal traits that predicted opiophobia. RESULTS: The professionalization process of medical training may reinforce negative attitudes. Psychologic characteristics were associated with reluctance to prescribe opioids, and fears of patient addiction and drug regulatory agency sanctions. CONCLUSIONS: Consistent attitudes were found in senior medical students with preferences for certain specialty areas and the practitioners of their future specialties, suggesting a "preselection" effect. Higher scores on reliance on high technology, external locus of control, and intolerance of clinical uncertainty were associated with higher scores on one or more of the three dimensions of opiophobia. Implications for medical education are discussed.

Physicians' attitudes toward pain and the use of opioid analgesics: results of a survey from the Texas Cancer Pain Initiative.

BACKGROUND: Despite extensive progress in the scientific understanding of pain in humans, serious mismanagement and undermedication in treating acute and chronic pain is a continuing problem. This study was designed to examine the barriers to adequate pain management, especially as they might be associated with community size and medical discipline. METHODS: A 59-item survey was used to measure physicians' attitudes, knowledge, and psychologic factors that contribute to pain management practices. RESULTS: Overall, a significant number of physicians in this survey revealed opiophobia (prejudice against the use of opioid analgesics), displayed lack of knowledge about pain and its treatment, and had negative views about patients with chronic pain. There were significant differences among groups of physicians based on size of geographic practice area and medical discipline. CONCLUSIONS: New educational strategies are needed to overcome these barriers and to improve pain treatment in routine medical practice. The effect of practice milieu must be taken into consideration.

Change in identity and self-concept: a new theoretical approach to recovery following a stroke.

OBJECTIVE: To determine whether respondents reported a change in identity following stroke. DESIGN: A cross-sectional comparison study of perceived changes in the self-concept of stroke respondents and matched hospital volunteers. A questionnaire was administered to stroke respondents in their own homes and to hospital volunteers in their work setting. PARTICIPANTS: Twenty-six first-time stroke survivors who had no severe communication, cognitive or perceptual difficulties or previous physical disability, and who had returned home from hospital up to two years previously. The comparison group were 26 hospital volunteers matched for age, gender and the time from which past self-concept was considered. MAIN OUTCOME MEASURES: Included the Hospital Anxiety and Depression Scale, Frenchay Activity Index and the Head Injury Semantic Differential Scale to assess past and present self-concept. RESULTS: Overall, individuals described themselves in more negative terms than prior to their stroke. They saw themselves as less interested, capable and independent, (p < 0.001) and less in control, satisfied and active (p < 0.05). They still saw themselves as friendly, calm, caring, hopeful and talkative. The overall self-concept of the comparison group remained positive and stable over a comparable time period. CONCLUSIONS: The stroke respondents reported a negative sense of self, reduced social activity and psychological morbidity despite inpatient and outpatient rehabilitation. Individuals following stroke may settle for a restricted future because of their expectations of life with a disability. Clinicians need to be aware of the meaning of the stroke within the life of each individual.