Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

Long term outcomes of nonmyeloablative allogeneic stem cell transplantation with TSEB TLI and ATG for Mycosis Fungoides and Sezary Syndrome.

Advanced stage (IIB-IVB) Mycosis Fungoides (MF) and Sezary Syndrome (SS) have a poor prognosis with median survival <5 years. We report long-term outcomes of a non-myeloablative allogeneic stem cell transplantation regimen consisting of total skin electron beam therapy, total lymphoid irradiation and antithymocyte globulin. Our prospective cohort consisted of 41 patients with a higher proportion of MF (34MF, 7SS). Acute GVHD Grade 2 to 4 was seen in 31.7% and chronic GVHD Grade 2 to 4 in 24%. The cumulative incidence of non-relapse mortality was 9.8% at 1 year and 12.6% at 2 years. At Day +90 post-transplant 66% of patients had a complete response (CR). With a median post-transplant follow up of 5.27 years, the 5-year overall survival rate was 37.7% (MF 36.7%, SS 57.1%). The 5-year cumulative incidence of progressive disease or relapse was 52.7% in all patients but only 20.8% in those with CR at transplant compared to 70.6% in those not in CR at transplant (p = 0.006). Long term survival is possible in advanced MF and SS with non-myeloablative transplantation and outcomes are improved in patients with CR at transplant.

Tau phosphorylation and PAD exposure in regulation of axonal growth.

Introduction: Tau is a microtubule associated phosphoprotein found principally in neurons. Prevailing dogma continues to define microtubule stabilization as the major function of tau in vivo, despite several lines of evidence suggesting this is not the case. Most importantly, tau null mice have deficits in axonal outgrowth and neuronal migration while still possessing an extensive microtubule network. Instead, mounting evidence suggests that tau may have a major function in the regulation of fast axonal transport (FAT) through activation of neuronal signaling pathways. Previous studies identified a phosphatase activating domain (PAD) at the tau N-terminal that is normally sequestered, but is constitutively exposed in tauopathies. When exposed, the PAD activates a signaling cascade involving PP1 and GSK3ß which affects cellular functions including release of cargo from kinesin. Furthermore, we discovered that PAD exposure can be regulated by a single phosphorylation at T205. Exposure of the PAD is an early event in multiple tauopathies and a major contributing factor to neurodegeneration associated with tau hyperphosphorylation. However, effects of tau PAD exposure on anterograde FAT raised the interesting possibility that this pathway may be a mechanism for physiological regulation of cargo delivery through site-specific phosphorylation of tau and transient activation of PP1 and GSK3ß. Significantly, there is already evidence of local control of PP1 and GSK3ß at sites which require cargo delivery. Methods: To investigate this hypothesis, first we evaluated cellular localization of tau PAD exposure, pT205 tau phosphorylation, and active GSK3ß in primary hippocampal neurons during development. Second, we analyzed the axonal outgrowth of tau knockout neurons following transfection with full length hTau40-WT, hTau40-ΔPAD, or hTau40-T205A. Results and Discussion: The results presented here suggest that transient activation of a PP1-GSK3ß signaling pathway through locally regulated PAD exposure is a mechanism for cargo delivery, and thereby important for neurite outgrowth of developing neurons.

The discovery of a galaxy-wide superwind from a young massive galaxy at redshift z approximately 3.

High-velocity galactic outflows, driven by intense bursts of star formation and black hole accretion, are processes invoked by current theories of galaxy formation to terminate star formation in the most massive galaxies and to deposit heavy elements in the intergalactic medium. From existing observational evidence (for high-redshift galaxies) it is unclear whether such outflows are localized to regions of intense star formation just a few kiloparsecs in extent, or whether they instead have a significant impact on the entire galaxy and its surroundings. Here we present two-dimensional spectroscopy of a star-forming galaxy at redshift z = 3.09 (seen 11.5 gigayears ago, when the Universe was 20 per cent of its current age): its spatially extended Lyalpha line emission appears to be absorbed by H i in a foreground screen covering the entire galaxy, with a lateral extent of at least 100 kpc and remarkable velocity coherence. This screen was ejected from the galaxy during a starburst several 10(8) years earlier and has subsequently swept up gas from the surrounding intergalactic medium and cooled. This demonstrates the galaxy-wide impact of high-redshift superwinds.

Bexarotene therapy for mycosis fungoides and Sézary syndrome.

BACKGROUND: Bexarotene (Targretin) is a synthetic retinoid which is licensed for the treatment of advanced refractory cutaneous T-cell lymphoma (CTCL). OBJECTIVES: To summarize our experience with bexarotene for patients with CTCL with the aim of assessing efficacy and safety. METHODS: A retrospective study of 66 patients (44 male, 22 female) with mycosis fungoides (40 patients) or Sézary syndrome (26 patients) who were commenced on bexarotene prior to August 2007 was carried out. Nineteen patients had early-stage (IB-IIA) refractory mycosis fungoides and 47 patients had advanced-stage CTCL (IIB-IVB). RESULTS: Fifty-two out of 66 (79%) patients completed over 1 month of therapy with an intention-to-treat response rate of 44% (29/66). Of the patients, six (9%) had a complete response, 23 (35%) had a partial response, 15 (23%) had stable disease and eight (12%) had progressive disease. Median time to maximal response was 3 months (1-9 months). Median response duration was 8 months (1 to > 48 months). Median time to progression was 9 months (3-44 months). Fourteen patients (21%) did not complete a month of bexarotene therapy. Adverse effects of the whole group included central hypothyroidism in 100% (all grade II and managed with thyroid replacement) and hyperlipidaemia in 100% (all managed with lipid-lowering therapy +/- dose reduction). Responses were seen in all stages and were higher in advanced stages: 26% (five of 19) with early-stage and 51% (24/47) of advanced-stage disease. Responses were seen in skin, blood and lymph nodes. Twenty-eight out of 66 patients were treated with bexarotene monotherapy and the remainder were on one or more additional anti-CTCL therapies. CONCLUSIONS: Our data demonstrate that bexarotene is well tolerated in most patients and responses are seen in almost half of patients with all disease stages. However partial responses were not graded and would include any improvement seen in the skin, blood and lymph node.

Compensatory ahpC gene expression in isoniazid-resistant Mycobacterium tuberculosis.

Mutations that eliminate KatG catalase-peroxidase activity prevent activation of isoniazid and are a major mechanism of resistance to this principal drug for the treatment of Mycobacterium tuberculosis infections. However, the loss of KatG activity in clinical isolates seemed paradoxical because KatG is considered an important factor for the survival of the organism. Expression of either KatG or the recently identified alkyl hydroperoxidase AhpC was sufficient to protect bacilli against the toxic effects of organic peroxides. To survive during infection, isoniazid-resistant KatG mutants have apparently compensated for the loss of KatG catalase-peroxidase activity by a second mutation, resulting in hyperexpression of AhpC.

Size does matter: can we reduce the radiotherapy field size for selected cases of anal canal cancer undergoing chemoradiation?

AIMS: Chemoradiation is the standard of care for the treatment of anal canal cancer, with surgery reserved for salvage. For tumours with uninvolved inguinal nodes, it is standard to irradiate the inguinal nodes prophylactically, resulting in large field sizes, which contribute to acute and late toxicity. The aim of this single-centre retrospective study was to determine if, in selected cases, prophylactic inguinal nodal irradiation could be avoided. MATERIALS AND METHODS: Between August 1998 and August 2004, 30 patients with biopsy-proven squamous cell anal canal cancer were treated with chemoradiation using one phase of treatment throughout. A three-field beam arrangement was used without attempting to treat the draining inguinal lymph nodes prophylactically. The radiotherapy dose prescribed was 50Gy in 25 daily fractions over 5 weeks. Concomitant chemotherapy was delivered with the radiation using mitomycin-C 7-12mg/m(2) on day 1 and protracted venous infusional 5-fluorouracil 200mg/m(2)/day throughout radiotherapy. RESULTS: All patients had clinically and radiologically uninvolved inguinal and pelvic nodes and all had primary lesions that were T3 or less. The median age at diagnosis was 65 years (range 41-84). The median follow-up was 41 months (range 24-113). The mean posterior field size was 14x15cm and the mean lateral field size was 12x15cm. All patients achieved a complete response. Ninety-four per cent of patients (28/30) were alive and disease free. The two patients who died did so of unrelated causes and were disease free at death. Four patients relapsed and all were salvaged with surgery; two for local disease requiring abdominoperineal resection, one with an inguinal nodal relapse requiring inguinofemoral block dissection and one for metastatic disease to the liver who underwent liver resection. CONCLUSIONS: This single-centre retrospective study supports the treatment for selected cases of anal canal cancer with smaller than standard radiation fields, avoiding prophylactic inguinal nodal irradiation. Hopefully this will translate into reduced acute and late toxicity. In future studies we would suggest that consideration is given as to whether omission of prophylactic inguinal nodal irradiation for early stage tumours should be explored.

The effect of joint translation constraint on within-participant variability of kinematics and kinetics during running in cerebral palsy.

BACKGROUND: Biomechanical data in cerebral palsy are inherently variable but no optimal model of translational joint constraint has been identified. The primary aim of this study was to determine which model of translational joint constraint resulted in the lowest within-participant variability of lower limb joint angles and moments. The secondary aim was to determine which model best distinguished known functional groups in Cerebral Palsy. METHODS: Three models (three degrees of freedom, six degrees of freedom and six degrees of freedom with specified joint translation constraint) were applied to data from running trials of 40 children with cerebral palsy. FINDINGS: Joint angle standard deviations were largest using the six degrees of freedom model and smallest using the constrained six degrees of freedom model (p < 0.050). For all joints in all planes of motion, joint moment standard deviations were largest using the six degrees of freedom model and smallest using the constrained six degrees of freedom model; standard deviations using the constrained model were smaller than the three degrees of freedom model by 10-30% of moment magnitude (0.01-0.03 Nm/kg; p < 0.001). The six degrees of freedom models distinguished functional subgroups with larger effect size than the three degrees of freedom model only for hip power generation in swing. INTERPRETATION: A model with specified joint constraint minimized within-participant variability during running and was useful for detecting differences in functional capacity in cerebral palsy.

Transversus abdominis and core stability: has the pendulum swung?

In the past decade there has been a focus on isolated transversus abdominis activation and how it contributes to lumbo-pelvic stability. This rationale has not only influenced the management of chronic low back pain (LBP); it has also been included in exercises for many other pathologies of the lower and upper limb and also for prophylaxis in pain-free subjects.

Permanent prostate brachytherapy: a century of technical evolution.

PURPOSE: To summarise the practical aspects of the development of techniques of interstitial permanent prostate brachytherapy (PPB) implantation. Prostate brachytherapy dates back to Pasteau's publication in 1913 describing the insertion of a radium capsule into the prostatic urethra to treat carcinoma of the prostate. Various implantation methods were employed but with unsatisfactory results until the development of the transrectal ultrasound in the 1980s. The subsequent two-stage Seattle technique allowed for a planned homogenous distribution of radioactive sources throughout the gland resulting in biochemical control comparable to surgical and external beam radiotherapy series. With the advent of advanced computer software and improved imaging, the technique has developed accordingly to a single stage procedure with on-table dosimetric assessment. The principles of targeting dose to the prostate while avoiding surrounding organs at risk remain as relevant today as nearly a century ago. There is an array of techniques to consider for the novice PPB provider. Whether the evolution of PPB techniques will translate into improved biochemical control is yet to be seen.

Using combined x-ray and MR imaging for prostate I-125 post-implant dosimetry: phantom validation and preliminary patient work.

Post-implantation dosimetry is an important element of permanent prostate brachytherapy. This process relies on accurate localization of implanted seeds relative to the surrounding organs. Localization is commonly achieved using CT images, which provide suboptimal prostate delineation. On MR images, conversely, prostate visualization is excellent but seed localization is imprecise due to distortion and susceptibility artefacts. This paper presents a method based on fused MR and x-ray images acquired consecutively in a combined x-ray and MRI interventional suite. The method does not rely on any explicit registration step but on a combination of system calibration and tracking. A purpose-built phantom was imaged using MRI and x-rays, and the images were successfully registered. The same protocol was applied to three patients where combining soft tissue information from MRI with stereoscopic seed identification from x-ray imaging facilitated post-implant dosimetry. This technique has the potential to improve on dosimetry using either CT or MR alone.

Effects of abdominal muscle fatigue on anticipatory postural adjustments associated with arm raising.

Anticipatory postural adjustments (APAs) are postulated to ameliorate the effects of the disturbance to posture caused by voluntary movement. The primary hypothesis tested in our study was that the magnitude of anticipatory trunk muscle activity is altered by abdominal muscle fatigue. A subsidiary aim of the present study was to examine the directional nature of APAs and use this information to elucidate the central or peripheral nature of changes in postural muscle activity associated with abdominal muscle fatigue. The present study was a within subject design, where abdominal muscle fatigue was induced by a static abdominal curl. Surface EMG was used to assess postural muscle activity in the following trunk muscles; rectus abdominis, erector spinae and internal oblique. Following abdominal muscle fatigue, the magnitude of muscle activity during APAs was significantly reduced by 20% in both the rectus abdominis (fatigued muscle) and the erector spinae (not fatigued) indicating a central rather than peripheral fatigue effect on muscle activity. Abdominal muscle fatigue also induced a 30% increase in the baseline muscle activity of the internal oblique. The changes in magnitude of APA muscle activity may reflect a change in system gain or a change in postural control perhaps related to a change in perceived postural stability. An increase in baseline muscle activity in the internal oblique may compensate partially for the reduction in APAs.

Differences in the use of vision and proprioception for postural control in autism spectrum disorder.

BACKGROUND: People with autism spectrum disorders (ASDs) also have poorer fundamental motor skills. The development of postural control underlies both social and motor skills. All three elements are facilitated by the active use of visual information. This study compares how adults with ASD and typically developed adults (TDAs) respond to a postural illusion induced using neck vibration. Adults with ASD unlike the TDA, were not expected to correct the illusion using vision. METHODS: The study used intermittent (15off, 5on) posterior neck vibration during 200 s of quiet stance to induce a postural illusion. In TDAs and only in the absence of vision this protocol induces a forward body lean. Participants (12 ASD, 20 TDA) undertook four conditions combining vibration and visual occlusion. RESULTS: As predicted, TDA were only affected by the postural illusion when vision was occluded (vibration condition: vision occluded (n=1) p=0.0001; vision available (n=3) p>0.2466). Adults with ASD were affected by the postural illusion regardless of the availability of vision (all conditions p<0.0007). CONCLUSIONS: Our findings indicated the adults with ASD did not use visual information to control standing posture. In light of existing evidence that vision-for-perception is processed typically in ASD, our findings support a specific deficit in vision-for-action. These findings may explain why individuals with ASD experience difficulties with both social and motor skills since both require vision-for-action. Further research needs to investigate the division of these visual learning pathways in order to provide more specific intervention opportunities in ASD.

Cloning, sequence analysis, overproduction in Escherichia coli and enzymatic characterization of the RNase HI from Mycobacterium smegmatis.

Activity gel analysis of cell extracts from slow- and fast-growing mycobacteria confirmed the presence of several RNase H activities in both classes of organism. The rnhA gene from Mycobacterium smegmatis (Ms) was subsequently cloned using an internal gene segment probe [Mizrahi et al., Gene 136 (1993) 287-290]. The gene encodes a polypeptide of 159 amino acids that shares 50% identity with the RNase HI from Escherichia coli (Ec). However, unlike its counterparts from Gram- bacteria, Ms rnhA does not form an overlapping divergent transcriptional unit with dnaQ (encoding the epsilon (proofreading) subunit of DNA polymerase III). Ms RNase HI was overproduced in Ec as an enzymatically active maltose-binding protein (MBP) fusion protein which cleaved the RNA strand of an RNA.DNA hybrid with a similar site selectivity to that of its Ec homologue.

Peptide nucleic acid probe detection of mutations in Mycobacterium tuberculosis genes associated with drug resistance.

The emergence of drug-resistant strains of Mycobacterium tuberculosis is a serious public health problem. Many of the specific gene mutations that cause drug resistance in M. tuberculosis are point mutations. We are developing a PCR-peptide nucleic acid (PNA)-based ELISA as a diagnostic method to recognize point mutations in genes associated with isoniazid and rifampin resistance in M. tuberculosis. Specific point mutation-containing sequences and wild-type sequences of cloned mycobacterial genes were PCR-amplified, denatured, and hybridized with PNA probes bound to microplate wells. Using 15-base PNA probes, we established the hybridization temperatures (50 degrees C-55 degrees C) and other experimental conditions suitable for detecting clinically relevant point mutations in the katG and rpoB genes. Hybridization of PCR-amplified sequences that contained these point mutations with complementary mutation-specific PNAs resulted in significant increases in ELISA response compared with hybridization using wild-type-specific PNAs. Conversely, PCR-amplified wild-type sequences hybridized much more efficiently with wild-type PNAs than with the mutation-specific PNAs. Using the M. tuberculosis cloned genes and PCR-PNA-ELISA format developed here, M. tuberculosis sequences containing point mutations associated with drug resistance can be identified in less than 24 h.

Differential effects of heparin on the early and late phases of hepatic ischemia and reperfusion injury in the pig.

The mechanisms by which heparin protects the liver during induced episodes of liver ischemia-reperfusion are poorly understood. Previous work in a swine model demonstrated that serum levels of glycohydrolases and lipid peroxide peaked within 3 h after 45 minutes of hepatic ischemia followed by reperfusion. Serum levels of lactate dehydrogenase and aspartate aminotransferase peaked 20-24 h later. The aim of this study was to evaluate the effect of heparin on these two-phases of enzyme release, using a pig model of hepatic ischemia-reperfusion injury. Twenty male swine were divided into control (n = 8) and heparin (n = 12) groups. In the heparin group, heparin was administered prior to and concurrent with ischemia-reperfusion. Following 45 min of hepatic ischemia, the levels of beta-galactosidase, beta-glucosidase, acid phosphatase, purine nucleoside phosphorylase, lipid peroxides, lactate dehydrogenase, and aspartate aminotransferase in serum were monitored for up to 166 h and compared to pre-ischemic and control levels. With heparin infusion, the peak levels of beta-galactosidase, beta-glucosidase, and the lipid peroxide were reduced to 50-60% of the control levels. Acid phosphatase and purine nucleoside phosphorylase activities in serum were reduced to 25% and 60%, respectively. The peak concentrations of lactate dehydrogenase and aspartate aminotransferase were reduced to about 25% of the control level. In addition, the serum enzymes of control pigs did not return to pre-ischemic levels until 2 weeks after hepatic ischemia, while they normalized in less than 1 week in the heparin-treated animals. Systemic heparinization had different protective effects on the first and secondary phases of liver injury. These differences may reflect heparin protection of different types of liver cells. The protection of the parenchymal cells may be the combined result of reduced sinusoidal cell injury and the anticoagulant properties of heparin.

Pressure control inverse ratio ventilation as a method to reduce peak inspiratory pressure and provide adequate ventilation and oxygenation.

Nineteen patients with ARDS or pneumonia who were ventilated with PcIRV on the Siemens-Elema Servo 900 C were retrospectively reviewed. The PcIRV reduced peak airway pressure, PEEP, increased Paw, and improved ventilation and oxygenation in these patients. When these patients were compared with themselves on prior conventional IPPV, all had a decrease in PIP, an increase in Paw and most had a decrease in VE, with no change in PaCO2 and an increase in PaO2. The increase in Paw may have contributed to this improved arterial oxygenation. High levels of PIP and PEEP during IPPV have been identified as risk factors in the development of barotrauma and residual parenchymal pulmonary damage. We propose that PcIRV allows for adequate ventilation and oxygenation with decreases in PIP, extrinsically added PEEP and inspired O2 concentration. This mode of ventilation may decrease the morbidity associated with IPPV utilizing high PIP and PEEP.

Insulin-like growth factor (IGF) suppression of IGFBP-1 production: evidence for mediation by the type I IGF receptor.

The regulation of insulin-like growth factor binding protein-1 (IGFBP-1) by its ligands, IGF-I and IGF-II, was studied in continuous cultures of HepG2 human hepatoma cells. Both IGF-I and IGF-II in concentrations as low as 1-10 nmol/l caused significant suppression of IGFBP-I protein levels. This suppression was accompanied by decreased IGFBP-1 mRNA levels occurring within 2-4 h of exposure to IGF-I or IGF-II, and by a significant decrease in IGFBP-1 promoter activity. IGF-I and IGF-II were equipotent in suppressing basal levels of IGFBP-1 protein, mRNA and promoter activity. IGF-I, IGF-II, and IGF-analogs with low IGFBP-1 affinity, (des 1-3)IGF-I and long R3IGF-I, all potently suppressed the previously characterized increase in IGFBP-1 protein levels and promoter activity induced by cAMP and theophylline. In contrast, [Leu-27]IGF-II, which interacts with the type II but not type I IGF receptor, had no effect on IGFBP-1 protein levels or promoter activity. Our data indicate that IGFBP-1 production is inhibited by its ligands, IGF-I and IGF-II, and that this effect is probably mediated at the transcriptional level. The effects of IGF-I and IGF-II apparently occur as a result of binding to the type I IGF receptor, and are similar to the previously characterized suppressive effects of insulin on IGFBP-1 transcription mediated through the insulin receptor. When considered with previous data regarding expression of IGFBP-1 and the type I IGF receptor, our results suggest that IGF regulation of IGFBP-1 may play an as yet undefined role in fetal development and postnatal hepatic regeneration.