Early change in apparent diffusion coefficient as a predictor of response to neoadjuvant androgen deprivation and external beam radiation therapy for intermediate- to high-risk prostate cancer.

AIM: To determine the role of serial apparent diffusion coefficient (ADC) as a biomarker for response to neoadjuvant androgen deprivation therapy (nADT) followed by external beam radiation therapy (EBRT) in intermediate- to high-risk prostate cancer (PCa) patients. METHODS: This Health Insurance Portability and Accountability Act (HIPAA)-compliant, institutional review board (IRB)-approved prospective study included 12 patients with intermediate- to high-risk PCa patients prior to nADT and EBRT, who underwent serial serum prostate-specific antigen (PSA) and multiparametric prostate magnetic resonance imaging (mpMRI) at baseline (BL), 8-weeks after nADT initiation (time point [TP]1), 6-weeks into EBRT delivery (TP2), and 6-months after nADT initiation (TP3). Tumour volume (tVOL) and tumour and normal tissue ADC (tADC and nlADC) were determined at all TPs. tADC and nlADC dynamics were correlated with post-treatment PSA using Pearson's correlation coefficient. Paired t-tests compared pre/post-treatment ADC. RESULTS: There was a sequential decrease in PSA at all TPs, reaching their lowest values at TP3 post-treatment completion. Mean tADC increased significantly from baseline to TP1 (917.8 ± 107.7 × 10-6 versus 1033.8 ± 139.3 × 10-6 mm2/s; p<0.01), with no subsequent change at TP2 or TP3. Both percentage and absolute change in tADC from BL to TP1 correlated with post-treatment PSA (r=-0.666, r=-0.674; p=0.02). Post-treatment PSA in good responders (<0.1 ng/ml) versus poor responders (≥ 0.1 ng/ml) was associated with a greater increase in tADC from BL to TP1 (169.2 ± 122.4 × 10-6 versus 22.9 ± 75.5 × 10-6 mm2/s, p=0.03). CONCLUSION: This pilot study demonstrates the potential for early ADC metrics as a biomarker of response to nADT and EBRT in intermediate to high-risk PCA.

Second Malignancy Probabilities in Patients With Breast Cancer Treated With Conventional Versus Hypofractionated External Beam Radiation Therapy in the Adjuvant Setting.

AIMS: For women with breast cancer, seminal studies have shown that adjuvant hypofractionated external beam radiation therapy (hEBRT) maintains similar outcomes and may reduce overall costs compared with conventionally fractionated external beam radiation therapy (cEBRT). However, it is unclear whether hEBRT may be associated with differential risk of development of radiation-induced second malignancies compared with cEBRT. Because the occurrence of second malignancies is small, large databases may improve our understanding of the relative risk of second malignancies between hEBRT and cEBRT. MATERIALS AND METHODS: Using the National Cancer Database, we carried out a retrospective cohort analysis of women diagnosed with non-metastatic, stage 0-III breast cancer from 2004 to 2017. All patients had a lumpectomy or mastectomy and a follow-up time of at least 60 months after diagnosis. The probability of second malignancies in women receiving adjuvant cEBRT or hEBRT was compared using multivariable logistic regression adjusting for sociodemographic, geographical, clinical and treatment factors, allowing for relative (but not absolute) comparison of second malignancy risk. Temporal sensitivity analyses stratified by year of diagnosis and length of follow-up time were also conducted. RESULTS: Of the 125 228 women in our study, 115 576 (92.3%) received cEBRT and 9652 (7.71%) received hEBRT. The median age of the cohort was 60 (interquartile range 51-68) years at diagnosis and the median follow-up time was 99.61 (interquartile range 77.5-128.49) months. Upon adjusting for sociodemographic and clinical factors, patients who received hEBRT had no difference in relative risk than patients who received cEBRT (odds ratio 0.937, 95% confidence interval 0.869-1.010, P = 0.091). In analyses stratified by year of diagnosis, and stratified by length of follow-up, there was no difference in second malignancy probability between patients who completed hEBRT and patients who completed cEBRT. CONCLUSIONS: In this analysis of over 120 000 women with non-metastatic breast cancer, hEBRT was not associated with different odds of developing second malignancies compared with cEBRT. Our findings may inform patient counselling in the choice of radiation regimens for breast cancer and further support the safety of hypofractionated regimens for breast cancer.

Extracorporeal shockwave therapy and therapeutic exercise for supraspinatus and biceps tendinopathies in 29 dogs.

Supraspinatus tendinopathy (ST) and biceps tendinopathy (BT) are common causes of forelimb lameness in large-breed dogs and have historically been treated with conservative management or surgery. Extracorporeal shockwave therapy (ESWT) and therapeutic exercise (TE) are thought to be treatment options for these conditions. The objectives of this study were to report the clinical presentations of dogs treated with ESWT for shoulder tendinopathies, to determine the association between shoulder lesion severity identified on ultrasonography or MRI and outcome, and to compare the outcomes of dogs treated with ESWT with and without TE. Medical records of 29 dogs diagnosed with shoulder tendinopathies and treated with ESWT were reviewed, and 24 dogs were diagnosed with either unilateral BT or BT and ST. None were found to have unilateral ST. Five dogs were diagnosed with bilateral disease. Eighty-five per cent of dogs had good or excellent outcomes determined by owner assessment 11-220 weeks after therapy. Outcomes were found to be better as tendon lesion severity increased (P=0.0497), regardless if ESWT was performed with or without TE (P=0.92). ESWT should be considered a safe primary therapeutic option for canine shoulder tendinopathies. Larger controlled prospective studies are needed to adequately assess these findings.

Radium-223 outcomes after multiple lines of metastatic castration-resistant prostate cancer therapy in clinical practice: implication of pre-treatment spinal epidural disease.

BACKGROUND: Magnetic resonance imaging (MRI) is not routinely performed before initiating radium-223 to document spinal epidural disease. However, radium-223 decays to form α-particles with very short path lengths that may not reach the epidural space. Herein, we investigate the impact of baseline spinal epidural disease on metastatic castration-resistant prostate cancer (mCRPC) patients treated with radium-223. METHODS: Between October 2013 to December 2014, 41 consecutive mCRPC patients at a large tertiary cancer center were prescribed radium-223 as part of standard of care. 29% of patients had pre-treatment epidural disease (posMRI), 27% had no epidural disease (negMRI), and 44% did not have a baseline MRI (noMRI). All patients had post-treatment spinal imaging. Actuarial survival times were calculated for overall survival (OS), spinal axis radiographic progression-free survival (spinePFS) and epidural progression-free survival (epiPFS) from time of first radium-223 treatment. RESULTS: For patients with posMRI (n=12), noMRI (n=18) and negMRI (n=11) cumulative rates of development or worsening of epidural disease and/or high-grade cord compression at time of last follow-up were 83%, 44% and 9%, respectively (P=0.001). For the posMRI, noMRI and negMRI groups the median OS was 6.3 months, 12.6 months and not reached (P=0.01), the median spinePFS was 3.2 months, 4.8 months and not reached (P=0.01), and the median epiPFS was 3.2 months, 10.4 months and not reached (P=0.001). Completing less than six cycles of radium-223 was significantly associated with worse OS (P<0.0001), spinePFS (P=0.007) and epiPFS (P=0.01). Greater than or equal to twenty osseous lesions pre-treatment was significantly associated with worse spinePFS (P=0.001) and epiPFS (P=0.03). CONCLUSIONS: In a heavily pre-treated small cohort, patients with baseline epidural disease frequently progressed to spinal cord compression and early cessation of radium-223 therapy. Studies are needed to determine the optimal timing of radium-223 with other mCRPC therapies given the predilection for epidural disease and treatment failure after multiple prior lines of mCRPC therapy.

Laboratory observations of slow earthquakes and the spectrum of tectonic fault slip modes.

Slow earthquakes represent an important conundrum in earthquake physics. While regular earthquakes are catastrophic events with rupture velocities governed by elastic wave speed, the processes that underlie slow fault slip phenomena, including recent discoveries of tremor, slow-slip and low-frequency earthquakes, are less understood. Theoretical models and sparse laboratory observations have provided insights, but the physics of slow fault rupture remain enigmatic. Here we report on laboratory observations that illuminate the mechanics of slow-slip phenomena. We show that a spectrum of slow-slip behaviours arises near the threshold between stable and unstable failure, and is governed by frictional dynamics via the interplay of fault frictional properties, effective normal stress and the elastic stiffness of the surrounding material. This generalizable frictional mechanism may act in concert with other hypothesized processes that damp dynamic ruptures, and is consistent with the broad range of geologic environments where slow earthquakes are observed.

Biological Features of Human Papillomavirus-related Head and Neck Cancers Contributing to Improved Response.

Head and neck squamous cell carcinomas (HNSCC) are the sixth most common malignancy globally, and an increasing proportion of oropharyngeal HNSCCs are associated with the human papillomavirus (HPV). Patients with HPV-associated tumours have markedly improved overall and disease-specific survival compared with their HPV-negative counterparts when treated with chemoradiation. Although the difference in outcomes between these two groups is clearly established, the mechanism underlying these differences remains an area of investigation. Data from preclinical, clinical and genomics studies have started to suggest that an increase in radio-sensitivity of HPV-positive HNSCC may be responsible for improved outcomes, the putative mechanisms of which we will review here. The Cancer Genome Atlas and others have recently documented a multitude of molecular differences between HPV-positive and HPV-negative tumours. Preclinical investigations by multiple groups have explored possible mechanisms of increased sensitivity to therapy, including examining differences in DNA repair, hypoxia and the immune response. In addition to differences in the response to therapy, some groups have started to investigate phenotypic differences between the two diseases, such as tumour invasiveness. Finally, we will conclude with a brief review of ongoing clinical trials that are attempting to de-escalate treatment to minimise long-term toxicity while maintaining cure rates. New insights from preclinical and genomic studies may eventually lead to personalised treatment paradigms for HPV-positive patients.

Coronal oblique imaging of the knee: can it increase radiologists' confidence in diagnosing posterior root meniscal tears?

AIM: To investigate the utility of the coronal oblique sequence in the interrogation of posterior root meniscal lesions. MATERIALS AND METHODS: Following international review board approval, 62 consecutive knee arthroscopy cases were referred to the musculoskeletal (MSK) radiologists from the same orthopaedic surgeon for imaging/surgical correlation of the posterior meniscal roots. Of 62 cases, 45 lateral and 46 medial menisci met the inclusion criteria. Imaging evaluation was performed with standard magnetic resonance imaging (MRI) sequences, including a coronal oblique proton density sequence. Two blinded fellowship-trained MSK radiologists independently evaluated the menisci on standard sequences indicating whether a tear was identified and then specifying a confidence score using a scale of 1-3 on each study interpreted. Immediately thereafter, the coronal oblique sequence was evaluated using the same method. Statistics were performed on meniscal lesions involving the posterior horn/root junction or isolated root tears comparing confidence scores. RESULTS: Reader A identified nine posterior horn/root junction tears and 14 isolated root tears. Following the addition of the coronal oblique sequence, confidence scores increased in three of 14 (21.4%) isolated root tears. All three final reads were concordant with arthroscopy. Reader B identified 10 posterior horn/root junction tears and 19 isolated root tears. The confidence score increased in six cases: five of 19 (26.3%) isolated root tears and one of 10 (10%) posterior horn/root junction tears. All six final reads were concordant with arthroscopy. Kappa coefficients indicated near perfect agreement. CONCLUSION: The coronal oblique sequence increased reader confidence in nearly 24% of the posterior root cases identified in this series.

Fiber optic sensing technology for detecting gas hydrate formation and decomposition.

A fiber optic-based distributed sensing system (DSS) has been integrated with a large volume (72 l) pressure vessel providing high spatial resolution, time-resolved, 3D measurement of hybrid temperature-strain (TS) values within experimental sediment-gas hydrate systems. Areas of gas hydrate formation (exothermic) and decomposition (endothermic) can be characterized through this proxy by time series analysis of discrete data points collected along the length of optical fibers placed within a sediment system. Data are visualized as an animation of TS values along the length of each fiber over time. Experiments conducted in the Seafloor Process Simulator at Oak Ridge National Laboratory clearly indicate hydrate formation and dissociation events at expected pressure-temperature conditions given the thermodynamics of the CH(4)-H(2)O system. The high spatial resolution achieved with fiber optic technology makes the DSS a useful tool for visualizing time-resolved formation and dissociation of gas hydrates in large-scale sediment experiments.

Deletion analysis and alternative splicing define a transactivation inhibitory domain in human oncoprotein REL.

Misregulation of REL, a nuclear factor-kappaB family transcription factor, has been implicated in several human lymphoid malignancies. REL has a conserved N-terminal DNA-binding/dimerization domain called the Rel homology domain (RHD) and a C-terminal transactivation domain (TAD). Here, we define the sequences (amino acids (aa) 323-422) between the RHD and TAD as a REL inhibitory domain (RID) because deletion of these sequences increases both REL transactivation and DNA binding. Furthermore, we have characterized two REL mRNA splice variants that encode proteins with alterations near RID: one lacking exon 9 sequences (aa 308-330; RELDelta9) and one with an exonized Alu fragment insertion of 32 aa after aa 307 (REL+Alu). Deletion of RID or exon 9-encoded sequences increases transactivation by GAL4-REL by approximately threefold. Moreover, deletion of RID or exon 9 sequences increases transactivation by full-length REL from certain kappaB site-containing promoters and increases DNA binding by REL. Deletion of RID does not affect REL's ability to transform chicken spleen cells. Reverse transcriptase-polymerase chain reaction analysis of mRNA from both primary lymphoma samples and several transformed tissue culture cell lines indicates that the RELDelta9 splice variant is preferentially expressed in lymphoma, suggesting that the REL transcript lacking exon 9 could serve as a marker for certain types of lymphoid tumors.

Mutation of an IKK phosphorylation site within the transactivation domain of REL in two patients with B-cell lymphoma enhances REL's in vitro transforming activity.

The human c-rel proto-oncogene (REL) encodes a subunit of the nuclear factor-kappaB (NF-kappaB) transcription factor. In this report, we have identified an identical point mutation in two human B-cell lymphomas (follicular (FL) and mediastinal) that changes serine (Ser)525 (TCA) to proline (Pro) (CCA) within the REL transactivation domain. This mutation was not identified in a similarly sized cohort of healthy individuals. In the mediastinal B-cell lymphoma, the mutation in REL is of germ-line origin. In both tumors, the S525P mutant allele is over-represented. REL-S525P shows enhanced in vitro transforming activity in chicken spleen cells. REL-S525P has a reduced ability to activate the human manganese superoxide dismutase (MnSOD) promoter in A293 cells; however, the MnSOD protein shows increased expression in REL-S525P-transformed chicken spleen cells as compared to wild-type REL-transformed cells. Ser525 is a site for phosphorylation by IkappaB kinase (IKK) in vitro. The S525P mutation reduces IKKalpha- and tumor necrosis factor (TNF)alpha-stimulated transactivation by a GAL4-REL protein. Furthermore, REL-S525P-transformed chicken spleen cells are more resistant to TNFalpha-induced cell death than cells transformed by wild-type REL. These results suggest that the S525P mutation contributes to the development of human B-cell lymphomas by affecting an IKKalpha-regulated transactivation activity of REL.

Inter-organizational relationships of seven Veterans Affairs Medical Centers and their affiliated medical schools: results of a multiple-case-study investigation.

PURPOSE: This study describes the costs and and value added to Veterans Affairs Medical Centers (VAMCs) through their affiliations with medical schools. The study also creates a conceptual framework for evaluating the critical dimensions across which these affiliations vary. METHOD: Case studies of seven VAMCs' affiliations with medical schools, ranging from two highly affiliated VAMCs to one with only one funded residency position, were conducted in 1997 and 1998 using a survey and in-depth interviews with 78 key individuals at the institutions. The qualitative data were then used to develop a conceptual framework for evaluating these affiliations. RESULTS: The results are reported in two stages. In stage one, three organizing themes emerged from the data that formed the conceptual framework for evaluating affiliations: (1) the characteristics of each VAMC and its environment, (2) the characteristics of the relationships between each VAMC and its medical school affiliates, and (3) the costs and value that medical school affiliations add to VAMCs. The affiliations that were most beneficial to VAMCs were characterized by a relationship of trust, extensively shared education and research programs, and a high degree of physician interaction. The achievement of these characteristics is influenced by the distance between the VAMCs and their affiliated medical schools, the VAMCs' levels of organizational complexity, the degree of managed care penetration, and the continuity and academic orientation of leadership at the VAMCs. In stage two, study data were used to create a conceptual framework to evaluate the characteristics of VAMCs and their affiliations with medical schools. CONCLUSIONS: The study supplied data to construct a conceptual framework that describes many of the relationships among the different affiliations in the study. The framework offers a tool for evaluating the dimensions across which affiliations vary and how these differences influence the costs and value of medical school affiliations to VAMCs.

Open chest cardiopulmonary resuscitation in out-of-hospital cardiac arrest.

Because closed chest cardiopulmonary resuscitation (CCCPR) achieve restoration of spontaneous circulation (ROSC) in less than 50% of cases, and because of the apparent physiological superiority of open-chest cardiopulmonary resuscitation (OCCPR), we evaluated OCCPR in out-of hospital cardiac arrest in cases who did not respond to standard external cardiopulmonary resuscitation with advanced life support. Over a period of 12 years, OCCPR was performed in 33 patients with out-of-hospital cardiac arrest arising from different causes, after unsuccessful attempts to achieve ROSC with CCCPR efforts over 7-121 min (median 25 min). With OCCPR, ROSC was achieved in 13/33 patients. Of these, two recovered to discharge (one with no neurological deficit and one with mild brain damage). The other 11 rearrested either in the emergency department after a median period of 70 min of resuscitation, or in the intensive care unit after a median period of 104 h. One case of iatrogenic cardiac injury was observed. The OCCPR attempts were well accepted by the public. Our data suggest that OCCPR is more effective than CCCPR in achieving ROSC outside hospital in patients with major cardiac disease and prolonged arrest. OCCPR is feasible in the out-of-hospital setting. Survival without neurological deficit cannot be expected when CCCPR with no-flow is continued beyond 25 min.

Different clinical manifestations of meningococcaemia: three patient reports.

Neisseria meningitidis, a ubiquitous Gram-negative diplococcus, is responsible for a spectrum of clinical manifestations. This is illustrated by the history of three patients recently admitted to our hospital. Because of the possibly rapid and dramatic evolution, awareness for meningococcal diseases remains obligatory. Adequate antibiotic treatment instituted as soon as the diagnosis is suspected and early application of aggressive supportive care can lead to more favourable outcome.

Experimental inhibition of peroxisomal beta-oxidation in rats: influence on brain myelination.

Oral administration of thioridazine, an inhibitor of peroxisomal beta-oxidation, to normal rats from weaning till day 60 causes a small increase of the very long chain fatty acid C26 in brain lipids. Myelination in the brain is decreased. In the genu of the corpus callosum the ratio of non-myelinated/myelinated axons is increased. In the commissura anterior the myelin sheaths of the axons are significantly thinner in treated than in control animals. Undernourishment caused by the drug is minimal in this experiment. Area and total DNA of glial nuclei are unaltered in both the genu and the commissura anterior of treated rats. The distribution of chromatin (texture), however, shows small differences in the corpus callosum.