81 research outputs found
A Phase I/II Trial of Fairly Brief Androgen Suppression and Stereotactic Radiation Therapy for High-Risk Prostate Cancer (FASTR-2): Preliminary Results and Toxicity Analysis
Purpose: FASTR was designed to provide a compact treatment course for high-risk prostate cancer patients but was discontinued because of excess toxicity. We present the results of FASTR-2, which used a lower dose to the prostate (35 Gy vs 40 Gy), smaller posterior PTV margin (4 mm vs 5 mm) and omitted nodal radiation to lower the volumes of rectum receiving high and intermediate doses compared with FASTR. Gastrointestinal (GI) and genitourinary (GU) toxicities at baseline, 6 weeks, 6 months, and 1 year and biochemical control rates are presented. Methods and Materials: Eligibility included high-risk prostate cancer (cT3/4, prostate-specific antigen \u3e20 or Gleason Score ≥8), age ≥70 or refused standard treatment, and no evidence of metastatic disease. Patients received 18 months of androgen deprivation therapy starting 2 months before radiation. Clinical target volume was defined as prostate plus proximal 1-cm seminal vesicles. PTV was a nonuniform expansion around clinical target volume (4 mm posteriorly, 5 mm in all other directions). Volumetric arc therapy was used for treatment delivery (35 Gy delivered in 5 weekly fractions of 7 Gy each), and cone beam computed tomography with soft tissue matching (no fiducial placement) was used for daily image guidance. Toxicity was assessed at 6 weeks, 6 months, and 1 year according to Common Toxicity Criteria. Results: In the study, 30 patients were enrolled in FASTR-2 between 2015 and 2017. Two patients were withdrawn owing to ineligibility after enrollment. One patient (3.7%) reported grade 2 GI toxicity at 6 weeks. There was no reported grade ≥2 GI toxicity at 6 months or 1 year. There were no reported episodes of rectal bleeding. Four patients (14.8%), 5 patients (17.9%), and 5 patients (21.7%) reported grade 2 GU toxicity at 6 weeks, 6 months, and 1 year, respectively. There were no reported cases of grade ≥3 GU toxicity. The most common toxicities were nocturia and urinary frequency or urgency. Conclusions: FASTR-2 was more tolerable than FASTR, with no grade ≥3 toxicities reported, in keeping with expectations based on our previous FASTR analysis. Long-term follow-up is necessary to ensure disease control and toxicity outcomes are comparable to conventional high-risk treatment paradigms
Ticagrelor Reduces Thromboinflammatory Markers in Patients With Pneumonia
Despite treatment advances for sepsis and pneumonia, significant improvements in outcome have not been realized. Antiplatelet therapy may improve outcome in pneumonia and sepsis. In this study, the authors show that ticagrelor reduced leukocytes with attached platelets as well as the inflammatory biomarker interleukin (IL)-6. Pneumonia patients receiving ticagrelor required less supplemental oxygen and lung function tests trended toward improvement. Disruption of the P2Y12 receptor in a murine model protected against inflammatory response, lung permeability, and mortality. Results indicate a mechanistic link between platelets, leukocytes, and lung injury in settings of pneumonia and sepsis, and suggest possible therapeutic approaches to reduce complications. (Targeting Platelet-Leukocyte Aggregates in Pneumonia With Ticagrelor [XANTHIPPE]; NCT01883869
Technology assessment of automated atlas based segmentation in prostate bed contouring
<p>Abstract</p> <p>Background</p> <p>Prostate bed (PB) contouring is time consuming and associated with inter-observer variability. We evaluated an automated atlas-based segmentation (AABS) engine in its potential to reduce contouring time and inter-observer variability.</p> <p>Methods</p> <p>An atlas builder (AB) manually contoured the prostate bed, rectum, left femoral head (LFH), right femoral head (RFH), bladder, and penile bulb of 75 post-prostatectomy cases to create an atlas according to the recent RTOG guidelines. 5 other Radiation Oncologists (RO) and the AABS contoured 5 new cases. A STAPLE contour for each of the 5 patients was generated. All contours were anonymized and sent back to the 5 RO to be edited as clinically necessary. All contouring times were recorded. The dice similarity coefficient (DSC) was used to evaluate the unedited- and edited- AABS and inter-observer variability among the RO. Descriptive statistics, paired t-tests and a Pearson correlation were performed. ANOVA analysis using logit transformations of DSC values was calculated to assess inter-observer variability.</p> <p>Results</p> <p>The mean time for manual contours and AABS was 17.5- and 14.1 minutes respectively (p = 0.003). The DSC results (mean, SD) for the comparison of the unedited-AABS versus STAPLE contours for the PB (0.48, 0.17), bladder (0.67, 0.19), LFH (0.92, 0.01), RFH (0.92, 0.01), penile bulb (0.33, 0.25) and rectum (0.59, 0.11). The DSC results (mean, SD) for the comparison of the edited-AABS versus STAPLE contours for the PB (0.67, 0.19), bladder (0.88, 0.13), LFH (0.93, 0.01), RFH (0.92, 0.01), penile bulb (0.54, 0.21) and rectum (0.78, 0.12). The DSC results (mean, SD) for the comparison of the edited-AABS versus the expert panel for the PB (0.47, 0.16), bladder (0.67, 0.18), LFH (0.83, 0.18), RFH (0.83, 0.17), penile bulb (0.31, 0.23) and rectum (0.58, 0.09). The DSC results (mean, SD) for the comparison of the STAPLE contours and the 5 RO are PB (0.78, 0.15), bladder (0.96, 0.02), left femoral head (0.87, 0.19), right femoral head (0.87, 0.19), penile bulb (0.70, 0.17) and the rectum (0.89, 0.06). The ANOVA analysis suggests inter-observer variability among at least one of the 5 RO (p value = 0.002).</p> <p>Conclusion</p> <p>The AABS tool results in a time savings, and when used to generate auto-contours for the femoral heads, bladder and rectum had superior to good spatial overlap. However, the generated auto-contours for the prostate bed and penile bulb need improvement.</p
Consanguinity Mapping of Congenital Heart Disease in a South Indian Population
Parental consanguinity is a risk factor for congenital heart disease (CHD) worldwide, suggesting that a recessive inheritance model may contribute substantially to CHD. In Bangalore, India, uncle-niece and first cousin marriages are common, presenting the opportunity for an international study involving consanguinity mapping of structural CHD. We sought to explore the recessive model of CHD by conducting a genome-wide linkage analysis utilizing high-density oligonucleotide microarrays and enrolling 83 CHD probands born to unaffected consanguineous parents. exons did not reveal causative mutations in Indian probands. In addition, genotyping of the linked allele (G) in 325 U.S. CHD cases revealed neither genotypic nor allele frequency differences in varied CHD cases compared to 605 non-CHD controls. may harbor recessive mutations leading to CHD in the Indian population. Further research involving large multinational cohorts of patients with specific subtypes of CHD is needed to attempt replication of the observed linkage peak on chromosome 14. In addition, we anticipate that a targeted re-sequencing approach may complement linkage analysis in future studies of recessive mutation detection in CHD
Supplementary data: Chemoradiotherapy in octogenarians as primary treatment for muscle-invasive bladder cancer
Chemoradiotherapy in octogenarians as primary treatment for muscle-invasive bladder cancer
Introduction: While radical cystectomy is the gold standard for muscle-invasive bladder cancer (MIBC), in octogenarians cystectomy results in a higher perioperative mortality rate (6.8‒11.1%) than in younger patients (2.2%). Trimodality therapy is a bladder-sparing regimen composed of transurethral resection of bladder tumour (TURBT) and chemoradiotherapy, with intent for salvage cystectomy, and has a 62.5‒90% initial complete response rate. In this study, we evaluate TURBT and chemoradiotherapy without salvage cystectomy in medically inoperable octogenarian patients. Methods: We identified a retrospective cohort of patients aged 80‒89 years with invasive urothelial carcinoma who received combination chemoradiotherapy between 2008 and June 2014. Outcomes were evaluated by Kaplan-Meier (KM) and Cox regression. Results: In 40 patients, the mean age was 84.5 years (interquartile range [IQR] 83‒86). Seventeen patients received hypofractionated, low-dose radiotherapy (LD) (37.5‒40 Gy), while 23 received conventionally fractionated radiotherapy (high-dose [HD]) (50‒65 Gy). Mean overall survival (OS) was 20.7 months (IQR 12.75‒23.25), while mean recurrence-free survival (RFS) was 13.75 months (IQR 3.75‒16.5). Patients receiving HD radiotherapy showed improved OS and local RFS (LRFS) without significant differences in Grade 3‒4 toxicities. Univariate Cox regression identified hydronephrosis as a predictor of worse OS and local recurrence and HD radiotherapy as a predictor of improved OS and local recurrence rates. Multivariate Cox regression identified hydronephrosis to be a significant predictor of LRFS. Conclusions: Primary chemoradiotherapy for inoperable patients with MIBC resulted in a three-year OS of 54.9% (comparable to cystectomy) and three-year RFS of 42.3%. Superior outcomes were associated with more aggressive chemoradiotherapy treatment. The results of the local control subanalyses in this study are hypothesis-generating due to the limited patient numbers in the cohort
Nuclear Activity in the Low Metallicity Dwarf Galaxy SDSS J0944-0038: A Glimpse into the Primordial Universe
Local low metallicity dwarf galaxies are relics of the early universe and
hold clues into the origins of supermassive black holes (SMBHs). In recent
work, coronal lines have been used to unveil a population of candidate
accreting black holes in dwarf galaxies with gas phase metallicities and
stellar masses well below the host galaxies of any previously known AGNs. Using
MUSE/VLT observations, we report the detection of [Fe X] 6374 coronal
line emission and a broad H line in the nucleus of SDSS
J094401.87003832.1, a nearby () metal poor dwarf galaxy at least
fifty times less massive than the LMC. The [Fe X] 6374 emission is
compact and centered on the brightest nuclear source, with a spatial extent of
100 pc. The [Fe X] luminosity is erg s,
within the range seen in previously identified AGNs in the dwarf galaxy
population. This line has never been observed in gas ionized by hot stars.
While it can be produced in supernova ejecta, the [Fe X] flux from SDSS
J094401.87003832.1 has persisted over the ~19 year time period between the
SDSS and MUSE observations, ruling out supernovae as the origin for the
emission. The FWHM of the broad component of the H line is
km s and its luminosity is erg s,
lower than the broad line luminosities of previously identified low mass broad
line AGNs. These observations, together with previously reported
multi-wavelength observations, can most plausibly be explained by the presence
of an accreting intermediate mass black hole in a primordial galaxy analog.
However, we cannot rule out the possibility that current stellar population
models of metal poor stars significantly under-predict the stellar ionizing
photon flux, and that metal poor stars can produce an extreme ionizing spectrum
similar to that produced by AGNs.Comment: 12 pages, 5 figures, 1 table, submitted to ApJL. Comments welcom
The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe
The preponderance of matter over antimatter in the early Universe, the
dynamics of the supernova bursts that produced the heavy elements necessary for
life and whether protons eventually decay --- these mysteries at the forefront
of particle physics and astrophysics are key to understanding the early
evolution of our Universe, its current state and its eventual fate. The
Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed
plan for a world-class experiment dedicated to addressing these questions. LBNE
is conceived around three central components: (1) a new, high-intensity
neutrino source generated from a megawatt-class proton accelerator at Fermi
National Accelerator Laboratory, (2) a near neutrino detector just downstream
of the source, and (3) a massive liquid argon time-projection chamber deployed
as a far detector deep underground at the Sanford Underground Research
Facility. This facility, located at the site of the former Homestake Mine in
Lead, South Dakota, is approximately 1,300 km from the neutrino source at
Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino
charge-parity symmetry violation and mass ordering effects. This ambitious yet
cost-effective design incorporates scalability and flexibility and can
accommodate a variety of upgrades and contributions. With its exceptional
combination of experimental configuration, technical capabilities, and
potential for transformative discoveries, LBNE promises to be a vital facility
for the field of particle physics worldwide, providing physicists from around
the globe with opportunities to collaborate in a twenty to thirty year program
of exciting science. In this document we provide a comprehensive overview of
LBNE's scientific objectives, its place in the landscape of neutrino physics
worldwide, the technologies it will incorporate and the capabilities it will
possess.Comment: Major update of previous version. This is the reference document for
LBNE science program and current status. Chapters 1, 3, and 9 provide a
comprehensive overview of LBNE's scientific objectives, its place in the
landscape of neutrino physics worldwide, the technologies it will incorporate
and the capabilities it will possess. 288 pages, 116 figure
Eggshell Composition of Squamate Reptiles: Relationship between Eggshell Permeability and Amino Acid Distribution
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Homologous recombination DNA repair defects in PALB2- associated breast cancers
Abstract: Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD
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