T-cell infiltration in estrogen receptor (ER)-negative breast tumours has been associated with longer survival. To investigate this association and the potential of tumour T-cell infiltration as a ...prognostic and predictive marker, we have conducted the largest study of T cells in breast cancer to date.
Four studies totalling 12 439 patients were used for this work. Cytotoxic (CD8+) and regulatory (forkhead box protein 3, FOXP3+) T cells were quantified using immunohistochemistry (IHC). IHC for CD8 was conducted using available material from all four studies (8978 samples) and for FOXP3 from three studies (5239 samples)-multiple imputation was used to resolve missing data from the remaining patients. Cox regression was used to test for associations with breast cancer-specific survival.
In ER-negative tumours triple-negative breast cancer and human epidermal growth factor receptor 2 (human epidermal growth factor receptor 2 (HER2) positive), presence of CD8+ T cells within the tumour was associated with a 28% 95% confidence interval (CI) 16% to 38% reduction in the hazard of breast cancer-specific mortality, and CD8+ T cells within the stroma with a 21% (95% CI 7% to 33%) reduction in hazard. In ER-positive HER2-positive tumours, CD8+ T cells within the tumour were associated with a 27% (95% CI 4% to 44%) reduction in hazard. In ER-negative disease, there was evidence for greater benefit from anthracyclines in the National Epirubicin Adjuvant Trial in patients with CD8+ tumours hazard ratio (HR) = 0.54; 95% CI 0.37-0.79 versus CD8-negative tumours (HR = 0.87; 95% CI 0.55–1.38). The difference in effect between these subgroups was significant when limited to cases with complete data (Pheterogeneity = 0.04) and approached significance in imputed data (Pheterogeneity = 0.1).
The presence of CD8+ T cells in breast cancer is associated with a significant reduction in the relative risk of death from disease in both the ER-negative supplementary Figure S1, available at Annals of Oncology online and the ER-positive HER2-positive subtypes. Tumour lymphocytic infiltration may improve risk stratification in breast cancer patients classified into these subtypes.
NCT00003577.
Under the U.S. Lung Allocation Score (LAS) system, older and sicker patients are prioritized for lung transplantation (LT). The impact of these changes on health‐related quality of life (HRQL) after ...transplant has not been determined. In a single‐center prospective cohort study from 2010 to 2016, we assessed HRQL before and repeatedly after LT for up to 3 years using the SF12‐Physical and Mental Health, the respiratory‐specific Airway Questionnaire 20‐Revised, and the Euroqol 5D/Visual Analog Scale utility measures by multivariate linear mixed models jointly modeled with death. We also tested changes in LT‐Valued Life Activities disability, BMI, allograft function, and 6‐min walk test exercise capacity as predictors of HRQL change. Among 211 initial participants (92% of those eligible), LT improved HRQL by all 5 measures (p < 0.05) and all but SF12‐Mental Health improved by threefold or greater than the minimally clinically important difference. Compared to younger participants, those aged ≥65 improved less in SF12‐Physical and Mental Health (p < 0.01). Improvements in disability accounted for much of the HRQL improvement. In the LAS era, LT affords meaningful and durable HRQL improvements, mediated by amelioration of disability. Identifying factors limiting HRQL improvement in selected subgroups, especially those aged ≥65, are needed to maximize the net benefits of LT.
In a prospective longitudinal adult cohort, the authors find that lung transplantation substantially improves health‐related quality of life and that this improvement is largely mediated by amelioration of physical disability, though older adults and those undergoing transplantation for diagnoses other than cystic fibrosis derive a smaller benefit in health‐related quality of life.
To determine whether human epidermal growth factor receptor 2 (HER2) status is an independent prognostic factor in metastatic gastric and gastroesophageal junction (GEJ) adenocarcinoma.
...Formalin-fixed paraffin-embedded tumor samples from 381 metastatic gastric/GEJ cancer patients enrolled at Krankenhaus Nordwest and Memorial Sloan–Kettering Cancer Centers on six first-line trials of chemotherapy without trastuzumab were examined for HER2 by immunohistochemistry (IHC) and in situ hybridization (ISH). IHC 3+ or ISH-positive tumors were considered HER2 positive.
Seventy-eight of 381 patients (20%) had HER2-positive disease. In the multivariate logistic model, there were significantly higher rates of HER2 positivity in patients with liver metastasis (liver metastasis 31%; no liver metastasis 11%; P = 0.025) and intestinal histology (intestinal 33%; diffuse/mixed 8%; P = 0.001). No significant differences in HER2 positivity were found between resections and biopsies or primaries and metastases. Patients with HER2-positive gastric cancer had longer median overall survival compared with HER2-negative gastric cancer patients (13.9 versus 11.4 months, P = 0.047), but multivariate analysis indicated that HER2 status was not an independent prognostic factor (hazard ratio 0.79; 0.44–1.14; P = 0.194).
Approximately 20% of Western patients with metastatic gastric cancer are HER2 positive. Unlike breast cancer, HER2 positivity is not independently prognostic of patient outcome in metastatic gastric or GEJ.
The Boston University-Five College Radio Astronomy Observatory Galactic Ring Survey is a new survey of Galactic super(13)CO J = 1 1 0 emission. The survey used the SEQUOIA multipixel array on the ...Five College Radio Astronomy Observatory 14m telescope to cover a longitude range of l = 18-55.7 and a latitude range of |b| < 1, a total of 75.4 deg super(2). Using both position-switching and On-The-Fly mapping modes, we achieved an angular sampling of 22, better than half of the telescope's 46 angular resolution. The survey's velocity coverage is -5 to 135 km s super(-1) for Galactic longitudes l, 40 and -5 to 85 km s super(-1) for Galactic longitudes l > 40. At the velocity resolution of 0.21 km s super(-1), the typical rms sensitivity is s(T super(*)A) 6 0.13 K. The survey comprises a total of 1,993,522 spectra. We show integrated intensity images (zeroth moment maps), channel maps, position-velocity diagrams, and an average spectrum of the completed survey data set. We also discuss the telescope and instrumental parameters, the observing modes, the data reduction processes, and the emission and noise characteristics of the data set. The Galactic Ring Survey data are available to the community online or in DVD form by request.
Small cell carcinoma of the ovary of hypercalcemic type (SCCOHT) is an extremely rare, aggressive cancer affecting children and young women. We identified germline and somatic inactivating mutations ...in the SWI/SNF chromatin-remodeling gene SMARCA4 in 75% (9/12) of SCCOHT cases in addition to SMARCA4 protein loss in 82% (14/17) of SCCOHT tumors but in only 0.4% (2/485) of other primary ovarian tumors. These data implicate SMARCA4 in SCCOHT oncogenesis.
We characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination.
We evaluated clinical ...phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients.
The most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses <10 mg daily or within 2 months of cessation. Immunotherapy, including maintenance prednisone (P=0.0004), intravenous immunoglobulin, rituximab and mycophenolate, all reduced median ARRs on-treatment. Treatment failure rates were lower in patients on maintenance steroids (5%) compared with non-steroidal maintenance immunotherapy (38%) (P=0.016). 58% of patients experienced residual disability (average follow-up 61 months, visual loss in 24%). Patients with ON were less likely to have sustained disability defined by a final EDSS of ≥2 (OR 0.15, P=0.032), while those who had any myelitis were more likely to have sustained residual deficits (OR 3.56, P=0.077).
Relapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation.
The accurate diagnosis of indeterminate pancreaticobiliary strictures presents a clinical dilemma. Probe-based confocal laser endomicroscopy (pCLE) offers real-time in vivo microscopic tissue ...examination that may increase sensitivity for the detection of malignancy. the objective of this study was to develop and validate a standard descriptive classification of pcle in the pancreaticobiliary system.
A total of 102 patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) with pCLE to assess indeterminate pancreaticobiliary strictures were enrolled in a multicenter registry; 89 of these patients were evaluable. Information and data on the following were collected prospectively: clinical, ERCP, tissue sampling, pCLE, and follow-up. A uniform classification of pCLE findings ("Miami Classification") was developed, consisting of a set of image interpretation criteria. Thereafter, these criteria were tested through blinded consensus review of 112 randomized pCLE videos from 47 patients, and inter-observer variability was assessed in 42 patients .
A consensus definition of the specific criteria of biliary and pancreatic pCLE findings for indeterminate strictures was developed. Single-image interpretation criteria did not have a high enough sensitivity for predicting malignancy. However, combining two or more criteria significantly increased the sensitivity and predictive values. The characteristics most suggestive of malignancy included the following: thick white bands (>20 µm), or thick dark bands (>40 µm), or dark clumps or epithelial structures. These provided sensitivity, specificity, positive predictive value, and negative predictive value of 97%, 33%, 80%, and 80% compared with 48%, 100%, 100%, and 41% for standard tissue sampling methods. Inter-observer variability was moderate for most criteria.
The Miami Classification enables a structured, uniform, and reproducible description of pancreaticobiliary pCLE. Combining individual characteristics improves the sensitivity for the detection of malignancy.
Lung transplantation is the only intervention that prolongs survival in idiopathic pulmonary fibrosis (IPF). Telomerase mutations are the most common identifiable genetic cause of IPF, and at times, ...the telomere defect manifests in extrapulmonary disease such as bone marrow failure. The relevance of this genetic diagnosis for lung transplant management has not been examined. We gathered an international series of telomerase mutation carriers who underwent lung transplant in the U.S.A., Australia and Sweden. The median age at transplant was 52 years. Seven recipients are alive with a median follow-up of 1.9 years (range 6 months to 9 years); one died at 10 months. The most common complications were haematological, with recipients requiring platelet transfusion support (88%) and adjustment of immunosuppressives (100%). Four recipients (50%) required dialysis for tubular injury and calcineurin inhibitor toxicity. These complications occurred at significantly higher rates relative to historic series (p<0.0001). Our observations support the feasibility of lung transplantation in telomerase mutation carriers; however, severe post-transplant complications reflecting the syndromic nature of their disease appear to occur at higher rates. While these findings need to be expanded to other cohorts, caution should be exercised when approaching the transplant evaluation and management of this subset of pulmonary fibrosis patients.
Biliary strictures remain the most challenging aspect of adult right lobe living donor liver transplantation (RLDLT). Between 04/2000 and 10/2005, 130 consecutive RLDLTs were performed in our center ...and followed prospectively. Median follow‐up was 23 months (range 3–67) and 1‐year graft and patient survival was 85% and 87%, respectively. Overall incidence of biliary leaks (n = 19) or strictures (n = 22) was 32% (41/128) in 33 patients (26%). A duct‐to‐duct (D‐D) or Roux‐en‐Y (R‐Y) anastomosis were performed equally (n = 64 each) with no difference in stricture rate (p = 0.31). The use of ductoplasty increased the number of grafts with a single duct for anastomosis and reduced the biliary complication rate compared to grafts ≥2 ducts (17% vs. 46%; p = 0.02). Independent risk factors for strictures included older donor age and previous history of a bile leak. All strictures were managed nonsurgically initially but four patients ultimately required conversion from D‐D to R‐Y. Ninety‐six percent (123/128) of patients are currently free of any biliary complications. D‐D anastomosis is safe after RLDLT and provides access for future endoscopic therapy in cases of leak or stricture. When presented with multiple bile ducts, ductoplasty should be considered to reduce the potential chance of stricture.
The pattern and management of biliary strictures after right‐lobe living donor liver transplantation (RLDLT) from this experience from a single Western center shows that, although biliary strictures are common in RLDLT, they can usually be managed non‐operatively and do not affect short‐term graft survival.
Spherical implosions in Inertial Confinement Fusion (ICF) are inherently sensitive to perturbations that may arise from experimental constraints and errors. Control and mitigation of low-mode (long ...wavelengths) perturbations is a key milestone to improving implosion performances. We present the first 3-D radiation-hydrodynamic simulations of directly driven ICF implosions with an inline package for polarized Crossed-Beam Energy Transfer (CBET). Simulations match bang times, yields (separately accounting for laser-induced high modes and fuel age), hot spot flow velocities and direction, for which polarized CBET contributes to the systematic flow orientation evident in the OMEGA implosion database. Current levels of beam mispointing, imbalance, target offset and asymmetry from polarized CBET degrade yields by more than 40%. The effectiveness of two mitigation strategies for low-modes is explored
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