Neoadjuvant anti-PD-1 may improve outcomes for patients with resectable NSCLC and provides a critical window for examining pathologic features associated with response. Resections showing major ...pathologic response to neoadjuvant therapy, defined as ≤10% residual viable tumor (RVT), may predict improved long-term patient outcome. However, %RVT calculations were developed in the context of chemotherapy (%cRVT). An immune-related %RVT (%irRVT) has yet to be developed.
The first trial of neoadjuvant anti-PD-1 (nivolumab, NCT02259621) was just reported. We analyzed hematoxylin and eosin-stained slides from the post-treatment resection specimens of the 20 patients with non-small-cell lung carcinoma who underwent definitive surgery. Pretreatment tumor biopsies and preresection radiographic ‘tumor’ measurements were also assessed.
We found that the regression bed (the area of immune-mediated tumor clearance) accounts for the previously noted discrepancy between CT imaging and pathologic assessment of residual tumor. The regression bed is characterized by (i) immune activation—dense tumor infiltrating lymphocytes with macrophages and tertiary lymphoid structures; (ii) massive tumor cell death—cholesterol clefts; and (iii) tissue repair—neovascularization and proliferative fibrosis (each feature enriched in major pathologic responders versus nonresponders, P<0.05). This distinct constellation of histologic findings was not identified in any pretreatment specimens. Histopathologic features of the regression bed were used to develop ‘Immune-Related Pathologic Response Criteria’ (irPRC), and these criteria were shown to be reproducible amongst pathologists. Specifically, %irRVT had improved interobserver consistency compared with %cRVT median per-case %RVT variability 5% (0%–29%) versus 10% (0%–58%), P=0.007 and a twofold decrease in median standard deviation across pathologists within a sample (4.6 versus 2.2, P=0.002).
irPRC may be used to standardize pathologic assessment of immunotherapeutic efficacy. Long-term follow-up is needed to determine irPRC reliability as a surrogate for recurrence-free and overall survival.
Tumor-associated inflammatory cells in classical Hodgkin lymphoma (CHL) typically outnumber the neoplastic Hodgkin/Reed-Sternberg (H/RS) cells. The composition of the inflammatory infiltrate, ...particularly the fraction of macrophages, has been associated with clinical behavior. Emerging work from animal models demonstrates that most tissue macrophages are maintained by a process of self-renewal under physiologic circumstances and certain inflammatory states, but the contribution from circulating monocytes may be increased in some disease states. This raises the question of the source of macrophages involved in human disease, particularly that of CHL. Patients with relapsed CHL following allogeneic bone marrow transplant (BMT) provide a unique opportunity to begin to address this issue. We identified 4 such patients in our archives. Through molecular chimerism and/or XY FISH studies, we demonstrated the DNA content in the post-BMT recurrent CHL was predominantly donor-derived, while the H/RS cells were derived from the patient. Where possible to evaluate, the cellular composition of the inflammatory infiltrate, including the percentage of macrophages, was similar to that of the original tumor. Our findings suggest that the H/RS cells themselves define the inflammatory environment. In addition, our results demonstrate that tumor-associated macrophages in CHL are predominantly derived from circulating monocytes rather than resident tissue macrophages. Given the association between tumor microenvironment and disease progression, a better understanding of macrophage recruitment to CHL may open new strategies for therapeutic intervention.
The FMS-like tyrosine kinase-3 (FLT3) gene is the most commonly mutated gene in acute myeloid leukemia (AML), and patients carrying internal tandem duplication (ITD) mutations have a poor prognosis. ...Long-term inhibition of FLT3 activity in these patients has been elusive. To provide a more complete understanding of FLT3 biology, a mass spectroscopy-based screen was performed to search for FLT3-interacting proteins. The screen identified dedicator of cytokinesis 2 (DOCK2), which is a guanine nucleotide exchange factor for Rho GTPases, and its expression is limited to hematolymphoid cells. We show that DOCK2 is expressed in leukemia cell lines and primary AML samples, and DOCK2 co-immunoprecipitates with wild-type FLT3 and FLT3/ITD. Knockdown (KD) of DOCK2 by shRNA selectively reduced cell proliferation and colony formation in leukemia cell lines with increased FLT3 activity, and greatly sensitized these cells to cytarabine treatment, alone and in combination with FLT3 tyrosine kinase inhibitors. DOCK2 KD in an FLT3/ITD-positive leukemia cell line also significantly prolonged survival in a mouse xenograft model. These findings suggest that DOCK2 is a potential therapeutic target for novel AML treatments, as this protein regulates the survival of leukemia cells with elevated FLT3 activity and sensitizes FLT3/ITD leukemic cells to conventional antileukemic agents.
In 2006, a marked increase in harbor porpoise Phocoena phocoena strandings were reported in the Pacific Northwest of the USA, resulting in the declaration of an unusual mortality event (UME) for ...Washington and Oregon to facilitate investigation into potential causes. The UME was in place during all of 2006 and 2007, and a total of 114 porpoises stranded during this period. Responders examined 95 porpoises; of these, detailed necropsies were conducted on 75 animals. Here we review the findings related to this event and how these compared to the years immediately before and after the UME. Relatively equal numbers among sexes and age classes were represented, and mortalities were attributed to a variety of specific causes, most of which were categorized as trauma or infectious disease. Continued monitoring of strandings during 4 yr following the UME showed no decrease in occurrence. The lack of a single major cause of mortality or evidence of a significant change or event, combined with high levels of strandings over several post-UME years, demonstrated that this was not an actual mortality event but was likely the result of a combination of factors, including: (1) a growing population of harbor porpoises; (2) expansion of harbor porpoises into previously sparsely populated areas in Washington's inland waters; and (3) a more well established stranding network that resulted in better reporting and response. This finding would not have been possible without the integrated response and investigation undertaken by the stranding network.
Neospora caninum has been reported to be an important cause of endemic fetal loss and occasional abortion epidemics in cattle around the world. This study examined 12,016 sera collected from 9723 ...Holstein cows on 125 herds across Ontario in 1998, 1999, and 2000. An enzyme-linked immunosorbent assay was used to examine the sera for antibodies to N. caninum. The overall prevalence of N. caninum antibodies in the cattle was 11.2% and the prevalence in individual herds varied from 0 to 70.4%. Among 3109 daughter-dam pairs, 619 positive dams had 252 positive daughters, giving a detected vertical transmission rate of 40.7%. In contrast, there were only 6.7% positive daughters from negative dams (167 of 2490). Pedigree edits left 8031 cows with 1463 sires for estimation of heritability. Five genetic models (sire model, animal model, sire-dam model, a sire-maternal grandsire model, and a maternal effects model) with fixed effects of bleeding year-month, age of the animals, and herd were fitted to the data. The estimated heritability of susceptibility to N. caninum ranged between 0.084 and 0.124. The sire-maternal grandsire model and the maternal effects model provided better fit than the other models because the maternal genetic variance was much greater than the direct genetic variance. To reduce the incidence of N. caninum infection, more emphasis should be placed on management practices than on genetic selection.
To determine whether alanine aminotransferase or gamma-glutamyltransferase levels, as markers of liver health and non-alcoholic fatty liver disease, might predict cardiovascular events in people with ...Type 2 diabetes.
Data from the Fenofibrate Intervention and Event Lowering in Diabetes study were analysed to examine the relationship between liver enzymes and incident cardiovascular events (non-fatal myocardial infarction, stroke, coronary and other cardiovascular death, coronary or carotid revascularization) over 5 years.
Alanine aminotransferase measure had a linear inverse relationship with the first cardiovascular event occurring in participants during the study period. After adjustment, for every 1 sd higher baseline alanine aminotransferase measure (13.2 U/l), the risk of a cardiovascular event was 7% lower (95% CI 4-13; P = 0.02). Participants with alanine aminotransferase levels below and above the reference range 8-41 U/l for women and 9-59 U/l for men, had hazard ratios for a cardiovascular event of 1.86 (95% CI 1.12-3.09) and 0.65 (95% CI 0.49-0.87), respectively (P = 0.001). No relationship was found for gamma-glutamyltransferase.
The data may indicate that in people with Type 2 diabetes, which is associated with higher alanine aminotransferase levels because of prevalent non-alcoholic fatty liver disease, a low alanine aminotransferase level is a marker of hepatic or systemic frailty rather than health.
The objective of this epidemiological study was to identify risk factors for
Neospora caninum-related abortions in Ontario Holstein dairy herds. A total of 88 herds, consisting of 5080 cattle, and ...utilizing Dairy Herd Improvement (DHI) services, were divided into three groups. Case (
n
=
30) and first control (
n
=
31) herds were selected from 1998 and 1999 fetal abortion submissions to the Animal Health Laboratory, University of Guelph, that were histopathologically positive or negative, respectively, for
N. caninum. A second control group (
n
=
27) was selected from multiple sources of herds sampled within the previous 4 years that had a low seroprevalence (<7%) to
N. caninum. Between May and December 1999, all available cows on all farms, in parity one or greater, were blood sampled. The sera were then analyzed for antibody to
N. caninum using a kinetic ELISA. A survey administered at the time of sampling recorded information on housing, animal species present, manure management, reproduction, biosecurity practices, wildlife observations, peri-parturient cow management, herd disease history and nutrition. Production and other herd parameters were obtained from DHI records. Logistic regression indicated that the following parameters were positively associated with a
N. caninum abortion in a herd: the
N. caninum herd seroprevalence (OR
=
1.1)
, the total number of dogs on a farm (OR
=
2.8), the frequency that dogs were observed defecating in mangers (OR
=
2.8), the number of horses on a farm (OR
=
3.1), the observed annual rate of retained fetal membranes (OR
=
1.2) and the observed annual rate of cows returning to estrus after pregnancy confirmation (OR
=
1.2). Factors negatively associated were the frequency of stray cats and wild canids observed on a farm (OR
=
0.4 and OR
=
0.7, respectively) and the housing of heifers on loafing packs (a housing pen divided into feed manger, scrape alley and bedded pack areas, OR
=
0.1).
To evaluate the efficacy of halofuginone lactate (Halocur; Intervet) when used prophylactically against cryptosporidiosis in dairy calves, 513 Holstein heifer calves were randomly distributed between ...two experimental groups. Those in the treatment group (n=259) received 0.1 mg halofuginone base per kg bodyweight daily in a 10 ml solution, for the first seven days following birth, while those in the control group (n=254) received an equal volume of a placebo solution. Faecal samples were collected weekly from all calves until three weeks of age to test for Cryptosporidium oocysts and to assess the diarrhoeal status. Growth parameters of the calves were also recorded at approximately four months of age. Calves that received halofuginone were significantly less likely to shed Cryptosporidium oocysts during the course of the study than placebo-treated calves (odds ratio 0.6, 95 per cent confidence interval 0.4 to 0.9, P=0.009). Mean growth measurements of calves in the treated group were consistently higher than those of the control calves (hipometer-derived P=0.052, wither height P=0.097) and mortality was lower in the treated group (P=0.07). However, these differences were not statistically significant (P>0.05). No association was found between the prophylactic use of halofuginone and the incidence of calf diarrhoea.
The Quality of Care Collaborative Australia (QuoCCA) provided pediatric palliative care education across Australia with the aim of improving the quality of services. The education was delivered ...through a collaboration of six tertiary pediatric palliative care services, through funding for Nurse Educators, Medical Fellows, a National Allied Health Educator, and national project staff.
Pre- and post-education surveys were completed by participants immediately following the education, and confidence and knowledge were measured along nine domains related to the care of the child and family, including managing a new referral, symptom management, medications, preparing the family, and using local agencies.
Education was provided to over 5,500 health and human service professionals in 337 education sessions across Australia between May 2015 and June 2017. Paired pre- and post-surveys were completed by 969 participants and showed a significant improvement in all the domains measured. Those with no experience in caring for children receiving palliative care showed greater improvement following QuoCCA education compared to those with experience, although the latter had higher scores both before and after education. Similarly, those with no previous education showed greater improvement, but those with previous education showed higher scores overall. Participants in full-day and half-day sessions showed greater improvement than those in short day sessions. Thus, the dosage of education in the length of the sessions and prior attendance impacted knowledge and confidence. Topics requested by the participants were analyzed. Educator learnings were that education was more effective when tailored to the needs of the audience, was interactive, and included story-telling, case studies, and parent experiences.
These results encouraged the continuation of the provision of education to novice and experienced professionals who care for children with a life-limiting condition, leading to higher levels of confidence and knowledge. The learnings from this evaluation will be transferred into the second round of funding for the national QuoCCA education project. The next stage will focus on developing simulation and interactive training, accessible training modules, and videos on a national website.
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