Prognostic value of hematogenous dissemination and biological profile of the tumor in early breast cancer patients: A prospective observational study

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to investigate the incidence and prognostic value of disseminated tumor cells in bone marrow of breast carcinoma patients with early disease, and to analyze this finding in relation to lymph node involvement, determined by sentinel lymph node (SLN) biopsy analysis, and to prognostic factors of interest.</p> <p>Methods</p> <p>104 patients with operable (T < 3 cm) breast cancer and clinically- and sonographically-negative axillary lymph nodes were scheduled for SLN biopsy. Bone marrow aspirates were collected before the start of surgery from both iliac crests, and mononuclear cell layers were separated by density centrifugation (Lymphoprep). Slide preparations were then examined for the presence of disseminated tumor cells by immunocytochemistry with anti-cytokeratin antibodies (A45-B/B3). Lymphoscintigraphy was performed 2 hours after intratumor administration of 2 mCi (74 MBq) of 99mTc colloidal albumin. The SLN was evaluated for the presence of tumor cells by hematoxylin-eosin staining and, when negative, by immunocytochemistry using anti-cytokeratin antibody (CAM 5.2). Survival analyses and comparative analyses were performed on the results of bone marrow determinations, SLN biopsy, and known prognostic factors, including breast cancer subtypes according to the simplified classification based on ER, PR and HER2.</p> <p>Results</p> <p>Lymph node and hematogenous dissemination occur in one-third of patients with early-stage breast cancer, although not necessarily simultaneously. In our study, disseminated tumor cells were identified in 22% of bone marrow aspirates, whereas 28% of patients had axillary lymph node involvement. Simultaneous lymph node and bone marrow involvement was found in only 5 patients (nonsignificant). In the survival study (60 months), a higher, although nonsignificant rate of disease-related events (13%) was seen in patients with disseminated tumor cells in bone marrow, and a significant association of events was documented with the known, more aggressive tumor subtypes: triple negative receptor status (21%) and positive ERBB2 status (29%).</p> <p>Conclusions</p> <p>Tumor cell detection in bone marrow can be considered a valid prognostic parameter in patients with early disease. However, the classic prognostic factors remain highly relevant, and the newer breast cancer subtypes are also useful for this purpose.</p

Mapping and linking supply- and demand-side measures in climate-smart agriculture. A review

Climate change and food security are two of humanity’s greatest challenges and are highly interlinked. On the one hand, climate change puts pressure on food security. On the other hand, farming significantly contributes to anthropogenic greenhouse gas emissions. This calls for climate-smart agriculture—agriculture that helps to mitigate and adapt to climate change. Climate-smart agriculture measures are diverse and include emission reductions, sink enhancements, and fossil fuel offsets for mitigation. Adaptation measures include technological advancements, adaptive farming practices, and financial management. Here, we review the potentials and trade-offs of climate-smart agricultural measures by producers and consumers. Our two main findings are as follows: (1) The benefits of measures are often site-dependent and differ according to agricultural practices (e.g., fertilizer use), environmental conditions (e.g., carbon sequestration potential), or the production and consumption of specific products (e.g., rice and meat). (2) Climate-smart agricultural measures on the supply side are likely to be insufficient or ineffective if not accompanied by changes in consumer behavior, as climate-smart agriculture will affect the supply of agricultural commodities and require changes on the demand side in response. Such linkages between demand and supply require simultaneous policy and market incentives. It, therefore, requires interdisciplinary cooperation to meet the twin challenge of climate change and food security. The link to consumer behavior is often neglected in research but regarded as an essential component of climate-smart agriculture. We argue for not solely focusing research and implementation on one-sided measures but designing good, site-specific combinations of both demand- and supply-side measures to use the potential of agriculture more effectively to mitigate and adapt to climate change

Incidental Findings in the Trauma Population: Interdisciplinary Approach and Electronic Medical Record Reminder Association with Pre-Discharge Reporting and Medicolegal Risk

Background: Incidental findings (IFs) are reported in 20% or more of trauma CT scans. In addition to the importance of patient disclosure, there is considerable legal pressure to avoid missed diagnoses. We reported previously that 63.5% of IFs were disclosed before discharge and with 20% were nondisclosed. We initiated a multidisciplinary systemic plan to effect predischarge disclosure by synoptic CT reports with American College of Radiology recommended follow-up, electronic medical records discharge prompts, and provider education. Study Design: Prospective observational series patients from November 2019 to February 2020 were included. Statistical analysis was performed with SPSS, version 21 (IBM Corp). Results: Eight hundred and seventy-seven patients underwent 1 or more CT scans for the evaluation of trauma (507 were male and 370 were female). Mean age of the patients was 57 years (range 14 to 99 years) and 96% had blunt injury. In 315 patients, there were 523 IFs (1.7 per patient); the most common were lung (17.5%), kidney (13%), and liver (11%). Radiology report compliance rate was 84% (210 of 249 patients). There were 66 studies from outside facilities. Sixteen IFs were suspicious for malignancy. A total of 151 patients needed no follow-up and 148 patients needed future follow-up evaluation. Predischarge IF disclosure compliance rate was 90.1% (286 patients); 25 were post discharge. Four patients remained undisclosed. Compared with our previous report, clearer reporting and electronic medical records prompts increased predischarge disclosure from 63.5% to 90.1% (p \u3c 0.01, chi-square test) and decreased days to notification from 29.5 (range 0 to 277) to 5.2 (range 0 to 59) (p \u3c 0.01, Mann-Whitney U test). Conclusions: Timely, complete disclosure of IFs improves patient outcomes and reduces medicolegal risk. Collaboration among trauma, radiology, and information technology promotes improved disclosure in trauma populations

Multiplexed single-cell transcriptional response profiling to define cancer vulnerabilities and therapeutic mechanism of action

Large-scale screens of chemical and genetic vulnerabilities in cancer are typically limited to simple readouts of cell viability. Here, the authors develop a method for profiling post-perturbation transcriptional responses across large pools of cancer cell lines, enabling deep characterization of shared and context-specific responses

Effects of recent increases in salinity and nutrient concentrations on the microbialite community of Lake Clifton (Western Australia): are the thrombolites at risk?

The Yalgorup lakes, a groundwater-fed system in south-western Australia recognized as a Ramsar wetland, hold significant scientific and conservation value due to the presence of a unique range of lake systems, resident waterfowl and, on the eastern shore of Lake Clifton, the presence of the only thrombolite reef in the southern hemisphere. Recent concern over changing physico-chemical conditions in the lakes, particularly an increase in salinity, prompted this study: the current status of the inherent thrombolite community is unknown. Salinity, total phosphorous (TP), phosphate, total nitrogen (TN), nitrate, chlorophyll-a and relative abundance of the thrombolite microflora were measured in Lake Clifton to analyse changing conditions in this lake and to determine the effect of these water parameters on the thrombolite community. Comparisons with historical data revealed a significant increase in salinity since 1985 and a possible increase in phosphorus concentrations in the lake in the recent decade, although historical nutrient data are rather sparse. The increased salinity may be due to concentration of lake water through a combination of high evaporation, long-term reduction in rainfall and increased groundwater abstraction. Comparison of the composition of the thrombolite community with historical data indicates a large reduction in relative abundance of Scytonema sp. and other filamentous cyanobacterial species, which are believed to be fundamental for the thrombolite structure. It is concluded the changing physico-chemical environment of the Yalgorup Lakes may have led to the decline in important genera in the thrombolite community; however, the mechanisms underlying this change remain unknown

Mitogenic and progenitor gene programmes in single pilocytic astrocytoma cells

Pilocytic astrocytoma (PA), the most common childhood brain tumor, is a low-grade glioma with a single driver BRAF rearrangement. Here, we perform scRNAseq in six PAs using methods that enabled detection of the rearrangement. When compared to higher-grade gliomas, a strikingly higher proportion of the PA cancer cells exhibit a differentiated, astrocyte-like phenotype. A smaller proportion of cells exhibit a progenitor-like phenotype with evidence of proliferation. These express a mitogen-activated protein kinase (MAPK) programme that was absent from higher-grade gliomas. Immune cells, especially microglia, comprise 40% of all cells in the PAs and account for differences in bulk expression profiles between tumor locations and subtypes. These data indicate that MAPK signaling is restricted to relatively undifferentiated cancer cells in PA, with implications for investigational therapies directed at this pathway

Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study

BACKGROUND: Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa. METHODS: Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival. RESULTS: FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20-0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10-3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25-0.94). CONCLUSIONS: FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis

Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma:implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study

BACKGROUND: Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa. METHODS: Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival. RESULTS: FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (P(interaction)=0.01, N=1422) and TCGA (P(interaction)=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20–0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10–3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25–0.94). CONCLUSIONS: FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis