We previously identified in a single-center study a 76-gene prognostic signature for lymph node-negative (LNN) breast cancer patients. The aim of this study was to validate this gene signature in an ...independent more diverse population of LNN patients from multiple institutions.
Using custom-designed DNA chips we analyzed the expression of the 76 genes in RNA of frozen tumor samples from 180 LNN patients who did not receive adjuvant systemic treatment.
In this independent validation, the 76-gene signature was highly informative in identifying patients with distant metastasis within 5 years (hazard ratio, HR, 7.41; 95% CI, 2.63 to 20.9), even when corrected for traditional prognostic factors in multivariate analysis (HR, 11.36; 95% CI, 2.67 to 48.4). The actuarial 5- and 10-year distant metastasis-free survival were 96% (95% CI, 89% to 99%) and 94% (95% CI, 83% to 98%), respectively, for the good profile group and 74% (95% CI, 64% to 81%) and 65% (53% to 74%), respectively for the poor profile group. The sensitivity for 5-yr distant metastasis-free survival was 90%, and the specificity was 50%. The positive and negative predictive values were 38% (95% CI, 29% to 47%) and 94% (95% CI, 86% to 97%), respectively. The 76-gene signature was confirmed as a strong prognostic factor in subgroups of estrogen receptor-positive patients, pre- and postmenopausal patients, and patients with tumor sizes 20 mm or smaller. The subgroup of patients with estrogen receptor-negative tumors was considered too small to perform a separate analysis.
Our data provide a strong methodologic and clinical multicenter validation of the predefined prognostic 76-gene signature in LNN breast cancer patients.
The role of macrophages (Mo) and their prognostic impact in diffuse large B‐cell lymphomas (DLBCL) remain controversial. By regulating the lipid metabolism, Liver‐X‐Receptors (LXRs) control Mo ...polarization/inflammatory response, and their pharmacological modulation is under clinical investigation to treat human cancers, including lymphomas. Herein, we surveyed the role of LXRs in DLBCL for prognostic purposes. Comparing bulk tumors with purified malignant and normal B‐cells, we found an intriguing association of NR1H3, encoding for the LXR‐α isoform, with the tumor microenvironment (TME). CIBERSORTx‐based purification on large DLBCL datasets revealed a high expression of the receptor transcript in M1‐like pro‐inflammatory Mo. By determining an expression cut‐off of NR1H3, we used digital measurement to validate its prognostic capacity on two large independent on‐trial and real‐world cohorts. Independently of classical prognosticators, NR1H3high patients displayed longer survival compared with NR1H3low cases and a high‐resolution Mo GEP dissection suggested a remarkable transcriptional divergence between subgroups. Overall, our findings indicate NR1H3 as a Mo‐related biomarker identifying patients at higher risk and prompt future preclinical studies investigating its mouldability for therapeutic purposes.
Aims
Pre‐clinical congestion markers of worsening heart failure (HF) can be monitored by devices and may support the management of patients with HF. We aimed to assess whether congestion‐guided HF ...management according to device‐based remote monitoring strategies is more effective than standard therapy.
Methods and results
A comprehensive literature research for randomized controlled trials (RCTs) comparing device‐based remote monitoring strategies for congestion‐guided HF management versus standard therapy was performed on PubMed, Embase, and CENTRAL databases. Incidence rate ratios (IRRs) and associated 95% confidence intervals (CIs) were calculated using the Poisson regression model with random study effects. The primary outcome was a composite of all‐cause death and HF hospitalizations. Secondary endpoints included the individual components of the primary outcome. A total of 4347 patients from eight RCTs were included. Findings varied according to the type of parameters monitored. Compared with standard therapy, haemodynamic‐guided strategy (4 trials, 2224 patients, 12‐month follow‐up) reduced the risk of the primary composite outcome (IRR 0.79, 95% CI 0.70–0.89) and HF hospitalizations (IRR 0.76, 95% CI 0.67–0.86), without a significant impact on all‐cause death (IRR 0.93, 95% CI 0.72–1.21). In contrast, impedance‐guided strategy (4 trials, 2123 patients, 19‐month follow‐up) did not provide significant benefits.
Conclusion
Haemodynamic‐guided HF management is associated with better clinical outcomes as compared to standard clinical care.
Summary effect estimates for different strategies of guided management versus standard therapy related to pathogenesis of worsening heart failure. CI, confidence interval; IRR, incidence rate ratio.
Designing targeted treatments for breast cancer patients after primary tumor removal is necessary to prevent the occurrence of invasive disease events (IDEs), such as recurrence, metastasis, ...contralateral and second tumors, over time. However, due to the molecular heterogeneity of this disease, predicting the outcome and efficacy of the adjuvant therapy is challenging. A novel ensemble machine learning classification approach was developed to address the task of producing prognostic predictions of the occurrence of breast cancer IDEs at both 5- and 10-years. The method is based on the concept of voting among multiple models to give a final prediction for each individual patient. Promising results were achieved on a cohort of 529 patients, whose data, related to primary breast cancer, were provided by Istituto Tumori “Giovanni Paolo II” in Bari, Italy. Our proposal greatly improves the performances returned by the baseline original model, i.e., without voting, finally reaching a median AUC value of 77.1% and 76.3% for the IDE prediction at 5-and 10-years, respectively. Finally, the proposed approach allows to promote more intelligible decisions and then a greater acceptability in clinical practice since it returns an explanation of the IDE prediction for each individual patient through the voting procedure.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Several implant-based remote monitoring strategies are currently tested to optimize heart failure (HF) management by anticipating clinical decompensation and preventing hospitalization. Among these ...solutions, the modern implantable cardioverter-defibrillator and cardiac resynchronization therapy devices have been equipped with sensors allowing continuous monitoring of multiple preclinical markers of worsening HF, including factors of autonomic adaptation, patient activity, and intrathoracic impedance.
We aimed to assess whether implant-based multiparameter remote monitoring strategy for guided HF management improves clinical outcomes when compared to standard clinical care.
A systematic literature research for randomized controlled trials (RCTs) comparing multiparameter-guided HF management versus standard of care was performed on PubMed, Embase, and CENTRAL databases. Incidence rate ratios (IRRs) and associated 95% confidence intervals (CIs) were calculated using the Poisson regression model with random study effects. The primary outcome was a composite of all-cause death and HF hospitalization events, whereas secondary endpoints included the individual components of the primary outcome.
Our meta-analysis included 6 RCTs, amounting to a total of 4869 patients with an average follow-up time of 18 months. Compared with standard clinical management, the multiparameter-guided strategy reduced the risk of the primary composite outcome (IRR 0.83, 95%CI 0.71–0.99), driven by statistically significant effect on both HF hospitalization events (IRR 0.75, 95%CI 0.61–0.93) and all-cause death (IRR 0.80, 95%CI 0.66–0.96).
Implant-based multiparameter remote monitoring strategy for guided HF management is associated with significant benefit on clinical outcomes compared to standard clinical care, providing a benefit on both hospitalization events and all-cause death.
Main findings of our meta-analysis: implant-based remote monitoring strategies for multiparameter-guided HF management is associated with a reduction of the composite endpoint of all-cause death and HF hospitalizations, driven by a benefit in both individual components. Display omitted
•A significant proportion of HF patients is under-managed and under-treated.•Modern ICD/CRT devices enable to remotely monitor patient parameters suggesting impending HF decompensation.•Our meta-analysis, including 4869 patients, is the first one to test the full implementation of ICD/CRT-based remote monitoring strategy to guide HF management.•This meta-analysis showed that multiparameter-guided remote monitoring strategy in HF patient reduces all-cause death and hospitalization events.•Further studies are needed to test the cost-effectiveness of such strategy.
Literature data indicate that mast cells (MCs) are involved in tumor angiogenesis due to the release of several pro-angiogenetic factors among which tryptase, a serine protease stored in MCs ...granules, is one of the most active. However, no data are available concerning the role of MCs in angiogenesis in primary human breast cancer. In this study, we have evaluated the correlations between the number of MCs positive to tryptase (MCDPT), the area occupied by MCs positive to tryptase (MCAPT) and microvascular density (MVD) and endothelial area (EA) in a series of 88 primary T1-3, N0-2 M0 female breast cancer, by means of immunohistochemistry and image analysis methods. Data demonstrated a significant (r = from 0.78 to 0.89; p-value from 0.001 to 0.002 by Pearson's analysis respectively) correlation between MCDPT, MCAPT, MVD, EA to each other. No correlation concerning MCDPT, MCAPT, MVD, EA and the main clinicopathological features was found. Our results suggest that tryptase-positive MCs play a role in breast cancer angiogenesis. In this context several tryptase inhibitors such as gabexate mesilate and nafamostat mesilate might be evaluated in clinical trials as a new anti-angiogenetic approach.
To elucidate the role of angiogenesis in the carcinogenesis and progression of oral cancer, we investigated microvessel density (mVd), mast cell density (mCd) and thymidine phosphorylase (TP) ...expression in a series of 50 patients with T1-3 N0-1 M0 oral squamous carcinoma (OSC) and 21 patients with non-dysplastic oral leukoplakia (NDOLP). Paraffin-embedded pathological tissue was utilised for the immunohistochemical analysis of mVd and TP expression. Toluidine blue histochemical method was employed for mast cell identification. OSC and NDOLP were not significantly different with respect to mVd (mVd mean value +/- SD: 30+/-17 and 27+/-18, respectively) and mCd characteristics (mCd mean value +/- SD: 8+/-6 and 7+/-6 units, respectively). Conversely, tumour epithelia showed some degree of TP immunostaining in 100% of cases compared with 76% in NDOLP samples (p< or =0.001 by Fisher's test). A good correlation was found between mVd and mCd in both NDOLP (c.c. 0.632; p=0.002) and OSC (c.c. 0.496; p=0.000) tissue, whereas no association between TP expression and mVd or between mCd and TP status was evident. At a median follow-up of 18 months, patients with high mVd tumours showed a greater probability of survival than those with low mVd (75 and 40%, respectively; p=0.04 log-rank test). Our results suggest that the development of oral cancer epithelia is associated with a significant increase in TP expression. Conversely, the clinical outcome of OSC seems inversely related specifically to mVd.
The prognostic relevance of mitotic activity was analyzed in a series of 306 patients with node-negative breast cancer treated with locoregional therapy alone, until early relapse. Mitotic activity ...was evaluated as the number of mitotic figures per 10 high-power fields (mitotic activity index) or per 1000 tumor cells (mitotic index). Counting was carried out blindly by two observers. A high correlation was observed between the two determinations (rs = .96, P < .001). For clinical analysis, three mitotic activity index subgroups (mitotic figures/field ≤ 9, 10–19 and more than 19, according to grading criteria) and three mitotic index subgroups (percentage of mitotic figures less than 0.10, 0.11–0.50 and more than 0.50, according to tertile criteria) were considered. No relation was observed between mitotic variables and 6-year disease-free survival, whereas distant disease-free survival was strongly related to mitotic figures per 10 fields (85%, 89% and 70%, P = .012) and to the percentage of mitotic figures out of a total 1000 tumor cells (87%, 86% and 75%, P = .017). Similarly, both mitotic indices were significantly related to 6-year overall survival (99%, 95% and 77%, P < .001, for mitotic figures per 10 fields and 99%, 93% and 82%, P < .001, for the percentage of mitotic figures). These findings were particularly evident in patients with tumors of 1–2 cm. In conclusion, a high number of mitotic figures is associated with a higher probability of developing distant metastases and a shorter survival. The critical point remains the standardization of the preanalytical and analytical steps within quality control programs.
The new computer-based interactive technologies in medicine, such as virtual reality (VR), have revolutionized education. The use of virtual microscopic images would be invaluable in the training of ...cyto-histopathologists. However, due to the vast amount of digital information on a scanned, conventional cyto-histological slide, which is enormous by current data storage standards, these systems are expensive and not widely used in pathological medicine. The authors propose an inexpensive system based on quicktime virtual reality (QTVR) technology (by Apple Computers Inc.), which accommodates a wide area of a slide at high magnification, generating a ‘virtual slide’ which makes it possible to navigate by conventional input devices. Commercial softwares that stitch consecutive, adjacent images of cyto-histological preparations onto a QTVR panorama were used. QTVR files have the ability to stand on their own as self-contained, multimedia applications and also have the ability to generate multinode scenes by means of ‘hot spots’. QTVR ‘movies’ can be played on Macintosh or Windows platforms, and on major web browsers. Virtual slides by QTVR is an inexpensive system of high educational value, which allows the creation of multimedia databases of cyto-histological preparations that can exist on an internet server or can be distributed on removable media.
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