To provide evidence explaining the poor association between pCR and patients’ long-term outcome at trial-level in neoadjuvant RCTs for breast cancer (BC), we performed a systematic-review and ...meta-analysis of all RCTs testing neoadjuvant treatments for early-BC and reporting the hazard ratio of DFS (HRDFS) for the intervention versus control arm stratified by pathological response type (i.e., pCR yes versus no).
The objective was to explore differences of treatment effects on DFS across patients with and without pCR.
We calculated the pooled HRDFS in the two strata of pathological response (i.e., pCR yes versus no) using a random-effects model, and assessed the difference between these two estimates using an interaction test.
Ten RCTs and 8496 patients were included in the analysis.
Patients obtaining pCR in the intervention-arm had a higher, although not statistically significant, risk of DFS-event as compared with patients obtaining pCR in the control-arm: the pooled HRDFS for the experimental versus control arm was 1.23 (95%CI, 0.91–1.65). On the opposite, the risk of DFS-event was higher for control as compared with the intervention-arm in the stratum of patients without pCR: the pooled HRDFS was 0.86 (95%CI, 0.78–0.95).
Treatment effect on DFS was significantly different according to pathological response type (interaction test p: 0.014).
We reported new evidence that contributes to explaining the poor surrogacy value of pCR at trial-level in neoadjuvant RCTs for early-BC.
•Pathological complete response (pCR) has been shown to be associated with long-term outcome at patient level but not at trial-level in neoadjuvant RCTs for breast cancer (BC).•One explanation could be that new neoadjuvant treatment regimens achieving substantially higher pCR rates might exert a dissociated effect on primary tumors versus micrometastases.•In this meta-analysis of recent RCTs testing neoadjuvant treatments for early-BC patients, there was a numerically higher risk of DFS-event for patients obtaining pCR in the intervention-arm as compared with those obtaining pCR in the control-arm.•On the opposite, the risk of DFS-event was higher for control as compared with the intervention-arm in the stratum of patients without pCR.
Background: Aromatase inhibitors (AI) are widely used for treating hormone-sensitive breast cancer (BC). Obesity, however, due to aromatase-mediated androgen conversion into estradiol in the ...peripheral adipose tissue, might impair AI inhibitory capacity. We aimed at identifying a cut-off of body mass index (BMI) with significant prognostic impact, in a cohort of stage I-II BC patients on systemic adjuvant therapy with AI. Methods: we retrospectively evaluated routinely collected baseline parameters. The optimal BMI cut-off affecting disease-free survival (DFS) in AI-treated BC patients was identified through maximally selected rank statistics; non-linear association between BMI and DFS in the AI cohort was assessed by hazard-ratio-smoothed curve analysis using BMI as continuous variable. The impact of the BMI cut-off on survival outcomes was estimated through Kaplan−Meier plots, with log-rank test and hazard ratio estimation comparing patient subgroups. Results: A total of 319 BC patients under adjuvant endocrine therapy and/or adjuvant chemotherapy were included. Curve-fitting analysis showed that for a BMI cut-off >29 in AI-treated BC patients (n = 172), DFS was increasingly deteriorating and that the impact of BMI on 2-year DFS identified a cut-off specific only for the cohort of postmenopausal BC patients under adjuvant therapy with AI. Conclusion: in radically resected hormone-sensitive BC patients undergoing neoadjuvant or adjuvant chemotherapy and treated with AI, obesity represents a risk factor for recurrence, with a significantly reduced 2-year DFS.
Madagascar is recognised as having both a high level of poverty and a food shortage. The contribution of the agricultural sector to the national income is higher than for any other sector, though ...this sector remains insufficiently developed to sustain national food demand. In order to increase food production, the diversification of staple food in conjunction with the detection of best-yield genotypes may be considered the simplest and least expensive alternative approach. For this reason, the response of productive parameters, protein content, phenolic compounds, and antioxidant capacity of maize (Zea mays L.) were tested in two different marginal uplands of southern Madagascar using 24 different genotypes. The length of the growing cycle and soil properties were shown to be key aspects for attaining optimal maize performances when cropped in the virgin soils of southern Madagascar. The results also indicated that maize may be considered a reliable alternative to the local staple food currently represented by rice, with sufficient protein and functional compounds for human health. The highest yields, protein content, total polyphenols, and antiradical power (ARP) were observed in the varieties Gasti, Local, Clariti, and Korimbos, respectively. To achieve a good compromise between yield and functional compounds, the varieties Maggi and Gasti are recommended for cultivation. The present results emphasise the effectiveness of maize cultivation in increasing food production in an undernourished country such as Madagascar. Further experiments are required to test maize performances under different soil, cultural and management conditions.
Cholangiocarcinoma (CCA) is a rare and aggressive cancer, mostly diagnosed at advanced or metastatic stage, at which point systemic treatment represents the only therapeutic option. Chemotherapy has ...been the backbone of advanced CCA treatment. More recently, immunotherapy has changed the therapeutic landscape, as immune checkpoint inhibitors (ICIs) have yielded the first improvement in survival and currently, the addition of either durvalumab or pembrolizumab to standard of care cisplatin plus gemcitabine represents the new first-line treatment option. However, the use of immunotherapy in subsequent lines has not demonstrated its efficacy and therefore, it is not approved, except for pembrolizumab in the selected microsatellite instability-high (MSI-H) population. In addition, advances in comprehensive genomic profiling have led to the identification of targetable genetic alterations, such as isocitrate dehydrogenase 1 (IDH1), fibroblast growth factor receptor 2 (FGFR2), human epidermal growth factor receptor 2 (HER2), proto-oncogene B-Raf (BRAF), neurotrophic tropomyosin receptor kinase (NTRK), rearranged during transfection (RET), Kirsten rat sarcoma virus (KRAS), and mouse double minute 2 homolog (MDM2), thus favoring the development of a precision medicine approach in previously treated patients. Despite these advances, the use of molecularly driven agents is limited to a subgroup of patients. This review aims to provide an overview of the newly approved systemic therapies, the ongoing studies, and future research challenges in advanced CCA management.Cholangiocarcinoma (CCA) is a rare and aggressive cancer, mostly diagnosed at advanced or metastatic stage, at which point systemic treatment represents the only therapeutic option. Chemotherapy has been the backbone of advanced CCA treatment. More recently, immunotherapy has changed the therapeutic landscape, as immune checkpoint inhibitors (ICIs) have yielded the first improvement in survival and currently, the addition of either durvalumab or pembrolizumab to standard of care cisplatin plus gemcitabine represents the new first-line treatment option. However, the use of immunotherapy in subsequent lines has not demonstrated its efficacy and therefore, it is not approved, except for pembrolizumab in the selected microsatellite instability-high (MSI-H) population. In addition, advances in comprehensive genomic profiling have led to the identification of targetable genetic alterations, such as isocitrate dehydrogenase 1 (IDH1), fibroblast growth factor receptor 2 (FGFR2), human epidermal growth factor receptor 2 (HER2), proto-oncogene B-Raf (BRAF), neurotrophic tropomyosin receptor kinase (NTRK), rearranged during transfection (RET), Kirsten rat sarcoma virus (KRAS), and mouse double minute 2 homolog (MDM2), thus favoring the development of a precision medicine approach in previously treated patients. Despite these advances, the use of molecularly driven agents is limited to a subgroup of patients. This review aims to provide an overview of the newly approved systemic therapies, the ongoing studies, and future research challenges in advanced CCA management.
The outcome of patients with metastatic tumors who discontinued immune checkpoint inhibitors (ICIs) not for progressive disease (PD) has been poorly explored. We performed a meta-analysis of all ...studies reporting the clinical outcome of patients who discontinued ICIs for reasons other than PD.
We searched PubMed, Embase and Scopus databases, from the inception of each database to December 2023, for clinical trials (randomized or not) and observational studies assessing PD-(L)1 and CTLA-4 inhibitors in patients with metastatic solid tumors who discontinued treatment for reasons other than PD. Each study had to provide swimmer plots or Kaplan–Meier survival curves enabling the reconstruction of individual patient-level data on progression-free survival (PFS) following the discontinuation of immunotherapy. The primary endpoint was PFS from the date of treatment discontinuation overall and according to tumor histotype, type of treatment and reason of discontinuation. The Combersure’s method was used to estimate meta-analytical non-parametric summary survival curves assuming random effects at study level.
Thirty-six studies (2180 patients) were included. The pooled median PFS (mPFS) was 24.7 months (95% CI, 18.8–30.6) and the PFS-rate at 12, 24, and 36 months was respectively 69.8% (95% CI, 63.1–77.3), 51.0% (95% CI, 43.4–59.8) and 34.0% (95% CI, 27.0–42.9). Univariable analysis showed that the mPFS was significantly longer for patients with melanoma (43.0 months), as compared with non-small cell lung cancer (NSCLC, 13.5 months) and renal cell carcinoma (RCC, 10.0 months; between-strata comparison test p-value < 0.001); for patients treated with anti-PD-(L)1 + anti-CTLA-4 as compared with anti-PD-(L)1 monotherapy (44.6 versus 19.9 months; p-value < 0.001), and in NSCLC when the reason of treatment discontinuation was elective as compared with toxicity onset (19.6 versus 4.8 months; p-value = 0.003). The multivariable analysis confirmed these differences.
The long-term outcome of patients who stopped ICIs for reasons other than PD was substantially affected by clinicopathological features: PFS after treatment discontinuation was longer in patients with melanoma, and/or treated with anti-PD-(L)1 + anti-CTLA-4, and shorter in patients with RCC or in those patients with NSCLC who stopped treatment for toxicity onset.
The Italian Ministry of University and Research (PRIN 2022Y7HHNW).
Background: The outcome of patients with metastatic tumors who discontinued immune checkpoint inhibitors (ICIs) not for progressive disease (PD) has been poorly explored. We performed a meta-analysis ...of all studies reporting the clinical outcome of patients who discontinued ICIs for reasons other than PD. Methods: We searched PubMed, Embase and Scopus databases, from the inception of each database to December 2023, for clinical trials (randomized or not) and observational studies assessing PD-(L)1 and CTLA-4 inhibitors in patients with metastatic solid tumors who discontinued treatment for reasons other than PD. Each study had to provide swimmer plots or Kaplan–Meier survival curves enabling the reconstruction of individual patient-level data on progression-free survival (PFS) following the discontinuation of immunotherapy. The primary endpoint was PFS from the date of treatment discontinuation overall and according to tumor histotype, type of treatment and reason of discontinuation. The Combersure’s method was used to estimate meta-analytical non-parametric summary survival curves assuming random effects at study level. Findings: Thirty-six studies (2180 patients) were included. The pooled median PFS (mPFS) was 24.7 months (95% CI, 18.8–30.6) and the PFS-rate at 12, 24, and 36 months was respectively 69.8% (95% CI, 63.1–77.3), 51.0% (95% CI, 43.4–59.8) and 34.0% (95% CI, 27.0–42.9). Univariable analysis showed that the mPFS was significantly longer for patients with melanoma (43.0 months), as compared with non-small cell lung cancer (NSCLC, 13.5 months) and renal cell carcinoma (RCC, 10.0 months; between-strata comparison test p-value < 0.001); for patients treated with anti-PD-(L)1 + anti-CTLA-4 as compared with anti-PD-(L)1 monotherapy (44.6 versus 19.9 months; p-value < 0.001), and in NSCLC when the reason of treatment discontinuation was elective as compared with toxicity onset (19.6 versus 4.8 months; p-value = 0.003). The multivariable analysis confirmed these differences. Interpretation: The long-term outcome of patients who stopped ICIs for reasons other than PD was substantially affected by clinicopathological features: PFS after treatment discontinuation was longer in patients with melanoma, and/or treated with anti-PD-(L)1 + anti-CTLA-4, and shorter in patients with RCC or in those patients with NSCLC who stopped treatment for toxicity onset. Funding: The Italian Ministry of University and Research (PRIN 2022Y7HHNW).
The contamination of the environment with pollutants, like heavy metals from human activity, has caused the loss of agricultural land. One possible solution could be the utilization of ...phytoremediation technique with particular plant, capable of absorbing the contaminants from soil. Jatropha curcas, an important plant for the biodiesel production, in particular in tropical areas, has the capacity to grown in marginal land, compromised for food cultivation. The experiment was conducted in hydroponic conditions with the objective to evaluate the response and growth parameters of juvenile plants grown in presence of different Pb levels (0-100-200 mg/L). It was possible to study the interaction in the plant between some mineral element (Ca, Mg, Zn and Fe) and morphological parameters and Pb, and evaluate some tolerance indicators. Results showed that the plants were able to grow in presence of Pb and to accumulate high levels of heavy metal in the roots, followed by the stems and leaves. However, Jatropha curcas subjected to Pb treatment demonstrated stunted growth and alterations in mineral elements contents. The results suggest that J. curcas may tolerate the levels of Pb imposed, but there is low translocation of heavy metal to aerial tissues, within the time period of analysis.
Effects of opiates on blood rheology Galante, A; De Luca, A; Pietroiusti, A ...
Journal of toxicology. Clinical toxicology,
1994, Volume:
32, Issue:
4
Journal Article
Peer reviewed
To evaluate the possible effect of opiates on blood rheology, the plasma fibrinogen, prothrombin time and leukocyte aggregation were measured in 75 heroin addicts categorized by the time of ...abstention from heroin and the administration of naltrexone (25 active heroin abusers, 25 abstaining for 1 week, 11 abstaining for at least 5 months and 14 abstaining for 1 month and taking naltrexone during this period). No difference was detected in prothrombin time, but the leukocyte aggregation and fibrinogen were significantly different among the four groups (p = 0.028 and p = 0.0001, respectively). In particular, fibrinogen was 318 +/- 10.9 mg/dL in heroin abusers, significantly higher than that of the remaining three groups; the percentage of aggregated leukocytes was 5.01 +/- 0.77 in heroin users, significantly higher than that of subjects abstaining for at least 5 months. The fibrinogen levels declined sharply with abstention and an additive effect was noted with the administration of naltrexone, but leukocyte aggregation changed more slowly, and the effect of naltrexone (if any) was weaker. These data indicate an adverse effect of opiates on blood rheology and suggest that further studies should be performed to evaluate whether naltrexone may be useful in the prevention of major ischemic syndromes in patients with hyperfibrinogenemia and, perhaps, in those with high levels of leukocyte aggregation.
