Dose–volume and biological-model based comparison between helical tomotherapy and (inverse-planned) IMAT for prostate tumours

BACKGROUND AND PURPOSE: Helical tomotherapy (HT) and intensity-modulated arc therapy (IMAT) are two arc-based approaches to the delivery of intensity-modulated radiotherapy (IMRT). Through plan comparisons we have investigated the potential of IMAT, both with constant (conventional or IMAT-C) and variable (non-conventional or IMAT-NC, a theoretical exercise) dose-rate, to serve as an alternative to helical tomotherapy. MATERIALS AND METHODS: Six patients with prostate tumours treated by HT with a moderately hypo-fractionated protocol, involving a simultaneous integrated boost, were re-planned as IMAT treatments. A method for IMAT inverse-planning using a commercial module for static IMRT combined with a multi-leaf collimator (MLC) arc-sequencing was developed. IMAT plans were compared to HT plans in terms of dose statistics and radiobiological indices. RESULTS: Concerning the planning target volume (PTV), the mean doses for all PTVs were similar for HT and IMAT-C plans with minimum dose, target coverage, equivalent uniform dose (EUD) and tumour control probability (TCP) values being generally higher for HT; maximum dose and degree of heterogeneity were instead higher for IMAT-C. In relation to organs at risk, mean doses and normal tissue complication probability (NTCP) values were similar between the two modalities, except for the penile bulb where IMAT was significantly better. Re-normalizing all plans to the same rectal toxicity (NTCP=5%), the HT modality yielded higher TCP than IMAT-C but there was no significant difference between HT and IMAT-NC. The integral dose with HT was higher than that for IMAT. CONCLUSIONS: with regards to the plan analysis, the HT is superior to IMAT-C in terms of target coverage and dose homogeneity within the PTV. Introducing dose-rate variation during arc-rotation, not deliverable with current linac technology, the simulations result in comparable plan indices between (IMAT-NC) and HT.     

Changes of HER2 status in circulating tumor cells compared with the primary tumor during treatment for advanced breast cancer

BackgroundHER2/neu status of tumor cells at metastatic sites in patients with advanced disease may differ from that of the primary tumor. Assessing the presence of target antigens on circulating tumor cells (CTCs) might affect treatment choice.Patients and MethodsFrom June 2007 to October 2008, we collected 23 mL of blood from each of the 76 consecutive patients before and during chemotherapy to determine CTC numbers and HER2 overexpression. CTCs were isolated with the CellSearch System® (Veridex, LLC; Raritan, NJ) and fluorescently stained with the Epithelial Cell Kit®. Tumor Phenotyping Reagent® was used to investigate HER2/neu overexpression.ResultsConcordance of HER2 status between the primary tumor and CTCs was 86% (49 out of 57 patients) at baseline and 82% (50 out of 61 patients) in the treatment samples. HER2 overexpression in CTCs was acquired in 8 out of 45 patients (18%) and lost in 3 out of 16 patients (19%) during a treatment containing trastuzumab. The overall discordance rate between the primary tumor and CTCs was 18% (11 out of 61 patients). Patients with HER2 overexpression in CTCs had poorer progression-free survival compared with those without CTCs or with HER2? CTCs (log-rank P =.036).ConclusionInformation on the presence or absence of HER2 overexpression can be obtained in CTCs. Larger trials are needed to evaluate the activity of HER2-targeted therapy in patients with acquired HER2 overexpression in CTCs.     

Metformin Decreases Circulating Androgen and Estrogen Levels in Nondiabetic Women With Breast Cancer

IntroductionDiabetic patients treated with metformin have a lower risk of developing BC or a better BC prognosis. Metformin might reduce cancer growth through direct antiproliferative effects or through indirect mechanisms, particularly the reduction of insulin. In a randomized study on nondiabetic BC patients in natural menopause with high testosterone levels, we observed a significant decrease in insulin and in testosterone levels with metformin 1500 mg/d compared with 1000 mg/d. We present the results of a new analysis of our study on the effect of metformin on the bioavailability of sex hormones.Patients and MethodsOne hundred twenty-four eligible women were initially invited to take metformin 500 mg/d for 3 months. The 108 women who completed the first 3 months continued the study using 1000 mg/d for 1 month. The women were then randomized into 2 groups, and, for the subsequent 5 months, 1 group increased the dose to 1500 mg/d, and the other group continued with 1000 mg/d.ResultsNinety-six women completed the study, 43 receiving metformin 1500 mg/day, and 53 receiving 1000 mg/day. The women receiving 1500 mg/d showed a greater and significant reduction of free testosterone (?29%) and estradiol (?38%), a borderline significant reduction of estrone and insulin-like growth factor-1, and a nonsignificant reduction of androstenedione. They also showed a nonsignificant increase of dehydroepiandrosterone sulfate.ConclusionMetformin does not interfere with the production of dehydroepiandrosterone sulfate. Besides, it decreases estradiol levels, basically through the reduction of testosterone. These hormonal changes might have clinical relevance.     

Assessment of the Impact of a Toll-like Receptor 2 Agonist Synthetic Lipopeptide on Macrophage Susceptibility and Responses to African Swine Fever Virus Infection

Toll-like receptor 2 (TLR2) ligands are attracting attention as prophylactic and immunopotentiator agents against pathogens, including viruses. We previously reported that a synthetic diacylated lipopeptide (Mag-Pam2Cys_P48) polarized porcine macrophages towards a proinflammatory antimicrobial phenotype. Here, we investigated its role in modulating monocyte-derived macrophage (moMΦ) responses against African swine fever virus (ASFV), the etiological agent of one of the greatest threats to the global pig industry. Two ASFV isolates were compared: the attenuated NH/P68 and the virulent 26544/OG10. No effect on virus infection nor the modulation of surface markers’ expression (MHC I, MHC II DR, CD14, CD16, and CD163) were observed when Mag-Pam2Cys_P48 treated moMΦ were infected using a multiplicity of infection (MOI) of 1. Mag-Pam2Cys_P48 treated moMΦ released higher levels of IL-1α, IL-1β, IL-1Ra, and IL-18 in response to infection with NH/P68 ASFV compared to 26544/OG10-infected and mock-infected controls. Surprisingly, when infected using a MOI of 0.01, the virulent ASFV 26544/OG10 isolate replicated even slightly more efficiently in Mag-Pam2Cys_P48 treated moMΦ. These effects also extended to the treatment of moMΦ with two other lipopeptides: Mag-Pam2Cys_P80 and Mag-Pam2Cys_Mag1000. Our data suggested limited applicability of TLR2 agonists as prophylactic or immunopotentiator agents against virulent ASFV but highlighted the ability of the virulent 26544/OG10 to impair macrophage defenses.     

Nosocomial outbreak by NDM-1-producing Klebsiella pneumoniae highly resistant to cefiderocol,Florence, Italy,August 2021 to June 2022

A nosocomial outbreak by cefiderocol (FDC)-resistant NDM-1-producing Klebsiella pneumoniae (NDM-Kp) occurred in a large tertiary care hospital from August 2021–June 2022 in Florence, Italy, an area where NDM-Kp strains have become endemic. Retrospective analysis of NDM-Kp from cases observed in January 2021–June 2022 revealed that 21/52 were FDC-resistant. The outbreak was mostly sustained by clonal expansion of a mutant with inactivated cirA siderophore receptor gene, which exhibited high-level resistance to FDC (MIC ≥ 32 mg/L) and spread independently of FDC exposure.     

COVID-19 and Guillain-Barré syndrome: A single-center prospective case series with a 1-year follow-up

Single reports of Guillain-Barré syndrome (GBS) have been reported worldwide during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. While case reports are likely to be biased toward uncommon clinical presentations, systematic assessment of prospective series can highlight the true clinical features and spectrum. In this prospective, observational study, we included all consecutive patients who developed GBS. In patients with SARS-CoV-2 infection as antecedent, the time-gap between the infection and GBS onset had to be ≤30 days. The referral was a neurological University Research Hospital, in the Italian Region more severely involved by the pandemic, and hospitalizing both COVID+ and non-COVID neurological diseases. Clinical, laboratory, cerebrospinal fluid, and electromyographic features of GBS diagnosed between March 2020 and March 2021 were compared to a retrospective series of GBS diagnosed between February 2019 and February 2020 (control population). Nasopharyngeal swab was still positive at GBS onset in 50% of patients. Mild-to-moderate COVID-related pneumonia, as assessed by X-ray (6 patients) or X-ray plus computerized tomography (2 patients) co-occurred in 6 of 10 patients. GBS diagnosed during the pandemic period, including 10 COVID-GBS and 10 non–COVID-GBS, had higher disability on admission (P = .032) compared to the GBS diagnosed between February 2019 and 2020, possibly related to later hospital referral in the pandemic context. Compared to non–COVID-GBS (n = 10) prospectively diagnosed in the same period (March 2020–2021), post–COVID-GBS (n = 10) had a higher disability score on admission (P = .028), lower sum Medical Research Council score (P = .022) and lymphopenia (P = .025), while there were no differences in GBS subtype/variant, severity of peripheral involvement, prognosis and response to treatment. Cerebrospinal fluid search for SARS-CoV-2 RNA and antiganglioside antibodies were negative in all COVID+ patients. Temporal clustering of cases, coinciding with the waves of the pandemic, and concomitant reduction of the incidence of COVID-negative GBSs may indicate a role for SARS-CoV-2 infection in the development of GBS, although the association may simply be related to a bystander effect of systemic inflammation; lack of prevalence of specific GBS subtypes in post–COVID-GBS also support this view. GBS features and prognosis are not substantially different compared to non–COVID-GBS.     

Extracellular vesicles mediate the communication between multiple myeloma and bone marrow microenvironment in a NOTCH dependent way

Multiple myeloma (MM) is an incurable hematologic neoplasm, whose poor prognosis is deeply affected by the propensity of tumor cells to localize in the bone marrow (BM) and induce the protumorigenic activity of normal BM cells, leading to events associated with tumor progression, including tumor angiogenesis, osteoclastogenesis, and the spread of osteolytic bone lesions. The interplay between MM cells and the BM niche does not only rely on direct cell-cell interaction, but a crucial role is also played by MM-derived extracellular vesicles (MM-EV). Here, we demonstrated that the oncogenic NOTCH receptors are part of MM-EV cargo and play a key role in EV protumorigenic ability. We used in vitro and in vivo models to investigate the role of EV-derived NOTCH2 in stimulating the protumorigenic behavior of endothelial cells and osteoclast progenitors. Importantly, MM-EV can transfer NOTCH2 between distant cells and increase NOTCH signaling in target cells. MM-EV stimulation increases endothelial cell angiogenic ability and osteoclast differentiation in a NOTCH2-dependent way. Indeed, interfering with NOTCH2 expression in MM cells may decrease the amount of NOTCH2 also in MM-EV and affect their angiogenic and osteoclastogenic potential. Finally, we demonstrated that the pharmacologic blockade of NOTCH activation by γ-secretase inhibitors may hamper the biological effect of EV derived by MM cell lines and by the BM of MM patients. These results provide the first evidence that targeting the NOTCH pathway may be a valid therapeutic strategy to hamper the protumorigenic role of EV in MM as well as other tumors.     

Perinatal exposure to tributyltin affects feeding behavior and expression of hypothalamic neuropeptide Y in the paraventricular nucleus of adult mice

Organotins such as tributyltin chloride (TBT), are highly diffused environmental pollutants, which act as metabolism disrupting chemicals, i.e. may interfere with fat tissue differentiation, as well as with neuroendocrine circuits, thus impairing the control of energetic balance. We have previously demonstrated that adult exposure to TBT altered the expression of neuropeptides in the hypothalamus. In this study, we orally administered daily a solution containing oil, or TBT (0.25, 2.5, or 25 μg/kg body weight/day) to pregnant females from gestational day 8 until birth, and to their pups from day 0 until post‐natal day 21. Our results showed that TBT exposure of female mice during gestation and of pups during lactation permanently altered the feeding efficiency of pups of both sexes and subcutaneous fat distribution in adult males. In addition, the neuropeptide Y system was affected at the level of the paraventricular nucleus, with a decrease in immunoreactivity in both sexes (significant in females for all TBT doses and in males only for intermediate TBT doses), while no effect was observed in other hypothalamic areas (arcuate, ventromedial and dorsomedial nuclei). Metabolic syndrome, as well as obesity and diabetes, which are significant health issues, are considered multifactorial diseases and may be caused by exposure to metabolic disruptors, both in adults and during perinatal life. In addition, our work indicates that TBT doses defined as the tolerably daily intake had a profound and sex‐specific long‐term effect.     

Baveno-VII criteria to predict decompensation and initiate non-selective beta-blocker in compensated advanced chronic liver disease patients

Background/AimsThe utility of Baveno-VII criteria of clinically significant portal hypertension (CSPH) to predict decompensation in compensated advanced chronic liver disease (cACLD) patient needs validation. We aim to validate the performance of CSPH criteria to predict the risk of decompensation in an international real-world cohort of cACLD patients.MethodscACLD patients were stratified into three categories (CSPH excluded, grey zone, and CSPH). The risks of decompensation across different CSPH categories were estimated using competing risk regression for clustered data, with death and hepatocellular carcinoma as competing events. The performance of “treating definite CSPH” strategy to prevent decompensation using non-selective beta-blocker (NSBB) was compared against other strategies in decision curve analysis.ResultsOne thousand one hundred fifty-nine cACLD patients (36.8% had CSPH) were included; 7.2% experienced decompensation over a median follow-up of 40 months. Non-invasive assessment of CSPH predicts a 5-fold higher risk of liver decompensation in cACLD patients (subdistribution hazard ratio, 5.5; 95% confidence interval, 4.0–7.4). “Probable CSPH” is suboptimal to predict decompensation risk in cACLD patients. CSPH exclusion criteria reliably exclude cACLD patients at risk of decompensation, regardless of etiology. Among the grey zone, the decompensation risk was negligible among viral-related cACLD, but was substantially higher among the non-viral cACLD group. Decision curve analysis showed that “treating definite CSPH” strategy is superior to “treating all varices” or “treating probable CSPH” strategy to prevent decompensation using NSBB.ConclusionsNon-invasive assessment of CSPH may stratify decompensation risk and the need for NSBB in cACLD patients.