Reversal of neurological deficits by painless nerve growth factor in a mouse model of Rett syndrome.

Rett syndrome is a rare genetic neurodevelopmental disease, affecting 1 in over 10 000 females born worldwide, caused by de novo mutations in the X-chromosome-located methyl-CpG-binding protein 2 (MeCP2) gene. Despite the great effort put forth by the scientific community, a therapy for this devastating disease is still needed. Here, we tested the therapeutic effects of a painless mutein of the nerve growth factor (NGF), called human NGF painless (hNGFp), via a non-invasive intranasal delivery in female MeCP2+/- mice. Of note, previous work had demonstrated a broad biodistribution of hNGFp in the mouse brain by the nasal delivery route. We report that (i) the long-term lifelong treatment of MeCP2+/- mice with hNGFp, starting at 2 months of age, increased the chance of survival while also greatly improving behavioural parameters. Furthermore, when we assessed the phenotypic changes brought forth by (ii) a short-term 1-month-long hNGFp-treatment, starting at 3 months of age (right after the initial presentation of symptoms), we observed the rescue of a well known neuronal target population of NGF, cholinergic neurons in the medial septum. Moreover, we reveal a deficit in microglial morphology in MeCP2+/- mice, completely reversed in treated animals. This effect on microglia is in line with reports showing microglia to be a TrkA-dependent non-neuronal target cell population of NGF in the brain. To understand the immunomodulatory activity of hNGFp, we analysed the cytokine profile after hNGFp treatment in MeCP2+/- mice, to discover that the treatment recovered the altered expression of key neuroimmune-communication molecules, such as fractalkine. The overall conclusion is that hNGFp delivered intranasally can ameliorate symptoms in the MeCP2+/- model of Rett syndrome, by exerting strong neuroprotection with a dual mechanism of action: directly on target neurons and indirectly via microglia.

A Pure Autologous Dermal Graft and Dermal Flap Pocket in Prepectoral Implant Reconstruction After Skin-Reducing Mastectomy: A One-Stage Autologous Reconstruction Alternative to Acellular Dermal Matrices.

Skin-reducing mastectomy (SRM) with subpectoral implant positioning represents a consolidated, oncologically safe and cosmetically effective method for the immediate reconstruction of large and ptotic breasts. Acellular dermal matrix (ADM) has been proposed as a substitute for the pectoralis major muscle in this surgical approach; this technique led to a progressive evolution toward prepectoral reconstructions even in skin-reducing mastectomies. Obese patients with macromastia who are typical candidates for SRM with ADM are at increased risk of complications associated with ADMs. Therefore, we avoided ADMs and developed a novel autologous technique for immediate breast reconstruction in large and ptotic breasts eligible for SRM. Specifically, an autologous dermal graft is harvested from contralateral healthy breast reduction to cover the upper pole of the prepectoral implant.Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Deep inspiration breath hold in post-operative radiotherapy for right breast cancer: a retrospective analysis.

Background: The aim of our study is to determine whether deep inspiration breath hold (DIBH) is effective for reducing exposure of the heart, left coronary artery (LAD) and both lungs in right breast radiotherapy. Materials and methods: We have analyzed 10 consecutive patients with right-sided breast cancer (BC), simulated during free breathing (FB) and in DIBH modality. For all patients we contoured breast PTV and organs at risk (right and left lungs, heart, LAD) on both CT scans (FB and DIBH). Finally, 5 patients were treated with IMRT and 5 with VMAT techniques. Results: All patients were able to end the treatments in DIBH modalities regardless of the longer treatment time in comparison to FB. The maximum and mean dose to the heart are lower in the DIBH modality. The mean values of the heart mean dose were 1.76 Gy in DIBH and 2.19 Gy in FB. The mean heart maximum dose in DIBH and FB were, respectively, 9.3 Gy and 11 Gy. Likewise, the maximum dose to the LAD is lower in DIBH; 2.57 Gy versus 3.56 Gy in FB. Noteworthy, 3 patients with hepatomegaly treated with the DIBH technique showed a higher ipsilateral lung dose than FB, but a decrease of liver dose. Conclusion: We report that the use of DIBH for right-sided BC allows the dose to the heart, LAD and to the liver to be reduced in case of hepatomegaly. This technique is well tolerated by patients, when adequately trained, and could be considered effective even in right sided BC.

Axillary Management Following Neoadjuvant Chemotherapy in Clinically Node-Positive Breast Cancer.

INTRODUCTION: Clinical trial data indicate that omitting axillary lymph node dissection (ALND) is feasible and may reduce morbidity for carefully selected patients with clinically node-positive breast cancer who achieve a pathological complete response (pCR) after neoadjuvant chemotherapy (NCT). However, there remains a need to understand how these findings translate to broader clinical practice and to identify which patients benefit most. This study utilizes a national dataset to assess outcomes in axillary management, aiming to inform best practice in axillary de-escalation. METHODS: The National Cancer Data Base was used to identify women diagnosed with clinically node-positive invasive breast cancer between 2012 to 2020 who received NCT and subsequent ALND. Associations between clinicopathologic factors and axillary pCR were analyzed statistically. RESULTS: Of the 59,791 patients included, 8,827 (14.76%) achieved nodal pCR. Patients with HR-negative and HER2-positive receptor status more frequently underwent ALND instead of sentinel lymph node biopsy. Conversely, patients over the age of 70, those with private or public insurance, and cases classified as ypT1 or ypT2 were less likely to undergo ALND. CONCLUSION: A subset of patients with clinically node-positive breast cancer received ALND despite achieving axillary pCR following NCT. This highlights an opportunity to enhance precision in identifying candidates for axillary de-escalation, potentially reducing morbidity and tailoring treatment more closely to individual patient needs.

Axillary de-escalation after neoadjuvant chemotherapy for advanced lymph node involvement in breast cancer.

INTRODUCTION: Sentinel lymph node biopsy reduces morbidity in patients with clinically node-positive breast cancer who achieve axillary pathologic complete response following neoadjuvant therapy (NACT). De-escalation trials primarily addressed cN1 disease, with underrepresentation of cN2 disease. This study evaluates the role of de-escalation in patients with cN2 breast cancer. METHODS: A retrospective analysis of the National Cancer Database (2013-2020) included women over 18 with T1-2 invasive breast cancer and clinical N2 disease who received NACT followed by ALND or SLNB then ALND. The primary outcome was pathologic nodal status post-NACT. RESULTS: Of 5852 cN2 patients treated, 18.15 â€‹% achieved ypN0, 0.97 â€‹% had isolated tumor cells, 19.14 â€‹% were ypN1, 49.64 â€‹% were ypN2, and 12.20 â€‹% were ypN3 following NACT. Achieving ypN0 was associated with pCR in the breast, HER2-positive and triple-negative receptor status, cT2 tumors, and younger age. CONCLUSION: Despite some patients with cN2 disease achieving ypN0, most exhibited residual axillary disease post-NACT. These findings indicate that axillary de-escalation may not be feasible for most patients with cN2 disease, underscoring the importance of meticulous patient selection and assessment.

Improving quality of breast conservative surgery for lower quadrants cancer in small and medium sized breasts: Crescent technique versus J mammoplasty.

Background: For medium/small size breast, breast conserving surgery (BCS) is usually associated to poor cosmetic results. The objective of the study is to evaluate oncological safety and cosmetic results comparing the "Crescent" and the "J" mammoplasty technique and to develop an algorithm for the treatment of breast cancer located in lower quadrants in medium/small breast. Methods: We retrospectively analysed all consecutive patients who underwent a "J" mammoplasty or a "Crescent" technique at AUSL IRCCS Reggio Emilia between 2016 and 2021. Fifty-eight patients were enrolled, the first group including 29 "Crescent" technique procedures and the second one including 29 patients who underwent the "J" mammoplasty technique. Oncological safety and surgical minor and major complications were evaluated. Aesthetic results were evaluated by two senior breast surgeons, independently, at least 6 months after radiotherapy (RT). Results: At follow-up of 36 months, no recurrences and no major complications were observed in both groups. Minor complications were observed in two (6.9%) "J" group cases and in six (20.7%) "Crescent" ones (P<0.05). The 96.6% of "Crescent" and the 73.5% of "J" cases were judged excellent/good. One (3.4%) "Crescent" was judged fair versus six (20.7%) "J" mammoplasty. Two (6.9%) "J" cases were judged poor, requiring ipsilateral re-operation. Conclusions: When a favourable ratio between tumor size and breast volume is present, BCS can be performed for tumors located in the lower quadrants. Evaluating patients' anthropometric characteristics, skin involvement and tumor features is the key to select the right technique and to obtain both great cosmetic result and low rate of complications.

Reduced levels of NGF shift astrocytes toward a neurotoxic phenotype.

Nerve growth factor (NGF) is critical for neuronal physiology during development and adulthood. Despite the well-recognized effect of NGF on neurons, less is known about whether NGF can actually affect other cell types in the central nervous system (CNS). In this work, we show that astrocytes are susceptible to changes in ambient levels of NGF. First, we observe that interfering with NGF signaling in vivo via the constitutive expression of an antiNGF antibody induces astrocytic atrophy. A similar asthenic phenotype is encountered in an uncleavable proNGF transgenic mouse model (TgproNGF#72), effectively increasing the brain proNGF levels. To examine whether this effect on astrocytes is cell-autonomous, we cultured wild-type primary astrocytes in the presence of antiNGF antibodies, uncovering that a short incubation period is sufficient to potently and rapidly trigger calcium oscillations. Acute induction of calcium oscillations by antiNGF antibodies is followed by progressive morphological changes similar to those observed in antiNGF AD11 mice. Conversely, incubation with mature NGF has no effect on either calcium activity nor on astrocytic morphology. At longer timescales, transcriptomic analysis revealed that NGF-deprived astrocytes acquire a proinflammatory profile. In particular, antiNGF-treated astrocytes show upregulation of neurotoxic transcripts and downregulation of neuroprotective mRNAs. Consistent with that data, culturing wild-type neurons in the presence of NGF-deprived astrocytes leads to neuronal cell death. Finally, we report that in both awake and anesthetized mice, astrocytes in layer I of the motor cortex respond with an increase in calcium activity to acute NGF inhibition using either NGF-neutralizing antibodies or a TrkA-Fc NGF scavenger. Moreover, in vivo calcium imaging in the cortex of the 5xFAD neurodegeneration mouse model shows an increased level of spontaneous calcium activity in astrocytes, which is significantly reduced after acute administration of NGF. In conclusion, we unveil a novel neurotoxic mechanism driven by astrocytes, triggered by their sensing and reacting to changes in the levels of ambient NGF.

Early Detection of Cardiotoxicity From Systemic and Radiation Therapy in Patients With Breast Cancer: Protocol for a Multi-Institutional Prospective Study.

BACKGROUND: The incidence of breast cancer is rising worldwide. Recent advances in systemic and local treatments have significantly improved survival rates of patients having early breast cancer. In the last decade, great attention has been paid to the prevention and early detection of cardiotoxicity induced by breast cancer treatments. Systemic therapy-related cardiac toxicities have been extensively studied. Radiotherapy, an essential component of breast cancer treatment, can also increase the risk of heart diseases. Consequently, it is important to balance the expected benefits of cancer treatment with cardiovascular risk and to identify strategies to prevent cardiotoxicity and improve long-term outcomes and quality of life for these patients. OBJECTIVE: This CardioTox Breast study aims to investigate the use of cardiac imaging, based on cardiac magnetic resonance and echocardiography, and to identify associated circulating biomarkers to assess early tissue changes in chemo-induced and radiation-induced cardiotoxicity in the time window of 12 months after the end of radiotherapy in patients with breast cancer. METHODS: The CardioTox Breast trial is a multicenter observational prospective longitudinal study. We aim to enroll 150 women with stage I-III unilateral breast cancer, treated with breast conserving surgery, who planned to receive radiotherapy with or without systemic therapy. Baseline and follow-up data include cardiac measurements based on cardiac magnetic resonance imaging, echocardiography, and circulating biomarkers of cardiac toxicity. RESULTS: This study details the protocol of the CardioTox Breast trial. Recruitment started in September 2020. The results of this study will not be published until data are mature for the final analysis of the primary study end point. CONCLUSIONS: The CardioTox Breast study is designed to investigate the effects of systemic and radiation therapy on myocardial function and structure, thus providing additional evidence on whether cardiac magnetic resonance is the optimal screening imaging for cardiotoxicity. TRIAL REGISTRATION: ClinicalTrials.gov NCT04790266; https://clinicaltrials.gov/ct2/show/NCT04790266. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31887.

Bifurcate inferior pedicle mammoplasty in large ptotic breast for tumor located at the upper outer quadrant with skin involvement-a novel technique allowing good cosmetic outcome: case report.

Breast oncoplastic techniques followed by radiotherapy represent nowadays the standard of care for breast cancer treatment. For tumours located at the upper outer quadrant in patients with large and ptotic breasts, the use of level II breast reduction mammoplasty, allows large quadrantectomies without compromising the breast natural shape and reducing the breast volume to be irradiated. When the skin overlying the tumour in the upper outer quadrant is involved, the removal of the skin during mammoplasty could lead to an extreme reduction of the breast, resulting in a bad outcome. Different strategies have been adopted to avoid a poor cosmetic result including a Z plastic or latissimus dorsi (LD) mini flap. At our institution we developed a new technique utilizing an inferior bifurcated pedicle mammoplasty with the preservation of a skin island for a patient with a residual tumour following chemotherapy involving the skin in the upper outer quadrant of the right breast. The patient did show no complications, with no delay for adjuvant radiotherapy treatment. Our method is a novel technique to treat malignancies in this location for patients with large and ptotic breasts when skin removal is indicated and it may represent an effective strategy to prevent excessive gland reduction, thus avoiding poor cosmetic result.