Dosimetric comparison of intensity-modulated proton radiotherapy versus intensity-modulated photon-based radiotherapy for breast cancer

Purpose: This study aims to compare the dosimetric differences in intensity-modulated proton therapy (IMPT) using pencil beam scanning technology and intensity-modulated photon-based radiotherapy (IMRT) in hypofractionated whole-breast irradiation (HF-WBI) and find out the more beneficial technique. Methods and Materials: Eight breast cancer (BC) patients with pathological stage T1 ~ 2N0M0 were immobilized and underwent 4D-CT scanning used deep inspiration breath-hold (DIBH) technology. The IMPT and IMRT plans were designed for each patient. The IMPT plans used two en-face beam angles. IMRT plans were designed using the field in field technique. The optimization constraints of the two types of plans were identical. Prescription dose and regimen was 40.05 Gy (relative biological effect [RBE])/15 fx with a 10 Gy (RBE)/5 fx boost, five fractions a week. A dose of 95% of the target volume should not be less than the prescribed dose. The target coverage was evaluated using D1, D2, D50, D95, D98, and D99. The target dose distribution and conformity were evaluated using the Conformity index (CI) and the homogeneity index (HI). The Organs at risk (OARs) were evaluated using mean dose (Dmean) and maximum dose (Dmax). Ipsilateral Lung and Contralateral Lung were evaluated additionally using V5, V10, V20, V30. Results: The mean dose (Dmean) of the Heart (P = 0.012), Ipsilateral Lung (P = 0.036), Contralateral Lung (P = 0.012), and Spinal Cord (P = 0.012) were significantly reduced in IMPT plans. The IMPT also showed a tendency to reduce the V20 (P = 0.05) and V30 (P = 0.05) of the Ipsilateral Lung. But there was no significant difference in target coverage, homogeneity, and conformity between the IMRT and IMPT plans. Conclusion: Compared to IMRT, the IMPT using pencil beam scanning technology can spare OARs without compromising target coverage in BC patients undergoing HF-WBI, which potentially reduce the incidence of radiation-related adverse effects and thus may positively impact long-term survival

Neurogenesis is enhanced by stroke in multiple new stem cell niches along the ventricular system at sites of high BBB permeability

AbstractPrevious studies have established the subventricular (SVZ) and subgranular (SGZ) zones as sites of neurogenesis in the adult forebrain (Doetsch et al., 1999a; Doetsch, 2003a). Work from our laboratory further indicated that midline structures known as circumventricular organs (CVOs) also serve as adult neural stem cell (NSC) niches (Bennett et al., 2009, 2010). In the quiescent rat brain, NSC proliferation remains low in all of these sites. Therefore, we recently examined whether ischemic stroke injury (MCAO) or sustained intraventricular infusion of the mitogen bFGF could trigger an up-regulation in NSC proliferation, inducing neurogenesis and gliogenesis. Our data show that both stroke and bFGF induce a dramatic and long-lasting (14day) rise in the proliferation (BrdU+) of nestin+Sox2+GFAP+ NSCs capable of differentiating into Olig2+ glial progenitors, GFAP+nestin-astrocyte progenitors and Dcx+ neurons in the SVZ and CVOs. Moreover, because of the upsurge in NSC number, it was possible to detect for the first time several novel stem cell niches along the third (3V) and fourth (4V) ventricles. Importantly, a common feature of all brain niches was a rich vasculature with a blood–brain-barrier (BBB) that was highly permeable to systemically injected sodium fluorescein. These data indicate that stem cell niches are more extensive than once believed and exist at multiple sites along the entire ventricular system, consistent with the potential for widespread neurogenesis and gliogenesis in the adult brain, particularly after injury. We further suggest that because of their leaky BBB, stem cell niches are well-positioned to respond to systemic injury-related cues which may be important for stem-cell mediated brain repair

Structural Basis for Calmodulin as a Dynamic Calcium Sensor

Calmodulin is a prototypical and versatile Ca2+ sensor with EF-hands as its high-affinity Ca2+ binding domains. Calmodulin is present in all eukaryotic cells, mediating Ca2+-dependent signaling. Upon binding Ca2+, calmodulin changes its conformation to form complexes with a diverse array of target proteins. Despite a wealth of knowledge on calmodulin, little is known on how target proteins regulate calmodulin’s ability to bind Ca2+. Here, we take advantage of two splice variants of SK2 channels, which are activated by Ca2+-bound calmodulin, but show different sensitivity to Ca2+ for their activation. Protein crystal structures and other experiments show that depending on which SK2 splice variant it binds to calmodulin adopts drastically different conformations with different affinities for Ca2+ at its C-lobe. Such target protein induced conformational changes make calmodulin a dynamic Ca2+ sensor, capable of responding to different Ca2+ concentrations in cellular Ca2+ signaling

Structural Basis for Calmodulin as a Dynamic Calcium Sensor

Calmodulin is a prototypical and versatile Ca2+ sensor with EF-hands as its high-affinity Ca2+ binding domains. Calmodulin is present in all eukaryotic cells, mediating Ca2+-dependent signaling. Upon binding Ca2+, calmodulin changes its conformation to form complexes with a diverse array of target proteins. Despite a wealth of knowledge on calmodulin, little is known on how target proteins regulate calmodulin’s ability to bind Ca2+. Here, we take advantage of two splice variants of SK2 channels, which are activated by Ca2+-bound calmodulin, but show different sensitivity to Ca2+ for their activation. Protein crystal structures and other experiments show that depending on which SK2 splice variant it binds to calmodulin adopts drastically different conformations with different affinities for Ca2+ at its C-lobe. Such target protein induced conformational changes make calmodulin a dynamic Ca2+ sensor, capable of responding to different Ca2+ concentrations in cellular Ca2+ signaling

Identification of Dual STRN-NTRK2 Rearrangements in a High Grade Sarcoma, With Good Clinical Response to First-Line Larotrectinib Therapy

BACKGROUND: Among the three NTRK genes, NTRK2 possesses a tremendous structural complexity and involves tumorigenesis of several types of tumors. To date, only STRN and RBPMS are identified in the fusion with NTRK2 in adult soft tissue tumors. More recently, the highly selective Trk tyrosine kinases inhibitors, including larotrectinib and entrectinib, have shown significant efficacy for treating tumors harboring NTRK fusions and were approved by FDA. CASE PRESENTATION: We report a case of sarcoma in a 35-year-old female harboring two STRN-NTRK2 gene fusions, with a good clinical response to first-line larotrectinib treatment. Core biopsy of the 16.5 cm gluteal mass showed a high-grade mesenchymal neoplasm with features reminiscent of a solitary fibrous tumor, but negative for STAT6. In-house next-generation sequencing gene fusion panel showed two in-frame STRN-NTRK2 fusions, which contain the same 5\u27 partner sequence (exon 1-3) of STRN, and the 3\u27 fusion partner starting from either the exon 15 or the exon 16 of NTRK2. Due to the large size and location of the tumor, first-line neoadjuvant therapy with larotrectinib was initiated. The patient has an excellent clinical response with an 83% tumor size reduction by imaging. The tumor was subsequently completely resected. After 130 days, larotrectinib was reinitiated for lung metastasis (up to 7 cm), and a complete resolution was achieved. When compared with NTRK1 and NTRK3, NTRK2 fusions are the least common. Of note, the only other report in the literature on NRTK2 fusion-positive sarcoma also showed solitary fibrous tumor (SFT)-like morphology, and the patient responded well to larotrectinib as the second line adjuvant therapy. CONCLUSIONS: In conclusion, the identification of NTRK2 fusions in patients with soft tissue tumors could significantly improve the clinical outcome through selective NTRK inhibitor therapy, especially in the first-line setting. Prompt RNA-based NGS testing at initial diagnosis may benefit these patients. Our case is among the first few in the literature on NTRK2 fusion sarcoma with first-line larotrectinib therapy in the primary and metastatic setting, with good clinical response and minimal side effects

Challenges and benefits of implementing DIBH for breast cancer radiotherapy: Experiences from Guangzhou Concord Cancer Center

Radiation therapy is used for breast cancer treatments to improve local control and overall survival but may also lead to unwanted complications such as cardiac toxicity and pneumonitis. Deep inspirational breath hold (DIBH) has been used to reduce doses to the heart and other organs near the treatment target to lower the risk of radiation-induced complications. In this study, we present our experience on the clinical implementation and application of DIBH for breast cancer patients, its dosimetric benefits in heart and other organ sparing based on comparisons with free breathing plans, effects on the treatment efficiency as represented by treatment imaging, and beam delivery times, as well as challenges during implementation and clinical application at our center

Classic and novel stem cell niches in brain homeostasis and repair

AbstractNeural stem cells (NSCs) critical for the continued production of new neurons and glia are sequestered in distinct areas of the brain called stem cell niches. Until recently, only two forebrain sites, the subventricular zone (SVZ) of the anterolateral ventricle and the subgranular zone (SGZ) of the hippocampus, have been recognized adult stem cell niches (Alvarez-Buylla and Lim, 2004; Doetsch et al., 1999a, 1999b; Doetsch, 2003a, 2003b; Lie et al., 2004; Ming and Song, 2005). Nonetheless, the last decade has been witness to a growing literature suggesting that in fact the adult brain contains stem cell niches along the entire extent of the ventricular system. These niches are capable of widespread neurogenesis and gliogenesis, particularly after injury (Barnabé-Heider et al., 2010; Carlén et al., 2009; Decimo et al., 2012; Lin et al., 2015; Lindvall and Kokaia, 2008; Robins et al., 2013) or other inductive stimuli (Bennett et al., 2009; Cunningham et al., 2012; Decimo et al., 2011; Kokoeva et al., 2007, 2005; Lee et al., 2012a, 2012b; Migaud et al., 2010; Pencea et al., 2001b; Sanin et al., 2013; Suh et al., 2007; Sundholm-Peters et al., 2004; Xu et al., 2005; Zhang et al., 2007). This review focuses on the role of these novel and classic brain niches in maintaining adult neurogenesis and gliogenesis in response to normal physiological and injury-related pathological cues.This article is part of a Special Issue entitled SI: Neuroprotection

Dosimetric comparison of intensity-modulated proton radiotherapy versus intensity-modulated photon-based radiotherapy for breast cancer

Purpose: This study aims to compare the dosimetric differences in intensity-modulated proton therapy (IMPT) using pencil beam scanning technology and intensity-modulated photon-based radiotherapy (IMRT) in hypofractionated whole-breast irradiation (HF-WBI) and find out the more beneficial technique. Methods and Materials: Eight breast cancer (BC) patients with pathological stage T1 ~ 2N0M0 were immobilized and underwent 4D-CT scanning used deep inspiration breath-hold (DIBH) technology. The IMPT and IMRT plans were designed for each patient. The IMPT plans used two en-face beam angles. IMRT plans were designed using the field in field technique. The optimization constraints of the two types of plans were identical. Prescription dose and regimen was 40.05 Gy (relative biological effect [RBE])/15 fx with a 10 Gy (RBE)/5 fx boost, five fractions a week. A dose of 95% of the target volume should not be less than the prescribed dose. The target coverage was evaluated using D1, D2, D50, D95, D98, and D99. The target dose distribution and conformity were evaluated using the Conformity index (CI) and the homogeneity index (HI). The Organs at risk (OARs) were evaluated using mean dose (Dmean) and maximum dose (Dmax). Ipsilateral Lung and Contralateral Lung were evaluated additionally using V5, V10, V20, V30. Results: The mean dose (Dmean) of the Heart (P = 0.012), Ipsilateral Lung (P = 0.036), Contralateral Lung (P = 0.012), and Spinal Cord (P = 0.012) were significantly reduced in IMPT plans. The IMPT also showed a tendency to reduce the V20 (P = 0.05) and V30 (P = 0.05) of the Ipsilateral Lung. But there was no significant difference in target coverage, homogeneity, and conformity between the IMRT and IMPT plans. Conclusion: Compared to IMRT, the IMPT using pencil beam scanning technology can spare OARs without compromising target coverage in BC patients undergoing HF-WBI, which potentially reduce the incidence of radiation-related adverse effects and thus may positively impact long-term survival

Patient with Multiple Genetically Distinct Thyroid Nodules Including Papillary Thyroid Carcinoma Harboring Novel YWHAG-BRAF Fusion

Next-generation sequencing (NGS) analysis of thyroid samples aids in risk stratification of cytologically indeterminate nodules and contributes to our understanding of molecular mechanisms in thyroid neoplasia. Several genes, including BRAF, RAS, and EIF1AX, are known to play a role in thyroid tumorigenesis. Here we report a case of papillary thyroid carcinoma (PTC) in which a single lesion harbored a novel YWHAG-BRAF fusion and EIF1AX mutation and displayed mixed morphological findings. The patient is a 74-year-old female with multiple incidentally discovered thyroid nodules, two of which were sampled by ultrasound-guided fine needle aspiration (FNA). Cytologic diagnosis for both nodules was suspicious for follicular neoplasm (Bethesda Category IV). NGS testing of one nodule detected a novel in-frame YWHAG-BRAF fusion and a concurrent EIF1AX A113 splice mutation. The subsequent surgical resection specimen showed that this nodule exhibited two distinct morphologic patterns, conventional (classical) type and follicular variant (FV) of PTC, which were sharply demarcated and were found to harbor unique genetic alterations. Of note, this is the first report of BRAF activation through novel rearrangement with a gene encoding a 14-3-3 protein as a pathogenic factor, which underlines its significance both as a prognostic measurement and as a therapeutic target

Identification of dual STRN-NTRK2 rearrangements in a high grade sarcoma, with good clinical response to first-line larotrectinib therapy

Abstract Background Among the three NTRK genes, NTRK2 possesses a tremendous structural complexity and involves tumorigenesis of several types of tumors. To date, only STRN and RBPMS are identified in the fusion with NTRK2 in adult soft tissue tumors. More recently, the highly selective Trk tyrosine kinases inhibitors, including larotrectinib and entrectinib, have shown significant efficacy for treating tumors harboring NTRK fusions and were approved by FDA. Case presentation We report a case of sarcoma in a 35-year-old female harboring two STRN-NTRK2 gene fusions, with a good clinical response to first-line larotrectinib treatment. Core biopsy of the 16.5 cm gluteal mass showed a high-grade mesenchymal neoplasm with features reminiscent of a solitary fibrous tumor, but negative for STAT6. In-house next-generation sequencing gene fusion panel showed two in-frame STRN-NTRK2 fusions, which contain the same 5’ partner sequence (exon 1–3) of STRN, and the 3’ fusion partner starting from either the exon 15 or the exon 16 of NTRK2. Due to the large size and location of the tumor, first-line neoadjuvant therapy with larotrectinib was initiated. The patient has an excellent clinical response with an 83% tumor size reduction by imaging. The tumor was subsequently completely resected. After 130 days, larotrectinib was reinitiated for lung metastasis (up to 7 cm), and a complete resolution was achieved. When compared with NTRK1 and NTRK3, NTRK2 fusions are the least common. Of note, the only other report in the literature on NRTK2 fusion-positive sarcoma also showed solitary fibrous tumor (SFT)-like morphology, and the patient responded well to larotrectinib as the second line adjuvant therapy. Conclusions In conclusion, the identification of NTRK2 fusions in patients with soft tissue tumors could significantly improve the clinical outcome through selective NTRK inhibitor therapy, especially in the first-line setting. Prompt RNA-based NGS testing at initial diagnosis may benefit these patients. Our case is among the first few in the literature on NTRK2 fusion sarcoma with first-line larotrectinib therapy in the primary and metastatic setting, with good clinical response and minimal side effects