Dosimetric Analysis of Neural and Vascular Structures in Skull Base Tumors Treated with Stereotactic Radiosurgery.

Objective To examine the relationship between the prescribed target dose and the dose to healthy neurovascular structures in patients with vestibular schwannomas treated with stereotactic radiosurgery (SRS). Study Design Case series with chart review. Setting SRS center from 2011 to 2013. Subjects Twenty patients with vestibular schwannomas treated at the center from 2011 to 2013. Methods Twenty patients with vestibular schwannomas were included. The average radiation dose delivered to healthy neurovascular structures (eg, carotid artery, basilar artery, facial nerve, trigeminal nerve, and cochlea) was analyzed. Results Twenty patients with vestibular schwannomas who were treated with fused computed tomography/magnetic resonance imaging-guided SRS were included in the study. The prescribed dose ranged from 10.58 to 17.40 Gy over 1 to 3 hypofractions to cover 95% of the target tumor volume. The mean dose to the carotid artery was 5.66 Gy (95% confidence interval [CI], 4.53-6.80 Gy), anterior inferior cerebellar artery was 8.70 Gy (95% CI, 4.54-12.86 Gy), intratemporal facial nerve was 3.76 Gy (95% CI, 3.04-4.08 Gy), trigeminal nerve was 5.21 Gy (95% CI, 3.31-7.11 Gy), and the cochlea was 8.70 Gy (95% CI, 7.81-9.59 Gy). Conclusions SRS for certain vestibular schwannomas can expose the anterior inferior cerebellar artery (AICA) and carotid artery to radiation doses that can potentially initiate atherosclerotic processes. The higher doses to the AICA and carotid artery correlated with increasing tumor volume. The dose delivered to other structures such as the cochlea and intratemporal facial nerve appears to be lower and much less likely to cause immediate complications when shielded

Targeted therapies and radiation in lung cancer

SCOPUS: ch.binfo:eu-repo/semantics/publishe

Dosimetric Analysis of Neural and Vascular Structures in Skull Base Tumors Treated with Stereotactic Radiosurgery.

Objective To examine the relationship between the prescribed target dose and the dose to healthy neurovascular structures in patients with vestibular schwannomas treated with stereotactic radiosurgery (SRS). Study Design Case series with chart review. Setting SRS center from 2011 to 2013. Subjects Twenty patients with vestibular schwannomas treated at the center from 2011 to 2013. Methods Twenty patients with vestibular schwannomas were included. The average radiation dose delivered to healthy neurovascular structures (eg, carotid artery, basilar artery, facial nerve, trigeminal nerve, and cochlea) was analyzed. Results Twenty patients with vestibular schwannomas who were treated with fused computed tomography/magnetic resonance imaging-guided SRS were included in the study. The prescribed dose ranged from 10.58 to 17.40 Gy over 1 to 3 hypofractions to cover 95% of the target tumor volume. The mean dose to the carotid artery was 5.66 Gy (95% confidence interval [CI], 4.53-6.80 Gy), anterior inferior cerebellar artery was 8.70 Gy (95% CI, 4.54-12.86 Gy), intratemporal facial nerve was 3.76 Gy (95% CI, 3.04-4.08 Gy), trigeminal nerve was 5.21 Gy (95% CI, 3.31-7.11 Gy), and the cochlea was 8.70 Gy (95% CI, 7.81-9.59 Gy). Conclusions SRS for certain vestibular schwannomas can expose the anterior inferior cerebellar artery (AICA) and carotid artery to radiation doses that can potentially initiate atherosclerotic processes. The higher doses to the AICA and carotid artery correlated with increasing tumor volume. The dose delivered to other structures such as the cochlea and intratemporal facial nerve appears to be lower and much less likely to cause immediate complications when shielded

Complex Oncological Decision-Making Utilizing Fast-and-Frugal Trees in a Community Setting-Role of Academic and Hybrid Modeling.

Non-small cell lung cancer is a devastating disease and with the advent of targeted therapies and molecular testing, the decision-making process has become complex. While established guidelines and pathways offer some guidance, they are difficult to utilize in a busy community practice and are not always implemented in the community. The rationale of the study was to identify a cohort of patients with lung adenocarcinoma at a City of Hope community site (n = 11) and utilize their case studies to develop a decision-making framework utilizing fast-and-frugal tree (FFT) heuristics. Most patients had stage IV (N = 9, 81.8%) disease at the time of the first consultation. The most common symptoms at initial presentation were cough (N = 5, 45.5%), shortness of breath (N = 3, 27.2%), and weight loss (N = 3, 27.2%). The Eastern Cooperative Oncology Group (ECOG) performance status ranged from 0-1 in all patients in this study. Distribution of molecular drivers among the patients were as follows: EGFR (N = 5, 45.5%), KRAS (N = 2, 18.2%), ALK (N = 2, 18.2%), MET (N = 2, 18.2%), and RET (N = 1, 9.1%). Seven initial FFTs were developed for the various case scenarios, but ultimately the decisions were condensed into one FFT, a molecular stage IV FFT, that arrived at accurate decisions without sacrificing initial information. While these FFT decision trees may seem arbitrary to an experienced oncologist at an academic site, the simplicity of their utility is essential for community practice where patients often do not get molecular testing and are not assigned proper therapy

Class switch recombination activity in B-cell specific <i>Ssb1</i>-deleted mice.

<p><i>Ssb1 ^fl/fl</i> mice were crossed with a <i>Cd19</i>-Cre transgene expressing C57BL/6J mice to specifically delete <i>Ssb1</i> in B cells. Splenic B cells were isolated and stimulated for 2, 3, and 4 days using anti-Cd40 antibodies plus IL-4 to induce CSR to IgG1. (A) Western blotting of whole cell extracts showed loss of Ssb1 protein in stimulated B cells from <i>Ssb1</i> knockout (<i>Ssb1</i> KO; <i>Cd19</i>Cre⁺: <i>Ssb1^−/−</i>) mice. Equal amounts of stimulated B cell extracts from heterozygous <i>Ssb1</i> (<i>Ssb1</i> Het; <i>Cd19</i>Cre⁺: <i>Ssb1^+/−</i>) and wild-type <i>Ssb1</i> (<i>Ssb1</i> WT; <i>Cd19</i>Cre⁺: <i>Ssb1^+/+</i>) mice were included for comparison. Equal loading was confirmed by probing for Hsp90α. (B) Western blotting of Ssb2 levels in B cells from <i>Ssb1</i> WT and <i>Ssb1</i> KO mice. (C) FACS analysis of CSR to IgG1 over time in stimulated B cells from mice of the indicated genotypes. Stimulated splenic B cells from <i>AID^−/−</i> (<i>AID</i> KO) mice served as a negative control. (D) Summary statistics of CSR activity to IgG1 and viability on day 3 of stimulation. Mean and S.E.M. from three independent experiments are shown. No statistically significant differences (two-tailed unpaired <i>t</i>-test) were found. (E) Switch region junction analysis. Sm-Sg1 junctions were amplified from IL4 plus anti-CD40 stimulated primary B cells (day 4) and sequenced. Percentage and total numbers of direct or microhomology-mediated joints are indicated. nt, nucleotides.</p

Testicular degeneration and impaired fertility in conditional <i>Rosa26</i>-CreER^T2: <i>Ssb1</i>^−/− male mice.

<p>(A) Representative image of testes from Rosa26-CreER^T2: <i>Ssb1</i>^−/− mice compared with those from <i>Rosa26</i>-CreER^T2: <i>Ssb1^+/−</i> littermates at 10 weeks of age. (B) Testis weight and (C) the gonado-somatic index (GSI) in conditional <i>Ssb1</i> deleted male mice compared with their littermates. Data represents the mean ± SEM of testis weight (<i>n</i> = 8, <i>***P</i>&lt;0.001; student's <i>t-</i>test) and the GSI (C) from 8 mice in each group. (D) Representative images of testis sections stained with Haematoxylin and eosin (left panels) and ApopTag for the detection of apoptotic cells (right panels). Note the multinucleated giant cells (black arrow) frequently present in the lumen in the testes from <i>Rosa26</i>-CreER^T2: <i>Ssb1</i>^−/− mice. Spermatogenic cells in <i>Rosa26</i>-CreER^T2: <i>Ssb1</i>^−/− testes showed an elevated apoptotic marker (black arrows, lower panel, right, <i>Scale = 25 µm</i>). (E) Haematoxylin and eosin staining showing epididymides of <i>Rosa26</i>-CreER^T2: <i>Ssb1</i>^−/− mice containing prematurely sloughed developing germ cells. The upper panel displays maturing spermatozoa in the wild type epididymis. In contrast, immature germ cells (black arrow) are present in the epididymis of <i>Rosa26</i>-CreER^T2: <i>Ssb1</i>^−/− mice (lower panel). Embedded images in the left corners show magnified views of the selected areas <i>(Scale = 50 µm</i>). (F) Litter size from <i>Rosa26</i>-CreER^T2: <i>Ssb1</i>^−/− male breeders (<i>n</i> = 4) with wild type female mice compared with those from <i>Rosa26</i>-CreERT2: <i>Ssb1^+/−</i> breeders (<i>n</i> = 6, *<i>P</i>&lt;0.05; student's <i>t-</i>test). (G) Litter interval in <i>Rosa26</i>-CreER^T2: <i>Ssb1</i>^−/− male mice (average of 63 days, <i>n</i> = 4) and Rosa26-CreER^T2: <i>Ssb1^+/−</i> males (average of 27 days, <i>n</i> = 6, ***<i>P</i>&lt;0.001; student's <i>t-</i>test).</p

Broad tumour spectrum in conditional <i>Ssb1</i>-deleted <i>Rosa26</i>-CreER^T2: <i>Ssb1</i>^−/− mice.

<p>(A) Long time survival cohort of <i>Rosa26</i>-CreER^T2: <i>Ssb1</i>^+/− (<i>n</i> = 35) and <i>Rosa26</i>-CreER^T2: <i>Ssb1</i>^−/− (<i>n</i> = 35) mice were monitored for 86 weeks after <i>Ssb1</i> deletion for tumour development. (A) Kaplan-Meier survival analysis showed tumour free survival rate of indicated genotypes over 90 weeks (**<i>P</i>&lt;0.01). (B) Tumour incidence and a spectrum in <i>Rosa26</i>-CreER^T2: <i>Ssb1</i>^−/− mice compared with <i>Rosa26</i>-CreER^T2: <i>Ssb1</i>^+/− mice. (C) Representative sections have T lymphoma in thymus (top panel) and B lymphomas in spleen (middle panel), which spread to lung in a <i>Rosa26</i>-CreER^T2: <i>Ssb1</i>^−/− mice (bottom panel). Representative images of Haematoxylin and eosin stained sections of tumours in indicated organs are shown. Immunohistochemical staining of Cd3 (top panel, right) confirmed T-cell lymphoma in thymus <i>(Scale bars, i = 40 µm, ii = 120 µm, iii = 20 µm, iv = 40 µm, v = 60 µm, vi = 80 µm)</i>. (D) Representative image of liver cancer (hepatocellular carcinoma, HCC) in a <i>Rosa26</i>-CreER^T2: <i>Ssb1</i>^−/− mouse. Representative images of tumour mass (upper panel) and Haematoxylin and eosin-stained liver section (middle and lower panels) are shown <i>(Scale bars, ii = 100 µm, iii = 140 µm)</i>.</p

<i>Ssb1</i> deletion causes multiple skeletal defects.

<p>(A) Alcian blue and Alizarin red staining of control (<i>Ssb1</i>^+/+, <i>Ssb1</i>^+/−) and <i>Ssb1</i>^−/− E18.5 ribcages. (B) Butterfly rib-spread of <i>Ssb1</i> control and <i>Ssb1</i>^−/− E18.5 ribcages. (C) Comparison of skull anatomy of <i>Ssb1</i> control and <i>Ssb1</i>^−/− E18.5 embryos. eo, exoccipital; so, supraoccipital; ip interparietal; pr, parietal; fr, frontal; mx, maxilla; md, mandible; bo, basioccipital; ptg, pterygoid; pmx, premaxilla; ppmx, palatal process maxilla; ppp, palatal process palatine; p, palatine; tr, tympanic ring. (D) Comparison of <i>Ssb1</i> control and <i>Ssb1</i>^−/− mandibles <i>(Scale = 1 mm)</i>. (E) Forelimb and (F) Hindlimb of E18.5 <i>Ssb1</i> control and <i>Ssb1</i>^−/− embryos. Sc, scapula; H, humerus; R, radius; U, ulna; F, femur; T, tibia. * designates missing fibula. (G) Quantification of long bone measurements of the forelimb and hindlimb of <i>Ssb1</i>^+/− and <i>Ssb1</i>^−/− E18.5 limbs. Data represent the mean ± SEM of bone length (<i>n</i> = 3 per condition, ***<i>P</i>&lt;0.001, student's <i>t</i>-test). (H) Whole-autopod (top) and skeletal preparation (bottom) of E18.5 forelimbs (left) and hindlimbs (right) from <i>Ssb1</i> control and <i>Ssb1</i>^−/− embryos.</p

<i>Ssb1</i> deletion causes perinatal lethality due to severe respiratory failure.

<p>(A) Comparison of size and appearance of E14.5 and P0 <i>Ssb1^+/+</i>, <i>Ssb1^+/−</i>, and <i>Ssb1</i>^−/− offspring. Note the cyanosis in P0 <i>Ssb1</i>^−/− pups. <i>Scale = 2 mm</i>. (B) Comparison of weights of E14.5 and E18.5 <i>Ssb1^+/+</i>, <i>Ssb1 ^+/−</i> and <i>Ssb1^−/−</i> embryos. Data represent the mean ± SEM, <i>n</i> = 3–16 embryos per group from a minimum of 3 litters per timepoint (***<i>P</i>&lt;0.001; student's <i>t</i>-test). (C) Haematoxylin and eosin staining of P0 lungs of <i>Ssb1</i>^+/+, <i>Ssb1</i>^+/− and Ssb1^−/− pups delivered by caesarian section.</p