Michael E. Zapadka

Angiotensin‐(1‐7) attenuates metastatic prostate cancer and reduces osteoclastogenesis

Angiotensin‐(1‐7) [Ang‐(1‐7)] is an endogenous, heptapeptide hormone with anti‐proliferative and anti‐angiogenic properties. The primary objective of this study was to determine whether Ang‐(1‐7) effectively reduces prostate cancer metastasis in mice.

Increased corpus callosum volume in children with chromosome 22q11.2 deletion syndrome is associated with neurocognitive deficits and genetic polymorphisms

Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with neurocognitive impairments. The neural substrates of cognitive impairments in 22q11DS remain poorly understood. Because the corpus callosum (CC) is found to be abnormal in a variety of neurodevelopmental disorders, we obtained volumetric measurements of the CC and its subregions, examined the relationship between these regions and neurocognition and selected genotypes within candidate genes in the 22q11.2 interval in 59 children with 22q11DS and 53 control subjects. The total CC, splenium and genu were significantly larger in children with 22q11DS and the enlargement was associated with better neurocognitive functioning in the 22q11DS group, suggestive of a compensatory increase in the CC volumes. The expected age-related increase in the volume of the CC was not seen in children with 22q11DS, indicative of dysmaturation of the CC in these children. The increased volumes in the genu, splenium and total CC in the 22q11DS group were associated with polymorphisms within the candidate genes: COMT (rs4680), ZDHHC8 (rs175174) and UFD1L (rs5992403). These findings indicate that alterations in the CC volume in children with 22q11DS are associated with cognition and specific genotypes in the 22q11.2 interval.

Altered Development of the Dorsolateral Prefrontal Cortex in Chromosome 22q11.2 Deletion Syndrome: An In Vivo Proton Spectroscopy Study

BACKGROUND Chromosome 22q11.2 deletion syndrome (22q11DS), the most common microdeletion in humans, is associated with multiple medical features, almost universal cognitive deficits, and a high risk of schizophrenia. The metabolic basis of the psychological/psychiatric features is not well understood. Volumetric brain imaging studies have shown that gray matter abnormalities in the dorsolateral prefrontal cortex (DLPFC), an area that is believed to be integral for higher neurocognition, as well as being involved in schizophrenia, are associated with the psychological manifestations. However, studies have not characterized any possible metabolite alterations within the DLPFC of children with 22q11DS and their correlations with the psychological findings. METHODS We conducted a short echo time, single-voxel, in vivo proton spectroscopy study involving children with 22q11DS (n = 26) and matched control subjects (n = 23). RESULTS Absolute N-acetylaspartate (NAA) levels from the DLPFC were significantly elevated in children with 22q11DS compared with control subjects and the elevations were associated with poor global functioning and higher rates of comorbid attention-deficit/hyperactivity disorder. Children with 22q11DS had a lack of an age-associated decrease in NAA levels, a trend seen in the control subjects. However, the results did not remain statistically significant after corrections for multiple comparisons were made. CONCLUSIONS These findings represent the first report of proton spectroscopy in children with 22q11DS. The elevated DLPFC NAA levels and the lack of decreasing trends in NAA with age in the 22q11DS group relative to control subjects suggest an alteration in cortical development. Also, such neuronal dysmaturation is associated with psychopathology in children with 22q11DS.

Radiation-induced adult medulloblastoma: a two-case report and review of the literature

Radiation-induced medulloblastoma is an exceedingly rare phenomenon for which treatment standards have not been established. The literature suggests that these tumors are high grade with aggressive behavior. We report two cases of radiation-induced medulloblastoma which have been treated with full dose re-irradiation with curative intent. In both cases, treatment toxicity and tumor progression proved to be insurmountable obstacles. Further reports are necessary in order to fully characterize this clinical entity so that more effective therapies may be sought.

Arterial spin labeling perfusion imaging demonstrates cerebral hyperperfusion in anti-NMDAR encephalitis

Anti-N-methyl-d-aspartate receptor encephalitis is an increasingly recognized autoimmune disorder that results in substantial morbidity, prolonged hospital stays, and even death. The diagnosis is often delayed or unrecognized entirely as a result of absent or only subtle initial magnetic resonance imaging findings and a nonspecific clinical syndrome. The discovery of early imaging findings in this disease may help clinicians to more aggressively treat this autoimmune encephalitis and to potentially lessen morbidity and mortality. We report a novel case of anti-N-methyl-d-aspartate receptor encephalitis characterized by early evidence of increased cerebral perfusion on arterial spin labeling perfusion imaging, a finding that preceded laboratory diagnosis and conventional magnetic resonance imaging abnormalities. Further investigation is needed to firmly establish the pathologic basis of this finding.

A 6-Year-Old Girl with Fever, Rash, and Increased Intracranial Pressure

BACKGROUND Rocky Mountain spotted fever (RMSF) is a well-described, potentially lethal, tick-borne zoonotic infection and has very effective therapy. However, the diagnosis might not be made early enough, often leading to worse outcomes. OBJECTIVE Our aim was to discuss the diagnostic dilemmas facing the physician when evaluating patients with suspected RMSF. METHODS We report a case of RMSF in a 6-year-old girl who presented to our hospital with a 7-day history of fever, headache, and a petechial rash. After blood cultures were obtained, the patient was treated empirically with doxycycline, vancomycin, and ceftriaxone. During the next 24 h, her clinical status worsened, with acute onset of altered mental status, posturing, and fixed and dilated pupils. A computed tomography scan of the brain demonstrated diffuse cerebral edema with evidence of tonsillar herniation. She died 24 h after admission. A serum specimen tested positive for immunoglobulin G to Rickettsia rickettsii at a titer of 128 dilutions, confirming recent infection. CONCLUSIONS We present this case to raise awareness of RMSF in patients who present with a nonspecific febrile illness in tick-endemic areas in the United States. Early diagnosis and treatment with doxycycline before day 5 of illness is essential and can prevent morbidity and mortality.

High resolution T2 MRI in the diagnosis of cerebellopontine angle and internal auditory canal lesions

High resolution T2 magnetic resonance imaging (MRI) can provide exquisite detail of internal auditory canal (IAC) and cerebellopontine angle (CPA) lesions. In this retrospective case series, blinded imaging sequences were delivered to three radiologists and compared with previously archived clinical reads that were non-blinded and incorporated both T1+C and T2 sequences together. This article demonstrates high sensitivity and specificity for high resolution T2 MRI particularly with lesions >5mm. This suggests a role for high resolution T2 MRI as an initial screening sequence or as a surveillance sequence.

Accelerated Unilateral Radiographic Huntingtonian Changes Following Neoadjuvant Chemotherapy for a Nongerminomatous Germ Cell Tumor Leading to Identification of Occult Disease in the Dorsal Striatum.

Basal ganglia nongerminomatous germ cell tumors comprise 10% to 15% of germ cell tumor and have substantial morbidity at the time of local failure. In this submitted image we present a case where neoadjuvant chemotherapy unmasked a unilateral caudate head loss consistent with Huntingtonian changes. Careful review of the patient’s imaging identified disease within the dorsal striatum that was not previously identified at the time of diagnosis. Review of the diffusion tensor fractional anisotropy imaging identified progressive white matter likely secondary to the occult disease within the dorsal striatum. Although this patient was asymptomatic and had no signs of a movement disorder, similar findings have been noted to be a prelude to such findings several months later. The occult disease was incorporated into the patient’s radiotherapy planning target volume as oversight of these changes would have led to a marginal miss and potential early disease relapse.

Abstract 550: Angiotensin-(1-7) inhibits prostate cancer angiogenesis and metastasis to bone

Prostate cancer is the most frequently diagnosed malignancy and the second-leading cause of cancer death in men. We previously showed that angiotensin-(1-7) [Ang-(1-7)], a seven amino acid peptide hormone, significantly inhibited the growth of human lung cancer cells and tumors, with an associated reduction in angiogenesis. Since previous epidemiological studies suggest that administration of anti-hypertensive drugs which increase Ang-(1-7) reduces the risk of sex-specific cancers, we investigated the effects of the heptapeptide on prostate cancer. Ang-(1-7) markedly reduced human LNCaP prostate tumor xenograft size by 72% in association with a decrease in Ki67 and CD34, markers of tumor proliferation and angiogenesis, respectively. Ang-(1-7) significantly decreased both vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) with a concomitant 12-fold increase in the soluble fraction of VEGF receptor 1 (sFlt-1); sFlt-1 is a decoy receptor that traps PlGF and VEGF, rendering the ligands unavailable to membrane-associated VEGF receptors. Ang-(1-7) also inhibits metastasis of prostate cancer to bone, which is the primary cause of mortality in prostate cancer patients. Human prostate cancer cells were injected into the circulation of SCID mice pretreated with Ang-(1-7), to determine the effect of the heptapeptide on the migration of cells to the metastatic environment. Six weeks following the injection of stably transfected luciferase tagged PC3 (PC3Luc) cells, 5 of the 6 untreated mice developed metastatic bone tumors, measured by bioluminescence and MRI imaging; in contrast, no detectable tumors were observed in mice administered Ang-(1-7). Circulating VEGF was significantly higher in untreated mice compared to mice treated with the heptapeptide. Ang-(1-7) also significantly reduced metastatic tumor formation in athymic mice injected with PC3Luc cells in the tibia as determined by bioluminescence, MRI imaging and immunohistochemistry. Osteolytic lesions as assessed by tartrate resistant acid phosphatase (TRAP) staining were observed surrounding the tibial tumors in control animals. A 50% reduction in osteoclastogenesis was observed when bone marrow cells were differentiated with RANK ligand and colony-stimulating factor in the presence of Ang-(1-7) [from 78.6 ± 8.0 TRAP+-multinucleated cells/field to 33.6 ± 4], suggesting that Ang-(1-7) hinders tumor survival in the bone microenvironment and prevents the formation of osteolytic lesions. Since VEGF is known to facilitate tumor growth and osteolytic disease by enhancing osteoclast survival, the inhibition of VEGF coupled with the reduction in osteoclastogenesis may mediate the inhibition of metastatic skeletal tumor formation. These results suggest that Ang-(1-7) may serve as an anti-proliferative, anti-angiogenic, and anti-metastatic agent for the treatment of prostate cancer that targets the tumor microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 550. doi:10.1158/1538-7445.AM2011-550