Saeed T. Vakili

Nf1-Dependent Tumors Require a Microenvironment Containing Nf1+/−- and c-kit-Dependent Bone Marrow

Interactions between tumorigenic cells and their surrounding microenvironment are critical for tumor progression yet remain incompletely understood. Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), a common genetic disorder characterized by complex tumors called neurofibromas. Genetic studies indicate that biallelic loss of Nf1 is required in the tumorigenic cell of origin in the embryonic Schwann cell lineage. However, in the physiologic state, Schwann cell loss of heterozygosity is not sufficient for neurofibroma formation and Nf1 haploinsufficiency in at least one additional nonneoplastic lineage is required for tumor progression. Here, we establish that Nf1 heterozygosity of bone marrow-derived cells in the tumor microenvironment is sufficient to allow neurofibroma progression in the context of Schwann cell Nf1 deficiency. Further, genetic or pharmacologic attenuation of c-kit signaling in Nf1+/- hematopoietic cells diminishes neurofibroma initiation and progression. Finally, these studies implicate mast cells as critical mediators of tumor initiation.

Disseminated toxoplasmosis resulting in graft failure in a cord blood stem cell transplant recipient.

Toxoplasmosis is an infrequent infection with a high mortality rate in hematopoietic stem cell transplant recipients, and is usually caused by reactivation of prior, latent infection upon intensive immunosuppression. We report a case of fatal disseminated toxoplasmosis, diagnosed at autopsy, in a 7‐year‐old boy who received a cord blood graft for recurrent acute lymphoblastic leukemia. This case represents both the first reported case of toxoplasmosis in an engrafted cord blood recipient, and also of graft failure due to toxoplasmosis. Recommendations for toxoplasmosis diagnosis, treatment, and prophylaxis in stem cell transplant recipients are reviewed. Pediatr Blood Cancer 2007;48:222–226.

Intracytoplasmic lumina in meningioma: an ultrastructural and immunohistological study.

Three surgically removed meningotheliomatous meningiomas with hyaline inclusions or pseudopsammoma bodies were studied. Ultrastructurally, the lumina seemed to be predominantly intracytoplasmic, defined by a systemic unit membrane; they displayed abundant microvilli and contained granular or filamentous material, vacuoles, vesicular bodies, and lamellar structure. The cytoplasm surrounding the intracytoplasmic lumina was electron-dense and contained tonofilaments and desmosomal junctions. All three meningiomas showed expression of carcinoembryonic antigen, cytokeratin, and epithelial membrane antigen in the cells surrounding the hyaline bodies. Keratin, alpha-1-antitrypsin, and immunoglobulin M showed weak positive staining. There was widespread vimentin except in the cells with hyaline inclusions. Glial fibrillary acidic protein and S100 were negative. These results provide additional confirmation of immunohistochemical data that can serve as evidence for epithelial and secretory differentiation in meningiomas.

Sudden unexpected death associated with atlanto-occipital fusion

A case of sudden, unexplained death in a 24-year-old male is presented. There were two previous spells of loss of consciousness. There was remarkable narrowing of the foramen magnum with indentation of the medulla. The atlas was partly fused with the occipital bone and a portion of abnormal bone compromised the foramen magnum from anterior reducing its anteroposterior dimensions to 16 mm (n 25-35 mm). Close clinical examination of this area in patients with acute intermittent symptomatology, or at the time of autopsy in cases of sudden unexpected death is stressed.

Familial oculoleptomeningeal amyloidosis associated with primary angiitis of the CNS

A 45-year-old woman related to a previously studied German family from Ohio1,2 with oculoleptomeningeal amyloidosis presented with progressive CNS dysfunction over 4 months. She was in good health until 3 years previously when she had a seizure. She remained asymptomatic until developing headache, emesis, anorexia, aphasia, facial weakness, progressive lower extremity paresthesia, weakness, and incontinence over 4 months. DNA sequence analysis showed a Val30Gly point mutation in the TTR gene, compatible with a diagnosis of oculoleptomeningeal amyloidosis in this kindred.2 Upon presentation, 4 months after onset of symptoms, she was paraplegic and reported visual impairment and bilateral deafness. Funduscopy yielded bilateral papilledema without evidence of vitreous opacities. She had weak left facial movements and upper extremities, and was unable to move her lower extremities. Muscle stretch reflexes were exaggerated in the upper extremities and absent in the lower extremities. She had no sensation below the level of T8. Intrathecal pressure was 240 mm H2O and CSF contained 170 mg/dL protein, 10 white and 14 red blood cells/μL. EMG and nerve conduction of the right arm were normal. Rectal …

Preclinical Evidence for the Use of Sunitinib Malate in the Treatment of Plexiform Neurofibromas.

Plexiform neurofibromas (pNF) are pathognomonic nerve and soft tissue tumors of neurofibromatosis type I (NF1), which are highly resistant to conventional chemotherapy and associated with significant morbidity/mortality. Disruption of aberrant SCF/c‐Kit signaling emanating from the pNF microenvironment induced the first ever objective therapeutic responses in a recent phase 2 trial. Sunitinib malate is a potent, highly selective RTK inhibitor with activity against c‐Kit, PDGFR, and VEGFR, which have also been implicated in the pathogenesis of these lesions. Here, we evaluate the efficacy of sunitinib malate in a preclinical Krox20;Nf1flox/− pNF murine model.

Amyloidoma of the Esophagus

TO THE EDITOR: We read with interest the article by Park et al. in the November issue of this journal (1). We applaud their efforts to highlight the possibility of implementing a small-caliber scope to achieve individualized and successful colonoscopy, especially with the current global need for screening for colorectal cancer. However, we would like to add constructive comments on this study. In this single-operator study, the colonoscopy withdrawal time was not mentioned. Adequate withdrawal time has been suggested to decrease the adenoma miss rate (2, 3), and at least 6 min of withdrawal time is recommended (3). In addition, the authors did not clarify whether a one-man maneuver or two-man maneuver was adopted in colonoscopic insertion, since a two-man maneuver is still popular in many Asian countries. Comparison of the use of a two-man maneuver with a standard colonoscope and the use of a one-man maneuver with an upper endoscope may exaggerate the advantage of the upper endoscope. Likewise, the question of whether a small-caliber upper endoscope (9.2 mm) can be inadvertently withdrawn faster than a large-caliber standard colonoscope (12.2 mm) remains to be answered. Another question concerns patients with past histories of abdominal or pelvic surgery. Kozarek et al. have reported the usefulness of a small-caliber endoscope after unsuccessful standard colonoscopy because of stenosis or angulation (4). It would be interesting to see the comparative performance in these specific subgroups to test a potentially beneficial role of an upper endoscope in these patients. In this study, multivariate logistic regression analysis revealed three independent predictors of painful colonoscopy: using an upper endoscope, female gender, and lower BMI. Our previous work has similarities and dissimilarities with this study (5, 6). Patient characteristics are similar and so is the number of polyps detected in each examinee (1.7 per examinee in our study) (5). In our previous prospective study on the factors determining postcolonoscopy abdominal pain (6), female gender similarly increased the likelihood of postcolonoscopy abdominal pain, as did the duration of colonoscopy. However, BMI (23.76 ± 3.29 kg/m2 in our participants) did not contribute significantly to pain in our study. A major dissimilarity is that up to 88% of our colonoscopies were under conscious sedation in a screening setting. Application of this study to all colonoscopists might have some limitations since only one operator was included (1). As cases of colorectal cancers are increasing worldwide, more studies and discussions on high-quality colonoscopy for individualized patients are certainly needed. Yet, the evidence for routine use of an upper endoscope in colonoscopy may still be too sparse to utilize. Tsung-Chun Lee, M.D.1 Han-Mo Chiu, M.D.2 Yi-Chia Lee, M.D.2 Hsiu-Po Wang, M.D.3 Shih-Pei Huang, M.D., Ph.D.2 Ming-Shiang Wu, M.D., Ph.D.2 Jaw-Town Lin, M.D., Ph.D.2 1Department of Internal Medicine National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan Departments of 2Internal Medicine and 3Emergency Medicine, National Taiwan University Hospital and College of Medicine National Taiwan University Taipei, Taiwan

Rapidly progressive AA cardiomyopathy

Cardiac involvement may occur with AA amyloidosis, but extensive deposition in the heart is rarely seen. We report a 58-year-old man who on autopsy showed massive cardiac AA amyloid deposition. He did not have history of a chronic inflammatory condition and died suddenly prior to diagnosis of amyloidosis. Autopsy revealed marked left ventricular hypertrophy. Although extensive eosinophilic deposits were present in cardiac and adrenal tissues, the deposits stained weakly with Congo red. Biochemical analysis of fibrils extracted from heart gave a protein sequence showing identity to serum amyloid A. Immunohistochemistry with anti-human AA monoclonal antibody revealed strong staining of amyloid deposits in cardiac and adrenal tissues. Based on these findings, a diagnosis of systemic AA amyloidosis was made. This case highlights the importance of considering AA amyloidosis when the causes of left ventricular hypertrophy are unknown, and demonstrates the usefulness of biochemical analysis for diagnosing amyloid type. Introduction: Systemic reactive amyloid A (AA) amyloidosis is a serious complication of chronic inflammatory diseases. AA amyloid fibrils are derived from the acute-phase reactant serum amyloid A (SAA). AA amyloidosis often affects the kidneys and gastrointestinal tracts. While cardiac involvement may occur with AA amyloidosis, extensive deposition in the heart is rarely seen. Here, we report a 58-yearold man who had no history of chronic inflammation and on autopsy showed massive cardiac AA amyloid deposition. Methods: Case history: A 58-year-old man had histories of type 2 diabetes, hypertension, and hyperlipidemia. The patient had a 4-vessel coronary artery bypass graft in 2003 and was diagnosed with congestive heart failure in June 2008. Echocardiography on 11 June 2008 demonstrated increased interventricular septum thickness (IVS) (14 mm) and left ventricular posterior wall thickness (LVPW) (15 mm). Electrocardiogram showed a marked ST elevation in the right precordial leads, and a history of syncope and family history of cardiac death were noted. Therefore a diagnosis of Brugada syndrome type 1 was made. A cardioverter defibrillator was implanted on 8 July. The patient was admitted to the hospital with abdominal pain and shortness of breath on 28 July 2008. Laboratory investigations at admission revealed increased serum levels of Creactive protein (CRP) (235.5 mg/l) and B-type natriuretic peptide (3758 pg/ml). Total protein, albumin, blood urea nitrogen, and creatinine were 7.5 g/dl, 3.9 g/dl, 27 mg/dl, and 1.0 mg/dl, respectively. There was no proteinuria by urinalysis. The patient died suddenly on 8 August 2008 prior to diagnosis. Autopsy revealed marked left ventricular hypertrophy and a heart weight of 1015 g. His IVS and LVPW were 21 mm and 22 mm, respectively. Amyloid analyses: Tissues sections were analyzed for amyloid by Congo red staining, electron microscopy, and immunohistochemistry using anti-human AA antibody generated in this laboratory. Biochemical analysis was performed on formalin-fixed, paraffin-embedded tissue scraped from slides. Tissues sections were deparaffinized in xylene and then denatured in 8 M guanidine-HCl under reducing conditions. Solubilized material was dialyzed against water and lyophilized. Isolated protein was then subjected to amino acid sequence analysis before and after trypsin digestion. Results and discussion: Cardiac and adrenal tissues contained extensive eosinophilic deposits which stained weakly with Congo red (Figure 1). Figure 1. A: Histology section of cardiac tissue stained with hematoxylin and eosin showing extensive interfiber deposition of amyloid, 6100. B: Histology section of adrenal tissue stained with hematoxylin and eosin showing extensive amyloid deposition, 6100. 203

Fatal athletic injuries

Death during athletic training or competition often brings public media attention. Recent endeavors to attract amateur athletic competitions to Marion County, Indiana prompted a review of athletic fatalities. Trauma during training, arteriosclerotic heart disease, and congenital heart defects cause most fatalities. A prospective study has been initiated to investigate and document these deaths