Diagnostic clues and more from photographs

During over 50 years of the first author’s career in neuropathology at Montefiore Medical Center in New York, we have come across certain interesting neuropathological findings. In this communication, some photographs showing macroscopic, microscopic and electron microscopic significant findings are selected to illustrate usefulness not only for the diagnosis but also for understanding of the nervous system. The six topics presented in this paper are: (i) unattached presynaptic terminals in cerebellar neuroblastoma; (ii) neurofibrillary tangle formation in the nucleus basalis of Meynert ipsilateral to a massive cerebral infarct; (iii) orderly arrangement of tumor cells in leptomeningeal carcinomatosis; (iv) interface between craniopharyngioma and brain tissue; (v) neurofibrillary tangles and Lewy bodies in a single neuron; and (vi) Cu/Zn superoxide dismutase positive Lewy body‐like hyaline inclusions in anterior horn cells in familial motor neuron diseases. Analyses of these findings are presented for an educational purpose.     

Association of p16 homozygous deletions with clinicopathologic characteristics and EGFR/KRAS/p53 mutations in lung adenocarcinoma

PURPOSE: The p16 gene is frequently inactivated in lung adenocarcinoma. In particular, homozygous deletions (HD) have been frequently detected in cell lines; however, their frequency and specificity is not well-established in primary tumors. The purpose of this study was to elucidate the prevalence and the timing for the occurrence of p16 HDs in lung adenocarcinoma progression in vivo. EXPERIMENTAL DESIGN: Multiple ligation-dependent probe amplification was used for the detection of p16 HDs in 28 primary small-sized lung adenocarcinomas and 22 metastatic lung adenocarcinomas to the brain. Cancer cells were isolated from primary adenocarcinoma specimens by laser capture microdissection. HDs were confirmed by quantitative real-time genomic PCR analysis. RESULTS: HDs were detected in 8 of 28 (29%) primary tumors, including 2 of 8 (25%) noninvasive bronchioloalveolar carcinomas, and 5 of 22 (26%) brain metastases, respectively. No significant associations were observed between p16 HDs and gender, age, smoking history, stage, and prognosis. HDs were detected with similar frequencies (17-29%) among adenocarcinomas with epidermal growth factor receptor (EGFR) mutations, with KRAS mutations, and without EGFR/KRAS mutations, and with similar frequencies (22-28%) between adenocarcinomas with and without p53 mutations. CONCLUSIONS: p16 HDs occur early in the development of lung adenocarcinomas and with similar frequencies among EGFR type, KRAS type, and non-EGFR/KRAS type lung adenocarcinomas. Tobacco carcinogens would not be a major factor inducing p16 HDs in lung adenocarcinoma progression.     

Efficacy and safety of tacrolimus as long-term monotherapy for myasthenia gravis

The objective was to evaluate the long-term efficacy and safety of tacrolimus monotherapy in myasthenia gravis (MG) patients. Immunosuppressive drug-naïve MG patients were administered tacrolimus, followed by thymectomy in some of the cases according to the clinical guideline for MG. Additional aggressive immunosuppressive therapies were allowed if the patients without thymectomy did not achieve minimal manifestation (MM) or better status after 3 weeks of tacrolimus administration or in the thymectomized patients by 1–2 weeks after the operation (i.e., 1st evaluation). Of all 14 patients included in this study, 8 of them (57%) achieved MM or better status at the 1st evaluation, and the remaining 6 (43%), who had failed to gain MM or better status at the 1st evaluation, also achieved MM or better status with 1 course of aggressive immunosuppressive therapy. The quantitative MG (QMG) scores, MG-Activities of Daily Living (ADL) scales, and anti-acetylcholine receptor (AchR) antibody levels were significantly decreased at 6 months and maintained thereafter. At the end of the follow-up period (41–70 months), all patients were in MM or better status. None of the patients experienced severe adverse effects. Our small preliminary study indicates that long-term tacrolimus monotherapy is possibly effective and safe for MG patients.     

Serum amyloid A as a useful index of disease activity in polymyalgia rheumatica]

PURPOSE: To clarify the usefulness of measuring serum amyloid A (SAA) levels in patients with polymyalgia rheumatica (PMR), we compared this parameter to C-reactive protein (CRP). SUBJECTS AND METHODS: The study included 10 patients with PMR, who could be prospectively followed up from the start of prednisolone (PSL) treatment until the CRP level decreased to 1 mg/dl or less. When the CRP level decreased, the subjects were divided into the group in which the symptom persisted (n = 6) and those in which the symptom disappeared (n = 4). RESULTS: In the group in which the symptom persisted, both CRP and SAA levels were significantly higher. When the CRP level decreased, there was no significant difference in the CRP level between the two groups. However, the mean SAA level in the group in which the symptom persisted (137.8 micrograms/ml) was significantly higher than that in the group in which the symptom disappeared (21.8 micrograms/ml). On the initial consultation, there was a positive correlation between CRP and SAA (R = 0.77). The SAA level was more sensitive than the CRP level (y = 94.899 x -51.22). When the CRP level decreased, SAA was much more sensitive (y = 222.92 x +6.9121), suggesting the usefulness of SAA after the start of PSL treatment. CONCLUSION: SAA may be a useful parameter of PMR activity.     

Marked increase in serum KL-6 and surfactant protein D levels during the first 4 weeks after treatment predicts poor prognosis in patients with active interstitial pneumonia associated with polymyositis/dermatomyositis

Objective

The aim of this study is to determine whether serum KL-6 and surfactant protein D (SP-D) levels predict the prognosis of patients with interstitial pneumonia (IP) in cases of polymyositis (PM) and dermatomyositis (DM).

Patients and methods

Fifty consecutive patients with PM (n = 17) or DM (n = 33) and active IP, 6 of whom died of respiratory failure, were enrolled in this study. Serum KL-6 and SP-D levels were measured every 2–4 weeks. Medical records were reviewed retrospectively. Univariate analyses and multivariate analyses with a logistic regression model were conducted.

Results

Serum KL-6 and SP-D levels were elevated in patients with active IP. At the time of diagnosis of active IP, the serum KL-6 level was within the normal range in 28 % of patients and the SP-D level was within the normal range in 46 % of patients. Serum KL-6 level increased up to 3 months after starting treatment and then decreased gradually to baseline, whereas SP-D level peaked within the first 4 weeks after treatment and decreased rapidly to normal levels. Patients with poor prognosis showed increases in KL-6 and SP-D levels during the first 4 weeks after treatment, which was confirmed by uni- and multivariate analyses. Comparing the marker levels at 2–4 weeks after treatment with those at 0 weeks, an increase in the ratio over 1.70 for KL-6 and over 1.75 for SP-D, and an increase in KL-6 over 850 U/ml during the first 4 weeks after treatment, were poor prognostic factors.

Conclusions

Increases in serum KL-6 and SP-D levels during the first 4 weeks after starting therapy, but not their levels at any one time point, predict poor prognosis in patients with PM/DM. When marked increases of KL-6 and SP-D levels during the first 4 weeks are found or are predicted by serial measurement of the markers, patients have risks of poor prognosis and additional therapy should be considered.     

Treatment of primary intraocular lymphoma with intravitreal methotrexate

PURPOSE: To report the efficacy of intravitreal chemotherapy for primary intraocular lymphoma (PIOL). METHODS: Retrospective, noncomparative interventional case reports are presented for six patients (ten eyes; mean age, 58.8 years) with pathologically confirmed PIOL who participated in this study and were treated at our hospital with intravitreal injections of methotrexate (MTX) between January 2004 and February 2007. Intravitreal injections of MTX (400 mug MTX/50 mul Opeguard-MA) were administered once or twice weekly for 1 month followed by ten monthly injections. Interleukin-10 (IL-10) and IL-6 were measured in the vitreous before and after injections to determine tumor activity. RESULTS: All eyes were clinically cleared of malignant cells. One eye lost vision. After intravitreal chemotherapy, the vitreous IL-10 concentration reached barely detectable levels. CONCLUSIONS: Intravitreal chemotherapy achieves clinical remission and preserves vision in patients with PIOL.     

Effects of oblique muscle surgery on the rectus muscle pulley

Purpose  

To determine the position of rectus muscle pulleys in Japanese eyes and to evaluate the effect of oblique muscle surgery on rectus muscle pulleys.     

Ependymoma‐like tumor with mesenchymal differentiation harboring C11orf95‐NCOA1/2 or ‐RELA fusion: A hitherto unclassified tumor related to ependymoma

Recurrent fusion genes involving C11orf95, C11orf95‐RELA, have been identified only in supratentorial ependymomas among primary CNS tumors. Here, we report hitherto histopathologically unclassifiable high‐grade tumors, under the tentative label of “ependymoma‐like tumors with mesenchymal differentiation (ELTMDs),” harboring C11orf95‐NCOA1/2 or ‐RELA fusion. We examined the clinicopathological and molecular features in five cases of ELTMDs. Except for one adult case (50 years old), all cases were in children ranging from 1 to 2.5 years old. All patients presented with a mass lesion in the cerebral hemisphere. Histologically, all cases demonstrated a similar histology with a mixture of components. The major components were embryonal‐appearing components forming well‐delineated tumor cell nests composed of small uniform cells with high proliferative activity, and spindle‐cell mesenchymal components with a low‐ to high‐grade sarcoma‐like appearance. The embryonal‐appearing components exhibited minimal ependymal differentiation including a characteristic EMA positivity and tubular structures, but histologically did not fit with ependymoma because they lacked perivascular pseudorosettes, a histological hallmark of ependymoma, formed well‐delineated nests, and had diffuse and strong staining for CAM5.2. Molecular analysis identified C11orf95‐NCOA1, ‐NCOA2, and ‐RELA in two, one, and two cases, respectively. t‐distributed stochastic neighbor embedding analysis of DNA methylation data from two cases with C11orf95‐NCOA1 or ‐NCOA2 and a reference set of 380 CNS tumors revealed that these two cases were clustered together and were distinct from all subgroups of ependymomas. In conclusion, although ELTMDs exhibited morphological and genetic associations with supratentorial ependymoma with C11orf95‐RELA, they cannot be regarded as ependymoma. Further analyses of more cases are needed to clarify their differences and similarities.