Predicting loss of independence and mortality in frontotemporal lobar degeneration syndromes.

OBJECTIVE: To test the hypothesis that in syndromes associated with frontotemporal lobar degeneration, behavioural impairment predicts loss of functional independence and motor clinical features predict mortality, irrespective of diagnostic group. METHODS: We used a transdiagnostic approach to survival in an epidemiological cohort in the UK, testing the association between clinical features, independence and survival in patients with clinical diagnoses of behavioural variant frontotemporal dementia (bvFTD n=64), non-fluent variant primary progressive aphasia (nfvPPA n=36), semantic variant primary progressive aphasia (svPPA n=25), progressive supranuclear palsy (PSP n=101) and corticobasal syndrome (CBS n=68). A principal components analysis identified six dimensions of clinical features. Using Cox proportional hazards and logistic regression, we identified the association between each of these dimensions and both functionally independent survival (time from clinical assessment to care home admission) and absolute survival (time to death). Analyses adjusted for the covariates of age, gender and diagnostic group. Secondary analysis excluded specific diagnostic groups. RESULTS: Behavioural disturbance, including impulsivity and apathy, was associated with reduced functionally independent survival (OR 2.46, p<0.001), even if patients with bvFTD were removed from the analysis. Motor impairments were associated with reduced absolute survival, even if patients with PSP and CBS were removed from the analysis. CONCLUSION: Our results can assist individualised prognostication and planning of disease-modifying trials, and they support a transdiagnostic approach to symptomatic treatment trials in patients with clinical syndromes associated with frontotemporal lobar degeneration.

Redefining the multidimensional clinical phenotypes of frontotemporal lobar degeneration syndromes.

The syndromes caused by frontotemporal lobar degeneration have highly heterogeneous and overlapping clinical features. There has been great progress in the refinement of clinical diagnostic criteria in the past decade, but we propose that a better understanding of aetiology, pathophysiology and symptomatic treatments can arise from a transdiagnostic approach to clinical phenotype and brain morphometry. In a cross-sectional epidemiological study, we examined 310 patients with a syndrome likely to be caused by frontotemporal lobar degeneration, including behavioural variant frontotemporal dementia, non-fluent, and semantic variants of primary progressive aphasia (PPA), progressive supranuclear palsy and corticobasal syndrome. We included patients with logopenic PPA and those who met criteria for PPA but not a specific subtype. To date, 49 patients have a neuropathological diagnosis. A principal component analysis identified symptom dimensions that broadly recapitulated the core features of the main clinical syndromes. However, the subject-specific scores on these dimensions showed considerable overlap across the diagnostic groups. Sixty-two per cent of participants had phenotypic features that met the diagnostic criteria for more than one syndrome. Behavioural disturbance was prevalent in all groups. Forty-four per cent of patients with corticobasal syndrome had progressive supranuclear palsy-like features and 30% of patients with progressive supranuclear palsy had corticobasal syndrome-like features. Many patients with progressive supranuclear palsy and corticobasal syndrome had language impairments consistent with non-fluent variant PPA while patients with behavioural variant frontotemporal dementia often had semantic impairments. Using multivariate source-based morphometry on a subset of patients (n = 133), we identified patterns of covarying brain atrophy that were represented across the diagnostic groups. Canonical correlation analysis of clinical and imaging components found three key brain-behaviour relationships, with a continuous spectrum across the cohort rather than discrete diagnostic entities. In the 46 patients with follow-up (mean 3.6 years) syndromic overlap increased with time. Together, these results show that syndromes associated with frontotemporal lobar degeneration do not form discrete mutually exclusive categories from their clinical features or structural brain changes, but instead exist in a multidimensional spectrum. Patients often manifest diagnostic features of multiple disorders while deficits in behaviour, movement and language domains are not confined to specific diagnostic groups. It is important to recognize individual differences in clinical phenotype, both for clinical management and to understand pathogenic mechanisms. We suggest that a transdiagnostic approach to the spectrum of frontotemporal lobar degeneration syndromes provides a useful framework with which to understand disease aetiology, progression, and heterogeneity and to target future treatments to a higher proportion of patients.

Proton magnetic resonance spectroscopy in frontotemporal lobar degeneration-related syndromes.

There is an urgent need for a better understanding of the pathophysiology of cognitive impairment in syndromes associated with frontotemporal lobar degeneration. Here, we used magnetic resonance spectroscopy to quantify metabolite deficits in sixty patients with a clinical syndrome associated with frontotemporal lobar degeneration (behavioral variant frontotemporal dementia n = 11, progressive supranuclear palsy n = 26, corticobasal syndrome n = 11, primary progressive aphasias n = 12), and 38 age- and sex-matched healthy controls. We measured nine metabolites in the right inferior frontal gyrus, superior temporal gyrus and right primary visual cortex. Metabolite concentrations were corrected for age, sex, and partial volume then compared with cognitive and behavioral measures using canonical correlation analysis. Metabolite concentrations varied significantly by brain region and diagnosis (region x metabolite x diagnosis interaction F(64) = 1.73, p < 0.001, corrected for age, sex, and atrophy within the voxel). N-acetyl aspartate and glutamate concentrations were reduced in the right prefrontal cortex in behavioral variant frontotemporal dementia and progressive supranuclear palsy, even after partial volume correction. The reduction of these metabolites was associated with executive dysfunction and behavioral impairment (canonical correlation analysis R = 0.85, p < 0.001).

A 20-year retrospective study of small-cell carcinomas in Taiwan.

BACKGROUND AND OBJECTIVES: Small-cell carcinomas (SCC) develop most commonly in the lung (small-cell lung carcinoma, SCLC) and only small percentages are present at extra-pulmonary sites. This study aimed to examine the distribution, treatment, and survival of SCCs. METHODS: The records for 922 SCC cases of various origins between January 1989 and December 2008 were retrieved and analyzed. RESULTS: The lung (89.2%) was the most common location, followed by the esophagus (1.8%), urinary bladder (1.6%), uterine cervix (1.5%), colorectum (1.4%), skin (1.0%), stomach (0.9%), head and neck (0.7%), prostate (0.3%), and small intestine (0.1%). Limited disease (LD) SCLC patients underwent surgery and chemotherapy had significantly higher survival rates than those who received chemotherapy alone, those who underwent combined radiotherapy and chemotherapy, and those who were administered supportive treatment. Actuarial 1-, 2-, and 3-year survival rate was 28.9%, 9.4%, and 4.8% for total SCLC cases, 41.3%, 17.5%, and 9.6% for LD-SCLC patients, and 21.9%, 4.2%, and 1.8% for extensive disease (ED)-SCLC patients (P < 0.001). The survival rates for lung and stomach SCC patients with LD were significantly better than for patients with ED; cervical SCC stages I and IIa patients had better survival rates than patients with stage IIb and above (P = 0.034). CONCLUSION: The lung was the most common location of SCCs, with 9.3% of cases being extra-pulmonary in origin. The need for combined surgery and chemotherapy in LD-SCLC patients deserves further evaluation.

Racial differences in compliance with NCEP-II recommendations for secondary prevention at a Veterans Affairs medical center.

OBJECTIVE: The current NCEP-II guidelines recommend that secondary prevention patients should lower their LDL-cholesterol (LDL-C) below 100 mg/dL. We implemented a Lipid Management Program to aggressively achieve this goal. We report on the impact of this intervention on compliance rates for African Americans (AA) vs Whites (W) treated with an HMG-Co-A reductase inhibitor for secondary prevention at the veterans affairs hospital. METHODS: We reviewed all patients with coronary artery disease (CAD) and/or diabetes mellitus (DM) at our institution on monotherapy with an HMG-Co-A reductase inhibitor in 1999. We examined the initial and post intervention lipid profiles for both races. RESULTS: The groups differed in that compared to the Whites, the AA were younger (65.8 vs 71.4, P = .0001); had a higher prevalence of type 2 DM (70.1% vs 40.8%, P = .001), had more obesity (57.5% vs 41.0%, P = .001), and were more likely to smoke (42.5% vs 9.6%, P = .001). AA had more clinic visits (5.04/pt vs 3.95/pt, P = .0001) and fasting lipid profiles (4.46/pt vs 3.0/pt, P = .0001). There was no difference in the prevalence of hypertension or HMG-CoA reductase inhibitor dose. AA were less likely to achieve the goal for LDL-C recommended by NCEP-II (40.94% vs 56.9%, P = .001). CONCLUSION: Despite equivalent doses of statin, AA were less likely to meet NCEP-II recommendations. This occurred even though AA had more clinic visits and lipid profiles. Our intervention did not narrow this racial gap in compliance rates. Possible explanations include: 1) variations in patient compliance; 2) impact of differences in lifestyle (DM, obesity, and smoking); and 3) the need for more intensive drug therapy in patients starting with a higher baseline LDL-C.

Parosteal osteosarcoma of the mastoid bone following radiotherapy for nasopharyngeal carcinoma.

Radiation-induced tumors subsequent to nasopharyngeal carcinoma are very rare. To date, no post-irradiation parosteal osteosarcoma of the craniofacial bone has been reported in the English literature. In October 2000, a 57-year-old Chinese woman presented 5 years after radiotherapy for nasopharyngeal carcinoma with a 6-month history of a gradually enlarging left postauricular mass. CT scans revealed a densely calcified mass with radiating bony spicules, applied to left mastoid tip. The lesion was excised en-bloc through a postauricular incision. The histologic diagnosis was a parosteal osteosarcoma. Because of inadequate safe margins and the patient refusal of another surgery, 6600 cGy of radiation was subsequently administered to the temporal bone. Post-operative follow-up in 3 years was negative for any evidence of tumor recurrence and post-irradiation complications.

Head and neck large cell neuroendocrine carcinoma should be separated from atypical carcinoid on the basis of different clinical features, overall survival, and pathogenesis.

According to the 2005 World Health Organization classification of head and neck tumors, neuroendocrine tumors can be subdivided into typical carcinoid, atypical carcinoid, and small cell carcinoma. Similar tumors diagnosed as large cell neuroendocrine carcinomas (LCNECs) in the lung are diagnosed as atypical carcinoids in the head and neck region. We studied neuroendocrine tumors and analyzed whether LCNEC should be separated from atypical carcinoid in the head and neck region. Twenty-three cases of primary head and neck neuroendocrine tumors were included and subdivided into typical carcinoid, atypical carcinoid, and small cell carcinoma according to the 2005 World Health Organization guidelines, and then LCNECs were separated from atypical carcinoids according to modified criteria using the Ki-67-labeling index and mitotic count. Clinical information and survival data were obtained, and immunohistochemical studies for p53 were conducted. The 5-year survival rates for the 2 typical carcinoids, 7 atypical carcinoids, 7 LCNECs, and 7 small cell carcinomas were 100.0%, 83.3%, 21.4%, and 20.8%, respectively (P=0.032). The LCNEC patients were older (mean age, 61 vs. 41 y; P=0.038), more commonly in advanced stage (stages III and IV 100% vs. 28.6%, P=0.01), with a poorer prognosis (5-year survival 21.4% vs. 83.3%, P=0.03), and more commonly had tumors overexpressing p53 (85.7% vs. 0%, P=0.005) as compared with atypical carcinoid patients. LCNECs should be separated from atypical carcinoids as a new entity of neuroendocrine carcinoma in the head and neck region. The new classification may provide better risk stratification and useful information for proper treatment.

Small cell carcinomas in gastrointestinal tract: immunohistochemical and clinicopathological features.

AIMS: To test the incidence of the expression of the immunohistochemical markers that aid diagnosis of gastrointestinal tract small cell carcinoma (GI-SmCC) and to evaluate the incidence of mixed endocrine-exocrine carcinomas in GI-SmCC. METHODS: Immunohistochemical studies of three antibodies against epithelial markers (CK8, AE1/AE3, EMA), four neuroendocrine differentiation markers (synaptophysin (Syn), neuron specific enolase (NSE), neuronal cell adhesion molecules (CD56), chromogranin A (CgA)), and a transcription factor (thyroid transcription factor 1 (TTF-1)) were performed. The incidence of non-endocrine carcinoma component was evaluated in 42 GI-SmCCs (11 in the oesophagus, 15 in the stomach, 15 in the colon, and 1 in the small intestine). RESULTS: The percentages of GI-SmCC with positive immunoreactivity were: CK8 92.9%, AE1/AE3 76.2%, EMA 71.4%, Syn 100%, NSE 100%, CD56 90.5%, CgA 61.9%, TTF-1 21.4%. The low molecular weight cytokeratin CK8 is more commonly expressed in GI-SmCC than is the expression of AE1/AE3 or EMA. Synaptophysin and NSE are expressed in all GI-SmCCs studied. Non-endocrine carcinoma components were demonstrated in 8 patients (4 in the oesophagus and 4 in the stomach). CONCLUSION: In detecting GI-SmCC, epithelial marker CK8 is more sensitive than AE1/AE3 or EMA, and neuroendocrine differentiation markers synaptophysin and NSE are the most useful markers. TTF-1 positivity is not uncommon in GI-SmCC, but cases with negative TTF-1 staining may indicate an extra-pulmonary primary. Non-endocrine carcinoma components were demonstrated in about 30% of oesophagus and stomach SmCC; the neoplasms should be diagnosed as mixed endocrine-exocrine carcinoma.

A 35-year retrospective study of carcinoid tumors in Taiwan: differences in distribution with a high probability of associated second primary malignancies.

BACKGROUND: A comprehensive study of carcinoid tumors from United States-based databases indicated that the small intestine, colon, rectum, and bronchopulmonary system are common locations for carcinoid tumors. In addition, certain carcinoid tumors, such as rectal carcinoids, appeared to be overrepresented in nonwhite populations in the United States. High frequencies of associated noncarcinoid malignancies were reported in some articles. The objective of the current study was to address the organ distribution, frequency of metastasis, and survival rates of carcinoid tumors and the associated noncarcinoid tumors in Taiwanese, Asian populations. METHODS: Two hundred twenty-eight patients with carcinoid tumors were identified and evaluated from the surgical pathology files and medical records of the Veterans General Hospital, Taipei, Taiwan from January 1970 to December 2005. RESULTS: In 228 carcinoid tumors that were analyzed, the rectum (60.5%) was the most common location followed by the lung (20.2%) and the thymus (6.6%). Metastatic lesions were demonstrated in 16.2% of patients. Disease extent was associated with survival. The 5-year survival rates for patients with localized, regional metastatic, and distant metastatic disease were 94.1%, 49.1%, and 0%, respectively (P< .001). Associated noncarcinoid malignancies were noted in 14% of patients with carcinoids, mainly in the gastrointestinal tract (52.9%), lung, and genitourinary system. CONCLUSIONS: A different organ distribution of carcinoids was observed in Taiwanese patients, who had with significantly more carcinoids located in the rectum and thymus compared with patients in Western countries. The patients with carcinoids in the current study had a high possibility of developing associated, noncarcinoid neoplasms. Surveillance of the colon, stomach, lung, and genitourinary system for second malignant tumors is recommended.