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Background: Mixed pathology is common at autopsy for a number of age-associated neurodegenerative disorders; however, the frequency of comorbid pathologies in multiple system atrophy (MSA) and their clinical correlations are poorly understood., Objective: We determined the frequency of comorbid pathologic processes in autopsy-confirmed MSA and assessed their clinical correlates., Methods: This study included 160 neuropathologically established MSA from the Mayo Clinic brain bank. Clinical information, including age at onset or death, clinical subtype, initial symptoms, antemortem clinical diagnosis, and cognitive dysfunction was collected. We assessed comorbid pathologies including Alzheimer's disease neuropathologic change, Lewy-related pathology, argyrophilic grain disease, age-related τ astrogliopathy, transactive DNA-binding protein 43 pathology, cerebral amyloid angiopathy, and cerebrovascular small vessel disease and examined their clinical impact., Results: The majority of MSA patients (62%) had no significant comorbid pathologies. There was a positive correlation between age at onset or death with the number of comorbid pathologies; however, even in the highest quartile group (average age at death 78 ± 6 years), the average number of comorbid pathologies was <2. Logistic regression analysis revealed that none of the assessed variables, including sex, age at onset, and the presence or absence of each comorbid pathology, were significantly associated with cognitive dysfunction., Conclusions: The majority of MSA patients do not have comorbid pathologies, even in advanced age, indicating that MSA is unique among neurodegenerative disorders in this regard. There was minimal clinical impact of comorbid pathologies in MSA. These findings warrant focusing on α-synuclein for the treatment strategy for MSA. © 2023 International Parkinson and Movement Disorder Society., (© 2023 International Parkinson and Movement Disorder Society.)

Objective: Recent evidence supports a link between increased TDP-43 burden and the presence of an APOE4 gene allele in Alzheimer's disease (AD); however, it is difficult to conclude the direct effect of APOE on TDP-43 pathology due to the presence of mixed AD pathologies. The goal of this study is to address how APOE isoforms impact TDP-43 pathology and related neurodegeneration in the absence of typical AD pathologies., Methods: We overexpressed human TDP-43 via viral transduction in humanized APOE2, APOE3, APOE4 mice, and murine Apoe-knockout (Apoe-KO) mice. Behavior tests were performed across ages. Animals were harvested at 11 months of age and TDP-43 overexpression-related neurodegeneration and gliosis were assessed. To further address the human relevance, we analyzed the association of APOE with TDP-43 pathology in 160 postmortem brains from autopsy-confirmed amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) in the Mayo Clinic Brain Bank., Results: We found that TDP-43 overexpression induced motor function deficits, neuronal loss, and gliosis in the motor cortex, especially in APOE2 mice, with much milder or absent effects in APOE3, APOE4, or Apoe-KO mice. In the motor cortex of the ALS and FTLD-MND postmortem human brains, we found that the APOE2 allele was associated with more severe TDP-43-positive dystrophic neurites., Interpretation: Our data suggest a genotype-specific effect of APOE on TDP-43 proteinopathy and neurodegeneration in the absence of AD pathology, with the strongest association seen with APOE2. ANN NEUROL 2023;93:830-843., (© 2022 American Neurological Association.)

Background: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease., Objective: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases., Methods: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898)., Results: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10 -6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4)., Interpretation: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Loss-of-function mutations in GRN are a cause of familial frontotemporal dementia, and common variants within the gene have been associated with an increased risk of developing Alzheimer's disease and Parkinson's disease. Although TDP-43-positive inclusions are characteristic of GRN-related neurodegeneration, Lewy body copathology has also been observed in many GRN mutation carriers., Objective: The objective of this study was to assess a Lewy body dementia (LBD) case-control cohort for pathogenic variants in GRN and to test whether there is an enrichment of damaging mutations among patients with LBD., Methods: We analyzed whole-genome sequencing data generated for 2591 European-ancestry LBD cases and 4032 neurologically healthy control subjects to identify disease-causing mutations in GRN., Results: We identified six heterozygous exonic GRN mutations in seven study participants (cases: n = 6; control subjects: n = 1). Each variant was predicted to be pathogenic or likely pathogenic. We found significant enrichment of GRN loss-of-function mutations in patients with LBD compared with control subjects (Optimized Sequence Kernel Association Test P = 0.0162). Immunohistochemistry in three definite LBD cases demonstrated Lewy body pathology and TDP-43-positive neuronal inclusions., Conclusions: Our findings suggest that deleterious GRN mutations are a rare cause of familial LBD. © 2022 International Parkinson Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA., (© 2022 International Parkinson Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Intronic variant rs564309 in tripartite motif containing 11 (TRIM11) is associated with clinical phenotypic differences in progressive supranuclear palsy (PSP), whereby the minor allele (A) is more common in atypical PSP than typical PSP (PSP-Richardson's syndrome). However, rs564309 has not been investigated relative to neuropathological outcomes., Objective: Evaluate the association of rs564309 with the neuropathologically assessed severity of tau pathology, as measured by semi-quantitative scores for neurofibrillary tangles, tufted astrocytes, neuropil threads, and oligodendroglial coiled bodies., Methods: 797 neuropathologically confirmed PSP cases were genotyped for TRIM11 rs564309 and assessed for tau pathology across 20 neuroanatomical regions. Tau pathology measures and age at death were examined for association with TRIM11 rs564309-A using multivariable linear regression models., Results: TRIM11 rs564309-A was associated with increased neurofibrillary tangles pathology (P = 0.050), but was not significantly associated with age at death, neuropil threads, coiled bodies, or tufted astrocytes tau pathology scores., Conclusions: TRIM11 rs564309 may influence burden of neurofibrillary tangles tau pathology in PSP; further study is warranted. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Background: Genetic variation at the microtubule-associated protein tau locus is associated with clinical parkinsonism. However, it is unclear as to whether microtubule-associated protein tau H1 subhaplotypes are associated with the burden of neuropathological features of Lewy body disease., Objectives: To evaluate associations of microtubule-associated protein tau haplotypes with severity of Lewy body pathology and markers of SN neuronal loss in Lewy body disease cases., Methods: Five hundred eighty-five autopsy-confirmed Lewy body disease cases were included. Six microtubule-associated protein tau variants (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521) were genotyped to define common microtubule-associated protein tau haplotypes. Lewy body counts were measured in five cortical regions. Ventrolateral and medial SN neuronal loss were assessed semiquantitatively. Nigrostriatal dopaminergic degeneration was quantified by image analysis of tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen., Results: The common microtubule-associated protein tau H2 haplotype did not show a strong effect on pathological burden in Lewy body disease. The rare H1j haplotype (1.3%) was significantly associated with a lower dorsolateral putaminal tyrosine hydroxylase immunoreactivity (and therefore greater dopaminergic degeneration) compared to other microtubule-associated protein tau haplotypes (P = 0.0016). Microtubule-associated protein tau H1j was also nominally (P ≤ 0.05) associated with a lower ventromedial putaminal tyrosine hydroxylase immunoreactivity (P = 0.010), but this did not survive multiple testing correction. Other nominally significant associations between microtubule-associated protein tau H1 subhaplotypes and neuropathological outcomes were observed., Conclusions: A rare microtubule-associated protein tau H1 subhaplotype (H1j) may be associated with more severe putaminal dopaminergic degeneration in Lewy body disease cases. Microtubule-associated protein tau H1j has been associated previously with an increased risk of PD, and therefore our exploratory findings provide insight into the mechanism by which H1j modulates PD risk. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Background: [ 11 C]pyridinyl-butadienyl-benzothiazole 3 is a PET imaging agent designed for capturing pathological tau aggregates in diverse neurodegenerative disorders, and would be of clinical utility for neuropathological investigations of PSP., Objectives: To explore the usefulness of [ 11 C]pyridinyl-butadienyl-benzothiazole 3/PET in assessing characteristic distributions of tau pathologies and their association with clinical symptoms in the brains of living PSP patients., Methods: We assessed 13 PSP patients and 13 age-matched healthy control subjects. Individuals negative for amyloid β PET with [ 11 C]Pittsburgh compound B underwent clinical scoring, MR scans, and [ 11 C]pyridinyl-butadienyl-benzothiazole 3/PET., Results: There were significant differences in binding potential for [ 11 C]pyridinyl-butadienyl-benzothiazole 3 between PSP patients and healthy control subjects (P = 0.02). PSP patients exhibited greater radioligand retention than healthy control subjects in multiple brain regions, including frontoparietal white matter, parietal gray matter, globus pallidus, STN, red nucleus, and cerebellar dentate nucleus. [ 11 C]pyridinyl-butadienyl-benzothiazole 3 deposition in frontoparietal white matter, but not gray matter, was correlated with general severity of parkinsonian and PSP symptoms, whereas both gray matter and white matter [ 11 C]pyridinyl-butadienyl-benzothiazole 3 accumulations in the frontoparietal cortices were associated with nonverbal cognitive impairments. Autoradiographic and fluorescence labeling with pyridinyl-butadienyl-benzothiazole 3 was observed in gray matter and white matter of PSP motor cortex tissues., Conclusions: Our findings support the in vivo detectability of tau fibrils characteristic of PSP by [ 11 C]pyridinyl-butadienyl-benzothiazole 3/PET, and imply distinct and synergistic contributions of gray matter and white matte tau pathologies to clinical symptoms. [ 11 C]pyridinyl-butadienyl-benzothiazole 3/PET potentially provides a neuroimaging-based index for the evolution of PSP tau pathologies promoting the deterioration of motor and cognitive functions. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., (© 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

Background: Dysregulation of the specialized lipid metabolism involved in myelin synthesis and maintenance by oligodendrocytes has been associated with the unique neuropathology of MSA. We hypothesized that apolipoprotein E, which is associated with neurodegeneration, may also play a role in the pathogenesis of MSA., Objective: This study evaluated genetic associations of Apolipoprotein E alleles with risk of MSA and α-synuclein pathology, and also examined whether apolipoprotein E isoforms differentially affect α-synuclein uptake in a oligodendrocyte cell., Methods: One hundred sixty-eight pathologically confirmed MSA patients, 89 clinically diagnosed MSA patients, and 1,277 control subjects were genotyped for Apolipoprotein E. Human oligodendrocyte cell lines were incubated with α-synuclein and recombinant human apolipoprotein E, with internalized α-synuclein imaged by confocal microscopy and cells analyzed by flow cytometry., Results: No significant association with risk of MSA or was observed for either Apolipoprotein E ɛ2 or ɛ4. α-Synuclein burden was also not associated with Apolipoprotein E alleles in the pathologically confirmed patients. Interestingly, in our cell assays, apolipoprotein E ɛ4 significantly reduced α-synuclein uptake in the oligodendrocytic cell line., Conclusions: Despite differential effects of apolipoprotein E isoforms on α-synuclein uptake in a human oligodendrocytic cell, we did not observe a significant association at the Apolipoprotein E locus with risk of MSA or α-synuclein pathology. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Background: Cognitive impairment is one of the core features of progressive supranuclear palsy. This study aimed to clarify the profile of cognitive impairment and its underlying pathology in progressive supranuclear palsy., Methods: We retrospectively reviewed medical records to evaluate the pattern and severity of cognitive impairment in 121 autopsy-confirmed progressive supranuclear palsy patients. A subset of 37 patients underwent neuropsychological evaluation as part of their clinical workup. The burden of progressive supranuclear palsy-related tau pathology (neurofibrillary tangles/pretangles, coiled bodies, tufted astrocytes, and threads) was semiquantitatively scored in 20 vulnerable brain regions. Concurrent pathologies potentially associated with cognitive impairment, such as Alzheimer's-type pathology, were also assessed. To evaluate possible genetic risk factors for cognitive impairment, genetic analysis for APOE and MAPT was performed., Results: Ninety patients (74%) had documented cognitive impairment based on neurologic evaluation. In a subgroup with neuropsychological testing (n = 37), executive functioning was the most severely impaired cognitive domain. A global cognitive impairment index (Spearman's rho, -0.49; P = 0.005) and executive functioning were negatively correlated with total tau burden (Spearman's rho, -0.51; P = 0.003), but not correlated with the Alzheimer's-type pathology. APOE ɛ4 carriers had more severe amyloid pathology, but total tau burden and a global cognitive impairment index did not differ from APOE ɛ4 noncarriers., Conclusion: Cognitive impairment in progressive supranuclear palsy, most notably executive dysfunction, is associated with severity of progressive supranuclear palsy-related tau pathology. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

Background: A number of genetic loci are associated with risk for Parkinson's disease (PD) based on genome-wide association studies; however, the relationship between genetic variants and nigrostriatal degeneration, which is the structural correlate of parkinsonism, has not been reported., Objectives: We quantified nigrostriatal dopaminergic integrity with image analysis of putaminal tyrosine hydroxylase immunoreactivity in 492 brains with Lewy body disease and used this pathologic endophenotype to explore possible association with PD genetic variants., Methods: The study cases had Lewy-related pathology and variable degrees of nigrostriatal degeneration. They were assigned to one of the following clinical subgroups according to their predominant clinical syndrome: parkinsonism-predominant, parkinsonism+dementia, and dementia-predominant. In addition to putaminal tyrosine hydroxylase immunoreactivity, semiquantitative scoring was used to assess substantia nigra neuronal loss. A total of 29 PD genetic risk variants were genotyped on each case., Results: When compared with controls, tyrosine hydroxylase immunoreactivity was reduced in Lewy body cases in the dorsolateral (79%) and ventromedial (57%) putamen. The dorsolateral region was better preserved in dementia-predominant cases than in cases with parkinsonism. Dorsolateral putaminal tyrosine hydroxylase immunoreactivity correlated with neuronal loss in the ventrolateral substantia nigra. Genetic analyses showed no significant association of PD risk variants with putaminal tyrosine hydroxylase immunoreactivity., Conclusions: The results confirm regional differences in putaminal dopaminergic degeneration and vulnerability of nigrostriatal pathway in Lewy body disorders with parkinsonism. The lack of association with PD genetic risk variants suggests that they may not be associated with quantitative endophenotypes of nigrostriatal degeneration, but more likely related to the risk of disease per se. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

Background: The tau PET ligand 2-((1E,3E)-4-(6-([ 11 C]methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol ([ 11 C]PBB3) binds to a wide range of tau pathology; however, binding property of PBB3 to non-tau inclusions remains unknown. To clarify whether [ 11 C]PBB3 binds to α-synuclein pathology, reactivity of PBB3 was assessed by in vitro fluorescence and autoradiographic labeling of brain sections from α-synucleinopathies patients., Method: Of 10 pure Lewy body disease and 120 multiple system atrophy (MSA) cases in the Mayo Clinic brain bank, we selected 3 Lewy body disease and 4 MSA cases with a range of α-synuclein severity based on the quantitative analysis of α-synuclein burden. PBB3 fluorescence labeling, double or single immunostaining for α-synuclein and phospho-tau, Prussian blue staining, and in vitro autoradiography with [ 11 C]PBB3 were performed for these selected samples., Results: PBB3 fluorescence labeled various α-synuclein lesions including Lewy bodies, Lewy neurites, spheroids, glial cytoplasmic inclusions, and neuronal cytoplasmic inclusions. Meanwhile, autoradiographic labeling with [ 11 C]PBB3 at 10 nM demonstrated no significant binding in Lewy body disease cases. In contrast, significant autoradiographic binding of [ 11 C]PBB3 to the striatopallidal fibers was found in 2 MSA cases, which had high densities of glial cytoplasmic inclusions without tau or iron deposits in this region., Conclusions: Given that the maximum concentration of [ 11 C]PBB3 in human PET scans is approximately 10 nM, the present data imply that α-synuclein pathology in Lewy body disease is undetectable by [ 11 C]PBB3-PET, whereas those in a subset of MSA cases with high densities of glial cytoplasmic inclusions could be captured by this radioligand. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

Background: The objectives of this study were to elucidate any potential association between α-synuclein pathology and cognitive impairment and to determine the profile of cognitive impairment in multiple system atrophy (MSA) patients. To do this, we analyzed the clinical and pathologic features in autopsy-confirmed MSA patients., Methods: We retrospectively reviewed medical records, including neuropsychological test data, in 102 patients with autopsy-confirmed MSA in the Mayo Clinic brain bank. The burden of glial cytoplasmic inclusions and neuronal cytoplasmic inclusions were semiquantitatively scored in the limbic regions and middle frontal gyrus. We also assessed concurrent pathologies potentially causing dementia including Alzheimer's disease, hippocampal sclerosis, and cerebrovascular pathology., Results: Of 102 patients, 33 (32%) were documented to have cognitive impairment. Those that received objective testing, deficits primarily in processing speed and attention/executive functions were identified, which suggests a frontal-subcortical pattern of dysfunction. Of these 33 patients with cognitive impairment, 8 patients had concurrent pathologies of dementia. MSA patients with cognitive impairment had a greater burden of neuronal cytoplasmic inclusions in the dentate gyrus than patients without cognitive impairment, both including and excluding patients with concurrent pathologies of dementia., Conclusions: The cognitive deficits observed in this study were more evident on neuropsychological assessment than with cognitive screens. Based on these findings, we recommend that clinicians consider more in-depth neuropsychological assessments if patients with MSA present with cognitive complaints. Although we did not identify the correlation between cognitive deficits and responsible neuroanatomical regions, a greater burden of neuronal cytoplasmic inclusions in the limbic regions was associated with cognitive impairment in MSA. © 2016 International Parkinson and Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)

Background: This study aimed to determine the frequency of transactive response DNA binding protein 43 kDa pathology in PSP, the clinical features of patients with this pathology, and genetic risk factors for it., Methods: Hippocampal sections were screened with immunohistochemistry for transactive response DNA binding protein 43 kDa in 945 PSP cases. A subset of 261 cases that were negative in hippocampus was screened in the amygdala. The density and disruption of this pathology, as well as regional tau burden, and clinical and genetic characteristics were analyzed., Results: We observed transactive response DNA binding protein 43 kDa pathology in 47 cases in the hippocampus and an additional 9 cases that only affected the amygdala. Hippocampal sclerosis was the strongest risk factor, followed by Alzheimer's disease pathology, argyrophilic grain disease, and older age at death. Five stages of transactive response DNA binding protein 43 kDa pathology were identified in PSP: Stage A had pathology only in the amygdala (16%); stage I had pathology confined to the hippocampus and entorhinal cortex (9%); stage II included both regions of stage A and I (38%); stage III spread further to medial occipitotemporal gyrus (20%); and stage IV had pathology in the dorsolateral frontal lobe (18%). Anatomical areas vulnerable to PSP pathology had varying degrees of this pathology in stage II and later. PSP with transactive response DNA binding protein 43 kDa pathology were older at disease onset and had lower median MMSE scores; however, the latter was driven by concurrent pathologies., Conclusions: Distribution and clinical characteristics of transactive response DNA binding protein 43 kDa pathology in PSP were influenced by concurrent pathologies. This is the first study to observe that PSP-vulnerable regions are also susceptible to this non-tau pathology. © 2016 International Parkinson and Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)

Background: Cerebellar ataxia is an exclusion criterion for the clinical diagnosis of progressive supranuclear palsy, but a variant with predominant cerebellar ataxia has been reported. The aims of this study were to estimate the frequency of progressive supranuclear palsy with predominant cerebellar ataxia in an autopsy series from the United States and to compare clinical, pathologic, and genetic differences between progressive supranuclear palsy with and without predominant cerebellar ataxia., Method: We selected 100 consecutive patients with pathologically confirmed progressive supranuclear palsy who had been evaluated at the Mayo Clinic (referred to as the Mayo Clinic patient series) from our brain bank database (N = 1085). We next enriched in cases likely to have cerebellar ataxia by searching the remaining 985 cases for (1) an antemortem diagnosis of multiple system atrophy or (2) neuropathologic evidence of prominent degeneration of the cerebellum or cerebellar afferent nuclei. Subsequently, clinical, pathologic, and genetic features were compared between the two groups., Results: One patient in the Mayo Clinic patient series (1%) met criteria for progressive supranuclear palsy with predominant cerebellar ataxia and had both cerebellar and mild midbrain atrophy on MRI. Four patients were identified with the targeted search. Four of the five patients were clinically misdiagnosed as multiple system atrophy. The severity of tau-related pathology and cerebellar degeneration were not different between the two groups. No differences were detected in tau genotypes., Conclusion: Although our data cannot provide definitive information about how to make an accurate clinical diagnosis, they should serve to raise awareness of progressive supranuclear palsy with predominant cerebellar ataxia in the differential diagnosis of multiple system atrophy. © 2016 Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)

Treatment options for chronic renal artery dissection, which is a rare cause of renal artery stenosis and renovascular hypertension, such as medical management, percutaneous intervention, and open surgical repair remain controversial. We describe a 55-year-old man with a chronic dissecting aneurysm of a renal artery complicated with renovascular hypertension that was initially diagnosed by computed tomography angiography, evaluated by intravascular ultrasound, and treated by stent implantation with coil embolization.© 2012 Wiley Periodicals, Inc., (Copyright © 2012 Wiley Periodicals, Inc.)

Purpose: To evaluate whether a pharmacokinetic analysis is useful for monitoring the response of oral cancer to chemoradiotherapy (CRT)., Materials and Methods: Twenty-nine patients were included. They underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) before and after CRT. The DCE-MRI data were analyzed using a Tofts and Kermode (TK) model. The histological evaluation of the effects of CRT was performed according to Ohboshi and Shimosato's classification., Results: None of the pre-CRT parameters were significantly different between the responders and nonresponders. The post-CRT volume of the extravascular extracellular space (EES) per unit volume of tissue (v(e) ) of responders (0.397 ± 0.080) was higher than that of nonresponders (0.281 ± 0.076) (P = 0.01). The change of the v(e) between the pre- and post-CRT of the responders (0.154 ± 0.093) was larger than that of the nonresponders (0.033 ± 0.073) (P = 0.001). Therefore, the increase in the v(e) strongly suggested a good tumor response to CRT, which reflected an increase of the EES secondary to the destruction of the cancer nest. The changes in the volume transfer constant (K(trans) ) were significantly different between the responders and nonresponders (P = 0.018)., Conclusion: Both the increase of the v(e) and the elevation of permeability (K(trans) ) were indicative of a good tumor response to CRT. The pharmacokinetic analysis had potential for monitoring the histopathological response to CRT., (Copyright © 2012 Wiley Periodicals, Inc.)

The roles of the hepatitis B virus (HBV), cigarette smoking and alcohol consumption in the etiology of hepatocellular carcinoma (HCC) were examined in a case-control study involving 204 patients with HCC and 410 control subjects in Fukuoka prefecture, where HCC risk is among the highest in Japan. Information on smoking and drinking habits was obtained by a detailed interview survey, and the results were analyzed in conjunction with serum hepatitis B surface antigen (HBsAg) status after adjustment for sex, age and other possible confounding factors. Individuals positive for serum HBsAg showed a relative risk (RR) for HCC of 13.8 (95% confidence interval, Cl 5.9 to 32.5), whereas heavy drinkers experienced about a 2-fold risk increase compared with non-drinkers. Light or moderate drinkers, however, demonstrated RRs near the unity. Some risk excess was observed among ex-smokers (RR = 1.5, 95% CI 0.8 to 2.8) and current smokers (RR = 1.5, 0.8 to 2.7) compared with non-smokers, but without evidence for a dose-response relationship in terms of pack-years. Analysis among HBsAg-negative subjects revealed similar non-significant association with smoking, and there was no clear interaction between alcohol and cigarette consumption on HCC risk. Other significant risk factors included positive histories of blood transfusion (RR = 3.7, 2.2 to 6.3) and familiar liver disease (RR = 2.6, 1.6 to 4.2). Attributable risk calculations suggest that chronic HBV infection and heavy drinking may account for 17% and 13% of HCC occurrence, respectively, in this high risk area. The association of cigarette smoking with HCC was not evident in our study.

To clarify the possible association between gastrectomy and the subsequent development of esophageal cancer, we studied the incidence of subjective gastroesophageal reflux in 287 patients and analyzed the nutritional status and results of endoscopic examination of the esophagus in 62 patients who had survived for a long period after gastrectomy for nonmalignant diseases. The incidence of postoperative reflux was 22.6%. None of the patients had severe deterioration of blood parameters or nutritional status. Endoscopic observation revealed esophagitis in 24.2% of patients, mainly in the lower esophagus. Histologically, there was a high incidence of infiltration of neutrophils and lymphocytes, enlarged papillae, and basal cell hyperplasia. Epithelial dysplasia was detected in 41.9% of patients, and of these there were more patients in whom the degree of dysplasia was more severe in the lower esophagus than in other areas. These data suggest that postgastrectomy gastroesophageal reflux is more likely than postgastrectomy changes in nutritional status to be a possible contributory factor to the development of subsequent esophageal cancer.

To assess the efficacy of proximal gastrectomy in the treatment of upper gastric carcinoma, we analyzed clinical data from patients with lesions confined to the upper third of the stomach (group 1) and from patients with lesions which, while primarily located in the upper portion of the stomach, showed spread to the body of the stomach (group 2). Patients in group 2 showed more metastatic lymph node involvement, particularly of the infrapyloric lymph nodes, which were not included in lymphadenectomy accompanying proximal gastrectomy. None of the group 1 patients demonstrated metastasis to the infrapyloric lymph nodes. The postoperative 5-year survival rate in curatively operated group 1 patients was not significantly different between those treated by proximal gastrectomy and those subjected to total gastrectomy. We conclude that proximal gastrectomy is indicated in patients with upper gastric carcinoma when it is confined to the upper third of the stomach.

We studied the prognostic significance of lymph vessel involvement in the gastric wall in 226 patients with advanced gastric cancer. There was no close correlation between the gross morphology of the cancer and the incidence of lymph vessel invasion. However, the more severe the degree of lymph vessel involvement, the higher was the incidence of lymph node metastasis. Severe lymph vessel invasion was found most frequently in poorly differentiated adenocarcinoma of the medullary type. Among patients with scirrhous carcinoma there were some in whom lymph vessel involvement was overlooked on routine histologic examination. Because the depth of lymph vessel invasion of the gastric wall was significantly related to the clinical course, we consider this to be of supplementary predictive value.

A retrospective analysis was undertaken of the association between blood transfusion and long-term results for 218 patients with stage III gastric cancer who were curatively treated by partial gastrectomy. One hundred and fifty-two patients received blood transfusion within the perioperative period. The postoperative 5-year survival rates were 49.3% for the transfused patients and 62.1% for the non-transfused patients (P less than 0.05). Furthermore, the postoperative survival of patients who had been transfused preoperatively was significantly lower than that of the non-transfused patients. The preoperatively transfused group of patients were found to have tumors that were larger than those of the non-transfused group. On the basis of the above data, it appears that the prognosis of patients with advanced gastric cancer is poorer when such patients receive preoperative blood transfusion than when patients do not receive transfusions, and that this adverse effect in the transfused patients is probably attributable to the larger size of their tumors, even though the stage of advancement of gastric cancer is the same in both groups of patients.

Between 1965 and 1985, 89 Japanese patients with esophageal squamous cell carcinoma underwent esophagectomy. In five of them (5.6%), a simultaneous metastatic lesion from the esophageal cancer was detected within the stomach in the resected specimens. Preoperative diagnosis of the gastric lesions had been made in none of the five patients because of an obstruction that was due to esophageal cancer. All gastric lesions were located at the gastric cardia, close to the esophagocardial junction, with a mean distance of 6.9 +/- 2.0 cm from the primary esophageal lesions. Provision of a gastric tube that contains metastatic lesions, for reconstruction of a new alimentary tract after esophagectomy, must be avoided. In cases of inadequate preoperative gastric examination, gastric lesions should be searched for intraoperatively, not only by serosal inspection and palpation, but also by mucosal inspection and palpation after partial proximal gastrectomy.

The pathologic characteristics of gastric cancer in 57 patients with hematogenous recurrence were pathologically analyzed by the site of recurrence. In recurrence of gastric cancer that developed in the liver, macroscopic observation revealed that cancers of Borrmann type 2 and 3 were most frequent. Microscopic examination revealed that the rate of occurrence of the medullary type of differentiated or poorly differentiated adenocarcinoma were high and that there were relatively frequent invasion by cancerous cells of the blood vessel that were closely related to the hematogenous metastasis. On the other hand, with respect to recurrence of gastric cancer that had developed in the lung or bone, Borrmann type 3 and 4, respectively, were more frequently observed. In these cases, microscopic analysis revealed that these cancers were poorly differentiated adenocarcinomas. In gastric cancer with bone recurrence, the rate of recurrence of the scirrhous type of tumor were higher than that of other types. It is important, for the management of patients after gastric cancer surgery, to predict possible hematogenous recurrence and its site by evaluation of the pathologic characteristics of the gastric cancer.

We studied the histology of resected specimens from 71 gastric cancer patients with synchronous and metachronous liver metastasis to assess the predominance of a particular histological pattern in gastric cancer with a tendency for liver metastasis. Poorly differentiated adenocarcinoma manifesting a medullary growth pattern was the most frequent histologic pattern (33%), followed by papillary adenocarcinoma (28%) in 39 patients with synchronous liver metastasis. In 32 patients who developed metachronous liver metastasis as the main pattern of recurrence, papillary adenocarcinoma was most frequent (47%), followed by poorly differentiated adenocarcinoma of the medullary type (28%). Scirrhous carcinoma was not encountered in patients manifesting metachronous liver metastasis. As most of the papillary adenocarcinomas exhibited a medullary growth pattern, we hypothesize that gastric cancer of the medullary type tends to metastasize to the liver, irrespective of the basic histologic pattern, and that poorly differentiated adenocarcinoma of the medullary type has a particularly high tendency for metastasizing to the liver.

Correlations between levels of tissue polypeptide antigen (TPA) in serum and histologic stage or progression of cancer were studied in 94 patients with gastric cancer. Levels of TPA in serum from patients with cancerous invasion into the vein of the stomach wall (v-invasion) were elevated in parallel to the progression of cancer by stage, and were significantly higher in each positive case than in each negative case of lymph node metastasis or of cancerous invasion into lymph vessels of the stomach wall (P less than 0.05 and P less than 0.01, respectively). There were no differences in levels of TPA in serum from patients without v-invasion when these cancers were classified by stage, progression, or histologic type. It appears that elevation of levels of TPA in serum is associated with v-invasion, and that a determination of the level of TPA in serum is useful for the prediction of hematogenic metastasis in cases of gastric cancer.