Single-incision plus one port laparoscopic anterior resection for rectal cancer as a reduced port surgery.

BACKGROUND: Only limited data in the literature about single-incision laparoscopic rectal surgery, because the laparoscopic stapler does not allow low rectal transection without sufficient distal margins from the umbilicus port. We have developed single-incision plus one port laparoscopic anterior resection of the rectum (SILS+1-AR) as a reduced port surgery in which we can utilize the incision for drainage as an additional access route for laparoscopic procedures including the transection the lower rectum. METHODS: A Lap protector (LP) mini was inserted through a 2.5 cm transumbilical incision, and an EZ-access was mounted to LP and three 5-mm ports were placed in EZ-access. A 12 mm port was inserted in right lower quadrant. Almost all the procedures were performed with usual laparoscopic instruments, and the operative procedures were much the same as in usual laparoscopic low anterior resection of the rectum using a flexible 5mm scope. The rectum was transected normally using only one endoscopic linear stapler inserted from the right lower quadrant port. RESULTS: We underwent modified SILS+1-AR in 16 patients with advanced rectal cancer. In all cases, there was no need to extend the skin incision. We transected the lower rectum with one laparoscopic stapler in all six cases. Postoperative follow-up did not reveal any umbilical wound complications or recurrences. CONCLUSIONS: The safety and feasibility of SILS+1-AR for advanced rectal cancer was established in this study. However, further studies are needed to prove the advantages of this procedure to conventional laparoscopic law anterior resection.

Pathological examination of spinal lesions in meningeal carcinomatosis.

For elucidation of the mechanism of spinal cord disorders associated with meningeal carcinomatosis, we investigated meningeal infiltration and parenchymal, vascular, and radicular damage in spinal cords subjected to pathological autopsy. Spinal cords were collected from 24 patients with a histopathological diagnosis of meningeal carcinomatosis. Infiltration from the subarachnoid space into the spinal cord occurred primarily along the perivascular tissue, and infiltration from the anterior median fissure to the anterior horn was found along the central artery in cases of marked meningeal dissemination. Meningeal dissemination was particularly evident with small cell carcinoma of lung, breast cancer and melanoma, and direct infiltration from the meninges into the spinal cord was found. Direct infiltration into the nerve roots was frequently observed, and infiltration was more evident in the dorsal roots than in the ventral roots, with loss of nerve fibers. Circular necrosis of the white matter in the periphery of the spinal cord was noted in cases of marked meningeal dissemination, which probably resulted from circulatory disturbance secondary to tumor infiltration. In cases of marked dorsal radiculopathy, there was secondary ascending degeneration of the posterior funiculus in cases of marked dorsal radiculopathy. These pathological changes associated with spinal cord disorders are important findings in reviewing spinal cord symptoms and radiographic findings in meningeal carcinomatosis.

Immunohistochemistry of symptomatic hypertrophy of the posterior longitudinal ligament with special reference to ligamentous ossification.

STUDY DESIGN: Immnunohistochemical staining of the thickened posterior longitudinal ligament of the cervical spine. OBJECTIVES: To clarify the histological characteristics of hypertrophy of the posterior longitudinal ligament (HPLL) of the cervical spine and the relationship between HPLL and ossification of the posterior longitudinal ligament (OPLL). SETTING: Aichi Medical University, Aichi, Japan. METHODS: Eight specimens of HPLL and two of OPLL were obtained during anterior decompressive surgery on the cervical spine from patients with myelopathy. Hematoxylin and eosin staining, alcian blue staining and immunohistochemical staining with antibodies against bone morphogenetic protein (BMP), transforming growth factor (TGF)-beta, proliferating cell nuclear antigen (PCNA), alkaline phosphatase (ALP) and osteopontin (OPN) were carried out on the specimens. RESULTS: HPLL showed hyalinoid degeneration, the proliferation of chondrocytes and fibroblast-like spindle cells, infiltration of vessels and small ossification. In four cases, chondroid tissue was prominent with chondrocytes, which were expressed by ALP and OPN. The cells in HPLL were weakly or moderately stained by BMP, TGF-beta and PCNA. Their expression was similar to that of OPLL. Immunohistochemical staining was negative for all cells in the control cases. CONCLUSIONS: Histological and biochemical evidence supports the hypothesis that HPLL transforms into OPLL. The positive expression of BMP and TGF-beta in HPLL cells of myelopathic patients, and their similarity to OPLL, suggest that these cells have the potential to differentiate into osteogenic cells. Of note, neither BMP nor TGF-beta was demonstrated in the PLL of control subjects. Furthermore, the expression of chondrocytes by ALP and OPN in cartilage-prominent HPLL suggests that the cartilage can be replaced by new bone.

Postmortem study of the spinal cord showing snake-eyes appearance due to damage by ossification of the posterior longitudinal ligament and kyphotic deformity.

UNLABELLED: CLINICAL DESIGN: A case report. OBJECTIVES: To elucidate the clinical role of snake-eyes appearance in this case, correlation between radiological, clinical and postmortem study was performed. SETTING: Aichi, Japan. CASE REPORT: A 73-year-old man developed weakness and pain in the upper limbs due to kyphotic deformity secondary to laminectomy for cervical ossification of the posterior longitudinal ligament. Axial magnetic resonance imaging revealed snake-eyes appearance from C4 to C6. He died of acute myocardial infarction 3 months after anterior decompressive surgery. RESULTS: A postmortem examination of the cervical spinal cord showed small cystic six necrotic areas at the junction of the central gray matter and the ventrolateral posterior column, one in the right and one in the left, in association with neuronal loss in the anterior horn. CONCLUSIONS: Bilateral small intramedullary high-signal areas known as 'snake-eyes appearance' located around the central gray matter and the ventrolateral posterior column, are associated with neuronal loss in the compressed anterior horn that played an important role in worsening weakness of the upper limbs.

Alpha-synuclein-positive structures in association with diffuse neurofibrillary tangles with calcification.

alpha-Synuclein is known to be a major constituent of the Lewy bodies (LBs) in Parkinson's disease (PD) and the neuronal and glial cytoplasmic inclusions (NCIs, GCIs) in multiple system atrophy. alpha-Synuclein-positive inclusions such as LBs, NCIs and GCIs sometimes show colocalization with tau-positive neurofilaments. Studies using alpha-synuclein immunohistochemistry have often found LBs in the amygdala of patients with familial or sporadic Alzheimer's disease (AD), as well as in patients with Down's syndrome and AD. However, no studies have reported alpha-synuclein-positive structures in cases of diffuse neurofibrillary tangles with calcification (DNTC), which is characterized by numerous neurofibrillary tangles (NFTs) throughout the cerebral cortex but few, if any, senile plaques. We investigated the distribution of alpha-synuclein-positive structures in two cases of DNTC: a 65-year-old woman (brain weight, 850 g) and a 75-year-old woman (brain weight, 800 g). In both cases, severe cerebral atrophy predominant in the temporal lobe was noted. Microscopically, alpha-synuclein-positive intracytoplasmic inclusions and neurites were found in the superior temporal lobe (within the temporal pole), amygdala, parahippocampus, entorhinal cortex and insula, the regions most affected by the NFTs. alpha-Synuclein-positive intracytoplasmic inclusions were rare or absent in other regions of the cerebral cortex and brainstem. This distribution pattern differs from that of PD or dementia with LBs. Our findings suggest that the accumulation pattern of alpha-synuclein is a pathological feature of DNTC, and that DNTC is associated with accumulation of both tau and alpha-synuclein.

Cervical amyotrophy caused by hypertrophy of the posterior longitudinal ligament.

STUDY DESIGN: A case report. OBJECTIVES: To report a case of cervical amyotrophy caused by hypertrophy of the posterior longitudinal ligament (HPLL). SETTING: Department of Neurological Surgery, Aichi Medical University, Aichi, Japan. METHODS: The patient had severe muscular atrophy in the deltoid and triceps with slight localized hypesthesia in the C5 area and severely unstable gait due to diminished vibration sense in the knees and ankles. Magnetic resonance imaging (MRI) showed expanded cord compression from C4 to C6 with intramedullary high-signal intensity due to HPLL. Transverse image MRI was useful to identify the HPLL. RESULTS: Resection of HPLL was achieved by an anterior approach. Histological findings of the surgical specimens showed thickening of the ligamentous tissue with proliferation of chondrocytes. CONCLUSIONS: HPLL should be included as a causative pathology of cervical spondylotic amyotrophy. Careful neurological examination including sensory examination of the lower limbs should be performed to avoid confusion with motor neuron disease.

Suppression of GST-P by treatment with glutathione-doxorubicin conjugate induces potent apoptosis in rat hepatoma cells.

A conjugate of doxorubicin and glutathione via glutaraldehyde (GSH-DXR) inhibited glutathione S-transferase (GST) activity of rat hepatoma AH66 cells, and treatment of the cells with GSH-DXR induced caspase-3 activation and DNA fragmentation. After treatment of AH66 cells with 0.1 microM GSH-DXR, GST-P (placental type of rat GST isozymes) mRNA and its protein increased transiently and then decreased thereafter compared with the levels in nontreated cells. Caspase-3 activation and DNA fragmentation were induced following the suppression of GST-P expression by treatment with GSH-DXR. When the cells were treated with 100 microM ethacrynic acid (ECA), an inhibitor of GST, DNA fragmentation and caspase-3 activation were observed. In contrast, treatment of AH66 cells with a low concentration of ECA (1 microM) that showed little inhibition of GST activity induced slight, but significantly enhanced expression and activity of GST-P, and consequent prevention of DXR- and GSH-DXR-induced DNA fragmentation. Overexpression of GST-pi (placental type of human GST isozymes) by transfection of GST-pi sense cDNA into AH66 cells decreased sensitivities to DXR and GSH-DXR, and the suppression of GST-P by transfection of the antisense cDNA into the cells increased drug sensitivity. On the other hand, there was little change in drug sensitivity caused by overexpression of site-directedly mutated GST-P in which the active-site residue Tyr39 was replaced with His (W39H) or the substrate-binding site residue Cys48 was replaced with Ser (C48S) by transfection of those cDNAs into AH66 cells. These results suggested that the suppression of GST-P in AH66 cells treated with GSH-DXR must play an important role in the induction of apoptosis.

Relationship between cytocidal activity and glutathione-S-transferase inhibition using doxorubicin coupled to stereoisomers of glutathione with different substrate specificity.

To determine the cytotoxic mode of action of a glutathione (GSH)--doxorubicin (DXR) conjugate, which exhibited potent cytotoxicity against various multidrug-resistant as well as DXR-sensitive cell lines, the molecular interaction between covalent GSH--DXR conjugates and glutathione-S-transferase (GST), a possible molecular target of the conjugates, was investigated. The following four GSH molecules with stereoisomeric forms were prepared: L-Glu--L-Cys--Gly (LL-GSH), D-Glu--L-Cys--Gly (DL-GSH), L-Glu--D-Cys--Gly (LD-GSH) and D-Glu--D-Cys--Gly (DD-GSH). The enzymic activity of GST against each GSH stereoisomer was 88, 38, 8 and 4 nmol/mg/min, respectively, suggesting that the L-form cysteine residue in the molecule was an important substrate of GST. Addition of DXR conjugated with each isomer (10 microM) to a GSH-containing GST assay mixture inhibited the GST activity to 32% for LL-GSH--XR, 16% for DL-GSH-DXR and 61% for LD-GSH-DXR as compared with the solvent control. Moreover, IC50 values for these conjugates were 30, 20 and 250 nM, respectively. The cytocidal activity of each conjugate corresponded to the substrate specificity of GST activity for the GSH isomer. These conjugates bound to the GST molecule, and the binding ability was 0.746, 0.627 and 0.462 mol/mol of GST for LL-GSH--XR, DL-GSH-DXR and LD-GSH--XR, respectively. These findings suggested that GSH--DXR interacted with the substrate-binding site of the GST molecule and inhibition of GST activity exhibited potent cytotoxicity.

Analysis of hypertrophy of the posterior longitudinal ligament of the cervical spine, on the basis of clinical and experimental studies.

OBJECTIVE: The goal of this study was to elucidate the pathophysiological features and treatment of hypertrophy of the posterior longitudinal ligament (HPLL) of the cervical spine. HPLL is defined as a pathological thickening of the posterior longitudinal ligament (PLL), causing spinal cord compression. Incomplete decompression via removal of only coexisting herniated intervertebral discs or spondylotic spurs might be performed, resulting in unsatisfactory surgical outcomes, when the PLL becomes abnormally thickened and contributes to myelopathy. METHODS: Patients with HPLL who underwent cervical decompression surgery were selected. Medical records and radiographs were retrospectively reviewed, to obtain data on the pre- and postoperative clinical conditions of the patients. Autopsy cases with HPLL proven by low-energy x-ray examinations were chosen for assessment of the pathological characteristics. RESULTS: Seventeen men and three women with HPLL underwent treatment via an anterior approach, with direct removal of HPLL. Nineteen patients developed myelopathy, whereas one patient developed radiculopathy. Radiologically, all HPLL cases exhibited coexisting herniated intervertebral discs and 10 exhibited small segmental ossifications of the PLL. Magnetic resonance imaging or computed tomographic myelography revealed extensive cord compression across the vertebral endplate level. The average preoperative Benzel modified Japanese Orthopaedic Association score was 10.8, and the average postoperative score was 13.2. Histological examinations revealed thickening of the PLL with proliferation of chondrocytes, together with various degenerative changes. CONCLUSION: Patients with HPLL can benefit from an anterior approach with direct removal of the HPLL and associated herniated intervertebral discs or ossification of the PLL. Cervical polytomography, computed tomography, and magnetic resonance imaging are useful in establishing a diagnosis of HPLL.

Morphological Purkinje cell changes in spinocerebellar ataxia type 6.

Spinocerebellar ataxia type 6 (SCA6) was recently identified as a form of autosomal dominant spinocerebellar ataxia associated with a small CAG repeat expansion of the gene encoding an alpha 1 A-voltage-dependent calcium channel gene subunit on chromosome 19p13. In this study 50-microm-thick sections of cerebellar tissue from one patient with SCA6 were subjected to free-floating immunohistochemical staining with calbindin-D and parvalbumin antibodies. Severe loss of Purkinje cells was found, particularly in the vermis, and various morphological changes in Purkinje cells and their dendritic arborizations were demonstrated. Many of the remaining Purkinje cells were found to have heterotopic, irregularly shaped nuclei, an unclear cytoplasmic membrane outline, and somatic sprouts. Increased numbers of spine-like protrusions from swelling dendritic arborizations were found in the molecular layer. The axonal arrangement was disordered, and many torpedos were found in the granular layer and white matters. These morphological changes are completely different from those observed in paraneoplastic cerebellar degeneration (PCD) and multiple system atrophy (MSA) and are considered to be related to the genetic abnormality that causes abnormal development of Purkinje cells.

Crescentic glomerulonephritis with positive antineutrophil cytoplasmic autoantibody specific for myeloperoxidase associated with autoimmune hemolytic anemia and thrombocytopenic purpura.

A 41-year-old woman was admitted to the hospital with severe uremia, hemolytic anemia, and thrombocytopenic purpura. Emergency hemodialysis with plasmapheresis was started in view of consideration of hemolytic uremic syndrome (HUS), which resulted in improvement of renal function and platelet count. Positive antineutrophil cytoplasmic autoantibody specific for myeloperoxidase (MPO-ANCA) suggested crescentic glomerulonephritis, which was pathologically evidenced by renal biopsy. The diagnosis of MPO-ANCA associated crescentic glomerulonephritis with autoimmune hemolytic anemia (AIHA) and thrombocytopenic purpura were confirmed. Three courses of steroid pulse therapy with heparin were successfully performed, followed by oral prednisolone and warfarin. Such a case has not been previously reported to our knowledge.

Endothelin-1 in the brain of patients with galactosialidosis: its abnormal increase and distribution pattern.

Endothelin-1 is a peptidic substrate in vitro of lysosomal protective protein/cathepsin A (PPCA) with serine carboxypeptidase activity. Endothelin-1-specific immunoreactivity has been demonstrated to be markedly increased and distributed abnormally in the neurons and glial cells within autopsied brain regions, including the cerebellum, hippocampal formation, and spinal cord, of patients affected with galactosialidosis, a human PPCA deficiency. The genetic defect of the endothelin-1 degrading activity of PPCA is suggested to cause some of the neurological abnormalities of this disease.

Calpain inhibitor inhibits secretory granule maturation and secretion of GH.

Clathrin- and AP-1-coated buds are present on immature secretory granules of endocrine cells that mature into clathrin-uncoated granules. The mechanism of clathrin and adaptor protein uncoating has remained obscure. Benzyloxycarbonyl-L-leucyl-L-leucinal (ZLLal), a calpain inhibitor, reduced growth hormone (GH) secretion with intracellular accumulation, in a GH-secreting rat pituitary tumor cell. Pulse and chase demonstrated that ZLLal retarded the turnover of clathrin (Clt.H) and adaptins. ZLLal-treatment co-immunoprecipitated the increased amounts of GH with Clt.H and adaptins compared to control cells, suggesting the intracellular accumulation of immature secretory granules. Clt.H and adaptins were limited-proteolyzed by m-calpain in vitro, indicating that calpain may be involved partly in the maturation of secretory granules in endocrine cells via the process of clathrin uncoating.

Late-onset familial amyloid polyneuropathy type I (transthyretin Met30-associated familial amyloid polyneuropathy) unrelated to endemic focus in Japan. Clinicopathological and genetic features.

Clinicopathological and genetic features were assessed on 35 Japanese families affected by late-onset familial amyloid polyneuropathy type I (transthyretin Met30-associated familial amyloid polyneuropathy, FAP TTR Met30) whose siblings were unrelated to endemic Japanese foci. In these patients (50 years or older), the most common initial symptom was paraesthesias in the legs. Autonomic symptoms were generally mild and did not seriously affect daily activities. The male-to-female ratio was extremely high (10.7 : 1). A family history was evident in only 11 out of 35 families, and other patients were apparently sporadic. The rate of penetrance was very low. Symptomatic siblings of familial cases showed a late age of onset, male preponderance and clinical features similar to those of the probands. Asymptomatic carriers, predominantly female, were detected relatively late in life. The geographical distribution of these late-onset, FAP TTR Met30 cases was scattered throughout Japan. In three autopsy cases and 20 sural nerve biopsy specimens, neurons in sympathetic and sensory ganglia were relatively preserved. Amyloid deposition was seen in the peripheral nervous system, particularly in the sympathetic ganglia, dorsal root ganglia and proximal nerve trunks such as sciatic nerve. These abnormalities were milder than those seen in typical early-onset FAP TTR Met30, as observed in two Japanese endemic foci of this disease. While axonal degeneration was prominent in myelinated fibres, resulting in severe fibre loss, unmyelinated fibres were relatively preserved. Our cases of late-onset FAP TTR Met30 showed features distinct from those of typical early-onset FAP TTR Met30 that occurred in the two Japanese endemic foci. Factors responsible for clinicopathological differences between these two forms of FAP TTR Met30 need to be identified.

Calpain inhibitor causes accumulation of ubiquitinated P-glycoprotein at the cell surface: possible role of calpain in P-glycoprotein turnover.

P-glycoprotein (Pgp) is a plasma-membrane glycoprotein that confers multi-drug resistance (MDR) on cells and displays ATP-driven drug pumping. The possible contribution of calpain-mediated proteolytic pathways to the functional regulation of the Pgp molecule was evaluated using K562/DXR, MDR cells. N-Acetyl-L-leucyl-L-leucyl-norleucinal was effluxed by Pgp, but N-benzyloxycarbonyl-L-leucyl-L-leucinal (zLLal), an inhibitor of calpain, retarded the degradation of Pgp leading to accumulation of the molecule largely at the cell surface membrane. Treatment with brefeldin A did not obstruct the zLLal-induced Pgp accumulation. NH4Cl increased the cytoplasmic Pgp level, with a slight to significant decrease at the cell surface membrane. Ubiquitin-ELISA and western blot analysis confirmed that the Pgp molecule, which accumulated mainly at the cell surface, was ubiquitinated. However, lactacystin did not show any accumulation of Pgp in either the cytoplasm or the cell surface membrane, suggesting that the proteasome did not participate in the phenomenon. Additionally, the Pgp was limitedly proteolyzed by calpain into two 98 kDa and 69 kDa, fragments within one minute. Despite the increased accumulation of Pgp at the cell surface after treatment with calpain inhibitor, the cytoplasmic doxorubicin level of the cells treated with a calpain inhibitor was higher than that of non-treated cells and approached that of parental cells. These results indicated that calpain involved Pgp turnover and that calpain inhibition induced ubiquitinated Pgp-accumulation mainly at the cell surface membrane with a reduction in its own functions suggesting that the modulation of Pgp-turnover involves MDR-reversal by another approach.

Upper motor neuron predominant degeneration with frontal and temporal lobe atrophy.

The autopsy findings of a 78-year-old man mimicking primary lateral sclerosis (PLS) are reported. He showed slowly progressive spasticity, pseudobulbar palsy and character change, and died 32 months after the onset of symptoms. Autopsy revealed severe atrophy of the frontal and temporal lobes, remarkable neuronal loss and gliosis in the precentral gyrus, left temporal lobe pole and amygdala, mild degeneration of the Ammon's horn, degeneration of the corticospinal tract, and very mild involvement of the lower motor neurons. The anterior horn cells only occasionally demonstrated Bunina body by cystatin-C staining, and skein-like inclusions by ubiquitin staining. This is a peculiar case with concomitant involvement in the motor cortex and temporal lobe in motor neuron disease predominantly affecting the upper motor neuron.

Modulation of cAMP-mediated vasorelaxation by endothelial nitric oxide and basal cGMP in vascular smooth muscle.

Recent in vitro evidence shows a role of endothelial nitric oxide (NO) in the modulation of isoproterenol-induced vasorelaxation. To elucidate roles of endothelial cells and NO in cyclic adenosine monophosphate (cAMP)-mediated vasodilators we examined the effects of removal of endothelium and a NO synthase (NOS) inhibitor on relaxant responses in vitro of rat aortic strips to beta-adrenoceptor stimulants and colforsin dapropate, a water-soluble forskolin, and changes in cAMP and cyclic guanosine monophosphate (cGMP) contents. Relaxant responses of rat aorta to isoproterenol, denopamine, salbutamol, colforsin, and dibutyryl cAMP (dbcAMP) were blunted by removal of endothelial cells or treatment with NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). Relaxant response of endothelium-intact segments to isoproterenol was associated with increases in tissue cAMP and cGMP contents. Removal of endothelium or treatment with L-NAME markedly reduced basal cGMP and abolished the isoproterenol-induced increase in cGMP but not cAMP content. In endothelium-removed segments, pretreatment with sodium nitroprusside (SNP) restored the diminished relaxant response to isoproterenol and increased basal cGMP (from 0.08 +/- 0.01 to 0.16 +/- 0.02 pmol/mg protein), whereas it did not affect the isoproterenol-induced increase in cAMP. The diminished relaxant response of endothelium-removed segments to dbcAMP was not restored by SNP pretreatment. The results suggest that relaxant response of rat aorta to cAMP-mediated vasodilators is mediated, in part, by NO production in endothelium and subsequent increase in cGMP in vascular smooth-muscle cells.

Nonneural nuclear inclusions of androgen receptor protein in spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy is an X-linked motor neuronopathy caused by the expansion of an unstable CAG repeat in the coding region of the androgen receptor (AR) gene. Nuclear inclusions of the mutant AR protein have been shown to occur in the spinal motor neurons of spinal and bulbar muscular atrophy (Li M, Kobayashi Y, Merry D, Tanaka F, Doyu M, Hashizume Y, Fischbeck KH, Sobue G: Nuclear inclusions in spinal and bulbar muscular atrophy. Ann Neurol 1998 (in press)). In this study, we demonstrate the tissue-specific distribution, immunochemical features, and fine structure of nuclear inclusions of spinal and bulbar muscular atrophy. Nuclear inclusions were observed in affected spinal and brainstem motor neurons, but not in other, nonaffected neural tissues. Similar nuclear inclusions occurred in nonneural tissues including scrotal skin, dermis, kidney, heart, and testis, but not in the spleen, liver, and muscle. These inclusions had similar epitope features detectable by antibodies that recognize a small portion of the N-terminus of the AR protein only, and they were ubiquitinated. Electron microscopic immunohistochemistry showed dense aggregates of AR-positive granular material without limiting membrane, both in the neural and nonneural inclusions. These findings indicate that nuclear inclusions of AR protein are present in selected nonneural tissues as well as in neurons that degenerate in spinal and bulbar muscular atrophy, suggesting that a common mechanism underlies in the formation of neural and nonneural nuclear inclusions.

Tissue distribution of pathological lesions and Hu antigen expression in paraneoplastic sensory neuronopathy.

We investigated the distribution of lesions and Hu antigen expression in two autopsied cases of anti-Hu antibody-positive paraneoplastic sensory neuronopathy (carcinomatous subacute sensory neuropathy). Pathological changes in both patients were limited to the primary sensory neurons, some of the sympathetic ganglia and hippocampal regions. The lesions showed a multifocal distribution that differed among the spinal segmental levels and in the individual dorsal root ganglia as well as in the nerve fascicles. Western blot analysis of the patients' serum revealed that Hu antigens were extensively and widely expressed throughout the central nervous system, sensory and sympathetic ganglia and cancer cells, but not in the non-neural visceral tissues. Reverse transcriptase-polymerase chain reaction also showed that the Hu D, Hu C, Hel-N1 and Hel-N2 mRNAs were extensively and widely expressed through the neural tissues and cancer cells, but not in the visceral tissues. Thus, the distribution of antigen expression was very different from that of the lesions. Taken together with the distribution of lesions and Hu antigen expression, it is suggested that factors other than anti-Hu antibodies are also involved in the pathogenesis of this neuronopathy.