Retrospective analysis of the survival benefit of chemotherapy for recurrent or advanced epithelial ovarian carcinoma in patients previously treated with paclitaxel plus platinum-based chemotherapy.

AIM: The outcomes of treatment for women with recurrent or advanced epithelial ovarian carcinoma previously treated with pacli- taxel plus platinum-based chemotherapy were analyzed. MATERIALS AND METHODS: Retrospective analysis was performed in a total of 65 series of treatments provided for 35 patients with a history of paclitaxel plus platinum-based chemotherapy. The chemotherapy regimens used were classified into the following four types for analysis: conventional paclitaxel plus carboplatin therapy (TC arm), pegylated liposomal doxorubicin-containing regimens (PLD arm), CPT-11-containing regimens (CPT-11 arm), and others. Disease-control rates (DCRs) were compared and subjected to univariate analysis. Progression-free survival (PFS) was determined from the date of the first cycle of each chemotherapy with the Kaplan-Meier method, and comparisons were performed using the log-rank test. RESULTS: DCR was 80%, 71%, and 26% for the TC, PLD, and CPT-l arms, respectively. The median PFS was 286, 372, and 76 days for the TC, PLD, and CPT-11 arms, respectively. There was no discernible difference in PFS between the TC and the PLD arm. In contrast, PFS of the CPT- 11 arm was significantly shorter than that of the TC and PLD arms. In addition, three of seven (42.9%) treatments in the PLD arm maintained a progression-free period for longer than one year, while only one of 25 (4%) treatments in the TC arm maintained a progression-free period for more than one year. CONCLUSIONS: The PFS of PLD is similar to that of TC. PLD-containing regimens might have a potential benefit with a higher PFS over one year than the TC regimen.

A retrospective analysis of endometrial carcinoma cases surgically treated with or without para-aortic lymph node dissection followed by adjuvant chemotherapy.

PURPOSE: To analyze the efficacies of para-aortic node (PAN) dissection for patients undergoing surgery and adjuvant chemotherapy for endometrial carcinomas. METHODS: At the Osaka University Hospital and the Kaizuka City Hospital in Osaka, Japan, either pelvic lymph nodes (PLN) plus para-aortic lymph nodes (PAN) or PLN-only dissections were performed for endometrial carcinomas. An adjuvant chemotherapy using paclitaxel, epirubicin, and carboplatin was conducted for all such patients. A retrospective comparison of the efficacy of PAN dissection was conducted. RESULTS: Disease-free and overall survivals and frequency of PAN involvement at the first recurrence did not exhibit a statistically significant difference between the PLN-only group and the PLN + PAN group. Operation time was significantly longer in the PLN + PAN group than the PLN-only group, and the total blood loss was also significantly greater in the PLN+PAN group. CONCLUSION: PAN dissection may be omitted, without adverse effect on prognosis, for endometrial carcinoma patients with recurrence risks who undergo adjuvant chemotherapy using platinum, anthracycline and taxane derivatives.

Lipoic acid improves nerve blood flow, reduces oxidative stress, and improves distal nerve conduction in experimental diabetic neuropathy.

OBJECTIVE: To determine whether lipoic acid (LA) will reduce oxidative stress in diabetic peripheral nerves and improve neuropathy. RESEARCH DESIGN AND METHODS: We used the model of streptozotocin-induced diabetic neuropathy (SDN) and evaluated the efficacy of LA supplementation in improving nerve blood flow (NBF), electrophysiology, and indexes of oxidative stress in peripheral nerves affected by SDN, at 1 month after onset of diabetes and in age-matched control rats. LA, in doses of 20, 50, and 100 mg/kg, was administered intraperitoneally five times per week after onset of diabetes. RESULTS: NBF in SDN was reduced by 50%; LA did not affect the NBF of normal nerves but improved that of SDN in a dose-dependent manner. After 1 month of treatment, LA-supplemented rats (100 mg/kg) exhibited normal NBF. The most sensitive and reliable indicator of oxidative stress was reduction in reduced glutathione, which was significantly reduced in streptozotocin-induced diabetic and alpha-tocopherol-deficient nerves; it was improved in a dose-dependent manner in LA-supplemented rats. The conduction velocity of the digital nerve was reduced in SDN and was significantly improved by LA. CONCLUSIONS: These studies suggest that LA improves SDN, in significant part by reducing the effects of oxidative stress. The drug may have potential in the treatment of human diabetic neuropathy.

Molecular cloning of a novel protein-tyrosine phosphatase containing a membrane-binding domain and GLGF repeats.

A full-length cDNA encoding a novel cytosolic protein-tyrosine phosphatase (PTP), PTP-BAS, was cloned from human basophils. Due to in-frame deletions in the coding region, PTP-BAS exists in three isoforms: 7,455 bp (2,485 aa) for type 1, 7,398 bp (2,466 aa) for type 2 and 6,882 bp (2,294 aa) for type 3. All three isoforms contain a single PTP catalytic domain at the carboxyl termini as well as two distinct structural sequences. Amino terminal sequences of 300 amino acids are homologous to membrane-binding domains of cytoskeleton-associated proteins. Three 90 amino acid internal repetitive sequences are homologous to the GLGF repeats found in guanylate kinase proteins. PTP-BAS was expressed in various human tissues, especially highly in the kidney and lung. Interestingly, the BAS mRNA level in the fetal brain was remarkably high.

Hereditary motor and sensory neuropathy type 2C is genetically distinct from types 2B and 2D.

BACKGROUND: Linkage analysis studies have identified 3 genetically different varieties of hereditary motor and sensory neuropathy type 2 (HMSN 2, also called Charcot-Marie-Tooth disease type 2, or CMT 2): HMSN 2A (linked to 1p35-p36), 2B (to 3q13-q22), and 2D (to 7p14). Hereditary motor and sensory neuropathy type 2C is characterized by diaphragmatic and vocal cord paresis; its disease locus has not been mapped. OBJECTIVE: To determine whether the HMSN 2C phenotype, previously shown not to be linked to the HMSN 2A locus, is linked to the HMSN 2B or HMSN 2D loci. DESIGN: Linkage analysis. SETTING AND PATIENTS: Thirty-three subjects, including 12 affected individuals and 11 individuals at risk, in a large family with HMSN 2C. RESULTS: Evidence was found against linkage of HMSN 2C phenotype to either the HMSN 2B or the 2D loci. CONCLUSIONS: HMSN 2C is genetically distinct from HMSN 2A, 2B, and 2D. We think that at least 4 genetically distinct varieties of autosomal dominant HMSN 2 exist.

Nerve growth factor maintains regulation of intracellular calcium in neonatal sympathetic neurons but not in mature or aged neurons.

We examined the effects of nerve growth factor on the regulation of intracellular calcium levels of superior cervical ganglion neurons in terms of postnatal maturation and ageing. Rat superior cervical ganglion neurons from three age groups (neonatal: 0 to one-day-old, young adult: three to six-month-old, and aged: more than 24-month-old) were dissociated and cultured in the presence or absence of 100 ng/ml of nerve growth factor. Intracellular free calcium levels ([Ca2+]i) were measured using the fura-2 microfluorometry. Nerve growth factor treatment increased the resting [Ca2+]i of neonatal neurons, although it had no effect on those of mature and aged neurons. We further examined the effects of nerve growth factor on the transient increase of [Ca2+]i induced by methacholine (0.1 mM), caffeine (20 mM) or high-potassium medium (40 mM K+). Nerve growth factor pre-treatment significantly increased the population of neonatal superior cervical ganglion neurons which responded to methacholine, whereas almost all young adult and aged neurons responded to methacholine regardless of pre-treatment of nerve growth factor. Caffeine induced a cyclic alteration of [Ca2+]i (oscillation) in 45% of the neonatal superior cervical ganglion neurons when they were maintained without nerve growth factor, but nerve growth factor treatment suppressed the oscillation to 10% of neurons. In contrast to neonatal neurons, all of the young adult and aged neurons showed only a transient increase of [Ca2+]i in response to caffeine independent of nerve growth factor treatment. There was no significant effect of nerve growth factor on K+ depolarization-induced [Ca2+]i elevations at any of the ages studied. Nerve growth factor did not substantially alter the pattern of the transients induced by these three agents. Our results indicate that exogenous nerve growth factor is necessary to maintain normal acetylcholine receptor-mediated [Ca2+]i responses as well as Ca(2+)-induced Ca2+ release from intracellular calcium storage in neonatal superior cervical ganglion neurons. In mature superior cervical ganglion neurons, Ca2+ homeostasis becomes independent of exogenous nerve growth factor, and Ca2+ homeostasis and its independency are well preserved in aged neurons.

Expression of glial cell line-derived neurotrophic factor and GDNFR-alpha mRNAs in human peripheral neuropathies.

The steady-state mRNA levels of glial cell line-derived neurotrophic factor (GDNF), GDNFR-alpha and RET were examined in various human peripheral neuropathies to determine the relationship with myelinated fiber pathology, and T cell and macrophage invasions in the diseased nerves. GDNF and GDNFR-alpha mRNA levels were elevated to variable extent in the diseased nerves, although they were not specific to the type of diseases. The increase of GDNFR-alpha mRNA levels was correlated with the extent of the nerves with axonal pathology, and was proportional to the extent of invasion of the nerves by T cells and macrophages. The GDNF mRNA levels were not related to axonal, demyelinating pathology, or inflammatory cell invasions. RET mRNA expression was not detected in normal nor diseased nerves. The GDNF and GDNFR-alpha expression in the diseased human nerves is regulated by an underlying pathology-related process, and could play a role in peripheral nerve repair.

Morphometric analysis of the sural nerve in experimental dorsal rhizotomy in rats.

To investigate the histological changes in the sural nerve by the damage to the centrally projected axon (CPA), we examined light-microscopic findings after dorsal rhizotomy. The L4-6 dorsal roots were cut unilaterally near the entry zone, with minimal laminectomy, in 27 anesthetized 8- to 10-week-old Sprague-Dawley rats. Animals were killed 1, 2, 4 and 8 weeks and 6 months after surgery, and morphometric results from the sural nerves on the side of the rhizotomy were compared with those from the unaffected side. There were no significant differences in total number, density, frequency distribution of diameters, thickness of myelin, and axonal circularity of myelinated fibers. In an analysis of teased fibers, neither demyelinated nor remyelinated fibers were found, and significant axonal degeneration was found in only 1 of 27 sural nerves on the side of the rhizotomy. These results suggest that pathological damage to the sural nerve is not the product of CPA lesions, even if the subject has dorsal root lesions at some distance from the ganglion.

Acidity is involved in the development of neuropathy caused by oxidized cellulose.

Recently we demonstrated that oxidized cellulose (OC), a surgical topical hemostatic agent, induces subjacent nerve fiber degeneration by a diffusible chemical mechanism. Since OC is highly acidic, we examined the role of acidity in the development of neuropathy by OC in this study. Fifteen minutes' exposure to culture media containing OC (2 mg/ml, pH 3.47 or 10 mg/ml, pH 2.57) suppressed the subsequent neurite outgrowth of precultured rat DRG neurons in vitro. However, the neurotoxicity of OC disappeared when the pH of the media was restored to 7.42. Topical application of 20 mg OC lowered the pH in the subperineurium of the adjacent rat sciatic nerve to around 3, and kept it below 4 for 2 h in vivo. Application of 0.1 ml neutralized physiological saline containing 40 mg OC did not produce pathological changes in the adjacent rat sciatic nerve in vivo, in contrast to the marked subperineurial nerve damage by direct application of 20 or 40 mg OC observed in our previous study. These results strongly indicate that local neurotoxicity of OC is due to its high acidity. Further care is needed to avoid direct application of large amounts of OC to peripheral nerve.

Age of onset influences clinical features of chronic inflammatory demyelinating polyneuropathy.

Chronic inflammatory demyelinating polyneuropathy (CIDP), which can occur through life from childhood to old age, presents a wide variety of clinical phenotypes. We investigated the relationship between age of onset and phenotype in 124 CIDP patients. Clinical symptoms, pathologic findings and electrophysiologic features were assessed according to age at onset: juvenile, younger than 20-years-old; adult, 20 to 64; and elderly, older than 64 (total n=124). Half of the juvenile group showed subacute progression initially, while most patients in the elderly group showed chronic insidious progression (chi(2)=23.2, P<0.0001). Motor dominant neuropathy was prominent in juveniles, while sensorimotor neuropathy was frequent in the elderly group (chi(2)=27.0, P<0.0001). A relapsing and remitting course predominated in the juvenile group (chi(2)=8.50, P=0.0143). Demyelinating and axonal degenerating features in sural nerve biopsy and in nerve conduction studies were common to three age groups. The subperineurial edema was more prominent in the juvenile and adult groups (P=0.006). Functional recovery was common in all three age groups, but was least apparent in the elderly group (P=0.00062). Demyelinating features in studies of nerve conduction and biopsy specimens was common to all three age groups, and was a useful diagnostic feature. Clinical features of CIDP differ by age of onset, which is a factor to consider in diagnosis, therapy, and prognosis.

Clinicopathological features of chronic inflammatory demyelinating polyradiculoneuropathy in childhood.

The clinical, electrophysiological, and pathological findings, and the therapeutic characteristics in ten children with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), whose onset age was less than 16 years, were evaluated. The clinical progression pattern of the initial phase divided the patients into two groups. One group (six patients) showed a subacute progression for up to 2 months after onset and a subsided progression over 3 months. Three patients in this group had a preceding febrile episode. The other group (four patients) showed a chronic insidious progression for more than 3 months. The former group of patients revealed a favourable response to corticosteroid therapy as compared with the latter group. However, other clinical and laboratory features at the peak impairment were not distinguishable between these two groups. Motor dominant neuropathy was common to all patients, and only three cases showed sensory disturbance on the distal limbs. No cases revealed cranial nerve involvement. Motor and sensory nerve conduction and sural nerve biopsy studies revealed the demyelinating nature of the neuropathy. These clinicopathological features suggest that the subacute progression form frequently associated with prodromal episode and rather favourable corticosteroid response is characteristic in childhood CIDP, while the chronic insidious progression form is indistinguishable from the common adult CIDP.

Sensory conduction study of cisplatin neuropathy: preservation of small myelinated fibers.

We report a patient with peripheral neuropathy caused by cisplatin for the treatment of testicular tumor. Routine studies of nerve conduction and somatosensory evoked potentials demonstrated large myelinated fiber neuropathy suggesting ganglioneuronopathy. We also performed a CO2 laser evoked potential study, and found that small myelinated fibers, which are related to pain sensation, were well preserved in this patient.

Origin and spread of intra-epithelial carcinoma of the esophagus. Histopathologic investigation of the junctions between intraepithelial carcinoma and non-cancerous epithelium.

Scrutinization of data on 56 patients of primary esophageal squamous cell carcinoma and not given preoperative irradiation therapy disclosed 36 areas (64.1%) of intra-epithelial carcinoma contiguous to the main lesion, and in 16 (28.7%) there was a multiple occurrence of squamous cell carcinoma, in which 13 were double and 3 were triple carcinomas. A total of 96 junctions between intra-epithelial carcinoma and non-cancerous epithelium were histologically investigated. These junctions could be grouped into two types: well-demarcated (29 areas, 30.2%) and ill-demarcated (67 areas, 69.8%) types. The latter was separable into 12 (12.5%) of whole layer, 33 (34.4%) of basal layer and 22 (22.9%) of irregular patterns. Epithelial dysplasia occurred in one (3.4%) of well-demarcated and ten (14.9%) of ill-demarcated junctions, and almost all lesions of dysplasia were moderate or severe. Thus, most carcinomatous transformation had occurred at the site of junction (in-situ carcinogenesis) and epithelial dysplasia may be a carcinoma rather than pre-cancerous lesion, per se.

Terminal sequences of the replicative form of RNA of the Japanese encephalitis virus.

The 5' and 3' terminal sequences of the replicative form (RF) of RNA of a flavivirus, the Japanese encephalitis (JE) virus, strain Ja0ArS982, have been determined by in vitro labelling and mobility shift analysis. The plus strand sequence was 5'AGAAGUUUAUCUGUGUGAA...UCUOH3', while the minus strand sequence was 5'AGAUCCUGUGUUCUUCCUCA...UCUOH3'. These sequences were similar to those of West Nile (WN) virus being identical in 12 nucleotides at the 5'terminal of the minus strand, and in the 5'terminal dinucleotides, 5'AG3'. Somewhat more internal hexanucleotides 5'CUGUGU3' are conserved among 3 flaviviruses, the JE, WN, and yellow fever viruses.

[A family of hereditary motor and sensory neuropathy with spastic paraplegia (HMSN type V)].

Three siblings with hereditary motor and sensory neuropathy with spastic paraplegia (HMN V) were described. Their grandfather was suspected to have the similar symptoms. Their parents were normal and not consanguineous. The first case was a 54-year-old woman. She has suffered from difficulty in walking since the age of 10 years. Distal muscular weakness and wasting began at 20 years old. She was admitted to our hospital for investigation in 1988. Results of examination of the brain, cranial nerve, and cerebellar function were normal. The deep reflexes were hyperactive in the arm and knee, while absent at the ankle. Babinski's sign was definitely positive. Muscular weakness and wasting were noted in intrinsic hand muscles and in those below her knees. There were pes cavus and hammer toes, and the gait was spastic. Mild sensory disturbance was noted in distal limbs. The conduction velocity of motor nerve fibers of her limbs was below normal and that of sensory nerve fibers normal. Muscle biopsy of biceps brachii revealed neurogenic changes. Sural nerve biopsy showed decreased number of myelinated fibers of large diameter and formation of small oinion-bulb. The second and third cases were her brothers and proven to have the similar condition, but their onset of illness were earlier and their affections were more severe. A few cases of HMSN V with nerve biopsy findings have so far been reported and the family presented here is the first report in Japan.

[Double filtration plasmapheresis (DFPP) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)].

We studied the therapeutic characteristics of double filtration plasmapheresis (DFPP) in 14 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). The patients were classified into 2 subgroups of the responders (7 patients) and the non-responders (7 patients) to DFPP. The responders to DFPP were designated as those showing the improvement 2 or more grades in measures the activity of daily living by the modified Rankin scale (MRS). All these patients underwent neurological assessment, CSF study, electrophysiological studies at the beginning and end of treatment. Sural nerve biopsy study was performed in 10 cases. Neurological function was assessed serially using a quantitative neurological disability score (NDS). At the beginning of treatment, there were no significant differences in various measurements between the responders and the non-responders except for the frequency of demyelination. In responders, significant improvement was found in mean changes in MRS, NDS, motor nerve conduction velocity, compound muscle action potential, distal motor latency, while in non-responders, all measures remained unchanged or worsened. Muscle wasting was seen in 3/7 responders and 4/7 non-responders, and denervation potentials in needle EMG were seen in 1/7 responders and 3/7 non-responders. Four patients of the responders were classified as chronic relapsing course, and 6 patients of the non-responders as chronic progressive course. We conclude that DFPP was useful for the subgroups of CIDP patients, but the underlying immuno-pathological background that determine the efficacy of plasmapheresis should be elucidated.

[A case of Guillain-Barré syndrome after Campylobacter jejuni enterocolitis: anti-ganglioside antibody levels with or without Guillain-Barré syndrome].

A 38-year old man developed enterocolitis one day after he had ingested raw chicken. Nine days later, his grip strength weakened. Eleven days later, he was admitted to our hospital with weakness of four limbs, dysphagia and dysarthria. Serum anti-Campylobacter jejuni antibody and anti-ganglioside antibodies (GM1, GD1a, GD1b, GalNAc-GD1a) were positive, and motor action potentials were not evoked at all extremities. He was diagnosed as having Guillain-Barré syndrome. After receiving immune absorption therapy and plasma exchange therapy, the patient improved. Another person who had also consumed the same raw chicken developed colitis only. Five weeks later, the anti-GalNAc-GD1a-IgG antibody titers (O.D. 490 nm) of the patient and the other man who developed colitis were 0.324 and 0.118, respectively. It was suggested that the pathogenesis of Guillain-Barré syndrome after Campylobacter jejuni enterocolitis may be related to the type and titer of anti-ganglioside antibodies and also to the sensitivity of the individual.

[Pharmacokinetic study on aspoxicillin transfer into pulmonary and tracheal tissues].

Each of 36 patients who underwent tracheotomy for removal of malignant or benign tumors or for treatment of pneumothorax was infused with 2 g of aspoxicillin (ASPC, Doyle injection) intravenously over 1-hour period. ASPC concentrations determined at 1 postoperative time-point in tissues of the lung and trachea and in serum of each patient were analyzed pharmacokinetically to elucidate the transfer of ASPC to the thoracic tissues. The preventive effect of ASPC against postoperative infections was also investigated in 39 tracheotomy patients. 1. The analysis of ASPC concentrations in 36 patients with tracheotomy gave the following results; 1) The peak blood level (about 80 micrograms/ml) was attained at the end of infusion. The serum level then decreased with time to below about 10 micrograms/ml at 6 hours after the start of infusion, with an elimination half-life of about 1.4 hours, which was comparable to that in healthy adults. 2) Peak levels in the lung and tracheal tissues were achieved at about 30 minutes after the start of infusion, at levels of about 30 and 40 micrograms/g, respectively, which decreased to about 5 micrograms/g in both tissues at 6 hours after the start of infusion. 2. Thirty nine patients who were treated with ASPC before operation were examined for the preventive effect of ASPC against postoperative infections for 1 week after operation. No postoperative infection was noted in any patients and ASPC was found to be useful for prevention of postoperative infections. 3. No side effects or abnormal laboratory findings were noted in any patients. Based on the results of the transfer into the tissues of respiratory organs and preventive effect against postoperative infections, we have concluded that ASPC is useful for prevention of infections after thoracic operation.

[Tissue distribution of cefotetan in the field of obstetrics and gynecology].

The concentrations of cefotetan (CTT) in serum, uterus, ovary and oviduct tissues were determined in 30 patients after single intravenous drip infusion of 1 g over 1 hour. 1. Peripheral blood level of CTT was determined from 3 to 24 hours after injection. The maximum level was observed at 3 hours after injection and the concentration went down gradually with time. 2. The tissue concentrations of CTT in intrapelvic organs also tended to decrease with time and hardly detected 24 hours after injection. 3. From 3 to 12 hours after injection, mean penetration rate of CTT into intrapelvic organs was 40% and more. 4. Among intrapelvic organs, penetration rate into portio was highest, and others were ovary, uterine cervix, oviduct, endometrium, myometrium and uterine myoma in order of lowering penetration rate. 5. The penetration rate into uterine myoma was approximately half that into normal tissue. Considering above results, CTT is expected to show sufficient effects against Gram-negative bacilli and Bacteroides sp. when reasonably dosed.

[A case of multiple myeloma with intracerebral metastasis].

Compared to leukemia, malignant lymphoma and other hematogenous tumors, multiple myeloma rarely metastasizes to the central nervous system. Intracerebral metastasis without involvement of the cranium itself is rarer. We report a case of Ig-G k-type multiple myeloma with metastasis to the left frontal lobe extending to the right basal ganglia without involvement of the cranium. A 71-year-old male complained of exertional dyspnea and lumbago. His laboratory data revealed hyperproteinemia and an abnormal increase in Ig-G (6117mg/dl) in his serum. Serum protein immunoelectrophoresis revealed an IgG k-type band, and Bence-Jones protein was detected in his urine. MMPP, VMCP, VIPP and MP chemotherapy was given, and serum IgG level decreased to a normal range. 21 months after his first admission, incontinence, disorientation, gait disturbance and apathy developed. CT-scan showed an isodense lesion with massive edema in the left frontal lobe and right basal ganglia. On MRI, a Gd-DTPA enhancing lesion was detected extending from the left frontal to the opposite frontal lobe through the splenium. No abnormal skull punched out lesions were noted. Left frontal lobectomy was performed. Histopathology revealed plasmablastic myeloma cells with clear nucleole and eccentric nucleus in the cerebrum. He was diagnosed as having intracerebral metastasis of multiple myeloma without involvement of the cranium. Unfortunately, he died of pancytopenia and pneumonia. Our case suggests the possibility of metastasis via blood into the cerebrum.