A phase I study of vaccination with autologous, irradiated melanoma cells engineered to secrete human granulocyte-macrophage colony stimulating factor.
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Genetic Engineering↗
Biomedical subjects
T Lynch
Publications and source records attributed to T Lynch.
Potential impact on survival of improved tumor downstaging and resection rate by preoperative twice-daily radiation and concurrent chemotherapy in stage IIIA non-small-cell lung cancer.
PURPOSE: The main objectives of this study were (a) to ascertain the feasibility and toxicity of preoperative twice-daily radiation therapy and concurrent chemotherapy, surgery, and postoperative therapy in stage IIIA (N2) non-small-cell lung cancer (NSCLC), and (b) to evaluate tumor response, resection rate, pathologic tumor downstaging, and survival. METHODS: Eligibility included biopsy-proven N2 lesion (stage IIIA) by mediastinoscopy, Karnofsky performance score > or = 70, and weight loss less than 5% in the 3 months before diagnosis. The treatment program consisted of two courses of preoperative cisplatin, vinblastine, and fluorouracil (5-FU); 42 Gy concurrent radiation at 1.5 Gy per fraction in two fractions per day; surgery on day 57; and one more course of postoperative chemotherapy and 12 to 18 Gy of concurrent twice-daily radiation. RESULTS: Forty-two patients with stage IIIA (N2) NSCLC (27 men and 15 women, age 38 to 77 years) were enrolled onto this prospective study. Forty of 42 patients tolerated the intended dose (42 Gy) of preoperative radiation and 37 of 39 resected patients received prescribed postoperative radiation. The intended dose of chemotherapy was given in 100%, 70%, and 60% of patients for the first, second, and third courses of chemotherapy. Marked dysphagia that required intravenous hydration was noted in 14% of patients (six of 42). Myelotoxicities included grade > or = 3 granulocytopenia in 23% and thrombocytopenia in 6% of 113 chemotherapy courses. Febrile neutropenia that required hospital admission was noted in 9% of 113 chemotherapy courses. Surgical resection was performed in 93% of patients. Treatment-related mortality was noted in 7% of patients. The overall survival rates by the Kaplan-Meier method were 66%, 37%, and 37% at 2,3, and 5 years, respectively, with a median follow-up time of 48 months. Pathologic examination of the surgical specimen showed a downward shift in tumor extent from stage IIIA (N2) to stage II (N1) in 33%, to stage I (NO) in 24% (10 of 42), and to stage 0 (TONO) in 9.5%, for a total of 67%. The degree of tumor downstaging was also translated into a survival benefit: 5-year survival rates from the time of surgery were 79%, 42%, and 18% for postoperative tumor stages 0 and I, II, and III, respectively (P = .04). CONCLUSION: Concurrent chemoradiotherapy using twice-daily radiation is an effective induction regimen that resulted in 67% tumor downstaging, and an encouraging 37% 5-year survival rate. The degree of tumor downstaging may be a useful intermediate end point for survival benefit in stage IIIA (N2) NSCLC.
Adult↗
Trials of 9-amino-20(S)-camptothecin in Boston.
9-Amino-20(S)-camptothecin (9-AC) is an analog of camptothecin with limited water solubility which has shown significant preclinical activity in a variety of human solid tumor xenografts. A Phase I trial using a soluble formulation of 9-AC, given as a 72-hour continuous infusion, has been completed. Thirty-one patients with resistant cancers received 5-60 micrograms/M2/h at three week intervals. The Maximum Tolerated Dose (MTD) was 45 micrograms/M2/hour. Neutropenia was the dose limiting toxicity, with few significant non-myelosuppressive toxicities. Minor responses were seen in 3/31 patients. Pharmacokinetic studies of 9-AC lactone (closed ring) showed substantial interpatient variability with a predicted half-life of 36 hours. A phase I/II trial of the same formulation of 9-AC is ongoing in refractory leukemia. Stomatitis and diarrhea are the non-myelosuppressive dose limiting toxicities. Evidence of antineoplastic activity has been seen in 3/15 patients. A Phase II trial in previously untreated metastatic breast cancer is also underway. A Phase I trial of a colloidal dispersion formulation, not yet completed, is better tolerated with a MTD > 45 micrograms/M2/h as a 72-hour continuous infusion. Evidence of antineoplastic activity has also been demonstrated.
Adult↗
Delayed-onset cerebellar syndrome.
BACKGROUND: Delayed-onset involuntary movements, including dystonia and myoclonus, have been reported after stroke or head trauma. Moreover, there have been reports of delayed-onset isolated intention tremor and, in several of these cases, gait ataxia. OBJECTIVE: To further define the clinical features of a delayed-onset cerebellar syndrome. DESIGN: Subjects with cerebellar tremor and either head trauma or stroke were identified using a computerized database, providing detailed demographic and clinical information of 4002 patients with involuntary movements other than Parkinson's disease seen at our center between 1983 and 1995. Medical records and videotaped neurological examinations were retrospectively reviewed. SETTING: The Center for Parkinson's Disease and Other Movement Disorders at Columbia-Presbyterian Medical Center, New York, NY. PATIENTS: Five patients with delayed-onset cerebellar syndromes. RESULTS: Five patients with stroke or head trauma developed a cerebellar syndrome 3 weeks to 2 years after the initial insult. The syndrome, characterized by intention tremor, ataxic dysarthria, nystagmus, dysmetria, dysdiadochokinesis, and gait ataxia, was progressive in at least one patient. In four patients, lesions were present on neuroimaging in the thalamus or brain stem (especially in the midbrain). CONCLUSIONS: A delayed-onset cerebellar syndrome may follow head trauma or stroke. The syndrome is sometimes progressive and often disabling. The delayed onset implies that the syndrome is not caused by the initial lesion itself but may be caused by development of post-synaptic supersensitivity or secondary reorganization of involved pathways.
Adolescent↗
Glial cytoplasmic inclusions in multiple system atrophy.
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Cerebellum↗
Chromosome 12-linked autosomal dominant scapuloperoneal muscular dystrophy.
Scapuloperoneal syndromes are characterized by their distribution of muscle weakness and wasting. The reported pattern of inheritance has been variable. Both neurogenic and myopathic forms of autosomally dominantly inherited scapuloperoneal syndrome have been described. It has been suggested that these are variants of other neuromuscular diseases. We examined 44 members from a family with 14 members affected with a scapuloperoneal syndrome. Physiological and histological analysis implied that this condition is predominantly myopathic. Linkage analysis was done to confirm the genetic etiology of the disease in this family and to evaluate the possibility that it is a allelic variant of other neuromuscular diseases. Genetic analysis demonstrated linkage of the disease to chromosome 12, which makes it genetically distinct from other loci known to cause neuromuscular disease. Muscle fibers with hyaline desmin-containing cytoplasmic inclusions in combination with focal myopathic changes may be a disease-specific morphological marker of the disease.
Adult↗
The neuropathology of chromosome 17-linked dementia.
We recently described a family with chromosome 17-linked dementia, characterized clinically by disinhibition-dementia-parkinsonism-amyotrophy complex. We report now the neuropathology of 6 affected family members. This included semiquantitative scoring of neuronal loss, gliosis, and spongiosis and immunocytochemical and ultrastructural characterization of neuronal and glial inclusions. The changes consisted of circumscribed neuronal loss, gliosis, and spongiosis of limbic neocortical areas and frontal, temporal, and occipital association areas. Similar changes were present in subcortical nuclei, most severe in the substantia nigra, but also involved the ventral striatum and amygdala. The hippocampus was spared except for degeneration of the afferent perforant tract, secondary to entorhinal nerve cell loss. Argyrophilic neuronal inclusions, with a characteristic immunocytochemical profile, were found in brainstem nuclei, hypothalamus and basal ganglia. Ultrastructurally, in 3 patients these inclusions showed hitherto undescribed abnormally assembled filaments. Glial cytoplasmic inclusions were widespread in white matter structures. Immunocytochemistry failed to demonstrate the protease-resistant prion protein. The pathology appears to be unique, involving various cortical and subcortical structures, and is consistent with the clinical findings of Kluver-Bucy-like syndrome, parkinsonism, and frontal lobe dementia. For this entity we suggest the term "chromosome 17-linked dementia."
Brain↗
Diagnostic guidelines in central nervous system Whipple's disease.
Many cases of central nervous system (CNS) Whipple's disease are not diagnosed until postmortem. Few reviews of CNS Whipple's disease have delineated the frequencies of abnormalities on neurological examination, cerebrospinal fluid studies, neuroimaging, and intestinal biopsy studies. Guidelines for diagnosis and treatment have not been proposed. In this review we present 3 new cases of CNS Whipple's disease and summarize the literature to determine the frequencies of neurological signs and abnormalities on diagnostic testing. We propose guidelines for diagnostic screening, selection for biopsy, and treatment. Review of the 84 cases of CNS Whipple's disease (81 in the literature, 3 new) revealed that 80% of the patients had systemic signs. Cognitive changes were frequent (71%), and 47% with cognitive changes also had psychiatric signs. Oculomasticatory myorhythmia and oculo-facial-skeletal myorhythmia, pathognomic for CNS Whipple's disease, were present in 20% of patients, and were always accompanied by a supranuclear vertical gaze palsy. Tissue biopsy was a sensitive technique; 89% of those who had biopsies had positive biopsy results. Diagnosis and treatment of definite CNS Whipple's disease should be based on the presence of pathognomic signs (oculomasticatory myorhythmia or oculo-facial-skeletal myorhythmia) or positive biopsy or polymerase chain reaction results. Possible CNS Whipple's disease should be diagnosed in the setting of unexplained systemic symptoms and neurological signs (supranuclear vertical gaze palsy, rhythmic myoclonus, dementia with psychiatric symptoms, or hypothalamic manifestations). Those with possible CNS Whipple's disease should undergo small-bowel biopsy.
Anti-Bacterial Agents↗
Reliability of patient completion of the historical section of the Unified Parkinson's Disease Rating Scale.
Evaluating the reliability of self-assessed disability in patients with Parkinson's disease (PD) is important for therapeutic trials epidemiologic surveys. This is the first study to examine the interrater reliability between physician and patient in the historical section of the Unified Parkinson's Disease Rating Scale (UPDRS). Thirty consecutive subjects with idiopathic PD self-administered the historical section of a modified UPDRS. This instrument was then readministered to these 30 subjects by a neurologist. Interobserver reliability was assessed with the weighted kappa statistic (kw). The kw for each of the 17 items in the historical section of the UPDRS ranged from 0.63 to 1.0 (moderate to excellent agreement). Total kw = 0.83 (95% confidence interval = 0.79-0.87). There were no correlations between kw and age, disease duration, dose of levodopa, Hoehn and Yahr score, Schwab and England score, or modified Mini-Mental State score. Nondemented subjects with PD may reliably assess their level of disability by self-administering the historical section of the UPDRS. This has important implications for the reliable use of self-administered disability instruments for clinical research.
Activities of Daily Living↗
Assessment of preoperative accelerated radiotherapy and chemotherapy in stage IIIA (N2) non-small-cell lung cancer.
Forty patients with N2 non-small-cell lung cancer (stage IIIA), as determined by mediastinoscopy, were entered into a preoperative neoadjuvant study of chemotherapy (platinum, 5-fluorouracil, vinblastine) and accelerated radiotherapy (150 cGy twice per day for 7 days) for two cycles. Surgical resection was then performed and followed up with an additional cycle of chemotherapy and radiotherapy. All patients completed preoperative therapy. A major clinical response was seen in 87% of patients. Thirty-five patients underwent resection (one preoperative death, one refused operation, one had deterioration of pulmonary function, and two had pleural metastases). Operative mortality rate was 5.7% (2/35). Sixty percent of patients had no complications. Major complications included pulmonary emboli (three), pneumonia (two), and myocardial infarction (one). Down-staging was seen in 46% of patients, with two patients (5.7%) having no evidence of tumor in the specimen, five patients having sterilization of all lymph nodes, and nine patients having sterilization of mediastinal nodes but positive N1 nodes. Median survival of 40 patients was 28 months, with a projected 5-year survival of 43%. Patients with downstaged disease had statistically significant improved survival compared with patients whose disease was not downstaged.
Antineoplastic Agents↗
The fate of the defunctioned bladder following supravesical urinary diversion.
OBJECTIVE: To determine the nature, incidence and severity of bladder complications after supravesical urinary diversion without cystectomy and to identify preventative risk factors. PATIENTS AND METHODS: A retrospective study of the last 25 years identified 35 patients who had supravesical urinary diversion without concomitant cystectomy (33 ileal loop diversions and two cutaneous ureterostomies). Urinary diversion was performed for a variety of lower urinary tract pathologies. Patients with urinary tract neoplasia were excluded. There were 15 males (mean age 41 years, range 13-72) and 20 females (mean age 49 years, range 15-81) with a mean follow-up of 5.2 years (range 1-25). RESULTS: There were bladder complications in 10 patients (28%) including pyocystis (one mild and two severe), haemorrhage (two mild and one severe) and pain/spasm (four mild and three severe). Patients with interstitial cystitis, bladder outflow obstruction and/or a vesical fistula appeared to have a higher risk of complications. Four patients required cystectomy to treat severe symptoms while the remaining six achieved control of symptoms with no surgery. No patient developed carcinoma during the follow-up. CONCLUSION: We recommend that cystectomy is considered at the time of supravesical urinary diversion, particularly in patients with interstitial cystitis, bladder outflow obstruction or a chronically infected bladder and especially in those with a vesical fistula.
Adolescent↗
Localization of the gene for rapidly progressive autosomal dominant parkinsonism and dementia with pallido-ponto-nigral degeneration to chromosome 17q21.
Rapidly progressive autosomal dominant parkinsonism and dementia with pallido-ponto-nigral degeneration (PPND) is a neurodegenerative disorder which begins later in life (> 30 years of age) and is characterized by rapidly progressive parkinsonism, dystonia, dementia, perservative vocalizations and pyramidal tract dysfunction. The disease is observed in a large American family that includes almost 300 members in nine generations with 34 affected individuals. In this kindred evidence for linkage to chromosome 17q21 was obtained with a maximum lod score of 9.08 for the D17S958 locus. Multilocus analysis positions the disease gene in an approximately 10 cM region between D17S250 and D17S943. Notably, the disease locus for a clinically distinct familial neurodegenerative disease named 'disinhibition-dementia-parkinsonism-amyotrophy complex' (DDPAC) was recently mapped to the same region of chromosome 17, suggesting that PPND and DDPAC may possibly originate from mutations in the same gene.
Adult↗
Topotecan today.
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Antineoplastic Agents↗
Evaluation of p53 protein expression in renal cell carcinoma: comparison of two antibodies.
The aims of this study were to establish a profile for the expression of p53 in primary renal cell carcinoma using the polyclonal antibody NCL-CB1 and the monoclonal antibody D07, and to compare the results of staining with both antibodies. Ninety-six cases were studied using formalin-fixed paraffin-embedded tissue. Positive nuclear staining ranged from 5% (D07) to 12% (NCL-CM1). Positive cytoplasmic staining ranged from 7% (D07) to 25% (NCL-CM1) of cases. Interobserver agreement was excellent. The findings suggest that such a low level of immunohistochemical positivity reduces any potential prognostic value for p53 in this tumour type.
Antibodies↗
ICE homologs: a Pandora's box.
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Animals↗
Generalized chorea in an infant with semilobar holoprosencephaly.
We report chorea in an infant with holoprosencephaly. Congenital structural brain disease has not been a reported cause of chorea. Cranial magnetic resonance imaging revealed small, fused frontal lobes with hypoplastic caudates. Our patient responded to symptomatic treatment with dopamine-depleting agents. It is likely that the mechanism for the chorea was a dysfunction of the striatum. The differential diagnosis of childhood chorea should include holoprosencephaly.
Child, Preschool↗
Response to "Sertraline and isocarboxazid cause a serotonin syndrome".
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1-Naphthylamine↗
Serotonin syndrome.
We describe a patient treated with trazodone, isocarboxazid, and methylphenidate hydrochloride who developed confusion, agitation, poor concentration, rigidity, myoclonus, involuntary movements, orthostatic hypotension, and hyperreflexia. CK was normal, and the syndrome resolved spontaneously over 12 hours. The serotonin syndrome occurs following the use of serotomimetic agents (serotonin reuptake inhibitors, tricyclic and tetracyclic antidepressants, tryptophan, 3,4-methylenedioxy-methamphetamine, dextromethorphan, meperidine, S-adenosylmethionine) alone or in combination with monoamine oxidase inhibitors. It is characterized by various combinations of myoclonus, rigidity, hyperreflexia, shivering, confusion, agitation, restlessness, coma, autonomic instability, low-grade fever, nausea, diarrhea, diaphoresis, flushing, and rarely, rhabdomyolysis and death.
Depressive Disorder↗