DNA adducts in human pancreatic tissues and their potential role in carcinogenesis.

Pancreas cancer is the fourth and fifth leading cause of cancer death for men and women, respectively, in the United States. Although the etiology of this cancer is poorly understood, smoking and dietary fat have been implicated by epidemiological studies. To test the hypothesis that DNA damage derived from carcinogen exposure and diet is involved in pancreatic carcinogenesis, aromatic and lipid peroxidation-related DNA adducts in 13 normal tissues adjacent to tumor and 20 tumors from pancreatic cancer patients were analyzed by 32P-postlabeling. Normal pancreatic tissues from 5 nonpancreatic cancer patients and 19 healthy organ donors served as controls. To correlate the DNA adduct level with patients' characteristics, information on age, sex, body mass index, and smoking status of pancreatic cancer patients were collected from medical records. A significantly higher level of total DNA adducts was detected in pancreatic cancer patients as compared with controls. The mean level of adducts/10(8) nucleotides in adjacent normal pancreatic tissues from pancreatic cancer patients (A tissues) was 102 +/- 21 compared with 39 +/- 6 and 13 +/- 1 in pancreatic tumor tissues (T tissues) and normal pancreatic tissues from controls (C tissues), respectively. Among the adducts observed, one single aromatic adduct (spot 1) was present in 100, 90, and 0% of the A, T, and C tissues, respectively. Two novel clusters of adducts (spots 2 and 3) were observed in 11 of 13, 12 of 20, and 2 of 24 of A, T, and C tissues, respectively, and the presence of these adducts was positively correlated with smoking status. In addition, the previously defined smoking-related diagonal radioactive zone was detected in three A samples only, although 50% (10 of 20) of the patients with pancreatic cancers in this study were ever smokers. Putative lipid peroxidation-related adducts were detected in all samples examined and were significantly higher in A than in T and C samples. Multiple regression analyses showed that body mass index was positively correlated to the levels of spot 1 and the lipid peroxidation-related adducts in A tissues and the total aromatic adducts in tumors. Smoking was also positively correlated to the level of total adducts. These observations are consistent with previous epidemiological findings and support the hypothesis that DNA damage related to carcinogen exposure and lipid peroxidation is involved in human pancreatic carcinogenesis.

Analysis of a diagnostic strategy for patients with suspected tumors of unknown origin.

PURPOSE: Diagnostic strategies designed to identify the underlying primary malignancies in patients with unknown primary tumors (UPTs) have relied on retrospective analyses. We analyzed 879 consecutive patients referred with suspected UPTs to determine the yield and cost of a limited diagnostic evaluation, assess the contribution of specific studies to diagnosis, and analyze the survival patterns of patients in whom the primary tumor was diagnosed. PATIENTS AND METHODS: Data from patients with a suspected UPT were entered into a computerized data base, and the patients underwent a predefined limited diagnostic evaluation. Primary malignancies were diagnosed by pathologic review alone or by pathologic criteria plus a physical or radiographic finding. Survival was measured from diagnosis, estimated using the Kaplan-Meier method, and compared using the Cox-Mantel log-rank test. RESULTS: A primary tumor was found in 179 of 879 patients (20%). The survival duration of patients in whom the primary tumor was diagnosed was superior to that of patients in whom the primary tumor remained unknown. Specific patient subsets contributed most to the improved survival duration of the group in which the primary tumor was found, including lymphoma patients diagnosed solely by pathologic criteria and female patients with primary breast or ovarian cancer. The cost of diagnosis was mostly due to the extensive use of computed tomography. Except for ovarian cancer, computed tomography rarely identified treatable primary tumors. CONCLUSION: The limited diagnostic evaluation used in this study identified patients with treatable malignancies and increased the survival duration of a population of suspected UPT patients. Primary malignancies with the best survival can be diagnosed through careful pathologic review and focused evaluations for breast and ovarian cancer in women.

Unknown primary carcinoma: natural history and prognostic factors in 657 consecutive patients.

PURPOSE: To evaluate the natural history, validate previous observations, and identify prognostic factors in patients with unknown primary carcinoma (UPC). PATIENTS AND METHODS: Nine hundred twenty-seven consecutive patients referred to the M.D. Anderson Cancer Center with a preliminary diagnosis of UPC were prospectively identified. A standardized evaluation narrowed the study population to 657 patients with UPC. All data were recorded and computerized for storage, retrieval, and analysis. The primary end point for the study was survival, which was calculated from the first day of patient registration. Survival curves were estimated using the Kaplan-Meier method and compared using the Cox-Mantel log-rank test. To identify important prognostic factors, univariate and multivariate analyses were conducted. RESULTS: The demographics of the UPC patient population mirrored those of the general population of patients referred to our cancer center except for an excess of men among the UPC patients. Most patients had histologic or cytologic evidence of adenocarcinoma and had more than one organ site metastatically involved. Univariate and multivariate analyses identified numerous important prognostic factors with a significant influence on survival, including sex, number of organ sites involved, specific organ sites involved, and pathologic subtypes. CONCLUSION: This study validated previously identified important prognostic factors for survival in UPC. Additional variables that had an impact on survival were identified and the complex interaction of the factors was explored. As patient numbers increase, this database will be able to provide further analyses of patient subsets and potentially relate specific clinical features to the evolving molecular and biochemical understanding of these malignancies.

Poorly differentiated carcinoma and poorly differentiated adenocarcinoma of unknown origin: favorable subsets of patients with unknown-primary carcinoma?

PURPOSE: The objectives of this study were to assess clinical outcomes and prognostic factors in unselected, consecutive patients with poorly differentiated carcinoma (PDC) or poorly differentiated adenocarcinoma (PDA). PATIENTS AND METHODS: The 1,400 patients analyzed were referred to our unknown-primary tumor (UPT) clinic from January 1, 1987 through July 31, 1994. Clinical data from these patients were entered into a computerized data base for storage, retrieval, and analysis. Survival was measured from the time of diagnosis; survival distribution was estimated using the product-limit method. Multivariate survival analyses were performed using proportional hazards regression and by recursive partitioning. RESULTS: Nine hundred seventy-seven patients were diagnosed with unknown-primary carcinoma (UPC) and 337 of these patients had PDC or PDA. No clinical differences were identified among patients with PDC, PDA, or UPC patients with other carcinoma or adenocarcinoma subtypes. PDC patients enjoyed better survival than PDA patients. Poor cellular differentiation was not an important prognostic variable. Variables predictive of survival included lymph node metastases, sex, number of metastatic sites, histology (PDC v PDA), and age. Although chemotherapy did not appear to influence survival for the entire group of PDC or PDA patients, a subset of patients with good prognostic features experienced median survival durations of up to 40 months. CONCLUSION: The long median survival and chemotherapy responsiveness of UPC patients with PDC and PDA could not be confirmed. However, subpopulations with prolonged median survival durations could be defined, and the value of chemotherapy in this group remains to be determined. Identification and exclusion of treatable or slow-growing malignancies may account for the poor survival of the PDC and PDA patients reported in this study.

Unknown primary tumors metastatic to liver.

PURPOSE: The objectives of this study were to identify prognostic factors for unknown primary tumor (UPT) patients with hepatic metastases, determine the common primary tumors identified, assess the yield of specific diagnostic studies, and evaluate the impact of therapy on survival. PATIENTS AND METHODS: The 1,522 patients analyzed were referred from January 1, 1987 through June 30, 1995. Clinical data from these patients were entered into a computerized database for storage, retrieval, and analysis. Survival was measured from the time of diagnosis; survival distribution was estimated by the product limit method. Multivariate survival analyses were performed by proportional hazards regression. RESULTS: Five hundred UPT patients had liver metastases. Primary tumors, usually lung, colorectal, or pancreatic neoplasms, were identified in 135 patients (27%). The remaining 365 unknown primary carcinoma (UPC) patients with liver involvement had a higher death rate than those without liver involvement (hazards ratio, 1.63; P < .0001). Neuroendocrine carcinoma patients had a lower death rate than patients without this histology (hazards ratio, 0.29; (P < .0001). Two hundred sixteen of 365 patients with UPC and liver metastases received chemotherapy. Chemotherapy-treated patients had a lower death rate than those who were not treated with chemotherapy (hazards ratio, 0.52; P < .0001). The effect of chemotherapy was most pronounced in patients with adenocarcinoma. CONCLUSION: Hepatic metastases in UPC patients portend a generally poor prognosis. However, subsets of patients with more favorable outcomes can be identified by available clinical and pathologic data. Chemotherapy may be beneficial for the large subset of UPC patients with adenocarcinoma that involves the liver.

Classification and regression tree analysis of 1000 consecutive patients with unknown primary carcinoma.

The clinical features and survival times of patients with unknown primary carcinoma (UPC) are heterogeneous. Therefore, the goals of this study were to apply a novel analytical method to UPC patients to: (a) identify novel prognostic factors; (b) explore the interactions between clinical variables and their impact on survival; and (c) illustrate explicitly how the covariates interact. The 1000 patients analyzed were referred to the University of Texas M. D. Anderson Cancer Center from January 1, 1987 through November 30, 1994. Clinical data from these patients were entered into a computerized database for storage, retrieval, and analysis. Multivariate analyses of survival were performed using recursive partitioning referred to as classification and regression tree (CART) analysis. The median survival for all 1000 consecutive UPC patients was 11 months. CART was performed with an initial split on liver involvement, and 10 terminal subgroups were formed. Median survival of the 10 subgroups ranged from 40 months (95% confidence interval, 22-66 months) for UPC patients with one or two metastatic organ sites, with nonadenocarcinoma histology, and without liver, bone, adrenal, or pleural metastases to 5 months (95% confidence interval, 4-7 months) in UPC patients with liver metastases, tumor histologies other than neuroendocrine carcinoma, age >61.5 years, and a small subgroup of patients with adrenal metastases. Two additional trees were also explored. These analyses demonstrated that important prognostic variables were consistently applied by the CART program and effectively segregated patients into groups with similar clinical features and survival. CART also identified previously unappreciated patient subsets and is a useful method for dissecting complex clinical situations and identifying homogeneous patient populations for future clinical trials.

A SOD1 gene mutation in a patient with slowly progressing familial ALS.

We report a new missense mutation (Gly12Arg) [corrected] in exon 1 of the Cu/Zn superoxide dismutase (SOD1) gene in a 67-year-old patient with familial ALS (FALS). The clinical course showed an unusually slow progression. The enzymatic activity of the mutated SOD1 was 80% of normal. At the molecular level, the Gly12Arg [corrected] mutation occurs in a region outside the active site and may lead to local distortion strain in the protein structure.

Underexpression of messenger RNA for peripheral myelin protein 22 in hereditary neuropathy with liability to pressure palsies.

Hereditary neuropathy with liability to pressure palsies (HNPP) is associated with a deletion in chromosome 17p11.2, including the gene for the peripheral myelin protein 22 (PMP-22). Because of the proposal that a decreased dosage of the PMP-22 gene was the cause of HNPP, we evaluated sural nerves from eight patients with the 17p11.2 deletion and from five normal controls. The relative amount of PMP-22 mRNA was significantly lower in HNPP patients compared with normal controls (p < 0.02) using a semiquantitative reverse transcriptase-polymerase chain reaction. There was no significant decrease of Pzero mRNA. Sural nerves from HNPP patients showed normal immunostaining with monoclonal antibodies against PMP-22, Pzero, and myelin basic protein, and only rare myelinated fibers, classified as "tomacula," showed a patchy staining of the compact myelin with monoclonal antibody against PMP-22. The significant underexpression of PMP-22 mRNA in HNPP patients compared with normal controls demonstrates that a decreased dosage of the PMP-22 gene is the most likely pathogenetic mechanism in HNPP.

The selective breakdown of frontal functions in patients with obsessive-compulsive disorder and in patients with schizophrenia: a double dissociation experimental finding.

In an our recent preliminary study, we reported the neuropsychological finding of a double dissociation in the frontal lobe functioning between 25 OCD patients and 25 schizophrenics. The first group performed normally in the Wisconsin Card Sorting Test (WCST), which is considered sensitive to Dorso-Lateral Prefrontal Cortex (DLPFC) dysfunctions and abnormally to the Object Alternation Test (OAT), which has been proposed as a tool sensitive to Orbito-Frontal Cortex (OFC); on the other hand, schizophrenics performed abnormally to the WCST and normally to the OAT. The present study, conducted on a new sample of 60 schizophrenic in-patients, 60 OCD in-patients and 30 normal subjects, matched according to age, educational level, handedness and duration of illness, confirms our preliminary data and it suggests a more selective impairment of OFC system in OCD and of DLPFC in schizophrenia. Moreover, schizophrenic patients with paranoid subtype showed worse WCST performance compared to non-paranoid subtype. Our results could open some interesting perspectives about the neuroanatomical systems involved in these two major psychiatric illnesses and so, about their pharmacological treatment, on the basis of the prominent catecholaminergic characterization of the DLPFC and, respectively, the cholinergic innervation of the OFC.

The Wisconsin Card Sorting Test discriminates schizophrenic patients and their siblings.

The following report is an evaluation of the performances of 35 schizophrenic patients and 35 of their siblings on the Wisconsin Card Sorting Test (WCST), a neuropsychological test considered sensitive to frontal lobe functioning. Thirty five normal subjects matched for age and education were the comparison group. The purpose of this study was to examine the relationship of the neurofunctional basis for schizophrenia to its familiar occurrence. Non-schizophrenic siblings of schizophrenic patients did not perform significantly different from normal subjects on the WCST; however, schizophrenic patients performed significantly worse than both their siblings and normal subjects. These results indicate that WCST dysfunction seems to be a characteristic related to the presence of the disease and that non-genetic factors could contribute to the WCST pathological profile.

Size of the corpus callosum and auditory comprehension in schizophrenics and normal controls.

19 schizophrenic patients and 15 normal controls, matched for sex and age, were evaluated by magnetic resonance imaging for corpus callosal size and had neuropsychological functioning assessed using an auditory comprehension test. Although the MRI data did not reveal any significant differences between groups, the degree of laterality to the left versus right ear response was significantly correlated with the size of the posterior part of the corpus callosum in male schizophrenics.

Frontal and callosal neuropsychological performances in schizophrenia. Further evidence of possible attention and mnesic dysfunctions.

Some level of frontal and callosal dysfunction has been reported in patients with schizophrenia. In the present study 68 normal controls and 117 schizophrenic patients were administered the Wisconsin Card Sorting Test (WCST), which involves the function of the frontal areas, and the Auditory Comprehension Test (ACT) which involves the corpus callosum and to a lesser degree attention and mnesic mechanisms. WCST correctly discriminated 69.8% of schizophrenics and 74.2% of controls, ACT 86.7% of schizophrenics and 90.2% of controls. Moreover, schizophrenics correctly classified by the WCST performed more poorly than schizophrenics incorrectly classified by the WCST on the related ACT indices for the attention and mnesic mechanisms. There were no differences in present age, age at onset, duration of the illness, diagnostic subtype and course of the disease between correctly and incorrectly classified schizophrenics by the WCST and the ACT. These data indicate a prevalent malfunctioning of attention and mnesic mechanisms in schizophrenia. Finally there seems to be no relationship between these neurofunctional abnormalities and demographic and clinical characteristics of the disease.

An assessment of the Wisconsin Card Sorting Test as an indicator of liability to schizophrenia.

In order to test the hypothesis that a poor performance in the Wisconsin test (WCST) may be an indicator of liability to schizophrenia, we compared the WCST performances of patients with DSM III-R schizophrenia, normal controls, and patients with schizotypal personality disorder (SZT PD). While schizophrenic patients performed significantly worse than subjects in the other two groups, schizotypal and normal subjects showed no significant differences in the WCST execution. Moreover, patients with SZT PD with or without positive family history for the schizophrenic spectrum had similar WCST performances. Our observations are in keeping with other studies employing the WCST in paradigms of heightened liability to schizophrenia, and suggest that a poor performance in the test is more probably a feature of the disease process, than a trait marker of vulnerability to the illness demonstrable in high-risk subjects.

Unknown primary cancer presenting as an adrenal mass: frequency and implications for diagnostic evaluation of adrenal incidentalomas.

BACKGROUND: Fine-needle aspiration biopsy to identify adrenal metastasis from an occult primary malignancy has been recommended as part of the evaluation of the patient who presents with an incidentally discovered adrenal mass. This recommendation was assessed by examining the frequency of adrenal involvement in patients with suspected unknown primary cancer. METHODS: Data from 1715 patients referred for evaluation of suspected unknown primary cancer were retrospectively reviewed. RESULTS: Of 1639 patients found to have cancer, the adrenal gland was identified as a site of involvement at presentation in 95 (5.8%). Involvement was limited to the adrenal gland in 4 patients (0.2%). All 4 patients had large (> or = 6 cm) adrenal tumors, 3 of 4 had bilateral involvement, and all had symptoms that otherwise mandated evaluation for an occult malignancy; none had a true adrenal incidentaloma. CONCLUSIONS: Although cancer of an unknown primary site occasionally involves the adrenal gland, metastatic cancer presenting as a true adrenal incidentaloma is extremely rare. Therefore, in the absence of a history of prior malignancy or symptoms, physical examination findings, radiographic findings, or laboratory findings suggestive of an occult malignancy, we do not recommend fine-needle aspiration biopsy as part of the diagnostic evaluation of the patient who presents with a unilateral adrenal mass.

Absence of antimycobacterial synergism between garlic extract and antituberculosis drugs.

Garlic extract inhibited the growth of four strains of Mycobacterium tuberculosis, three strains of Mycobacterium avium-intracellulare, and three strains of Mycobacterium kansasii in concentrations ranging from 0.98 mg/ml to 2.94 mg/ml. Synergism could not be demonstrated when garlic extract was added to various concentrations of four commonly used antituberculous drugs.

Assessment of motor neuron excitability in parkinsonian rigidity by the F wave.

F-wave responses from abductor pollicis brevis muscle occurred more frequently, with a larger amplitude and longer duration in rigid parkinsonian patients than in age-matched normal controls. F-wave potentiation during voluntary contraction was impaired in parkinsonian patients. These findings suggest that spinal motor neuron excitability is enhanced in rigidity. F-wave amplitude was significantly correlated to the clinical evaluation of motor disability, so that the F wave may be regarded as a useful approach to quantitative evaluation of rigidity.

Motor evoked potentials following cervical electrical stimulation in brachial plexus lesions.

The diagnostic relevance of recording motor evoked potentials (MEPs) after electrical stimulation of the cervical region, as compared with conventional needle electromyography (EMG), was evaluated in 26 patients with brachial plexus (BP) damage of different aetiology, severity and topography. MEP abnormalities (absence or latency increase) were observed in at least one muscle of all the patients, with a global incidence of 61.5% of the muscles examined. Neurogenic EMG signs were present in all but one patient with an incidence of 62.2% of the muscles examined. Combining the two methods, the global incidence of abnormalities rose to 69.9%. MEP abnormalities were consistent with the clinical topography and severity of BP lesions and were fairly parallel with EMG findings. Recording MEPs after percutaneous electrical stimulation of the cervical region may be regarded as a rapid, non-invasive method for quantitative electrophysiological assessment of BP damage.

Molecular diagnosis of hereditary neuropathy with liability to pressure palsies (HNPP) by detection of 17p11.2 deletion in Italian patients.

Hereditary neuropathy with a liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent pressure palsies generally precipitated by minor trauma; weakness and paraesthesia usually improve and recover completely in a few months. By Southern blotting and fluorescent in situ hybridization analysis we confirm the presence of a 17p11.2 deletion in familial and in isolated cases of HNPP, suggesting that molecular analysis of the 17p11.2 region could also be a reliable and non-invasive method of diagnosis in sporadic cases, where a correct diagnosis usually requires a nerve biopsy. Although HNPP is a mild disease and not all patients seek medical attention, a presymptomatic diagnosis is useful for assessing the risk during genetic counselling, due to the inheritance of the mutation.

Testing for pre-synaptic and post-synaptic changes in the soleus H reflex pathway following selective muscle vibration in humans.

Muscle vibration does not affect post-synaptic excitability of the corresponding motoneuronal pool, the concurrent depression of the monosynaptic reflex resulting from a pre-motoneuronal block of Ia spindle afferents. Indeed (1) both homonymous and heteronymous soleus responses (to electrical stimulation of the posterior tibial nerve (TN) and femoral nerve (FN), respectively) are clearly depressed during selective vibration of the homologous muscle (namely soleus (S) or quadriceps (Q)), but remain completely unchanged during vibration of the heterologous muscle (i.e. Q or S); (2) the effectiveness of facilitatory conditioning of FN and TN Ia afferents, respectively on the S motoneuronal pool is definitely reduced during vibration of the homologous muscle (namely Q and S).

Use of cosH1 probe in hereditary neuropathy with liability to pressure palsies: a reliable genetic test for demonstration of identical size of 17p11.2 deletion in unrelated patients.

We describe pulsed-field gel electrophoresis (PFGE) analysis of 10 unrelated Italian families and seven isolated cases with hereditary neuropathy with liability to pressure palsies (HNPP). Our sample includes patients with different clinical features, varying from classical liability to pressure palsies to ingravescent polyneuropathy. The frequency and the uniformity in size of the 17p11.2 deletion was evaluated by using cosH1 probe from the Charcot-Marie-Tooth neuropathy type 1A (CMT1A)-REP region. The presence of the deletion was demonstrated in all our patients; furthermore, the deletion was of identical size, although our patients had different clinical features. Molecular analysis of the 17p11.2 region by PFGE method proved to be a reliable and non-invasive method of diagnosis in HNPP cases both familial and isolated.