Self-reported gastrointestinal disorders among veterans with gulf war illness with and without posttraumatic stress disorder.

BACKGROUND: Gulf War Illness (GWI) is a chronic, multi-symptom disorder affecting 25%-32% of Gulf War veterans. Veterans with GWI disproportionately suffer from gastrointestinal (GI) disorders. Given the increasing evidence supporting a gut-brain axis, we explore the relationship between post-traumatic stress disorder (PTSD), GWI, and self-reported GI disorders among GW veterans. METHODS: Veterans from the Gulf War Era Cohort and Biorepository responded to a mail-based survey (N = 1058). They were stratified by GWI (Centers for Disease Control definition) and PTSD status. This yielded three groups: GWI-, GWI+/PTSD-, and GWI+/PTSD+. Multivariable logistic regression adjusting for demographic and military characteristics examined associations between GWI/PTSD groups and GI disorders. Results were expressed as adjusted odds ratios (aOR) with 95% confidence intervals (95% CI). KEY RESULTS: The most frequently reported GI disorders were irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), and colon polyps (CP). The GWI+/PTSD+ group had a higher odds of these disorders than the GWI+/PTSD- group (aORIBS  = 3.12, 95% CI: 1.93-5.05; aORGERD  = 2.04, 95% CI: 1.44-2.90; aORCP  = 1.85, 95% CI: 1.23-2.80), which had a higher odds of these disorders than the GWI- group (aORIBS  = 4.38, 95% CI: 1.55-12.36; aORGERD  = 2.51 95% CI: 1.63-3.87; aORCP  = 2.57, 95% CI: 1.53-4.32). CONCLUSIONS & INFERENCES: GW veterans with GWI and PTSD have significantly higher odds of specific self-reported GI disorders than the other groups. Given the known bidirectional influences of the gut and brain, these veterans may benefit from a holistic healthcare approach that considers biopsychosocial contributors to the assessment and management of disease.

HIV knowledge and condom intention among sexually abstinent Chinese students.

AIMS: To (a) assess the HIV/AIDS knowledge and sources of HIV/sexually transmitted infection (STI) information among sexually abstinent college students in China; (b) examine whether constructs from the transtheoretical model (TTM) are applicable to this study population regarding condom use intention; and (c) evaluate the association between genders and TTM constructs, and HIV/AIDS knowledge. BACKGROUND: Chinese college students are vulnerable to HIV and other STIs. Strategies targeting abstinent students are more cost-effective than providing treatment for diseases. METHODS: We surveyed 390 students enrolled in two universities in China. Data were collected from June 2009 to March 2010. RESULTS: Only 11% and 24% were aware of HIV spread by infected semen and of the protective effects of condom use against HIV. The mass media were major sources of HIV/STI information. Individuals who had higher levels of self-efficacy and reported more perceived benefits and fewer perceived barriers were more likely to be in TTM contemplation stage of condom use than those in precontemplation. Females were less likely to discuss HIV/STIs through online chat or email with strangers than males. Individuals who had higher levels of self-efficacy and reported more perceived benefits and fewer perceived barriers were more likely to be in TTM contemplation stage of condom use than those in precontemplation. CONCLUSION: Sexually abstinent college students in China may be more likely to transition from precontemplation to contemplation if they know the benefits of condom use for the prevention of HIV/STIs and if they learn to successfully minimize potential barriers related to condom use.

Beauty product-related exposures and childhood brain tumors in seven countries: results from the SEARCH International Brain Tumor Study.

Data from 1218 cases of childhood brain tumors (CBT) diagnosed between 1976 and 1994 and 2223 matched controls from the general population were included in an analysis of maternal beauty product exposure and beauty-related employment in 9 centers in 7 countries. A 50% increased odds ratio (OR) [95% confidence interval (CI) = 1.0-2.1] for CBT was observed among children of mothers who were exposed via personal use of and/or possible ambient contact with beauty products during the 5 years preceding the index child's birth compared with children of mothers never exposed to beauty products during this time period. Overall maternal personal use of hair-coloring agents in the month before or during the pregnancy of the index child's birth was not associated with CBT (OR = 1.0, CI = 0.83-1.3) or with astroglial (OR = 1.1, CI = 0.85-1.4), PNET (OR = 1.0, CI = 0.71-1.5) and other glial subtypes (OR = 1.0, CI = 0.62-1.0). Similarly, no statistically increased ORs or discernable pattern of risk estimates were observed for period of use or for number of applications per year for maternal personal use of hair-coloring agents overall or by histologic type. Among children born on or after 1980, increased ORs for CBT were associated with maternal non-work-related exposure to any beauty products (OR = 2.6, CI = 1.2-5.9), hair-dyes (OR = 11, CI = 1.2-90), and hair sprays (OR = 3.4, CI = 1.0-11). No overall increased OR for CBT was observed among children of mothers employed in beauty-related jobs during the 5 years preceding the index child's birth compared with those who reported no beauty-related employment. In general, other specific beauty product-related exposures were not associated with increased ORs for CBT. Data from our study provide little evidence of an increased risk for CBT with mothers' exposures to beauty products.

Mutant, wild type, or overall p53 expression: freedom from clinical progression in tumours of astrocytic lineage.

Abnormalities of the p53 tumor-suppressor gene are found in a significant proportion of astrocytic brain tumours. We studied tumour specimens from 74 patients evaluated over 20 years at the Massachusetts General Hospital, where clinical outcome could be determined and sufficient pathologic material was available for immunostaining. p53 expression studies employed an affinity-purified p53 monoclonal antibody, whose specificity was verified in absorption studies and, in a minority of cases, a second antibody recognising a different epitope of p53. Significant overexpression of p53 protein was found in 48% of the 74 tumours included in this series and high levels of expression were associated with higher mortality from astrocytic tumours (P<0.001, log rank). Multivariate analyses revealed that immunohistochemically detected p53 was an independent marker of shortened progression-free and overall actuarial survival in patients with astrocytic tumours, suggesting that increased expression of p53 plays an important role in the pathobiology of these tumours. In a subset of 36 cases, coding regions of the p53 gene were completely sequenced via SSCP and direct DNA sequencing, revealing that overexpression of p53 protein is not always associated with point mutations in conserved exons of the p53 gene. Finally, we confirmed p53 protein expression in early-passage human glioma cell lines of known p53 mutational status and immunostaining scores. Although grade continues to be the strongest prognostic variable, the use of p53 staining as a prognostic indicator, in contrast to mutational DNA analyses, may be a useful adjunct in identifying patients at higher risk of treatment failure.

Predictors of mortality in stroke patients admitted to an intensive care unit.

OBJECTIVE: Improved pathophysiologic insight and prognostic information regarding in-hospital risk of mortality among stroke patients admitted to an intensive care unit. DESIGN: Retrospective analysis. SETTING: Neurology/neurosurgery intensive care unit in a tertiary care university medical center. PATIENTS: A total of 63 consecutive ischemic stroke patients. INTERVENTIONS: Patients were classified according to in-hospital mortality. Charts were reviewed to retrospectively generate an admitting Acute Physiology and Chronic Health Evaluation (APACHE) II score. The APACHE II score and its individual components were assessed for predicting subsequent death. MEASUREMENTS AND MAIN RESULTS: Of 63 patients, 13 died and 50 survived to either discharge or surgical intervention. The mean admitting APACHE II score of survivors (6.9) was lower than that of patients who died (17.2; p < .0001). None of the 33 patients with a score <9 died, compared with 43% of those with a score > or =9. A score > or =18 was uniformly associated with fatal outcome (n = 8). Univariate analysis identified APACHE II total score, Glasgow Coma Scale score, temperature, pH, and white blood cell count as significant predictors of death. Among multivariate logistic regression models examining the components of the APACHE II score, the model containing white blood cells, temperature, and creatinine best predicted death. CONCLUSIONS: Several features of the APACHE II score are associated with risk of death in this patient population. The findings suggest particular physiologic derangements that are associated with, and may contribute to, increased mortality in critically ill patients with acute ischemic stroke.

Megavoltage radiation therapy for axial and inoperable giant-cell tumor of bone.

BACKGROUND: Treatment of giant-cell tumor of bone generally involves wide en bloc resection of the lesion and the surrounding bone or curettage with or without bone-grafting or the use of cement. Radiation therapy has been used for patients who cannot be operated on for medical reasons or who have a tumor that is technically difficult to resect or that cannot be resected because of its location. We performed the present study to evaluate the efficacy of megavoltage radiation in terms of lack of tumor progression and treatment-related morbidity. METHODS: Twenty patients who had giant-cell tumor of bone were managed with a single course of megavoltage radiation (forty to seventy gray administered at 1.8 to 2.0 gray per fraction with an average total duration of treatment of five to seven weeks) between March 1973 and March 1992. We used megavoltage photons, 160-megaelectron-volt proton beams, or a combination of the two. RESULTS: After a median duration of follow-up of 9.3 years, the tumor had not progressed in seventeen of the twenty patients. Thus, the actuarial ten-year rate for lack of progression was 85 percent. Local regrowth was evident in one patient who had received radiation alone and in two of the thirteen patients who had been managed with partial resection and radiation. Operative treatment was successful in the three patients in whom the radiation treatment had failed. No radiation-induced tumors were observed in our series. CONCLUSIONS: We concluded that giant-cell tumor of bone was effectively treated with megavoltage radiation in our series of twenty patients in whom operative resection would have been difficult or was not feasible. The rate of tumors that did not progress with this regimen of radiation is similar to that reported by investigators from several other centers. Furthermore, these results closely rival those obtained with modern curettage procedures. Malignant sarcomatous transformation was not observed in our series. A longer duration of follow-up of a larger group of patients is necessary to provide a better estimate of the risk of malignant transformation.

Temporal lobe (TL) damage following surgery and high-dose photon and proton irradiation in 96 patients affected by chordomas and chondrosarcomas of the base of the skull.

PURPOSE: To determine the temporal lobe (TL) damage rate in 96 patients treated with high-dose proton and photon irradiation for chordomas and chondrosarcomas of the base of the skull. METHODS AND MATERIALS: The records of 96 consecutive patients treated at Massachusetts General Hospital (MGH) and Harvard Cyclotron Laboratory (HCL) between June 1984 and 1993, for chordomas and chondrosarcomas of the base of the skull were reviewed. All the patients had undergone some degree of resection of the tumor prior to radiation therapy. Seventy-five patients were classified as "primary tumors" and 21 as recurrent or regrowing tumors after one or more surgical procedures. All the patients were randomized to receive 66.6 or 72 cobalt Gray equivalent (CGE) on a prospective dose-searching study by proton and photon irradiation (Radiation Therapy Oncology Group #85-26) with conventional fractionation (1.8 CGE/day, 5 fractions/week). All treatments were planned using the three-dimensional (3D) planning system developed at the Massachusetts General Hospital, and the dose was delivered using opposed lateral fields for the photon component and a noncoplanar isocentric technique for the proton component. Clinical symptoms of TL damage were classified into 4 grades. Computerized tomography (CT) and magnetic resonance imaging (MRI) scans were evaluated for white matter changes. Abnormalities associated with persistent or recurrent tumor were distinguished from radiation-induced changes. TLs were delineated on the original scans of the 10 patients with damage and those of a group of 33 patients with no clinical or MRI evidence of injury. Dose distributions were calculated and dose-volume histograms were obtained for these patients. RESULTS: Of the patients, 10 developed TL damage, with bilateral injury in 2 and unilateral injury in 8. The cumulative TL damage incidence at 2 and 5 years was 7.6 and 13.2%, respectively. The MRI areas suggestive of TL damage were always separated from the tumor bed. Symptoms were severe to moderate in 8 patients. Several baseline factors, tumor- or host-related, were analyzed to evaluate their predictivity for TL damage: age, gender, tumor site, histology, type of presentation, type and number of surgical procedures, primary tumor volume, prescribed dose, normal tissue involvement, and volume of TL receiving doses ranging between 10 and 50 CGE or more. Only gender, in a univariate analysis (log rank) was a significant predictor of damage (0.0155), with male patients being at significantly higher risk of TL injury. In a stepwise Cox regression that included gender as a variable, no other baseline variable improved the prediction of damage. CONCLUSIONS: The 2- and 5-year cumulative TL damage rates were 7.6 and 13.2%, respectively. Despite the different TL damage rates related to age, tumor volume, number of surgical procedures prior to radiation therapy, and prescribed doses to the tumor, only gender was a significant predictor of damage (p = 0.0155) using a univariate (log rank) test. Chordomas and chondrosarcomas of the base of the skull may represent an interesting model to evaluate the TL damage rates because of their extradural origin, displacing the white matter instead of infiltrating it as gliomas do, because of their longer local recurrence-free survival other than gliomas and other brain tumors and because of the high doses of irradiation delivered to the target volume to obtain local control.

Individualizing management of aggressive fibromatoses.

PURPOSE: To examine prognostic indicators in aggressive fibromatoses that may be used to optimize case-specific management strategy. METHODS AND MATERIALS: One hundred and seven fibromatoses presenting between 1971 and 1992 were analyzed. The following treatment modalities were utilized: (a) surgery alone for 51 tumors; (b) radiation alone for 15 tumors; and (c) radiation and surgery (combined modality) for 41 tumors. Outcome analysis was based on 5-year actuarial local control rates. RESULTS: Control rates among surgery, radiation therapy, and combined modality groups were 69%, 93%, and 72%. Multivariate analysis identified age < 18 years, recurrent disease, positive surgical margins, and treatment with surgery alone as predictors for failure. Patients treated with surgery alone had control rates of 50% (3 of 6) for gross residual, 56% for microscopically positive margins, and 77% for negative margins. Radiation and surgery resulted in rates of 59% for gross residual, 78% for microscopically positive margins, and 100% (6 of 6) for negative margins. For recurrent vs. primary tumors, control was achieved in 48% vs. 77%, 90% vs. 100% (5 of 5), and 67% vs. 79% in the Surgery, Radiation, and Combined modality Groups, respectively. Patients presenting with multiple disease sites tended to have aggressive disease. A radiation dose-control relation to > 60 Gy was seen in patients with unresected or gross residual disease. Of the patients, 23 with disease involving the plantar region had a control rate of 62%, with significantly worse outcomes in children. CONCLUSIONS: These results are consistent with those found in the relevant literature. They support primary resection with negative margins when feasible. Radiation is a highly effective alternative in situations where surgery would result in major functional or cosmetic defects. When negative surgical margins are not achieved in recurrent tumors, radiation is recommended. Perioperative radiation should be considered in other high-risk groups (recurrent disease, positive margins, and plantar tumors in young patients). Doses of 60-65 Gy for gross disease and 50-60 Gy for microscopic residual are recommended. Observation may be considered for primary tumors with disease remaining in situ when they are located such that progression would not cause significant morbidity. Although plantar lesions in children may represent a group at high risk for recurrence or aggressive behavior, the greater potential for radiation-induced morbidity in this group must also temper its use. Given the inconsistent nature and treatment response of this tumor, it is fundamental that treatment recommendations should be made based on the risk:benefit analysis for the individual patient, dependent on tumor characteristics and location, as well as patient characteristics and preferences.

MIB-1 (Ki-67) index and transforming growth factor-alpha (TGF alpha) immunoreactivity are significant prognostic predictors for meningiomas.

Mitotic index > 6, proliferating cell nuclear antigen (PCNA) index > 5%, high tumour grade and absence of progesterone receptors (PR) are significant predictors for poor outcome in meningiomas. Since MIB-1 (Ki-67) is a more specific cell proliferation marker, and overexpression of TGF-alpha is also associated with tumour progression, we compared the prognostic significance of these factors with the other indices. Intracranial meningiomas from 21 men and 36 women (age 54.5 +/- 1.7, mean +/- SEM) were classified as 24 benign, 24 atypical and nine malignant. Twenty-one of the 57 tumours recurred (mean interval to recurrence was 57.3 +/- 13.1 months). The mean follow-up period for patients without tumour recurrence was 81.9 +/- 8.7 months. MIB-1 labelling index (LI) was expressed as percentage of labelled nuclei to total tumour nuclei counted in the most densely labelled areas. Analysis of variance revealed significant differences between tumour grades for MIB-1 labelling indices (0.75 +/- 0.21 for benign, 3.2 +/- 0.57 for atypical 6.04 +/- 1.48 for malignant; P < or = 0.0066), and between malignant and non-malignant meningiomas for TGF alpha staining scores (P < or = 0.029). MIB-1 LI also correlated with mitotic and PCNA indices (P < or = 0.0001), but not with age of the patients. Male patients had higher tumour MIB-1 LI than females (P < or = 0.0128). Univariate analysis indicated that MIB-1 LI > 3%, TGF alpha score > 4 (scoring scale 0-5), mitotic index > 6, and negative PR status were significant factors for worse outcome. Higher MIB-1 LI, TGF alpha score and mitotic index as continuous variables were also significant negative predictors. With multivariate analysis, both MIB-1 LI and TGF alpha score remained significant factors when paired with all other variables: TGF alpha or MIB-1 LI, respectively, mitosis, PCNA, tumour grade, PR status, age, sex, postoperative radiation therapy. We conclude that MIB-1 LI and TGF alpha score are important independent prognostic indicators for patients with meningiomas.

Pharmacological elevation of blood pressure in acute stroke. Clinical effects and safety.

BACKGROUND AND PURPOSE: Lowering of blood pressure can adversely affect ischemic symptoms in acute stroke. The aim of our study was to determine whether induced hypertension in stroke is safe and to examine its effects on neurological deficits in patients presenting with acute cerebral ischemia. METHODS: We retrospectively reviewed all patients admitted to our neurological intensive care unit with the diagnosis of ischemic stroke over a 2.5-year period. Thirty-three patients were not given a pressor agent (Ph- group), while 30 were treated with phenylephrine (Ph+ group) in an attempt to improve cerebral perfusion. RESULTS: Baseline characteristics showed few differences between the Ph+ and Ph- groups. Intracerebral hemorrhage, brain edema, cardiac morbidity, and mortality were not increased in the Ph+ group. In 10 of 30 Ph+ patients, a systolic blood pressure threshold was identified below which ischemic deficits worsened and above which deficits improved. The mean threshold was 156 mm Hg (range, 120 to 190 mm Hg). The mean number of stenotic/occluded cerebral arteries was greater in those Ph+ patients with an identified clinical blood pressure threshold (mean, 2.1 per patient) than in Ph+ patients without a threshold (mean, 1.2 per patient; P < .05). CONCLUSIONS: The results suggest that careful use of phenylephrine induced hypertension is not associated with an increase in morbidity or mortality in acute stroke. Although based on a retrospective analysis of clinical practice, this report suggests that a subset of patients, particularly those with multiple stenosis of cerebral arteries, may improve neurologically upon elevation of the blood pressure.

Use of MIB-1 (Ki-67) immunoreactivity in differentiating grade II and grade III gliomas.

The grading of glial tumors has traditionally relied on histological assessment, but the distinction between grade II and grade III gliomas is still a subject of debate. We examined the value of the monoclonal antibody MIB-1 (Ki-67) labeling index (LI) in the differentiation between grade II and grade III gliomas by either the 1993 WHO grading scheme or the St. Anne-Mayo grading scale. The MIB-1 Li in the most densely labeled areas from 80 diffuse cerebral hemispheric gliomas was determined. The tumors included 16 grade II, 31 grade III and 33 grade IV gliomas by the WHO scale. The mean LIs (%) were 0.88 +/- 0.29 for grade II, 8.75 +/- 1.71 for grade III, and 9.12 +/- 1.55 for grade IV gliomas. Analysis of variance indicated a significant difference in mean LIs between grades II and III and grades II and IV (p < or = 0.0001), but not between grades III and IV. Seven tumors were classified differently by the 2 systems (grade III by WHO, but grade 2 by St. Anne-Mayo), and all had MIB-1 LI over 3%. Univariate analysis showed that MIB-1 LI with a cut-off point at 1.5% was a significant prognostic factor (p < or = 0.0005). High tumor grade (WHO, p < or = 0.0002; St. Anne-Mayo, p < or = 0.0006) and patient age > 50 (p < or = 0.0001) were also significant factors for shorter survival. Using Cox Regression Multivariate Analysis, MIB-1 LI > 1.5% was a significant independent predictor of shorter disease survival when paired with tumor grade (p < or = 0.032), patient age (p < or = 0.0065), or gender (p < or = 0.0007). We conclude that the MIB-1 immunoreactivity is useful in distinguishing grade II from grade III gliomas, and maybe more sensitive in assigning aggressive gliomas to grade III than the St. Anne-Mayo grading system.

[Soft tissue sarcoma of the head and neck area in adults. Outcome of combined surgery and irradiation and radiotherapy alone]. / Weichteilsarkome des Kopf-Hals-Bereichs beim Erwachsenen. Ergebnisse der kombinierten Operation und Bestrahlung und der alleinigen Strahlentherapie.

PURPOSE: To analyse the experience treating soft tissue sarcomas of the head and neck at the Massachusetts General Hospital, Boston. Detailed results have been published previously [17]. PATIENTS AND METHOD: Between 1972 and 1993, 57 patients were treated curatively with radiation alone (n = 13) or combined surgery and pre- and/or postoperative irradiation (n = 44). Gross complete resection was achieved in 82% of patients and margins were negative in 5 patients. Doses ranged from 36.0 to 79.2 Gy (median 64.8 Gy), usually conventionally fractionated. In 16 patients protons were used. Median follow-up time was 4.3 years (range 1.1 to 16.8 years). RESULTS: After 5 years, patients with angiosarcomas (n = 11) and patients with other tumor types (n = 46) had locoregional control rates of 24% and 69%, distant failure rates of 58% and 17%, and overall survival rates of (for overall survival) and T stage (for locoregional control) (p < 0.05). Particularly, gross completely resected T1 tumors had a locoregional control rate of 91%. Patients with locoregional recurrence were at an increased risk to die (p = 0.004 in multivariate analysis). Patients with and without direct tumor extension to neurovascular structures, bones, organs, or skin had distant failure rates of 27% and 0%, respectively (p = 0.031). In multivariate analysis, direct extension was additionally a negative prognosticator of overall survival (p = 0.034). CONCLUSION: 1. Angiosarcomas of the head and neck have a considerably poorer prognosis than other soft tissue sarcomas of this region. 2. Head and neck sarcomas have a higher local recurrence rate than for example soft tissue sarcomas of the extremities. Optimisation of local treatment through combination of surgery and high-dose irradiation, however, can achieve improved results, especially for prognostically favourable subgroups. 3. In addition to tumor grade and size, direct tumor extension may be a useful additional staging parameter.

Progesterone and estrogen receptors in meningiomas: prognostic considerations.

Meningiomas often contain steroid hormone receptors, but the correlation of receptor presence with patient outcome or mitotic index is unclear. Intracranial meningiomas from 70 patients (27 males and 43 females, mean age 52.9 + 1.7 years [mean +/- standard error of the mean], range 15-78 years) were evaluated immunocytochemically for female sex hormone receptors using specific monoclonal antibodies. Prognostic correlations were determined using statistical analyses that included clinical and histological variables. Twenty-eight tumors were benign, 27 had atypical features, and 15 were malignant. Thirty tumors were meningotheliomatous, 11 were fibroblastic, 28 were transitional, and one was secretory. Twenty-nine of the 70 primary tumors recurred (mean interval to recurrence 50.1 +/- 10 months). The mean progression-free follow-up period for patients without recurrence was 82.1 +/- 7.7 months. Nuclear staining for the progesterone receptor (PR) was found in 58 cases (83%) and PR status was scored as 0 (0% nuclei positive), 1 (< 1%), 2 (1-9%), 3 (10-49%), or 4 (> 50%). Only six tumors (8.6%) contained nuclear estrogen receptor (ER) staining, which was limited to a small number of nuclei (< 1%). Fisher's exact test (two-tailed) showed an inverse correlation between tumor grade and PR staining score (p < or = 0.001), with 96% of benign and 40% of malignant meningiomas containing PR-positive nuclei. No correlation between age or histological subtype and PR score was detected. Meningiomas from female patients had more PRs (p < or = 0.05). Analysis of variance revealed that the mitotic index (total counts of mitoses per 10 high-power fields) for tumors with 0 PR staining (18 +/- 4.4) was higher (p < or = 0.0001) than for those with PR scores of 1 to 4 (4.3 +/- 1.9, 5.1 +/- 2, 2.2 +/- 0.8, and 1.7 +/- 0.9, respectively). Univariate analysis indicated that the absence of PR, high mitotic index, and higher tumor grade were significant factors for shorter disease-free intervals. Multivariate analysis showed that a three-factor interaction model, with a PR score of 0, mitotic index greater than 6, and malignant tumor grade, was a highly significant predictor (p < or = 0.0001) for worse outcome in patients harboring meningiomas. These data indicate that the presence of PRs, even in a small number of tumor cells, is a favorable prognostic factor for meningiomas.

Cell kinetic study of thymic epithelial tumors using PCNA (PC10) and Ki-67 (MIB-1) antibodies.

We performed an immunohistochemical cell kinetic study with monoclonal antibodies to proliferating cell nuclear antigen (PCNA)-PC10-and Ki-67-MIB-1-on 62 thymic epithelial tumors, to evaluate whether there is correlation between the proliferation indices of the neoplastic epithelial cells and histological subtype, stage, and risk of relapse. The 62 cases of thymic epithelial tumors were classified as medullary thymoma (4 cases), composite (mixed) thymoma (17 cases), organoid thymoma (predominantly cortical) (11 cases), cortical thymoma (10 cases), well-differentiated thymic carcinoma (18 cases), and poorly differentiated thymic carcinoma (2 cases). Labeling indices were expressed as percentage of epithelial cells with positive nuclear immunostaining by random counting of 1,000 epithelial tumor cells, using an oil immersion 100 x objective. PCNA labeling indices were consistently higher than those of Ki-67, and they correlated with each other. Well-differentiated thymic carcinoma showed higher labeling indices (3.11% +/- 3.53%) by Ki-67 antibody compared with the medullary type (0.60% +/- 0.07%) (P < .05) but there were no statistically significant differences between the other histological subtypes. Stage IV cases showed higher PCNA labeling indices (PCNA: 11.07% +/- 7.35%, Ki-67: 6.86% +/- 5.87%) than cases of the other stages (P < .05), but there were no statistically significant differences in either labeling index between the other stages. The number of patients who relapsed was too small to permit meaningful correlation between labeling indices and relapse. Our results indicate that the differences in biological behavior of the different histological subtypes of thymic epithelial tumors may be in part explained by differences in tumor growth fraction. Analysis of a larger group of patients will be required to determine whether proliferation fraction as determined by this method can be used to predict outcome in individual cases.

CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated.

p16 is involved in a cell cycle regulatory cascade that includes cyclin-dependent kinase 4 (cdk4), cyclin D1, and pRb (retinoblastoma). Alterations of each of these components have been described in primary human glioblastoma multiforme (GBM) or in GBM cell lines. Because perturbation of any component in this pathway may have similar oncogenic effects, we studied the relationship between abnormalities of CDKN2/p16 and RB, the two commonly involved tumor suppressor genes, in 55 astrocytic gliomas (42 GBMs, 8 anaplastic astrocytomas, and 5 astrocytomas). By using comparative multiplex PCR, homozygous deletions of the CDKN2/p16 gene were detected in 24 GBMs (57%) and in 2 anaplastic astrocytomas. Two additional GBMs and one anaplastic astrocytoma had allelic loss of chromosome 9p, as assessed by microsatellite polymorphisms flanking the CDKN2/p16 region. Single-strand conformation polymorphism and DNA sequencing analysis of all three coding exons of CDKN2/p16 revealed a frameshift mutation (four-bp deletion) in one of the three GBMs that had lost the remaining 9p allele. Allelic loss of chromosome 13q at the RB gene, RB gene mutations, or loss of pRb expression was noted in 14 GBMs (33%) and 2 anaplastic astrocytomas. Thirty-six of 42 GBMs (86%) had alterations of either CDKN2/p16 (n = 22), RB (n = 10), or both (n = 4); these two genetic changes, however, were relatively exclusive (P = 0.003). Furthermore, of the six GBMs without either CDKN2/p16 or RB gene abnormalities, one case had CDK4 gene amplification. These data indicate that the vast majority of GBMs probably have inactivation of the p16-cdk4/cyclin D1-pRb pathway. The findings also provide corroborative evidence that CDKN2/p16 and RB are the critical glioma tumor suppressor genes on chromosomes 9p and 13q, respectively.

Chronic lymphocytic leukemia and the central nervous system: a clinical and pathological study.

Chronic lymphocytic leukemia is the most common human leukemia but infrequently causes neurologic symptoms. We have reviewed all previously reported cases of chronic lymphocytic leukemia in the CNS along with three new cases; one patient was diagnosed antemortem and treated with immediate improvement and 4-year survival. In addition, we reviewed all autopsy cases since 1972 and available lumbar puncture data on patients with chronic lymphocytic leukemia admitted to the Massachusetts General Hospital. Invasion of the CNS by chronic lymphocytic leukemia often leads to confusional state, meningitis with cranial nerve abnormalities, optic neuropathy, or cerebellar dysfunction. Lumbar puncture shows a lymphocytosis consisting of monoclonal B cells, but CSF cytology studies are of limited value in establishing the diagnosis. Long-term survival may be related to the stage of chronic lymphocytic leukemia at the time of CNS disease and may be associated with intrathecal chemotherapy. A mild, asymptomatic infiltration of the brain, frequently noted in late-stage chronic lymphocytic leukemia in autopsy series, may explain the CSF lymphocytosis in some patients with late-stage chronic lymphocytic leukemia.

Adult soft tissue sarcomas of the head and neck treated by radiation and surgery or radiation alone: patterns of failure and prognostic factors.

PURPOSE: To analyze our experience treating soft tissue sarcomas of the head and neck in adults, and to identify patterns of failure and prognostic factors. METHODS AND MATERIALS: The records of 57 patients with Stage M0 disease treated by radiation with or without surgery between 1972 and 1993 were reviewed. Median follow-up time was 4.3 years (range, 1.1-16.8 years). A group of potential prognostic factors was evaluated, including age at diagnosis, sex, initial tumor presentation (primary vs. recurrent), grade, T-stage, direct tumor extension, tumor depth, duration of treatment, and radiation dose. RESULTS: The subset of angiosarcomas (11 out of 57 patients) had a considerably adverse effect on treatment outcome for the total group of sarcomas, with actuarial 5-year overall survival (OS), locoregional control (LRC), and freedom from distant metastasis (FDM) rates being 31%, 24%, and 42%, respectively. In contrast, for the remaining 46 patients with other histopathological tumor types, OS, LRC, and FDM rates were significantly higher (74%, 69%, and 83%, respectively). For this group of patients, significant prognostic factors identified by uni- and multivariate analysis included tumor grade as a predictor of OS and T-stage as a predictor of LRC (p < or = 0.050). Those patients who experienced a locoregional recurrence were at a significantly increased risk of dying (p = 0.004 in a multivariate model). All 17 patients without direct tumor extension to neurovascular structures, bone, contiguous organs, or skin remained free from distant failure. In contrast, 27% of 29 patients with direct extension had developed distant metastases at 5 years. In multivariate analysis, the absence of direct extension was a positive predictor of FDM (p = 0.007) and of OS (p = 0.034). CONCLUSIONS: 1) Angiosarcomas of the head and neck have a considerably poorer prognosis than other soft tissue sarcomas of this site. 2) In addition to tumor grade and size, direct tumor extension may be a useful additional staging parameter. 3) High rates of locoregional failure in the head and neck area, a potential cause of morbidity and death, indicate a need for improved treatment strategies.

TGF alpha expression in meningioma--tumor progression and therapeutic response.

Little is known of the molecular genetic mechanisms contributing to meningioma tumor progression. We evaluated a total of 26 clinical cases of meningioma: twenty three patients with meningioma treated at our institution between 1978 and 1990 and three asymptomatic cases found initially at autopsy. In addition, histologically normal meninges obtained at post-mortem examination from 5 cases were evaluated. There were 13 men and 10 women in the patient group with a median age of 48.7 years, treated by surgery and/or irradiation. Median follow-up was 46 months (range 16-152 months). Archival cases and age-matched normal meningeal tissue obtained at autopsy during the same time period were obtained for study. Patients with TGF alpha scores greater than 3.0 were more likely to fail treatment and had lower overall survival times than those with immunostaining scores of 1 or 2. Three autopsy cases where meningioma had been silent clinically had overall staining scores of 0.75, while 10 samples of normal meninges harvested from 5 cases at autopsy had staining scores of 0. Two patients each underwent 3 surgeries for recurrent tumor, serial specimens showed increased TGF alpha expression over time, though all material from these procedures was consistent with the diagnosis of histologically benign meningioma.

Prognostic role of urokinase-type plasminogen activator in human gliomas.

Urokinase-type plasminogen activator (u-PA) is a 54-kd enzyme shown to participate in tissue degradation under certain normal and pathological conditions, including cancer invasion and metastasis. Increased u-PA expression has been found in cancers of the breast, lung, colon, and prostate, and correlated with worse outcome in patients with lung and breast cancer. We examined the correlation between u-PA expression in gliomas and patient survival. Seventy-seven gliomas from 41 men and 36 women (ages 2 to 73) were immunostained for u-PA using monoclonal antibody 394 directed against human urokinase. The tumors included 32 grade 4, 16 grade 3, and 20 grade 2 astrocytomas (Daumas-Duport scale), and 9 pilocytic astrocytomas. Strong cytoplasmic staining was found in tumor cells of all grade 4, most of the grade 3, and a few of the lower grade tumors. Adjacent normal brain tissue showed faint staining associated with subpial cell processes and white matter fibers. The fiber staining was stronger in brain tissue infiltrated by tumor cells. Cytoplasmic u-PA staining in tumor cells was scored from 0 (no staining) to 6 (strong and widespread staining). The mean u-PA scores were 5.08 +/- 0.19 (mean +/- SEM) for grade 4, 3.97 +/- 0.46 for grade 3, 1.65 +/- 0.39 for grade 2, and 1.22 +/- 0.60 for pilocytic astrocytomas. The statistical analysis was based on cytoplasmic staining only. Analysis of variance revealed significant differences between the mean u-PA scores of different grades (P < 0.02 between grades 4 and 3, and P = 0.0001 between grades 4 or 3 and 2, and between grades 4 or 3 and pilocytic), except between grade 2 and pilocytic astrocytomas. Univariate analysis indicated that u-PA score > or = 4 (P = 0.0001), tumor grade 4 (P = 0.01), and age > 50 (P < 0.001) were all significant predictors for shorter disease survival. A three-way interaction model by multivariate analysis indicated that u-PA score > or = 4, tumor grade 4, and age > 50, taken together, were significant factors for shorter patient survival (P < 0.02). We conclude that u-PA may be used as a prognostic tool in conjunction with tumor grade and patients' age in predicting survival for patients with gliomas.