Postnatal rebuilding and otosclerotic bone formation in the region of the otic capsule.
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BACKGROUND: Imbalances between oxidant formation and antioxidative defense are associated with the pathogenesis of several chronic inflammatory disorders of the respiratory tract. Therefore, a role of oxidative stress in chronic upper airway tract infections can be anticipated. OBJECTIVE: To determine if patients with chronic sinusitis demonstrate a reduced antioxidative tissue status. DESIGN: The levels of 3 biologically important antioxidants, reduced glutathione and oxidized glutathione, uric acid, and vitamin E, were determined biochemically in mucosal biopsy specimens from the uncinate process of patients with chronic sinusitis and healthy controls. SUBJECTS: Inflamed mucosa samples were obtained from 9 patients with chronic sinusitis during functional endoscopic sinus surgery. Normal mucosa samples were collected from 10 healthy controls during surgery for nasal obstruction. RESULTS: The data (presented as mean +/- SD) show a significant reduction (P < or = .05) of reduced glutathione levels (0.3 +/- 0.1 mumol/g wet weight) and uric acid levels (2.7 +/- 0.4 mumol/g wet weight) in mucosa samples obtained from patients with chronic sinusitis compared with healthy controls (0.6 +/- 0.2 and 3.4 +/- 0.6 mumol/g wet weight, respectively). No difference was found in oxidized glutathione (24 +/- 8 vs 25 +/- 15 nmol/g wet weight) and vitamin E (20.5 +/- 7.9 vs 22.5 +/- 6.9 nmol/g wet weight) levels between both groups. CONCLUSIONS: Decreased levels of both reduced glutathione and uric acid in patients with chronic sinusitis lead to a diminished antioxidant defense, which may be associated with the pathogenesis of upper respiratory tract disorders. The vitamin E level seems less important. This finding may offer perspectives for pharmacotherapeutic intervention with antioxidants.
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In 15 patients with unilateral internal carotid artery occlusion and contralateral internal carotid artery stenosis of pressure significance (75% cross-sectional area or greater), the ocular pneumoplethysmograph (OPG-Gee) has documented bilateral improvement in the ophthalmic systolic pressure in 12/15 patients who underwent endarterectomy of the stenosed carotid artery as the sole operative procedure. External carotid to internal carotid shunt on the side of the internal carotid occlusion need be entertained only in those patients who remain symptomatic on the side of the internal carotid occlusion after contralateral stenosis endarterectomy.
BACKGROUND: Tumors of borderline malignancy are still a controversial subgroup of ovarian neoplasms. The expression of several cell regulatory proteins was studied to characterize the molecular phenotype of these tumors, and to compare them with their benign and malignant counterparts. METHODS: Specimens from 22 patients with tumors of borderline malignancy (11 serous and 11 mucinous tumors), 12 patients with benign tumors, and 16 patients with invasive ovarian carcinomas were evaluated for expression of epidermal growth factor receptor (EGFR), HER-2/neu, PTP1B, and p53 by immunohistochemical techniques. RESULTS: One or both of the tyrosine kinase growth factor receptors EGFR and HER-2/neu was expressed by 42% of benign, 59% of borderline, and 81% of malignant ovarian tumors. EGFR was expressed in a significantly greater fraction of malignant lesions (69%) than borderline lesions (18%) (P< 0.004). EGFR expression was not observed among the 11 mucinous borderline tumors. HER-2/neu was expressed by 50% of borderline tumors and was not a marker for malignancy. The tyrosine phosphatase PTP1B was expressed by a similar fraction of benign (17%), borderline (27%), and malignant (19%) tumors. The number of cases studied precluded correlation of kinase and phosphatase activity. However, among 12 tumors with PTP1B expression, 9 also expressed EGFR or HER-2/neu. Overexpression of p53 was observed only in malignant serous tumors and was not found in malignant mucinous, borderline, or benign lesions. CONCLUSIONS: Either EGFR or HER-2/neu was detected in a majority of borderline cancers. PTP1B was present only in a minority of these cancers. Frankly malignant serous lesions differed from borderline and benign tumors with regard to expression of EGFR and overexpression of p53.
BACKGROUND: Vinorelbine given by weekly bolus injection is active and less toxic than bolus vinblastine in the treatment of patients with metastatic breast carcinoma. Vinblastine given by 5-day continuous infusion showed a steep dose-response curve. Pharmacokinetic studies of vinorelbine showed that it is possible to achieve a comparable antitumor effect with a smaller amount of the drug if it is given by continuous infusion. The purpose of this study was to determine the efficacy of vinorelbine given by 96-hour continuous infusion to patients with refractory metastatic breast carcinoma patients. METHODS: Between May 1996 and August 1997, 47 patients with metastatic breast carcinoma were registered into the study. All patients previously had received doxorubicin and 70% had undergone prior paclitaxel treatment. Approximately 56% of the patients had >/=2 metastatic sites. All patients received vinorelbine according to the following dose schedule: 8 mg bolus followed by 11 mg/m(2) by continuous infusion over 24 hours every 4 days every 3 weeks. RESULTS: Forty-four patients were evaluable for response. A total of 193 cycles were administered. The overall response rate was 16% (2 patients achieved a complete response and 5 patients achieved a partial response). The median duration of response was 4.3 months and the median overall survival was 8.6 months. Patients with visceral metastases and/or multiple sites of involvement had shorter durations of response than patients with only soft tissue disease or single-site metastasis (3.1 months vs. 4. 9 months) and shorter overall survival (8.1 months vs. 12 months). Dose reductions were necessary due to cumulative stomatitis and/or fatigue in 12 cycles and neutropenia and/or infection in 13 cycles. CONCLUSIONS: Due to toxicity, a revised maximum tolerated dose for continuous infusion vinorelbine is proposed by the authors: 8 mg intravenously over 10 minutes followed by 10 mg/m(2) by continuous infusion over 24 hours every 4 days. The current dose schedule did not offer an advantage either in response rates or survival over the weekly vinorelbine bolus injection in doxorubicin-resistant and paclitaxel-resistant patients.
Multidrug resistance is an increasing problem in the treatment of cancer. We evaluated in vitro the effect of an anti-CD138 plasma-cell-specific immunotoxin (IT, B-B4-SO6) in combination with the chemotherapeutic drug doxorubicin on drug-sensitive and drug-resistant variants of the multiple-myeloma (MM)-derived cell line RPMI8226 and freshly isolated malignant-myeloma cells. Drug-resistant RPMI8226 cells were still sensitive to the IT, although to a lesser extent than drug-sensitive cells. In the clonogenic assay, using 10 nM B-B4-SO6, at least 5 logs kill was found for drug-sensitive RPMI8226 cells, vs. 2.5 logs kill for the drug-resistant RPMI8226 cells. When a sub-optimal dose of 1 nM IT was combined with 3 ng/ml doxorubicin, which was toxic for drug-sensitive but not for drug-resistant cells, an additive effect was found for drug-sensitive RPMI8226 cells. The IT did not influence the sensitivity of resistant cells for doxorubicin. We therefore speculate that this type of IT, may be of more value in combination with primary chemotherapy. The effect of B-B4-SO6 on malignant-myeloma cells of patients was investigated in a viability assay. Both drug-sensitive and drug-resistant cells from MM patients were sensitive to B-B4-SO6. After 2 days, a 50% kill of malignant cells was found when 10 nM IT were used. Doxorubicin was effective only on sensitive cells, and there was a tendency for an additive effect in the combination of these cells.
In our previous work, we had characterized ARHI as an imprinted putative tumor-suppressor gene in ovarian and breast cancers. ARHI is expressed in primary breast and ovarian cell lines but largely absent from the corresponding malignant tumors. Moreover, the non-imprinted functional allele is typically deleted in malignant cells. Since ARHI had been mapped to 1p31, a common deletion site in breast and ovarian cancer and male germ-cell tumors, in this study, we set out to define precisely the physical location of ARHI at 1p31 and to determine if this location lies within the smallest common region of deletion in breast and ovarian cancers. To this end, we first carried out radiation hybrid mapping of ARHI and surrounding markers, followed by a high-resolution study of loss of heterozygosity at 1p31 in 49 ovarian and breast cancers. Combining a radiation hybrid map and a physical map of the region encompassing ARHI, 3 discrete regions of minimal deletion were found at 1p31 in breast and ovarian cancers. ARHI is the most common deletion region at 1p31. Two other less common regions of deletion were found centromeric to this gene. One of them centered on D1S207 and the other one included and was proximal to D1S488. We also confirmed the preferential loss of non-imprinted functional allele in 7 of 9 tumor specimens. These data support the possibility that ARHI is a tumor-suppressor gene and suggest that additional tumor-suppressor genes may lie proximal to ARHI at 1p31. The data obtained from our study should aid in the identification and characterization of genes in this novel imprinted region.
METHODS: Twenty aluminum welders (mean age 33 years; range 21-52), who had been exposed to aluminum for an average of 8.1 years (range 2-21), were tested for tremor and reaction time and screened for neuropsychiatric symptoms in a cross-sectional study. The welders' median urinary aluminum concentration was 1.5 micromol/L (range 0. 7-4.8). Aluminum in air, measured inside the respiratory protection, was 0.9 mg/m(3) (range 0.6-3.8). The welders were compared with twenty construction workers matched for age. RESULTS: Welders reported more symptoms than referents did (median 2 vs. 1; P=0.047). Although the welders as a group performed better than the referents on a tremor test, years of exposure, but not age, was predictive of poorer performance. The welders' reaction times were rapid by clinical standards (mean simple reaction time (SRT): 221 milliseconds; mean continuous performance test (CPT): 364 milliseconds). Although, as a group, they performed better than the referents, there was a statistically significant relation between longer reaction times and aluminum in air (air-Al). CONCLUSIONS: The relations between hand steadiness and years exposed, and between reaction time and air-Al, could indicate slight effects from exposure to aluminum. The possibility of selection of workers with high manual skills into welding work and a possible job-related training effect, might partly serve to explain the good performance among the welders.
The lack of a practical model has hampered attempts to study the pathophysiology of muscle cramps. We investigated the feasibility, efficacy, and reproducibility of repetitive magnetic stimulation in producing experimental cramps. In 14 healthy subjects, the tibial nerve at the ankle was stimulated with a magnetic stimulator at rates beginning at 4 Hz to a maximum of 20 Hz. The frequency was gradually increased until a cramp was produced. Ten of 14 subjects demonstrated a muscle cramp. All subjects rated the discomfort of the procedure to be mild or moderate. Repeat testing yielded values that were highly reproducible. This technique holds promise for clinical studies and therapeutic trials.
Peripheral T-cell lymphoma is the most common type of T-cell lymphoma seen in adults in the United States. Clinical data were reviewed from 134 cases of peripheral T-cell lymphoma diagnosed in three centers. The median age of the patients was 57 years (range, 4-97 years), 59% were male, and 36 patients (27%) had a history of a preceding disorder of the immune system. The tumors were grouped histologically into large cell (43%), mixed large and small cell (40%), and small cell (17%). The stage at diagnosis was I (7%), II (21%), III (22%), and IV (50%). B symptoms were present in 57%. The most frequent sites of extranodal involvement were bone marrow (35%), skin (13%), and lung (11%). Eighty patients were treated with a multiagent chemotherapy regimen with proven curative potential in aggressive non-Hodgkin's lymphomas and the remainder of the patients received less intensive chemotherapy (36 patients), radiotherapy (nine patients), or no treatment (nine patients). Fifty percent of the intensively treated patients achieved complete remission and the actuarial 4-year survival was 45%. However, the 4-year, disease-free survival in patients with Stage IV disease was only 10%. Although peripheral T-cell lymphomas appeared similar in many ways to their B-cell counterparts, disease-free survival by stage was low and patients with Stage IV disease had an especially poor outlook.
A clinicopathologic analysis of 22 cases of mantle zone lymphoma (MZL) was performed. In lymph node sections, MZL was characterized by the proliferation of neoplastic small lymphoid cells in wide mantles around benign germinal centers. Eighteen cases were of the intermediate lymphocytic type and four cases were of the small lymphocytic type. Immunohistologic analysis of paraffin sections revealed the following characteristic immunophenotype of MZL: L26, LN2, NUB1 and T2/48 positive, and LN5, LN1, AF6 and UCHL1 negative. The immunophenotype of MZL was identical to that of normal primary lymphoid follicles and the mantle zones of secondary follicles, except for the absence of staining with LN5 in MZL. The median age of the patients was 63 years, and the male-to-female ratio was 1.2:1. B symptoms were present in 55% of the patients, and 81% had splenomegaly. An absolute lymphocytosis was present at the time of initial diagnosis in 13% of the patients, and 67% had bone marrow involvement by lymphoma. Thirteen percent of the patients had Stage II disease, 23% had Stage III disease, and 64% had Stage IV disease. All 22 patients received some form of therapy, with 73% receiving multiagent chemotherapy. Eleven patients achieved a complete remission at some time during their course. The overall median survival of the entire group was 88 months. Clinical features which appeared to influence survival adversely included an absolute lymphocyte count above 4000/microliters, a platelet count less than 100,000/microliters, and male sex. Achievement of a complete remission at any time favorably influenced survival. Pathologic features which appeared to influence survival adversely were a mitotic rate of 10 or more per 10 high-power fields (HPF) and the presence of 40 or more large lymphoid cells per 10 HPF. These findings lead the authors to conclude that MZL is a distinctive form of low-grade non-Hodgkin's lymphoma.
The use of a tumor marker not only depends upon its sensitivity and specificity, but also upon its ability to influence decisions between alternative plans for patient management. Use of beta human chorionic gonadotropin (hCG) for monitoring gestational trophoblastic neoplasia has set the standard to which other assays must be compared. Beta hCG and alphafetoprotein have provided useful markers for ovarian germ cell tumors. Recently, a monoclonal antibody-based immunoassay for CA 125 antigen has been used to monitor the treatment of epithelial ovarian carcinomas. Persistent elevation of CA 125 in serum has generally reflected persistence of disease at second look surveillance procedures. CA 125 levels can, however, return to within normal limits and residual disease can be found at laparoscopy or laparotomy. CA 125 shows promise for distinguishing benign from malignant pelvic masses. Trials are currently underway to evaluate the potential of CA 125 in combination with other markers to facilitate earlier detection of occult ovarian cancer.
Controversy has recently arisen as to whether diffuse intermediate lymphocytic lymphoma (ILL) should be considered a low-grade or an intermediate-grade non-Hodgkin's lymphoma for clinical purposes. Therefore, the authors performed a clinicopathologic study to determine the biologic course of diffuse ILL (40 cases) and compared it with small lymphocytic lymphoma (SLL; 51 cases) and diffuse small cleaved cell lymphoma (DSCCL; 14 cases). They found that patients with diffuse ILL having pseudofollicular proliferation centers (PC) had a significantly longer median survival (84 months) than those without PC (46.5 months; P = 0.03). The median survival of patients with SLL was 72 months, whereas those with DSCCL had a median survival of only 18 months. Based on these findings, the authors conclude that diffuse ILL with PC should be included in the low-grade category of SLL for clinical purposes, whereas diffuse ILL without PC (true diffuse ILL) should be considered an intermediate-grade non-Hodgkin's lymphoma. True diffuse ILL is similar to centrocytic lymphoma in the Kiel classification and should be accorded a similar status in a modified Working Formulation.
Three hundred seventeen patients with non-Hodgkin's lymphoma (NHL) (54 low grade, 180 intermediate grade, 76 high grade, and seven unclassified) treated with chemotherapy were evaluated for the presence of hematologic abnormalities at diagnostic staging. Anemia was present in 42%, leukopenia in 6%, thrombocytopenia in 13%, leukocytosis in 26%, and thrombocytosis in 14% at presentation. The presence of bone marrow involvement by lymphoma was more likely to be associated with leukopenia and thrombocytopenia than the absence of bone marrow involvement. Although anemia was slightly more common in patients with bone marrow lymphoma than in those without marrow lymphoma, the difference was not statistically significant. Hematologic parameters were similar for patients with B-cell or T-cell lymphoma. Evidence of bone marrow failure with multiple cytopenias was present in 26 patients (8%). Leukoerythroblastosis was present in 2%. Circulating lymphoma was present in 9.5%. Anemic patients had a shorter survival time than nonanemic patients, whether bone marrow was involved by lymphoma or not. Survival was not affected by the presence of leukopenia or mild leukocytosis, but, in patients without marrow lymphoma, leukocytosis with a leukocyte count greater than 20 x 10(9)/l was associated with short survival length. Thrombocytopenia was associated with short survival time only in patients with bone marrow involvement by lymphoma. Patients with multiple cytopenias or leukoerythroblastosis had short survival times, but the presence of circulating lymphoma did not alter survival when compared with other patients with bone marrow involvement by lymphoma. These data suggest that hematologic evaluation at the time of diagnostic staging of NHL provides useful prognostic information that may have therapeutic implications.