T classification and clivus margin as risk factors for determining locoregional control by radiotherapy of nasopharyngeal carcinoma

A sensitive and specific liquid chromatographic-mass spectrometric assay has been developed for the determination of 22-oxacalcitriol (OCT), which is a new analog of 1alpha,25-dihydroxyvitamin D3. The analyte was isolated from serum by two solid-phase extraction steps on a C18 cartridge and NH2 cartridge. The recovery of OCT through two extraction steps was more than 90%. A related substance (ED-94), i.e. OCT with the side-chain shortened by one carbon, was used as an internal standard. Extracts were chromatographed on a C18 reversed-phase column interfaced to the electrospray ionization source. The mass spectrometer was operated in the positive-ion mode of selected reaction monitoring. The chromatographic run-time for one injection was less than 6 min. The intra- and inter-assay coefficients of variation for the lowest concentration examined (30 pg ml[-1]) were 9.83 and 10.67, respectively. And the analytical recovery of OCT added to serum was quantitative. Assay linearity was obtained in the range of 20-640 pg ml(-1).     

Method for determining optimal intracavitary radiotherapy conditions for carcinoma of the uterine cervix with tumor infiltration of the vaginal wall

Stage III carcinoma of the uterine cervix is occasionally accompanied by tumor infiltration of the vaginal wall. Currently, the vaginal wall has to be irradiated in the same manner as the uterine cervix. The authors have developed a system for determining the optimal irradiation conditions for treating the two regions, uterine cervix and vaginal wall, at the same time. A comparison of two methods is shown in simulation, and then a clinical case is reported. The first method consists of two treatment plans, one for the uterine cervix without tumor infiltration of the vaginal wall, and the other for the vaginal wall without carcinoma of the uterine cervix. The second, newly developed method considers the two regions together. Irradiation times of ovoid sources obtained with the second method are 15-25% less than those of the first method. Isodose curves obtained with the two methods are very different, and thus the uterine cervix and vaginal wall must be considered together in order to determine irradiation conditions.     

Modelling and control of coiling entry temperature using interval type-2 fuzzy logic systems

Abstract

The set-up of the cooling water applied to the strip as it traverses the runout table in order to achieve the coiler entry temperature was made by an intelligent model implemented using interval type-2 fuzzy logic systems. The model uses as inputs the targets for coiling entry temperature, strip thickness, finish mill exit temperature and finishing mill exit speed. The experiments of this application were carried out for three different types of coil in a real hot strip mill. The results proved the feasibility of the system developed for coiler entry temperature prediction. Comparison with the online type-1 fuzzy logic based model shows that the proposed interval type-2 fuzzy logic system improves performance in coiler entry temperature prediction under the tested condition.     

Can pretreatment computed tomography predict local control in T3 squamous cell carcinoma of the glottic larynx treated with definitive radiotherapy?

PURPOSE: To determine if pretreatment computed tomography (CT) can predict local control in T3 squamous cell carcinoma of the glottic larynx treated with definitive radiotherapy (RT). METHODS AND MATERIALS: Forty-two patients with previously untreated T3 squamous cell carcinoma of the glottic larynx were treated for cure with RT alone; all had a minimum 2-year follow-up. Tumor volumes and extent were determined by consensus of two head and neck radiologists on pretreatment CT studies. A tumor score was calculated and assigned to each primary lesion depending on the extent of laryngeal spread. Sclerosis of any laryngeal cartilage was recorded. The specific CT parameters assessed were correlated with local control. RESULTS: Tumor volume was a significant predictor of local control. For tumors measuring < 3.5 cm3, local control was achieved in 22 of 26 patients (85%), whereas for tumors > or = 3.5 cm3, local control was achieved in 4 of 16 patients (25%) (p = 0.0002). Sensitivity and specificity using this cutpoint were 85% and 75%, respectively. Tumor score as a measure of anatomic extent was also found to be a significant predictor of local control. The local control rate for tumors assigned a low tumor score (< or = 5) was 78% (21 of 27) compared to 33% (5 of 15) for tumors assigned a high tumor score (6, 7, or 8) (p = 0.008). A significant decrease in the local control rate was observed for cancers involving the paraglottic space at the false vocal cord level (14 of 16 [88%] vs. 12/26 [46%]) (p = 0.010), cancers involving the face of the arytenoid (15 of 18 [83%] vs. 11 of 24 [46%]) (p = 0.024), and tumors involving the interarytenoid region (25 of 36 [69%] vs. 1 of 6 [17%]; p = 0.020). There were 12 patients with sclerosis of both the ipsilateral arytenoid and the adjacent cricoid cartilage. These patients showed a significant decrease in local control (4 of 12 [33%]). CONCLUSION: Pretreatment CT can stratify patients with T3 glottic carcinoma into groups more or less likely to be locally controlled with definitive RT. The local control rate for these tumors can be improved using a CT-based tumor profile; the ideal CT profile for a radiocurable T3 glottic larynx carcinoma is volume < 3.5 cm3 and no or single laryngeal cartilage sclerosis.     

Tumor proliferation, p53 expression, and apoptosis in laryngeal carcinoma: relation to the results of radiotherapy

BACKGROUND: Radiotherapy is used in the treatment of laryngeal carcinoma. The search for biologic parameters that could be used to identify patients who will respond to radiotherapy is crucial. The aim of this study was to determine whether the Ki-67 and p53 indices and the pretreatment apoptotic index would be useful in predicting local control and survival for a group of laryngeal carcinoma patients given postoperative radiotherapy. METHODS: Fifty-seven patients with laryngeal carcinoma treated between 1988 and 1993 were included in this study. Postoperative radiotherapy was given to a mean dose of 57.7 gray (Gy) (range, 50-68; median, 60) in 2-Gy daily fractions. Ki-67 and p53 immunostaining were performed on paraffin-embedded tissue. Cells were evaluated for apoptosis using hematoxylin and eosin-stained slides. Clinicopathologic tumor characteristics were studied in relation to Ki-67, p53, and apoptotic indices, and as prognostic factors for local control and survival in both univariate and multivariate analysis. RESULTS: The Ki-67, p53, and pretreatment apoptotic indices were not related to any clinicopathologic tumor characteristics. Five-year actuarial local control for the whole group was 47%. Patients with tumors that had low Ki-67 proliferation had better long term local control (P < 0.01). and survival (P < 0.03). p53 expression was not predictive of local control or survival in this study. Patients with tumors that had low pretreatment apoptotic indices had better local control (P < 0.049) and survival (P < 0.056) than patients with highly apoptotic tumors. Tumor extension and the pretreatment apoptotic index were significant predictive factors for local control and survival in multivariate analysis. CONCLUSIONS: Ki-67 proliferation measurement and the pretreatment apoptotic index are useful in predicting the clinical outcome of laryngeal carcinoma patients referred for radiotherapy. The role of p53 oncoprotein determination in predicting these outcomes is unclear. Assessment of biologic tumor characteristics could aid in the selection of patients for different treatment strategies.     

The peptide recognized by HLA-A68.2-restricted, squamous cell carcinoma of the lung-specific cytotoxic T lymphocytes is derived from a mutated elongation factor 2 gene

The identification of naturally processed tumor peptides that can stimulate a tumor-specific, CTL response is crucial to the development of a vaccine-based, immunotherapeutic approach to cancer treatment. One type of cancer in which a tumor-specific, CTL response has been observed is squamous cell carcinoma of the lung. In the system investigated here, the tumor-specific CTLs are HLA-A68.2 restricted. Immunoaffinity chromatography was used to isolate the HLA-A68.2 molecules from the tumor cell line, and peptide was eluted with acid from the HLA-A68.2 molecules and subjected to three rounds of separation by reversed phase-high performance liquid chromatography (RP-HPLC). To determine which fractions contained the peptide recognized by the tumor-specific CTLs, an aliquot of each RP-HPLC fraction was added to the autologous, B-lymphoblastoid cell line, and the cells were then tested as targets for tumor-specific CTLs. After the third round of RP-HPLC, mass spectrometry was used to sequence individual peptide candidates, and a peptide with a m/z of 497 was identified as the active peptide. Collision-activated dissociation of m/z 497 allowed identification of the peptide sequence as ETVSEQSNV. With the exception of a single amino acid difference (glutamic acid versus glutamine as the sixth position in the peptide), this peptide is identical to residues 581 to 589 of elongation factor 2. The PCR was used to amplify the elongation factor 2 gene in both the tumor cells and the autologous B cell line, and DNA sequencing of the products revealed the presence of a heterozygous mutation in the tumor cells that accounts for the difference between the two peptide sequences. Although a similar analysis did not reveal the presence of the mutation in three additional lung cell carcinomas, this does not rule out the possibility that a survey of a larger population of tumor cells would reveal the presence of the mutation at a low frequency. These results demonstrate the utility of this approach for identifying tumor-specific antigens that are the targets of a CTL response.     

Novel formula for cell kinetics in xenograft model of hepatocellular carcinoma using histologically calculable parameters

Hepatocellular carcinoma (HCC) is associated with increased expression and function of inhibitory guanine nucleotide regulatory proteins (Gi-proteins). This study addresses the effects of chronic ethanol exposure on the expression and function of adenylyl cyclase (AC)-linked G-proteins (Gs and Gi) and growth in experimental HCC. G-protein expression and function was determined by immunoblot in the hepatic tumorigenic H4IIE cell line and isolated cultured hepatocytes in the absence or presence of ethanol (5-100 mmol/L). Chronic exposure (24 hours) to ethanol dose-dependently increased Gialpha1/2 expression in the H4IIE cell line, but not in cultured hepatocytes. Gsalpha-protein expression remained unchanged in both H4IIE cells and cultured hepatocytes following ethanol treatment. In addition, ethanol directly activated a Gi-protein, because pertussis toxin (PTx)-catalyzed, adenosine diphosphate (ADP)-dependent ribosylation of Gialpha substrates decreased following ethanol treatment. The increased functional activity of Gialpha1/2-protein expression was confirmed by demonstrating that ethanol dose-dependently inhibited basal and stimulated AC activity in H4IIE cells, while not significantly altering basal AC activity in isolated cultured hepatocytes. Furthermore, while ethanol had no significant effect on basal mitogenesis in H4IIE cells or hepatocytes, increased mitogenesis caused by direct Gialpha-protein stimulation (mastoparan M7; 10-5,000 nmol/L) was further enhanced in the presence of ethanol, an effect that was completely blocked following Gi-protein inhibition (PTx; 100 ng/mL). In contrast, activation of Gi-proteins using M7 failed to alter cellular mitogenesis in isolated cultured hepatocytes, whether in the absence or presence of ethanol. Finally, analysis of mitogen-activated protein kinase (MAPK) activity demonstrated that chronic ethanol treatment further enhanced Gi-protein-stimulated MAPK activity in hepatic tumorigenic cells. In conclusion, these data demonstrate that ethanol enhances cellular mitogenesis in experimental HCC as a result of, at least in part, a Gi-MAPK-dependent pathway. Furthermore, this effect may be caused by ethanol's direct up-regulation of the expression and activity of Gi-proteins in HCC.     

Curative radiotherapy for stage II-III squamous cell carcinoma of the glottic larynx

Cystic mesothelioma of peritoneum is a rare neoplasia that was identified as a individual entity by ultrastructural and immunoistochemical studies. It is more frequent in young woman and often it tends to recur. Because of its rarity and difficulty in differential diagnosis, the Authors describe a case of cystic mesothelioma observed.     

Differentiation and stability of T helper 1 and 2 cells derived from naive human neonatal CD4+ T cells, analyzed at the single-cell level

The development of CD4+ T helper (Th) type 1 and 2 cells is essential for the eradication of pathogens, but can also be responsible for various pathological disorders. Therefore, modulation of Th cell differentiation may have clinical utility in the treatment of human disease. Here, we show that interleukin (IL) 12 and IL-4 directly induce human neonatal CD4- T cells, activated via CD3 and CD28, to differentiate into Th1 and Th2 subsets. In contrast, IL-13, which shares many biological activities with IL-4, failed to induce T cell differentiation, consistent with the observation that human T cells do not express IL-13 receptors. Both the IL-12-induced Th1 subset and the IL-4-induced Th2 subset produce large quantities of IL-10, confirming that human IL-10 is not a typical human Th2 cytokine. Interestingly, IL-4-driven Th2 cell differentiation was completely prevented by an IL-4 mutant protein (IL-4.Y124D), indicating that this molecule acts as a strong IL-4 receptor antagonist. Analysis of single T cells producing interferon gamma or IL-4 revealed that induction of Th1 cell differentiation occurred rapidly and required only 4 d of priming of the neonatal CD4+ T cells in the presence of IL-12. The IL-12-induced Th1 cell phenotype was stable and was not significantly affected when repeatedly stimulated in the presence of recombinant IL-4. In contrast, the differentiation of Th2 cells occurred slowly and required not only 6 d of priming, but also additional restimulation of the primed CD4+ T cells in the presence of IL-4. Moreover, IL-4-induced Th2 cell phenotypes were not stable and could rapidly be reverted into a population predominantly containing Th0 and Th1 cells, after a single restimulation in the presence of IL-12. The observed differences in stability of IL-12- and IL-4-induced human Th1 and Th2 subsets, respectively, may have implications for cytokine-based therapies of chronic disease.     

Combined surgery and postoperative radiotherapy for carcinoma of the base of radiotherapy for carcinoma of the base of tongue: analysis of treatment outcome and prognostic value of margin status

BACKGROUND: Choice of treatment for base of tongue carcinoma is controversial, with options including surgery alone, radiotherapy alone, or multimodality treatment. Given the highly aggressive nature of these tumors, it has been our institutional policy to manage this disease with combined partial glossectomy (with attempt to avoid laryngectomy if possible) with planned postoperative radiotherapy (RT). We reported on our institutional experience with this approach. METHODS: A retrospective review of the charts of 17 patients with primary base of tongue squamous cell carcinoma treated with surgery and postoperative RT was performed. Patients treated with chemotherapy as part of their management were excluded. All patients underwent partial, hemi-, or subtotal glossectomy; 15/17 patients underwent ipsilateral radical or modified radical neck dissection. All patients received comprehensive postoperative RT (median dose 6000 cGy; range 5040-6920 cGy). Stage distribution was as follows: stage I, 2; stage II, 3; stage III, 2; stage IV, 10. Positive margins for invasive carcinoma were found in 9/17 patients. Median follow-up of surviving patients is 46 months; median follow-up for all patients is 31 months. RESULTS: For the entire group of patients, the actuarial 3-year local-regional control rate was 68%. The actuarial 3-year overall survival rate was 46%. The local-regional control rate was 83% for patients with stage I-III disease versus 50% for stage IV disease. There were no local failures among eight patients with negative margins (local control 100%) compared with an actuarial local control rate of 36% among patients with positive margins (p = .03). Survival, disease-specific survival, and locoregional control were also highly correlated with margin status (p = .003). Late major complications included 5/17 patients requiring permanent G-tubes and/or tracheostomy to prevent aspiration. CONCLUSIONS: Surgery plus postoperative RT is an intensive treatment for carcinoma of the base of tongue which offers high locoregional control in patients in whom negative margins are achieved. Positive margins indicate a high risk of locoregional and systemic failure, and these patients should be considered for innovative clinical trials after surgery.     

Indications for percutaneous radiotherapy in carcinoma of the thyroid gland. Freiburg consensus

At the University of Freiburg, a consensus was arrived at concerning the place of external radiotherapy in the management of thyroid cancer. External irradiation is always indicated in papillary and folliculary carcinoma in the pT4 stage of pTNM classification but not in those in pT1-3 pN0 stage. In the presence of lymph-node metastases and distant metastases, an individual treatment concept is recommended, which should be set up in an interdisciplinary conference regarding all risk factors, especially the age and sex of the patient, the histology and grading of the tumor and the completeness of tumor resection. Finally, radiotherapy is usually not indicated in medullary thyroid carcinoma, whereas it is always indicated in anaplastic carcinoma.     

Expression of the sialosyl-Tn epitope on CD45 derived from activated peripheral blood T cells

The cell surface protein tyrosine phosphatase CD45 is a major target of IgM anti-T cell autoantibodies in systemic lupus erythematosus (SLE). The autoreactive determinants on CD45 are O-linked glycans expressed on activated T cells and certain T cell lines, rather than linear or conformational polypeptide epitopes or N-linked glycans. To identify oligosaccharide structures that may play a role in the functional interactions of CD45 or are candidate target epitopes of SLE anti-CD45 autoantibodies, autoreactive CD45 purified from Jurkat T cells and non-autoreactive CD45 purified from CLL B cells were tested by ELISA for expression of mucin-type O-glycan structures. Monoclonal antibodies (mAbs) directed against blood group A, type 1 H chains, type 2 H chains, T, Le(a), sialylated-Le(a), Le(b), sialylated-Le(c), Le(x), sialylated-Le(x), multi-fucosylated Le(x), Le(y), and sialylated-extended Le(v) failed to react with CD45 from either B cells or T cells. However, mAbs directed against Tn (galNAcalpha1-->O-ser/thr) or sialosyl-Tn (neuNAcalpha2-6gaINAcalpha1-->O-ser/thr) structures reacted with CD45 derived from Jurkat T cells, but not from CLL B cells. Anti-Tn mAbs also reacted in western blotting procedures with CD45 isolated from Jurkat T cells, but did not react with CD45 isolated from CEM, MOLT-3, or PEER T cells; Daudi, Raji, or CLL B cells; or resting or Con A-activated PBL. However, anti-sialosyl-Tn mAbs stained blots of CD45 isolated from Jurkat and CEM T cells and Con A-activated PBL, a pattern of reactivity similar to that of the anti-CD45 autoantibodies. Flow cytometric analyses demonstrated that the sialosyl-Tn epitopes are expressed on a subpopulation of CD4 +/CD8- T cells.     

Distinction of basaloid carcinoma of the prostate from benign basal cell lesions by using immunohistochemistry for bcl-2 and Ki-67

The distinction of rare basaloid carcinomas (BC) of the prostate from more common basal cell hyperplasia may be difficult, because basal cell hyperplasia (BCH) may have prominent nucleoli and may appear infiltrative. Using immunohistochemistry, we studied bcl-2 and p53 expression and Ki-67 proliferation index in eight cases of typical BCH, eight cases of BCH with nucleoli, and six cases of BC. Bcl-2 expression (P < .0001) and Ki-67 index (P=.005) were elevated in BC compared with typical BCH or BCH with nucleoli, whereas there was no significant difference between typical BCH and BCH with nucleoli. P53 was not discriminative in separating benign from malignant basal cell lesions of the prostate. Bcl-2 may play a role in the pathogenesis of basal cell lesions of the prostate. Elevated expression of bcl-2 and higher Ki-67 index may aid in the diagnosis of basal cell proliferative lesions of the prostate.     

Supraomohyoid neck dissection in the treatment of T1/T2 squamous cell carcinoma of oral cavity

BACKGROUND: Recent studies in patients with previously untreated T1 and T2 squamous cell carcinoma (SCC) of the tongue and floor of the mouth have shown a relationship between tumor thickness, neck metastasis, and survival. Our study was conducted to determine the indication of elective neck dissection in patients with early oral cavity SCC. PATIENTS AND METHODS: Sixty-seven patients were stratified by stage (T1 and T2 NO), and those in each stage were randomized to receive one of two types of treatment; resection alone (RA) or resection plus elective supraomohyoid neck dissection (RSOND). Fifty-two patients (78%) were men and 15 (22%) were women. The median age was 57 years old (range 34 to 95). RESULTS: Twenty-six (39%) patients had tumor in the floor of the mouth and 41 (61%), in the tongue. Using the criteria of the Union Internationale Contre le Cancer (UICC), 1987, we classified 31 tumors (46%) as T1 lesions and 36 (54%) as T2 lesions. Thirty patients had a tumor thickness < or = 4 mm and 37 had a tumor thickness > 4 mm. Thirty-three (49%) patients were treated with RA, and 34 patients (51%) were treated with RSOND. Seven (21%) patients of the RSOND group had occult cervical metastasis. There were recurrences in 14 (42%) patients of the RA group and 8 (24%) patients of the RSOND group. The disease-free survival rates at 3.5 years for RA and RSOND patients were 49%, and 72%, respectively. The impact of sex, age, site, cancer stage, and tumor thickness was assessed by the Mantel-Haenszel chi-square procedure. Later stage (P = 0.05) and increased tumor thickness (P = 0.005) were significantly associated with treatment failures. CONCLUSION: Neck dissection remains mandatory in the early stage of oral SCC, because of better survival rates compared to RA and the poor salvage rate. In particular, patients with tumor thickness > 4 mm treated with RSOND had significant benefit on disease-free survival.