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J Bosq
Publications and source records attributed to J Bosq.
Analysis of p53 serum antibodies in patients with head and neck squamous cell carcinoma.
BACKGROUND: Mutation of the p53 tumor suppressor gene (also known as TP53) often leads to the synthesis of p53 protein that has a longer than normal half-life. Mutant p53 protein that accumulates in tumor cell nuclei can be detected by means of immunohistochemical staining techniques. Serum antibodies directed against p53 protein (p53-Abs) have been detected in some cancer patients. PURPOSE: We assayed serum samples from 80 patients with head and neck squamous cell carcinoma (HNSCC) for the presence of p53-Abs, and we evaluated potential associations between the presence of these antibodies and other histopathologic and clinical features. METHODS: Serum was collected from each patient at the time of diagnosis. In addition, tumor biopsy specimens were obtained before the initiation of treatment. An enzyme-linked immunosorbent assay was used to detect p53-Abs. The accumulation of p53 protein in tumor cell nuclei was assessed immunohistochemically by use of the anti-p53 monoclonal antibody DO7. Patient treatment consisted of radiotherapy alone, primary chemotherapy followed by radiotherapy, or surgery and postoperative radiotherapy. Relapse-free and overall survival from the beginning of treatment were estimated by use of the Kaplan-Meier method; survival comparisons were made by use of the logrank statistic. Univariate and multivariate analyses were conducted to identify factors associated with survival. Reported P values are two-sided. RESULTS: Fifteen (18.8%) of the 80 patients had p53-Abs. Tumor cell nuclei in 43 (58.9%) of 73 assessable biopsy specimens exhibited strong p53 immunostaining. Patient treatment method and the accumulation of p53 protein in tumor cell nuclei were not associated with increased risks of relapse or death. In univariate analyses, advanced tumor stage (> T1 [TNM classification]) and the presence of p53-Abs were significantly associated with an increased risk of death (P for trend = .007 and P = .002, respectively), whereas advanced tumor stage, substantial regional lymph node involvement (> N1), and the presence of p53-Abs were associated with an increased risk of relapse (P for trend = .002, P = .02, and P < .0001, respectively). In multivariate analyses, advanced tumor stage and the presence of p53-Abs were significantly associated with increased risks of relapse (p for trend = .04 and P = .003, respectively) and death (P for trend = .04 and P = .03, respectively). At 2 years of follow-up, the overall survival proportion was 63% (95% confidence interval [CI] = 47%-80%) when no p53-Abs were detected compared with 29% (95% CI = 4%-54%) when p53-Abs were detected. Relapse-free survival at 2 years was 62% (95% CI = 49%-76%) if no p53-Abs were detected compared with 13% (95% CI = 0%-31%) if p53-Abs were detected. CONCLUSIONS AND IMPLICATIONS: The proportion of patients with HNSCC who have serum p53-Abs is smaller than that of patients exhibiting tumor cell accumulation of p53 protein. The presence of p53-Abs is significantly associated with increased risks of relapse and death.
Potential doubling time and clinical outcome in head and neck squamous cell carcinoma treated with 70 GY in 7 weeks.
PURPOSE: To study the predictive value of pretreatment potential doubling time and labeling index, as measured by flow cytometry in patients with head and neck squamous cell carcinoma treated with conventional radiotherapy. METHODS AND MATERIALS: 70 patients with a squamous cell carcinoma of the oropharynx and 4 patients with another involved head and neck site were entered in this prospective study. The duration of the S phase (TS), the labeling index (LI), and the potential doubling time (Tpot) were obtained by flow cytometry measurements of a tumor biopsy obtained after i.v. injection of 200 mg bromodeoxyuridine to the patient. The treatment consisted of 70 Gy in 7 weeks, 2 Gy per fraction and five fractions per week. RESULTS: The mean and median LI were 7.7% (standard deviation, SD: 5.0) and 6.3%, respectively. The mean and median TS were 9.3 h (SD: 3.6) and 8.3 h, respectively. The mean and median Tpot were 5.6 days (SD: 5.4) and 4.6 days, respectively. No significant relationship was found between the Tpot or LI and the tumor stage (T), nodal status (N), histological grade, and the site of the primary within the oropharynx. The only parameter significantly associated with an increased risk of local relapse was the tumor stage (p < 0.001). The mean Tpot for the group of tumors that relapsed locally was 5.3 days (SD: 3.3), compared to 6.1 days (SD: 4.08) for those who did not relapse locally (NS). Two parameters were significantly associated with a decrease in disease-free (DFS) and overall survival, namely the tumor stage (p < 0.005, and p < 0.001, respectively, for DFS and overall survival) and nodal involvement (p = 0.02 and (p < 0.005, respectively, for DFS and overall survival). The TS, LI, DNA index, and Tpot were not significantly associated with local relapse, DFS, and survival, either in the univariate or in the multivariate analysis. CONCLUSIONS: The method used to evaluate tumor cell kinetics did not provide clinically relevant kinetic parameters for this type of cancer. The classic prognostic factors (tumor stage and nodal status) were strongly associated with clinical outcome.
Alternating chemotherapy and radiotherapy for limited-stage intermediate and high-grade non-Hodgkin's lymphomas: long-term results for 96 patients with tumors > 5 cm.
BACKGROUND: The role and timing of radiotherapy for optimal treatment of localized aggressive non-Hodgkin's lymphoma (NHL) is controversial. We report the long-term results of a single-institution pilot study of alternating chemotherapy (CT) and radiotherapy (RT) in patients with clinical stages I or II tumors exceeding 5 cm. PATIENTS AND METHODS: From 1981 to 1992, 96 patients with stages I-II aggressive NHL received an alternating regimen of CT and RT consisting of 8 cycles of CT with 3 courses of RT interjected after the 2nd, 3rd and 4th cycles of CT. The CT combined cyclophosphamide, doxorubicin, teniposide and prednisone every 28 days. Each RT course was started 8 to 10 days after CT (15 Gy in 6 fractions to initially involved and contiguous areas). RESULTS: The median age was 54 years. The disease predominantly located in the head and neck area was stage II in 63% of patients. Bulky tumors (10 cm or larger) were found in 24% of patients. Six patients discontinued CT because of acute toxicity (mucositis). The mean relative dose intensity achieved for doxorubicin, cyclophosphamide and teniposide were 72%, 82%, and 78%, respectively. Late toxicity consisted mostly of severe xerostomia lasting more than 2 years in 7 patients irradiated in Waldeyer's ring. The complete response (CR) rate was 91%; 20 of the 86 patients in CR relapsed (3 locally only). The median follow-up was 61 months, and at 5 years, overall survival (OS) was 77%. Classification according to the International Prognostic Factor Index was possible for 54 patients, all but three of whom were in the 'low risk' group (0-1 factor). Bulky disease was the only unfavorable prognostic factor (P < 0.001) for CR, freedom from progression (FFP) and OS rates; the low relative dose intensity of CT achieved in this study did not affect outcome. CONCLUSION: Alternating chemo-radiotherapy for localized aggressive NHL was feasible and yielded long-term results comparable to those obtained with standard treatments, despite a reduction in dose intensity considerably below that of CHOP which suggested synergistic effects of CT and RT in this scheme.
Radiologic assessment of intranodal vascularity in head and neck squamous cell carcinoma. Correlation with histologic vascular density.
RATIONALE AND OBJECTIVES: Nodal response to chemotherapy in head and neck squamous cell carcinoma depends on the vascularization. The authors assessed different techniques in detecting nodal vascularization. METHODS: Fourteen patients with head and neck tumor were included before surgical treatment. The largest metastatic lymph node (mean axial scanographic diameters 30 x 20 mm) was studied by color and pulsed Doppler, and dynamic magnetic resonance images, processed by factor analysis of medical image sequences (FAMIS), which estimates physiologic contrast enhancement kinetics (factors) and their spatial distributions (factor images). Results were compared with the histologic microvessel density (MVD). Using light microscopy, MVD was estimated by the vascular surface (by staining endothelial cells) to the stroma surface ratio x 100. RESULTS: Three factors were identified by FAMIS: a constant factor in necrosis, an earlier F1 factor and a later F2 factor in normal lymphoid areas and neoplastic stroma. Color flow signal was detected when the MVD was greater than 6.36. CONCLUSIONS: Only one model of vascularization was extracted by FAMIS, with no difference between neoplastic and spared lymphoid areas. The presence of color-flow signals could help predict the response of metastatic lymph nodes to chemotherapy.
CT and MR imaging of squamous cell carcinoma of the tongue and floor of the mouth.
Because contemporary treatment of oral cavity cancer involves procedures that spare the tongue and mandible, an adequate assessment of the oral cavity is essential for appropriate surgical and radiation therapy planning. Computed tomography (CT) and magnetic resonance (MR) imaging, which allow differentiation between soft tissues, are valuable tools for assessing this complex region. Their main advantage resides in their capacity to show at best the normal anatomy and the exact extent of a low-lying tumor. For display of soft tissues and tumor, MR imaging, being a multiplanar and multicontrast technique, is superior to CT. Nonenhanced T1-weighted MR imaging is better for defining the exact extent of medullary bone invasion, which appears as a low-signal-intensity area within hyperintense medullary fat. CT is optimal in detection of cortical bone invasion, which appears as an interruption or erosion of the peripheral hyperattenuating rim. Thus, in cancer of the tongue, MR imaging should be performed first. If tumor extension to the mandible is suspected (due to clinical or MR imaging findings), CT should be added. In cancer of the floor of the mouth, both MR imaging and CT should be performed in the initial work-up, especially in those cases in which there is a clinical doubt about mandibular extension of disease. The main drawback of both modalities is their lack of specificity; other methods are needed to discriminate between tumors and inflammatory or infectious diseases, particularly in the mandible. However, once the diagnosis has been confirmed histologically, treatment can be chosen based on complementary information obtained from CT and MR imaging.
Squamous cell carcinoma involving the calvaria and base of the skull.
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Can clinical data help to screen patients with lymphoma for MR imaging of bone marrow?
BACKGROUND: Previous studies have suggested combining magnetic resonance (MR) imaging and biopsy in patients with lymphoma but association between MR results and clinical symptoms have never been investigated. The purpose of this retrospective study was to better delineate patients profiles requiring bone marrow (BM) imaging in lymphoma. MATERIAL AND METHODS: 50 MR studies and blind biopsies (BB) were reviewed in 40 patients with lymphoma. MR results were compared to clinical, laboratory-based and BM follow-up data to determine potential associations between MR results and these parameters. RESULTS: 46% of MR studies were abnormal with a normal BB; 2% were normal with an abnormal BB. Abnormal MR results were significantly associated with subsequent bone marrow involvement (p < 0.01). Abnormal MR studies were significantly associated with constitutional symptoms, bone pains (p < 0.05) and an elevated alkaline phosphatase level (p < 0.01). MR imaging excluded malignancy in three patients and caused therapy to be modified in three. CONCLUSION: Abnormal clinical and laboratory-based data should be used to screen patients with normal BB for MR imaging, especially in patients with Hodgkin's disease and high grade non-Hodgkin's lymphoma.
Localized stage non-Hodgkin's lymphoma of the testis: a retrospective study of 16 cases.
The present report concerns a retrospective study of 16 patients with localized intermediate- or high-grade non-Hodgkin's lymphoma of the testis treated in one institution from 1973 to 1990. Ann Arbor stage of disease was IE in 11 and IIE in 5 cases. All except one patient underwent initial inguinal orchidectomy, 11 were disease free after surgery and 12 received inverted Y radiation therapy. All patients achieved a complete remission (CR). Relapse occurred in 8 of 9 patients who did not receive initial chemotherapy, but in only 3 of 7 patients initially treated with chemotherapy including anthracyclins. In 3 cases relapse was confined to the CNS, while diffuse relapse in 8 others included 4 cases of CNS involvement. Eight patients are now alive in CR (5 in first CR, 1 in second CR and 2 in third CR) with a median follow-up of 68.5 months (range 54-101). Chemotherapy thus emerges as the initial treatment of preference for localized testicular lymphoma. Therapy should be preceded by a thorough assessment of the stage of disease and due to the high frequency of CNS relapse, CNS prophylaxis should be considered for all patients.
Second primary cancers in patients continuously disease-free from Hodgkin's disease: a protective role for the spleen?
Second primary cancers are a serious late occurrence for patients surviving Hodgkin's disease (HD). In addition to previously described risk factors such as age, gender, clinical stage, and treatment modalities, splenectomy was found to correlate with an increase in risk for secondary acute leukemia. We assumed that splenic irradiation inducing functional hyposplenia and splenectomy could have similar consequences on second cancer risk. We studied a series of 892 continuously disease-free HD adult patients treated at a single institution between 1960 and 1984. The risk of second cancer was analyzed (1) relative to the general population and (2) between risk subgroups using the Cox proportional hazards model. Fifty-six patients developed a second cancer (8 acute leukemias, 3 myelodysplastic syndromes, 8 non-Hodgkin's lymphomas, and 37 solid tumors; basal cell and in situ cervix carcinomas were excluded). The 15-year cumulative incidence rate (with 95% confidence limits) was 13.2% (9.3% to 17.2%). Relative to the general population incidence data, the risk of second cancer was multiplied by 4.68 (3.51 to 6.12; P < .001); it was multiplied by 2.80 (1.63 to 4.48; P < .001) in patients whose spleen was not treated and multiplied by 6.87 (4.81 to 9.51; P < .001) in splenectomized patients or patients whose spleen was irradiated. Multivariate regression analysis that controlled for confounding variables (age, gender, clinical stage, extent of radiation therapy, and chemotherapy regimen) showed that, in addition to age above 40 years (relative risk [RR] = 3.72; P < .001), combination of MOPP chemotherapy and regional irradiation (RR = 4.99; P = .015) and combination of MOPP chemotherapy and extended irradiation (RR = 10.86; P < .001), splenic irradiation (RR = 3.67; P = .003), and splenectomy (RR = 2.54; P = .018) also significantly correlated with an increased risk. The results of this hospital-based registry study strongly suggest that splenic irradiation and splenectomy might increase the risk for treatment-related second cancer. These findings, if confirmed, have to be considered in future HD treatment policies.
Correlation between p53 gene expression and tumor-cell proliferation in oropharyngeal cancer.
The aim of our study was to analyze the correlation between tumor-cell kinetics measured in vivo and p53 gene expression in a series of 49 oropharyngeal cancers. The duration of the S phase (TS), the labelling index (LI) and the potential doubling time (Tpot) were obtained by flow-cytometry measurements of a tumor biopsy obtained after i.v. injection of 200 mg bromodeoxyuridine into patients. An adjacent section of the same samples was studied by immunohistochemistry for the detection of p53 protein. Over-expression of the p53 protein, as defined by strong p53 immunostaining of tumor nuclei, was found in 23/49 of the samples. Aneuploid tumors showed a higher LI, a shorter Tpot and a higher proportion of p53 gene over-expression. A significant correlation was seen between p53 over-expression and short Tpots. Indeed 87.5% of the tumors with a very short Tpot (< or = 3 days) had p53 over-expression, as compared with 27% of tumors with a longer Tpot (> 3 days). Our data strongly suggest that over-expression of the p53 gene is associated with rapid tumor-cell proliferation in this type of cancer.
Lymph node prognostic factors in head and neck squamous cell carcinomas.
BACKGROUND: This retrospective study included 914 patients who underwent a lymph node dissection at our institute between 1980 and 1985. The primary tumor sites were oral cavity, 287; hypopharynx, 249; larynx, 247; and oropharynx, 131. PATIENTS AND METHODS: On the basis of anatomic considerations, the sentinel nodes for well-lateralized oral cavity tumors were defined as homolateral levels I, II, and III; for oropharyngeal, hypopharyngeal, and laryngeal tumors, the sentinel nodes were defined as levels II and III. We took into account the ipsilateral side of the neck for well-lateralized tumors, and both sides for medium or large tumors. For clinically positive nodes of more than 3 cm, a radical neck dissection was performed. Other patients underwent a selective neck dissection on sentinel nodes, with immediate pathologic evaluation. Modified radical neck dissections with contralateral selective dissection were performed when frozen sections were positive. Patients with positive nodes were given postoperative radiotherapy. RESULTS: The prognostic factors studied, using the Cox survival model adjusted on the primary tumor site, surprisingly showed a nonsignificant value for extracapsular spread (P = 0.09), and a significant value for the number of positive nodes (P < 0.001) and for the positive node in or out of the sentinel node sites (P < 0.001). Although the node location factor can be used instead of positive node in or out of the sentinel node site, it has a less significant prognostic value. CONCLUSIONS: The most significant prognostic factors are the site of the positive node in or out of the sentinel node and the number of positive nodes; and a more accurate approach can be obtained by combining both factors. Node location in the upper or lower neck remains a substitute prognostic factor for the site of the positive node in or out of the sentinel node.
Coexistent cutaneous T-cell lymphoma and B-cell malignancy. French Study Group on Cutaneous Lymphomas.
BACKGROUND: The coexistence of cutaneous T-cell lymphoma (CTCL) and a B-cell malignancy (BCM) is rare. OBJECTIVE: Our aim was to assess the clinical and pathologic aspects of coexistent CTCL and BCM and to examine potential explanations for this association. METHODS: We report six cases of concurrent CTCL and BCM in which B- and T-cell lineages were demonstrated by immunologic studies. The literature includes 13 additional cases. All 19 CTCL-BCM cases are reviewed. RESULTS: CTCL either preceded or followed the BCM, which was a low-grade malignancy in most cases (16 of 19). Possible explanations for the association include a genetic predisposition, underlying viral infection, chemotherapy-induced carcinogenesis, stimulation of a B-cell clone by malignant helper T cells, and alterations in progenitor cells before determination of B- and T-cell lineage. CONCLUSION: An alteration in progenitor cells, with subsequent oncogenic activation of variable origin, might account for most cases of coexistent CTCL and BCM.
Direct evidence to support the immunosurveillance concept in a human regressive melanoma.
The concept of immunosurveillance against cancer has been an extensively debated question over the last decades. Multiple indirect arguments have supported the view that the immune system may control, at least in certain cases, malignant cell growth while direct demonstration is still lacking in the human. In an attempt to address this issue, we have selected a study model, namely spontaneously regressive melanoma. In previous series of experiments, the variability of T cell receptors (TCRs) in the lymphocytes infiltrating a regressive tumor lesion was investigated. Results demonstrated that clonal T cell populations, precisely defined through their V-D-J junctional sequences, were amplified in situ. One clone was predominant, expressing the V beta 16 variable gene segment. A specific anti-V beta 16 TCR mAb was generated here to purify and functionally characterize the corresponding cells. A tumor-infiltrating lymphocyte-derived V beta 16+ T cell line was developed using this reagent. These in vitro cultured cells were found to express the in vivo predominant TCR sequence exclusively and to display an HLA-B14-restricted cytotoxic activity against the autologous tumor cells. Immunohistochemical experiments, performed with the anti-V beta 16 mAb, showed that the corresponding CTLs are present in the tumor area, some of them being closely opposed to the melanoma cells. Together, these studies demonstrate the existence of a local adaptive immune response clinically associated to tumor regression, thus strongly supporting the validity of the immunosurveillance concept in certain human tumors.
Rapid tumor cell proliferation after induction chemotherapy in oropharyngeal cancer.
Tumor cell kinetics were studied in vivo in a series of 97 patients with oropharyngeal cancer. The duration of S phase (tS), the labeling index (LI), and the potential doubling time (Tpot) were obtained by flow cytometry measurements of a tumor biopsy obtained after intravenous injection of 200 mg 5-bromodeoxyuridine to the patient. The mean LI was 9.7% (standard deviation [SD], 5.4), the mean tS was 10.1 hours (SD, 3.6), and the mean Tpot was 4.6 days (SD, 3.5). No significant relationship was found between the Tpot or LI and the size of the tumor, nodal status, histological grade, or the site of the primary within the oropharynx. Conversely, aneuploid tumors had longer tS (P < .001), higher LI (P < .001), and shorter Tpot (P < .05) than the diploid tumors. The mean LI and Tpot of the tumors obtained after induction chemotherapy were significantly higher and shorter, respectively, than those measured before any treatment. The data strongly suggest that rapid tumor cell proliferation frequently occurs in oropharyngeal cancer which had responded poorly to chemotherapy.
Factor analysis of medical image sequences in MR of head and neck tumors.
PURPOSE: To evaluate factor analysis of medical image sequences (FAMIS), a means whereby physiologic contrast enhancement kinetics, called factors, and their spatial distribution, termed factor images, are estimated after acquisition of dynamic MR images. The method is intended to recognize and characterize the different tissue kinetics automatically. METHODS: This method was evaluated in a series of 22 patients with head and neck tumors. Eleven patients presented with a previously untreated lesion. Six were examined for tumor recurrence, previously treated by multiple therapies. Five patients had preoperative chemotherapy and underwent MR before and after chemotherapy. In all cases, MR images were correlated with surgical and pathologic data. MR examinations were performed on a 1.5-T unit with static sequences and dynamic sequences acquired after bolus injection of gadolinium and processed by FAMIS. RESULTS: FAMIS was able to identify three factors representing contrast-enhancement kinetics and their associated factor images. The neoplastic component was associated with the earlier factor image, F1. Fibrosis and chemotherapy and/or radiation-induced changes were associated with the two later factors, F2 and F3. The limits of this method were highly vascularized tissues whose earlier factor was similar to that of neoplastic tissues (mucosae and salivary glands), patient motion, responsible for artifacts in FAMIS, and lesions of less than 5 mm. CONCLUSION: FAMIS of dynamic MR studies was useful for differentiating neoplastic tissue from tissue having undergone changes by chemotherapy and/or radiotherapy, but it did not improve the ability of MR to characterize neoplastic tissues in previously untreated patients.
[Malignant granuloma of the face and angiocentric T-cell lymphoma. A review of the literature apropos of a case].
The authors report the observation of a lethal midline granuloma in a 43 years old man, at first seen with repeated left sinusitis disease, the histo-pathological study of a biopsy of the external middle third of the left side of the nose made the diagnosis of midline lethal granuloma, classically called Stewart granuloma by french authors. General Medical Investigations to find some peripheral extension, done in specialized services were negative, Epstein Barr DNA was not found by the immuno-histochemical investigations and so don't prove the filiation of this case with angiocentric T cell immunoproliferative lesion. By the light of this observation and of a literature review, the authors debate about the difficulty of diagnosis and about the relations with the other granulomatosis lesions of the face, non Hodgkins' lymphoma and angiocentric T cell immuno-proliferative lesions.
In vivo measurement of the potential doubling time by flowcytometry in oropharyngeal cancer treated by conventional radiotherapy.
PURPOSE: Experimental and clinical studies suggest that the pre-treatment potential doubling time could be predictive of tumor control in patients treated by conventional radiotherapy and could help to identify the rapidly growing tumors for which accelerated radiotherapy is required. METHODS AND MATERIALS: To test this hypothesis, we studied prospectively 48 patients with a squamous cell carcinoma of the oropharynx and treated by conventional radiotherapy (70 Gy/7 weeks). The duration of S phase, the labeling index and the potential doubling time were obtained by flowcytometry measurements of a tumor biopsy obtained after injection of 200 mg bromodeoxyuridine to the patient. RESULTS: Three parameters were significantly associated with an increased risk of relapse namely the tumors size (T4; p < 0.01), the nodal status (> or = N2; p < 0.05) and the site of the primary within the oropharynx (p = 0.08). The S phase, labeling index, DNA index and potential doubling time were not significantly associated with an increased risk of relapse. However when considering only the T2 subgroup of patients, high labeling indexes and short potential doubling time were associated with an increased risk of relapse: the mean pre-treatment potential doubling time of the tumors which relapsed was 3.21 versus 5.5 days when there was no evidence of local relapse (p < 0.05). The mean labeling index for the group of tumors associated with a tumor recurrence was 11.7% compared to 7.3% when there was no evidence of relapse (p = 0.02). CONCLUSION: Factors other than proliferation play a role in determining the outcome of oropharyngeal cancers treated by conventional radiotherapy. However there was a significant correlation between short potential doubling time, high labeling index and tumor recurrence in the T2 subgroup of patients. The finding of significance for potential doubling time and labeling index in the T2 subset of tumors may be a reflexion of the more homogeneous nature of these tumors with regard to prognostic variables.