Patients with advanced Hodgkin disease (HD) who have a relapse after first-line chemotherapy can achieve further remissions with high-dose chemotherapy and transplantation of hematopoietic stem cells. Unfortunately, relapse or disease progression after autologous transplant occurs in a significant proportion of cases, and no clear treatment guidelines exist for these patients. We report the case of a patient with a refractory localized HD who had a sustained long-term remission (39 months) after surgery alone. A 22-year-old male student was seen in November 1995 with B signs and superior vena cava syndrome. HD of the nodular sclerosis type was diagnosed at stage IIIB with bulky mediastinum. The patient was treated with 6 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine to achieve a complete remission, consolidated by 40-Gy radiotherapy to initial sites of bulky mediastinum and by 30-Gy radiotherapy to neck and axillary areas. Two years after completion of therapy, the disease recurred as a localized left lung suprahilar nodule within the previously irradiated field. The patient was successfully treated with 3 courses of etoposide, vinblastine, cytarabine, and cisplatin chemotherapy, followed by high-dose chemotherapy (carmustine, etoposide, cytarabine, and melphalan) and autologous hematopoietic stem cell transplantation in December 1998. The disease recurred at the same location in November 1999. The patient was treated with 4 cycles of standard bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone therapy, with complete remission. However, this discrete lesion reappeared in February 2001. Because this localized HD was not sensitive to chemotherapy and complementary irradiation was excluded because of location at the margin of the previously irradiated field, a surgical approach was elected. The patient underwent a left upper pulmonary lobectomy with radical mediastinal lymph node dissection in March 2001. The pathologic examination confirmed the presence of a discrete, well-defined lesion showing the histologic characteristics of HD of the nodular sclerosis subgroup, without lymph node dissemination. Complete remission persists as of May 2004, with negative results of fluorodeoxyglucose positron emission tomographic scan and no evidence of recurrence on chest computed tomography. Patients with advanced HD that relapses after first-line chemotherapy may have further remissions with salvage treatment. High-dose chemotherapy and transplantation of hematopoietic stem cells improves freedom from treatment failure in patients with chemosensitive first relapse of HD, irrespective of delay after initial remission.1Schmitz N. Pfistner B. Sextro M. Sieber M. Carella A.M. Haenel M. et al.Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease a randomised trial.Lancet. 2002; 359: 2065-2071Abstract Full Text Full Text PDF PubMed Scopus (833) Google Scholar, 2Diehl V. Stein H. Hummel M. Zollinger R. Connors J.M. Hodgkin’s lymphoma biology and treatment strategies for primary, refractory, and relapsed disease.Hematology (Am Soc Hematol Educ Program). 2003; : 225-247Crossref PubMed Scopus (127) Google Scholar, 3Diehl V. Thomas R.K. Re D. Part II Hodgkin’s lymphoma—diagnosis and treatment.Lancet Oncol. 2004; 5: 19-26Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar Unfortunately, relapse or disease progression after autologous transplantation occurs in a significant proportion of patients with HD, and no clear-cut therapeutic guidelines exist for these patients for whom both first-line and high-dose salvage regimens have failed.4Paltiel O. Rubinstein C. Or R. Nagler A. Gordon L. Deutsch L. Polliack A. et al.Factors associated with survival in patients with progressive disease following autologous transplant for lymphoma.Bone Marrow Transplant. 2003; 31: 565-569Crossref PubMed Scopus (40) Google Scholar Gemcitabine, monoclonal antibodies, and active immunotherapy may be tested as alternatives to the option of conventional or nonmyeloablative allogeneic transplantation.3Diehl V. Thomas R.K. Re D. Part II Hodgkin’s lymphoma—diagnosis and treatment.Lancet Oncol. 2004; 5: 19-26Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 5Zinzani P.L. Tani M. Gabriele A. Gherlinzoni F. de Vivo A. Ricci P. et al.High-dose therapy with autologous transplantation for Hodgkin’s disease the Bologna experience.Haematologica. 2003; 88: 522-528PubMed Google Scholar The favorable course observed in our patient suggests that elective surgery might be an alternative for highly selected patients with recurrent localized HD, especially pulmonary recurrence.

We describe two new resected cases of primary pulmonary hemangiopericytoma and the review of cases published in the period 1954-2002. The first patient has a large pulmonary mass of the right apex revealed by scapular pain. The right upper lobectomy with free margins reveals hemangiopericytoma. Pelvic and pulmonary metastases appear two years after surgery, treated by two series of chemotherapy without clinical response. After acute nephrotoxicity controlled by hemodialysis, the patient dies with distant metastases three years and an half after thoracotomy. The second patient develops dry cough and thoracic pain with discovery of a cavitary mass in the right pulmonary field. Fine needle aspiration cytology suggests a mesenchymatous lesion. Three months after extended pneumonectomy, the intrathoracic tumour relapses and regresses partially under chemotherapy. Femoral and brain metastases are irradiated. The patient dies 22 months after thoracotomy. Histology and immunohistochemistry of both tumours closely related to solitary fibrous tumour confirm malignant hemangiopericytoma. Primary pulmonary hemangiopericytoma is rare and may be benign or malignant. Radical resection is the best treatment. Chemotherapy and radiotherapy may improve the prognosis. Compared with lung cancer, the tumour is a slow growing mass, often voluminous, with delayed symptoms, very few lymph node dissemination, rare brain metastasis, more frequent cutaneous or retroperitoneal dissemination, often after long-term and requiring indeed a 10 to 20 years follow-up.

In animals, tumor-derived heat shock proteins (HSP) induce immune-mediated protection against autologous cancer. We investigated whether HSP-70 derived from human lung carcinoma are also complexed to tumor-specific antigens. Peripheral blood mononuclear cells collected 10 days after surgery from patients with lung cancer were stimulated with HSP-70 purified from autologous and heterologous tumors. The stimulation index (SI) obtained when stimulating cells with autologous tumor-derived HSP-70 averaged 3.07 +/- 0.75 in patients with lung cancer and 1.57 +/- 0.33 in control subjects (p < 0.001 by analysis of variance). No significant stimulation was observed with HSP-70 derived either from the majority of heterologous tumors or from autologous tumor-free lung tissue. SI decreased from 3.59 +/- 0.65 to 1.65 +/- 0.38 in six patients tested again 3 months after surgery (p = 0.02 by Wilcoxon test for paired data). HSP-70 derived from lung carcinoma are shown to be associated with T cell antigens. The T cell reactivity appears transient and restricted to antigens complexed to HSP-70 derived from autologous tumors only. This suggests that the antigenicity of human lung tumors is unique, which may be crucial for the design of new vaccines.

Strong expression of high-molecular-weight (HMW) heat-shock proteins (HSP) by lung carcinoma has been documented using immunohistochemistry. Far less is known about the expression of low-molecular-weight (LMW) HSP in lung cancer. We compared the quantitative expression of HMW (HSP-60, HSP-70) and LMW (HSP-27, ubiquitin) HSP in tumor and non-tumor lung tissue obtained from 47 patients undergoing surgical resection of lung carcinoma. HSP levels were determined in cell lysates from tissue samples by ELISA using streptavidin-biotin technology. Results were normalized to total protein content measured by spectrophotometry. Compared to disease-free lung tissue, tumor tissue samples showed higher levels of both HSP-60 (median value: 227 pg versus 96 pg per mg protein (P<0.001 by Wilcoxon Rank test for paired data) and HSP-70 (median value: 525 ng versus 401 ng per mg protein (P=0.01 by Wilcoxon Rank test for paired data). Tumor and tumor-free tissues show similar levels of ubiquitin and HSP-27. Neither the survival rate nor the histologic type and extent of cancer are correlated with the observed differences in HSP-60 and HSP-70 expression (P>0.1 by one way analysis of variance for repeated measures with one between subject factor). Our data confirm, on a quantitative basis, the increased expression of HSP-60 and HSP-70 in non-small-cell lung carcinoma. However, no prognostic value was found to be associated with this over-expression. In contrast, LMW stress proteins such as ubiquitin and HSP-27, although implicated in cellular processes potentially related to malignant transformation, show no increased expression in lung carcinoma.

The purpose of this study was to characterize ligands for galectins, natural galactoside-binding immunoglobulin G subfractions and sarcolectin and also the expression of calcyclin in various benign and malignant thyroid lesions. The extent of the binding of eight glycochemical probes was quantitatively assessed using computer-assisted microscopy on 76 thyroid lesions including 10 not-otherwise-specified multinodular goiters (S_MNG), 11 multinodular goiters with adenomatous hyperplasia (AH_MNG), 8 normomacrovesicular (NM_ADE) and 12 microvesicular (MIC_ADE) adenomas, and 9 papillary (P_CAR), 10 follicular variants of papillary (FvarP_CAR), 7 follicular (F_CAR) and 9 anaplastic (A_CAR) carcinomas. The 8 histochemical probes included 5 animal lectins (including galectins and sarcolectin), 1 polyclonal antibody (raised against calcyclin) and 2 immunoglobulin G subfractions from human serum with selectivity to alpha- and beta-galactosyl residues. The results show that multinodular goiters with adenomatous hyperplasia exhibited histochemical characteristics intermediate to those of normal multinodular goiters and microvesicular adenomas. Normomacrovesicular adenomas behaved very distinctly from microvesicular ones. Microvesicular adenomas were more closely related to differentiated thyroid carcinomas than any other type of benign thyroid lesions of epithelial origin. Papillary and follicular carcinomas seemed to represent the two extremes of the same biological entity with the follicular variant of the papillary carcinoma serving as a biological link between these two extremes. Anaplastic carcinomas behaved in a significantly different manner when compared to the differentiated forms of thyroid carcinomas. The results suggest that the patterns of expression of the glycoconjugates investigated in the present study may constitute useful tools for characterizing lesions in the human thyroid.

Fine-needle aspiration biopsy (FNAB) is safe, inexpensive, minimally invasive, and highly accurate in the diagnosis of nodular diseases of the thyroid. However, FNAB does not provide a reliable benign versus malignant diagnosis for 100% of the cases analysed. It is possible to increase the accuracy of the cytological diagnosis by means of information contributed by different clinical variables. In the present study we evaluate the diagnostic value of 10 variables in addition to FNAB on a series of 218 specimens for which we obtained histological diagnoses including 37 cancers (17%). The diagnostic information contributed by these variables was analyzed by means of the Decision Tree technique, an artificial intelligence-related method which forms part of the Supervised Learning algorithms. The results show that Decision Trees enable some subpopulations of patients with uncertain FNAB results to be characterized.

This study describes the ploidy level and proliferation rate in a series of 74 multinodular goiters (MNGs), 17 cases of Hashimoto's disease, 33 cases of Basedow's disease, 113 adenomas, 139 primary carcinomas, and 31 cervical lymph node metastases from 376 patients. Both ploidy level and proliferation rate were assessed by digital cell image analyses of Feulgen-stained nuclei from formalin-fixed, paraffin-embedded tissues. The ploidy level of each sample was assessed using both its DNA index and its DNA histogram type. The proliferation index assessments corresponded to the determination of the proportion of cells in the S-phase fraction. The data reveal that the proportion of aneuploid cases increases according to the following sequence: simple MNGs and normomacrovesicular adenomas → MNGs with adenomatous hyperplasia and microvesicular adenomas and Hürthle cell adenomas → papillary and Hürthle cell carcinomas → follicular and medullary carcinomas → anaplastic carcinomas. This suggests the preneoplastic nature of the microvesicular adenomas and even of MNGs with adenomatous hyperplasia. The ploidy levels of 99% of the 407 cases of the thyroid tumor series could be described using six DNA histogram types: diploid, hyperdiploid, triploid, hypertriploid, tetraploid, and polymorphic. It was possible to assess the proliferation rate of 279 samples. The results show that a significantly higher proportion of malignant compared with benign thyroid tumors (35.5% ν 10.5%, respectively) exhibited a proliferation index higher than 5%, and that, whether benign or malignant, the hypertriploid thyroid tumors proliferated significantly less than the nonhypertriploid thyroid tumors.

The effects of thyroid-stimulating antibodies (TSAb) and of thyrotropin (TSH) were compared, on the generation of cyclic AMP and inositol phosphates (InsP), in human thyroid slices incubated in vitro, and on the Rapoport cyclic AMP bioassay. The TSAb positive sera were obtained from 19 patients with Graves' disease. In 14 experiments with the slices system, TSH significantly increased cyclic AMP accumulation (TSH, 0.03-10 mU/ml) as well as the cyclic AMP-independent inositol trisphosphate (InsP3) generation (TSH, 1-10 mU/ml). In the same 14 experiments, TSAb (0.10-28 mg/ml) enhanced cyclic AMP intracellular levels as expected while they did not induce any InsP accumulation. Even when TSAb increased cyclic AMP levels to the same or higher values as those obtained with TSH concentrations allowing InsP3 generation. TSAb were still unable to activate the phosphatidylinositol-Ca2+ cascade. The patterns of the response curves of TSAb and TSH on cyclic AMP accumulation were different, suggesting that different mechanisms may be involved. In addition, unlike TSH, TSAb were not able to stimulate H2O2 generation, which in human tissue mainly depends on the activation of the phosphatidylinositol-Ca2+ cascade. Immunoglobulins from six additional Graves' patients lacking measurable cyclic AMP-stimulating activity in both slices and cells systems did not activate phospholipase C either. In conclusion, our results show that TSAb do not share all the metabolic actions of TSH on human thyroid tissue. The data provide support for the concept that the pathogenesis of Graves' disease can be fully accounted for by the ability of TSAb to stimulate adenylate cyclase. This work also confirms that TSH activates the cyclic AMP and the phosphatidylinositol cascade by independent pathways in the human thyroid.

The "in vitro" characteristics of H2O2 generation, iodide, cAMP and PI metabolism, have been compared in tissues from autonomously functioning thyroid nodules and their quiescent counterpart to test the hypothesis that autonomy may result from constitutive activation of the tissue's TSH-IP's, or TSH-cAMP regulatory pathway. The enhanced iodide uptake is entirely due to increased transport capacity, the affinity of iodide transport and the fractional binding of iodide to protein remaining unchanged. The basal IP's accumulation is slightly higher in seven cases where it was studied but the response to TSH was markedly decreased. The cAMP-protein phosphorylation regulatory axis is not constitutively activated. Under TSH and forskolin stimulation, a 20K protein is not phosphorylated in nodular tissue as it is in its quiescent counterpart. The others, possible points of deviation in the cAMP cascade, studied in these tissues, i.e. basal cyclic AMP, desensitization to TSH, iodide inhibition, responses to other hormones or neurotransmitters were not systematically different in nodular tissue. The 20K protein, not phosphorylated in response to TSH in the nodules, could represent an absent negative controlling element. The absence of a 20K protein substrate of cAMP dependent protein kinases remains the most interesting clue about the mechanism of autonomy. We are now trying to purify and clone this protein.