Neoadjuvant, hyperfractionated irradiation induces apoptosis and decreases proliferation in squamous cell cancer of the oral cavity.

Twenty-eight patients with squamous cell carcinoma of the oral cavity were treated with a total dose of 20 Gy. Tissue samples for immunohistochemistry were taken at the time of diagnostic biopsy and at surgery after radiotherapy (RX). For detection of proliferating cells, the immunoperoxidase reaction with Ki67 was performed. Apoptotic cells were detected by the TdT-mediated biotin dUTP nick end labeling (TUNEL) method. RX reduced proliferation in 27 patients, only in one case did the proliferation index (PI) increase. Delta PI (PI before RX PI following RX) amounted to 4.11% (SD=3.2%; P<0.0001). The apoptotic index (AI) increased significantly subsequent to neoadjuvant RX. Delta AI (AI after RX--AI before RX) measured 1.82% (SD=0.9; P<0.001). These data indicate that RX of patients suffering from squamous cell carcinoma of the oral cavity with a dosis of 20 Gy induces apoptosis and inhibits proliferation of tumor cells.

Mesalazine changes apoptosis and proliferation in normal mucosa of patients with sporadic polyps of the large bowel.

BACKGROUND AND STUDY AIMS: Regular intake of nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the occurrence of colorectal adenoma and carcinoma, possibly by inducing apoptosis and/or decreasing proliferation in colorectal epithelial cells. Mesalazine is widely used in the treatment of patients with inflammatory bowel disease, and well tolerated. We investigated its effect on apoptosis and proliferation of colorectal mucosa in 21 patients with sporadic polyps of the large bowel. PATIENTS AND METHODS: In total, 17 patients with sporadic colorectal polyps (> or = 5 mm) underwent polypectomy and biopsy of uninvolved mucosa before and after treatment with 1 g/d mesalazine for 1, 3, 7 or 14 days. Four additional patients served as untreated controls. Apoptotic index (AI) was measured by terminal deoxynucleotidyl transferase-mediated d-uridine triphosphate nick-end labeling (TUNEL) assay; proliferation index (PI) was measured by immunohistochemical examination with anti-Ki67 antibody. RESULTS: AI was significantly increased 1 and 3 days after initiation of treatment with mesalazine compared with controls (P= 0.0107 for the 1-day treatment group and P=0.0142 for the 3-day treatment group), and seemed to remain largely unchanged after longer treatment duration. Proliferation appeared to be decreased by mesalazine in all treatment groups, while proliferation in controls did not change (P=0.0107 for the 1-day treatment group and P= 0.0142 for the 3-day treatment group compared with controls. CONCLUSIONS: Mesalazine significantly induces apoptosis and decreases proliferation in colorectal mucosa in patients with sporadic polyps of the large bowel. This may be clinically relevant in that it may lower the rate of polyp recurrence after polypectomy, thereby possibly contributing to the chemoprevention of sporadic colorectal carcinoma.

Antigenic phenotyping of lymphoid cells and B cell gene rearrangement in type B gastritis and in gastritis not associated with Helicobacter pylori colonization.

Marginal-zone B cells of the mucosa-associated lymphoid tissue (MALT) are the normal counterpart of the neoplastic cells in MALT lymphoma. In both cases these lymphocytes express surface immunoglobulins, but are negative when stained for B cell associated antigens like CD10 and CD23. Furthermore, the B cell gene rearrangement has been found in Helicobacter pylori associated chronic gastritis and in extranodal type of marginal-zone lymphoma. The aim of this study was to quantify the number of IgM-, CD10-, and CD23-positive lymphocytes in patients with type B gastritis and to compare the results with the antigen profile of mononuclear cells in patients with gastritis not associated with H. pylori. Additionally, the immunoglobulin heavy-chain (IgH) gene rearrangement in H. pylori positive and H. pylori negative gastritis was studied. From 23 patients with a positive urease test and/or histologically proven H. pylori infection and chronic gastritis and from 22 patients with H. pylori negative chronic gastritis mucosa biopsy specimens were taken. Single-cell suspensions were obtained following enzymatic digestion. For immunocytochemistry, an alkaline phosphatase-antialkaline phosphatase method was applied. IgH gene rearrangement in formalin-fixed, paraffin-embedded specimens was determined by polymerase chain reaction in 11 patients with chronic gastritis. An increase in mu-positive plasma cells and B lymphocytes was detected in patients with H. pylori positive gastritis as compared with patients with H. pylori negative gastritis (10.0 vs. 3.9%, p < 0.001, and 4.3 vs. 1.6%, p < 0.01, respectively). In both groups, the proportion of CD10- and CD23-positive lymphocytes was <1%. IgH gene rearrangement was not restricted to type B gastritis; single bands were also present in 3 of 7 patients with H. pylori negative chronic gastritis. Our finding of IgH gene rearrangement in some of the patients with H. pylori negative chronic gastritis indicates that additional factors may be critical for these genotypical changes and for the pathogenesis of gastric MALT lymphoma.

[Endosonographically controlled fine needle aspiration cytology--indications and results in routine diagnosis]. / Endosonographisch gesteuerte Feinnadelaspirationszytologie--Indikationen und Ergebnisse in der Routinediagnostik.

UNLABELLED: The usefulness and clinical utility of routine EUS-guided fine needle aspiration cytology (FNA) in the diagnosis of lesions adjacent to the upper gastrointestinal tract was prospectively studied. METHODS: EUS/FNA was performed in 122 patients for 125 lesions: Mediastinal lymph nodes (n = 56), pancreatic lesions (n = 45), paragastric masses (n = 12), submucosal tumors (n = 4) and small hepatic lesions (n = 2) were successfully punctured for cytological diagnosis. RESULTS: Adequate material was gained in 119 out of 125 punctures (95%). Overall sensitivity, specifity, positive and negative predictive value were 90%, 98%, 98% and 89%. Results of EUS/FNA in mediastinal lymph nodes were superior (95%, 100%, 100%, 90%) to those in pancreatic lesions (80%, 100%, 100%, 80%). In paragastric masses sensitivity was 100% whereas specifity was only 67%--due to one false-positive result. Out of four submucosal tumors diagnosis was revealed in three. Two liver metastasis were successfully punctured. 35 out of 56 mediastinal nodes showed malignancy. 27 metastases of lung-, three of gastric-, two of renal cancer and three Non-Hodgkins's lymphoma were diagnosed. The cytological results of 45 pancreatic lesions showed cancer in 19 and chronic inflammation in 21, two abscesses and three benign cysts. There were no complications. 37 patients were treated on outpatient's basis. CONCLUSIONS: EUS-guided FNA is an accurate and safe technique to sample cytology from lesions adjacent to the wall of the upper gastrointestinal tract. New indications may be established for the diagnosis of lung cancer or metastases of other spreading out into the mediastinum or the celiac axis.

Diagnostic value of endoscopic ultrasonography-guided fine-needle aspiration cytology of mediastinal masses in patients with intrapulmonary lesions and nondiagnostic bronchoscopy.

Several procedures are available for the cytopathological diagnosis of mediastinal lesions. The purpose of this study was to evaluate the diagnostic value of endoscopic ultrasonography (EUS)-guided fine-needle aspiration (FNA) in patients with mediastinal mass lesions/lymph node enlargement. All patients had intrapulmonary lesions on chest X ray and/or CT scan, and inconclusive findings by endobronchial forceps biopsy and/or brush cytology. EUS-guided FNA was performed in 16 patients using a modified oblique forward-viewing gastroscope with an electronic multielement curved linear ultrasound transducer. After the region of interest was localized, a 22-gauge Vilmann-Hancke needle was introduced via the 2-mm biopsy channel. The cytological diagnosis of EUS-guided FNA was conclusive for cancer in 9 patients and in the other 7 patients the aspirated samples revealed a benign lesion. In 10 patients the final diagnosis was cancer, thus EUS-guided FNA was diagnostic for malignancy in all but 1 of the lesions (sensitivity 90.0%). In 1 patient epitheloid cell granuloma was detected by cytological examination of the FNA. Following tuberculostatic treatment the lesions disappeared completely on CT scan and EUS. The overall accuracy in this study amounted to 93.7%. From this and other studies discussed, it is assumed that the procedure is an accurate and safe technique to examine nodular lesions suggestive of metastatic lymph node involvement.

Thrombopoietin serum concentration in patients with reactive and myeloproliferative thrombocytosis.

We wished to test whether thrombopoietin (TPO) is entirely regulated by receptor binding or if other factors may play a role in the mechanism of TPO regulation. Therefore, we analyzed the TPO serum levels in 43 patients with reactive (secondary) thrombocytosis and in 37 with myeloproliferative thrombocytosis. Thrombocytosis was defined as a platelet level greater than 440 x 10(9)/l. Forty-two patients (98%) with reactive thrombocytosis had high concentrations of IL-6 correlating with elevated C-reactive protein levels. Twenty-three patients (53%) in this group had TPO serum concentrations of more than 300 pg/ml (normal: below 300 pg/ml). Only nine patients (24%) with myeloproliferative thrombocytosis had TPO serum levels above normal range, whereas 28 patients (76%) had normal levels of TPO. No correlation between the TPO serum levels and the concentrations of IL-6 or EPO was established. The other investigated thrombopoietic cytokines (IL-3, IL-11, GM-CSF) were unmeasurable; therefore, a correlation could not be assessed. We conclude that TPO concentrations are not strictly inversely related to platelet count. TPO serum levels are elevated especially in a considerable percentage of patients with reactive thrombocytosis, arguing for the existence of additional mechanisms of TPO regulation.

c-kit mutation and osteopetrosis-like osteopathy in a patient with systemic mast cell disease.

We describe the case of a 69-year-old man with systemic mastocytosis and severe osteopetrosis who carries a somatic activating mutation in the c-kit proto-oncogene. The patient initially presented with urticaria pigmentosa, progressing to systemic mast cell disease with severe anemia due to bone marrow involvement, chronic diarrhea, and hepatosplenomegaly. Direct sequencing using amplimers from reverse transcriptase-polymerase chain reactions (RT-PCR) from skin mast cell-derived RNA revealed a point mutation in the c-kit proto-oncogene at position 2468, introducing a new recognition site for the restriction endonuclease HinfI. Treatment with interferon-alpha 2a, prednisone, and erythropoietin was initiated. Subsequently, clinical symptoms improved significantly and hemoglobin levels are now stable at 13 g/dl.

[Management of hematologic systemic diseases and rare tumor entities with manifestations in the oromaxillofacial area]. / Management hämatologischer Systemerkrankungen und seltener Tumorentitäten bei Manifestation im Mund-Kiefer-Gesichtsbereich.

Malignant lymphomas, hematological malignancies, sarcomas, occult head and neck primaries, Merkel cell carcinomas and malignant melanomas are among the tumors that are rarely seen in the head and neck region. Almost 20% of patients with acute leukemia initially present with symptoms of the oral cavity (ulcerations, gingival hypertrophy, etc.). If a malignant lymphoma is suspected, the lymph node should be removed in toto to ascertain diagnosis. Furthermore, in order to make sure that the immunohistological work-up or electron microscopic analysis is adequate, the pathologist should be informed prior to extirpation of the suspicious lymph node. The same diagnostic procedure is indicated for metastases from undifferentiated or small cell cancer of an unknown primary. Metastatic squamous cell or undifferentiated carcinoma to a solitary cervical lymph node from an unknown primary can be cured by multimodal therapy (extirpation, radical neck dissection and adjuvant radiation) in 30% of the cases. Following polychemotherapy, long-term survival may also be achieved in disseminated stages of undifferentiated carcinoma or poorly differentiated adenocarcinoma in an occult primary. When osteosarcoma of the jaw is suspected, core biopsy has to be planned carefully: in order to prevent tumor seeding, the needle track has to be excised during definitive surgery. Most authors propose (neo-)adjuvant chemotherapy (or chemoradiation) for head and neck osteosarcoma, especially when additional risk factors, i.e. a large primary or poorly differentiated sarcoma, are present. Patients with positive margins should receive adjuvant radiotherapy in soft tissue sarcoma. Local control of angiosarcoma is possible exclusively by radiation. Adjuvant radiation is also indicated in Merkel cell carcinoma. Because this tumor spreads in a "cascade" fashion, elective node dissection may also provide a chance for cure. Excision with wide margins is the principal therapeutic step in malignant melanoma. Due to the anatomic localization, adequate resection may not be possible in mucosal melanoma of the head and neck. When regional lymph nodes are involved, radical lymph node dissection and adjuvant radiation have to be added to the therapeutic concept. There is an emerging role for adjuvant interferon alpha in intermediate and high-risk melanoma.

Chemotherapy with cisplatin and paclitaxel in patients with locally advanced, recurrent or metastatic oesophageal cancer.

Single-agent therapy with paclitaxel is effective against both squamous cell carcinoma and adenocarcinoma of the oesophagus. However, only limited data are available on the combination of paclitaxel with other cytotoxic drugs in this entity. Patients with unresectable stage III, recurrent or metastatic tumours were treated in a multicentre setting with paclitaxel 90 mg m(-2) given over 3 h intravenously, followed by cisplatin 50 mg m(-2). The courses were repeated every 14 days. Twenty patients with squamous cell carcinoma or adenocarcinoma of the oesophagus were evaluable for response. The overall remission rate was 40% (8/20), including 15% (3/20) clinically complete responses. Clinical benefit response, defined as relief of dysphagia and/or significant gain in weight, was achieved in 70% of the patients. Neutropenia of CTC grade 3 occurred only in 10% of the patients; no grade 4 neutropenia and no severe thrombocytopenia was encountered. CTC grade 4 neurotoxicity was seen in 5% of patients. Cisplatin/paclitaxel administered every 14 days, was effective in patients with poor prognosis oesophageal cancer and toxicity was acceptable.

Effect of small doses of iodine on thyroid function in patients with Hashimoto's thyroiditis residing in an area of mild iodine deficiency.

OBJECTIVE: Several studies have suggested that iodine may influence thyroid hormone status, and perhaps antibody production, in patients with autoimmune thyroid disease. To date, studies have been carried out using large amounts of iodine. Therefore, we evaluated the effect of small doses of iodine on thyroid function and thyroid antibody levels in euthyroid patients with Hashimoto's thyroiditis who were living in an area of mild dietary iodine deficiency. METHODS: Forty patients who tested positive for anti-thyroid (TPO) antibodies or with a moderate to severe hypoechogenic pattern on ultrasound received 250 microg potassium iodide daily for 4 months (range 2-13 months). An additional 43 patients positive for TPO antibodies or with hypoechogenicity on ultrasound served as a control group. All patients were TBII negative. RESULTS: Seven patients in the iodine-treated group developed subclinical hypothyroidism and one patient became hypothyroid. Three of the seven who were subclinically hypothyroid became euthyroid again when iodine treatment was stopped. One patient developed hyperthyroidism with a concomitant increase in TBII titre to 17 U/l, but after iodine withdrawal this patient became euthyroid again. Only one patient in the control group developed subclinical hypothyroidism during the same time period. All nine patients who developed thyroid dysfunction had reduced echogenicity on ultrasound. Four of the eight patients who developed subclinical hypothyroidism had TSH concentrations greater than 3 mU/l. In 32 patients in the iodine-treated group and 42 in the control group, no significant changes in thyroid function, antibody titres or thyroid volume were observed. CONCLUSIONS: Small amounts of supplementary iodine (250 microg) cause slight but significant changes in thyroid hormone function in predisposed individuals.

Helicobacter pylori induces apoptosis in mucosal lymphocytes in patients with gastritis.

BACKGROUND: Previous studies suggest that Helicobacter pylori (H. pylori) induces apoptosis and compensatory hyperproliferation in gastric epithelial cells possibly explaining the carcinogenic capacity of the bacteria. The aim of this study was to measure the effect of H. pylori on apoptosis of gastric lymphoid cells in view of the development of gastric lymphoma. METHODS: 16 H. pylori-positive and 19 H. pylori-negative individuals were enrolled. Single cell suspensions were prepared from antral biopsies and apoptosis was measured by staining with the TUNEL-assay and the fluorochrome Hoechst 33342. Lymphocyte subsets were simultaneously identified by immunocytochemistry. RESULTS: The apoptotic index of all gastric mucosal cells was significantly higher in H. pylori-positive mucosa compared to negative controls. Additionally, H. pylori-infected patients showed a significant increase in apoptosis of mucosal B-lymphocytes. Apoptosis of T cells and plasma cells was unaffected by H. pylori. CONCLUSION: H. pylori induces apoptosis in mucosal B cells which might be important in the development of gastritis and possibly B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT).

Assessment of satisfaction with the communication process during consultation of cancer patients with potentially curable disease, cancer patients on palliative care, and HIV-positive patients.

The aim of this study was to evaluate the attitudes of cancer patients towards the medical interview and to determine their psychosocial satisfaction subsequent to the dialogue. The answers given by patients with curable cancer were compared to those given by cancer patients whose treatment intent was palliative and to the replies of patients infected with the human immunodeficiency virus (HIV), a nonmalignant but also incurable state. The subject population comprised a total of 139 patients. Patients had to complete a questionnaire with a total of 34 items. The answers to the questions were rated on a 5-point scale with response options ranging from 1 to 5 or consisting of true-false statements. Cancer patients, palliative and curative, and HIV-positive patients considered their physicians to be honest (x = 4.34, x = 4.58, and x = 4.30, respectively; p = 0.104), and they emphasized that he/she took enough time answering their questions (x = 4.00, x = 4.30 and x = 4391, respectively; p = 0.12). Cancer patients treated with potentially curable disease were more frequently afraid of being informed about additional diagnostic examinations and about the disclosure of results as compared to cancer patients on palliative care (p < 0.05 for both questions). Patients with HIV-infection considered themselves less informed about the treatment they received as compared to curative cancer patients (x = 3.73 and x = 4.28, respectively; p < 0.046). Only 8.0% of the tumor patients on palliative care, but 63.6% of the HIV-positive patients realized that their medication was given with the objective to relieve symptoms (p < 0.001). When asked about additional goals of treatment, 48% of the palliative cancer patients and 15.1% of the HIV-positive patients checked "cure" (p < 0.002). In conclusion, particularly patients with curable cancer were afraid of information they might receive during the medical interview. Cancer patients considered themselves better informed compared to patients with HIV-infection. This is in significant contrast with the actual, measurable knowledge about their disease in the latter group. It is indeed surprising that only a small minority of incurable cancer patients realized that the goal of the medical care they received was relief of symptoms, the principle objective of palliation.

Antibody responses of splenectomized patients with non-Hodgkin's lymphoma to immunization with polyvalent pneumococcal vaccines.

The serum antibody responses of splenectomized patients with non-Hodgkin's lymphoma (NHL) who had been immunized with a polyvalent pneumococcal vaccine (Pneumovax 23) were evaluated by an enzyme-linked immunosorbent assay with the 23-valent pneumococcal vaccine as the antigen. A response to immunization, defined as a twofold-or-higher rise of the prevaccination titer of antibodies against Streptococcus pneumoniae polysaccharide, was elicited in 5 of 11 patients with NHL. No significant difference in the level of antibodies against S. pneumoniae polysaccharide between lymphoma patients and patients who had undergone splenectomy for other reasons was detected (P = 0.83 and 0.87 before and after vaccination, respectively). NHL patients who did not respond to the first immunization received a booster dose of the polysaccharide vaccine. This injection did not increase the pneumococcal-antibody titer significantly (P = 0.7). We conclude that vaccination with pneumococcal polysaccharides in splenectomized patients with NHL elicits an adequate antibody response in 45.4% of the cases and should therefore be administered. Revaccination of the nonresponders does not further increase the pneumococcal-antibody levels.