Prognostic factors affecting long-term outcomes in patients with resected stage IIIA pN2 non-small-cell lung cancer: 5-year follow-up of a phase II study.

The aim was to investigate the efficacy of neoadjuvant docetaxel-cisplatin and identify prognostic factors for outcome in locally advanced stage IIIA (pN2 by mediastinoscopy) non-small-cell lung cancer (NSCLC) patients. In all, 75 patients (from 90 enrolled) underwent tumour resection after three 3-week cycles of docetaxel 85 mg m-2 (day 1) plus cisplatin 40 or 50 mg m-2 (days 1 and 2). Therapy was well tolerated (overall grade 3 toxicity occurred in 48% patients; no grade 4 nonhaematological toxicity was reported), with no observed late toxicities. Median overall survival (OS) and event-free survival (EFS) times were 35 and 15 months, respectively, in the 75 patients who underwent surgery; corresponding figures for all 90 patients enrolled were 28 and 12 months. At 3 years after initiating trial therapy, 27 out of 75 patients (36%) were alive and tumour free. At 5-year follow-up, 60 and 65% of patients had local relapse and distant metastases, respectively. The most common sites of distant metastases were the lung (24%) and brain (17%). Factors associated with OS, EFS and risk of local relapse and distant metastases were complete tumour resection and chemotherapy activity (clinical response, pathologic response, mediastinal downstaging). Neoadjuvant docetaxel-cisplatin was effective and tolerable in stage IIIA pN2 NSCLC, with chemotherapy contributing significantly to outcomes.

Lethal Epstein-Barr virus associated NK/T-cell lymphoma with primary manifestation in the conjunctiva.

BACKGROUND: Lethal midline granulomas (LMG) are very rare angiocentric NK/T-cell lymphomas in association with Epstein-Barr virus. LMG are reported mainly in East Asia occurring in immune compromised patients. HISTORY AND SIGNS: A 41-year old male patient presented with a conjunctival swelling of his upper left eyelid. The lesion had increased over a period of 2 months despite topical corticosteroid treatment. Conjunctival biopsy revealed a highly malignant, CD3 + and BCL2 + extranodal T-cell lymphoma with features of an NK/T-cell origin (CD56 +, TIA + TCR-rearrangement: germline). All lymphoma cells were positive for Epstein-Barr virus RNA. The proliferation rate was highly elevated at 100 %. THERAPY AND OUTCOME: Systemic 1 (st) cycle chemotherapy with cyclophosphamide, doxorubicin, vincristin and prednisone resulted in a complete remission of the swelling within 4 days. However, one week later a massive conjunctival tumour reappeared with only partial regression after combined chemo- and radiotherapy. The patient died within a month because of untreatable pancytopenia due to malignant bone marrow infiltration. CONCLUSIONS: LMG is a rare but highly malignant Epstein-Barr virus associated NK/T-cell lymphoma that can occur in healthy, immune competent Caucasians. This is the first reported case of an LMG in an immune-competent Caucasian patient with primary ocular manifestation. The LMG has a high mortality rate despite systemic treatment and can be lethal within a few months or even weeks.

Rituximab-EPOCH, an effective salvage therapy for relapsed, refractory or transformed B-cell lymphomas: results of a phase II study.

BACKGROUND: Relapsed or refractory diffuse large B-cell and mantle-cell lymphoma have a poor prognosis. The EPOCH regimen and rituximab monotherapy have demonstrated activity as salvage therapies. Because of their non-overlapping toxicity, we evaluated their combination as salvage therapy in a phase II study. PATIENTS AND METHODS: Patients with relapsed or refractory CD20-positive large B-cell and mantle-cell lymphoma were offered treatment with rituximab 375 mg/m2 intravenously (i.v.) on day 1, doxorubicin 15 mg/m2 as a continuous i.v. infusion on days 2-4, etoposide 65 mg/m2 as a continuous i.v. infusion on days 2-4, vincristine 0.5 mg as a continuous i.v. infusion on days 2-4, cyclophosphamide 750 mg/m2 i.v. on day 5 and prednisone 60 mg/m2 orally on days 1-14. RESULTS: Fifty patients, with a median age of 56 years (range 23-72), entered the study. Twenty-five had primary diffuse large B-cell lymphoma, 18 transformed large B-cell lymphoma and seven mantle-cell lymphoma. The median number of prior chemotherapy regimens was 1.7 (range one to four). The median number of treatment cycles was four (range one to six). Possible treatment-related death occurred in two patients. Objective responses were obtained in 68% of patients (28% complete responses, 40% partial responses). Nineteen patients received consolidating high-dose chemotherapy with autologous stem-cell transplantation. The median follow-up was 33 months. Three patients developed a secondary myelodysplastic syndrome. The median overall survival was 17.9 months; the projected overall survival at 1, 2 and 3 years was 66, 42 and 35%, respectively. The median event-free survival was 11.8 months; the projected event-free survival at 1, 2 and 3 years was 50, 30 and 26%, respectively. CONCLUSION: The rituximab-EPOCH regimen is effective and well tolerated, even in extensively pretreated patients with relapsed or refractory large B-cell lymphoma and mantle-cell lymphoma.

Weekly paclitaxel and carboplatin combination chemotherapy in patients with advanced squamous cell carcinoma of the head and neck.

BACKGROUND: The combination of paclitaxel and carboplatin is active in the treatment of squamous cell carcinoma of the head and neck (SCCHN). However, considerable toxicity develops with 3-weekly drug administration. Treatment on a weekly basis may allow for a higher dose intensity with less adverse effects. PATIENTS AND METHODS: Enrolled in this study were 31 patients with locally advanced, metastatic or relapsed SCCHN, most of them pretreated. They received weekly i.v. infusions of 80 mg/m(2) paclitaxel over 1 h combined with carboplatin at an area under the concentration time curve of 2 mg/ml/min over 30 min. RESULTS: The overall response rate was 52% with 1 complete response and 16 partial responses. Median progression-free survival was 5.4 months, median overall survival 12.8 months. Grade 3/4 hematologic adverse events occurred in 7 patients and grade 3 peripheral neuropathy in one. 10 patients required dose reduction or treatment delay due to neutropenia, thrombocytopenia or neuropathy. CONCLUSIONS: Weekly administration of paclitaxel and carboplatin appears to be safe and efficacious in patients with advanced, metastatic or recurrent SCCHN.

Vinorelbine in androgen-independent metastatic prostatic carcinoma--a phase II study.

The purpose of this study was to evaluate the efficacy of vinorelbine treatment in terms of prostate-specific antigen (PSA) response and clinical benefit (decrease of pain or analgesic score for the subgroup of patients with pain), as well as its toxicity in patients with progressive metastatic androgen-independent prostatic carcinoma. 44 patients with prostatic carcinoma progressing after orchiectomy or during treatment with hormonal agents were treated with vinorelbine at a dose of 30 mg/m(2) intravenously (i.v.) on days 1 and 8 of a 21-day cycle. Inclusion criteria were metastatic progressive prostatic carcinoma with prostate-specific antigen (PSA) serum levels >/=3 x upper limit of normal, World Health Organization (WHO) performance status /=2 was observed on the day of scheduled vinorelbine administration. 9 patients received less than three cycles, 6 due to rapid tumour progression. Treatment at day 1 had to be delayed in 13.7% of 183 cycles. Treatment at day 8 had to be omitted in 19.7% of all cycles. Grade >/=3 granulocytopenia occurred in 18% of patients. 4 patients had severe constipation. In 7 patients (15.9%, Confidence Interval (CI) 6.6-30.1%), a PSA response (>/=50% reduction of PSA levels) was observed. Among 8 patients with measurable disease, 3 had partial remission and 1 no change. Median time to PSA progression in 43 assessable patients was 11.9 weeks (range 3-52 weeks). Median duration of PSA response was 14 weeks (9-30 weeks). Clinical benefit was seen in 7 of 31 cases (23%) with baseline pain, there was no association with PSA response. Vinorelbine is a fairly well tolerated drug with a moderate single agent activity in patients with androgen-refractory prostate cancer.

A comparative study of the expression of cytotoxic proteins in allergic contact dermatitis and psoriasis: spongiotic skin lesions in allergic contact dermatitis are highly infiltrated by T cells expressing perforin and granzyme B.

Recent reports indicate that cytotoxic T cells are critically involved in contact hypersensitivity reactions in animals. In this study we sought to investigate the in vivo expression of cytotoxic granule proteins in the elicitation phase of allergic contact dermatitis in humans. Skin biopsy specimens were obtained from patients with allergic contact dermatitis (n = 8) and psoriasis (n = 6) and from controls with normal skin (n = 6). Expression of perforin and granzyme B was investigated by in situ hybridization and immunohistochemistry. In contrast to normal skin and psoriasis, a significant enhancement of perforin and granzyme B gene expression and immunoreactivity was observed in the mononuclear cell infiltrate of allergic contact dermatitis. Immunoreactivity for perforin and granzyme B was mainly found in the cytoplasm of lymphocytic cells, which were located in the dense perivascular infiltrate as well as at sites of marked spongiosis in the epidermis. Double immunostaining revealed that both CD4+ and CD8+ T cells are capable of expressing perforin and granzyme B. In conclusion, our data suggest that T-cell-mediated mechanisms involving cytotoxic granule proteins may elicit epidermal cell injury in vivo and thereby strongly contribute to the development of allergic contact dermatitis in humans.

Down-regulation of IL-12 by topical corticosteroids in chronic atopic dermatitis.

BACKGROUND: Previous reports indicate that IL-12 may be involved in the development of chronic atopic dermatitis. However, the cellular source of this cytokine in the skin and its expression during successful treatment of the skin lesions are not known. OBJECTIVE: Our purpose was to delineate the precise in situ localization of IL-12 and its modulation under topical treatment with corticosteroids. METHODS: Skin biopsy specimens were obtained from nonlesional, lesional, and treated skin of patients with atopic dermatitis and from healthy skin of nonatopic control subjects. IL-12 was investigated by real-time quantitative reverse transcriptase-PCR and immunohistochemistry. RESULTS: Expression of IL-12 p40 mRNA was significantly enhanced in lesional skin from atopic dermatitis and strongly down-regulated after treatment with topical corticosteroids for 9 to 10 days. In contrast, similar levels of IL-12 p35 transcripts were found in all the samples without any significant differences after treatment. In addition, a strong enhancement of IL-12 immunoreactivity was observed on the mononuclear cell infiltrate in the lesional skin samples, which was also markedly reduced after treatment. IL-12 immunoreactivity was mainly located in the cytoplasm of dermal dendritic cells and macrophages as well as some Langerhans cells. CONCLUSION: Our data suggest that the enhanced local production of IL-12 in dendritic cells and macrophages may be responsible for up-regulating production of IFN-gamma in chronic lesions and strengthen the idea that IL-12 may have a pivotal role in promoting inflammation in atopic dermatitis.

T cells isolated from positive epicutaneous test reactions to amoxicillin and ceftriaxone are drug specific and cytotoxic.

In order to investigate the function of T cells in cutaneous adverse drug reactions, skin-derived T cells were analyzed in two patients with a drug-induced exanthem. Skin biopsy specimens were obtained from positive epicutaneous test reactions to amoxicillin and ceftriaxone. Immunohistochemical analysis revealed that the majority of the cell infiltrate in both biopsy specimens was composed of activated T cells, of which some expressed perforin. By limiting dilution 36 amoxicillin-specific and 10 ceftriaxone-specific T cell clones were raised. All of these T cell clones expressed CD4/T cell receptor alphabeta. Cytokine analysis after antigen stimulation of the seven best proliferating T cell clones (four specific for amoxicillin and three for ceftriaxone) revealed that these cells secrete high amounts of interleukin-5 and mostly lower or no amounts of tumor necrosis factor alpha, interleukin-4, and interferon-gamma. A part of these CD4+ T cell clones were cytotoxic, i.e., two selected ceftriaxone-specific T cell clones killed target cells after antigen stimulation. The amoxicillin-specific T cell clones failed to show drug-specific cytotoxicity, but killed target cells in the presence of concanavalin A, indicating a principal ability to be cytolytic. In correlation with the in situ expression of perforin on T cells, the ceftriaxone-specific T cell clones also expressed perforin in vitro. In conclusion, a substantial part of the T cells in drug-induced epicutaneous test reactions are drug specific and are composed of a heterogeneous cell population. Drug-specific T cells producing interleukin-5 may contribute to eosinophilia, whereas cytotoxic CD4+ T cells may account for tissue damage. These data underline the role of T cells in delayed-type cutaneous adverse drug eruptions and drug-induced epicutaneous test reactions.

Infiltration of cytotoxic T cells in drug-induced cutaneous eruptions.

BACKGROUND: Previous in vitro data indicate that perforin containing drug-specific cytotoxic T cells are involved in cutaneous drug reactions. OBJECTIVE: The aim of this study was to investigate the in situ expression of perforin and granzyme B together with the nature of the inflammatory infiltrate in acute drug-induced exanthem. Furthermore, expression of interleukin (IL)-12 and interferon (IFN)-gamma, which are known to stimulate cytotoxic T cells, was investigated. METHODS: Skin biopsy specimens were obtained from 10 patients with a generalized maculopapular exanthem and from nine controls with normal skin. Expression of CD3, CD4, CD8, CD56, CD1a, CD68, CD25, HLA-DR, CD54, perforin, granzyme B, IL-12 and IFNgamma was analysed using immunohistochemistry. RESULTS: In contrast to the controls, the skin of patients with an exanthem was mainly infiltrated by T cells (CD4 > CD8) and showed a marked enhancement of perforin and granzyme B immunostaining. Double immunostaining revealed that perforin and granzyme B were expressed in both CD4+ and CD8+ cells, which were partly located at the dermoepidermal junction and in the epidermis. In addition, strong immunreactivity for IL-12 and IFNgamma was observed in the mononuclear cells infiltrate, indicating that these cytokines may be important in activation of these cytotoxic T cells. CONCLUSION: The increased numbers of perforin and granzyme B containing T cells infiltrating the dermoepidermal junction may contribute to the damage of epidermal cells, which is frequently observed as a typical feature of interface dermatitis in drug-induced exanthem. Our data provide further evidence that cytotoxic T cells play an essential role in cutaneous drug reactions.

Antigen-presenting cells and keratinocytes express interleukin-12 in allergic contact dermatitis.

Interleukin-12 (IL-12) has previously been suggested as playing a major rôle in the activation of cytotoxic lymphocytes. Recent reports indicate that cytotoxic CD8+ cells are critically involved in the elicitation phase of contact hypersensitivity reactions. In this study, the in situ expression of IL-12 was investigated in normal human skin and in allergic contact dermatitis by immunohistochemistry. Skin biopsy specimens were obtained from allergic patch test reactions after 3 days, and from normal skin in 8 subjects. In contrast to normal skin, a strong enhancement of IL-12 immunoreactivity was observed in the mononuclear cell infiltrate of allergic contact dermatitis. IL-12 immunoreactivity was mainly located in the cytoplasm of dermal dendritic cells and macrophages as well as of some Langerhans cells. IL-12-positive cells were often found in close apposition to lymphocytes. Furthermore, positive immunostaining was also detected in keratinocytes at sites of marked exocytosis and spongiosis in the epidermis. In conclusion, the enhanced in situ expression of IL-12 may contribute to the activation of cytotoxic lymphocytes and thereby represent an important factor in the pathogenesis of contact hypersensitivity reactions in humans.

[The appearance of Sweet's syndrome during the transition from a myelodysplastic syndrome to erythroleukemia]. / Auftreten eines Sweet-Syndroms beim Ubergang von einem myelodysplastischen Syndrom in eine Erythroleukämie.

HISTORY AND CLINICAL FINDINGS: Two months after being diagnosed as having refractory anaemia with an excess of blasts in transformation (RAEB-T), a 62-year-old man presented in the emergency room with fever (40 degrees C) for two weeks and scattered deep-red macular indolent efflorescences over the chest, back, face and thighs. Other than splenomegaly there were no significant findings on physical examination. INVESTIGATIONS: Erythrocyte sedimentation rate was increased to 38 mm in the first hour. Haemoglobin concentration and platelet count were at the lower limits of normal, white cell count within the normal range. Differential count: 60 erythroblasts per 100 leukocytes and 33.5 blast cells. Two skin biopsies revealed massive oedema in the upper corium and focal erythrocyte extravasations. There were perivascular and perifollicular inflammatory infiltrates in the deeper layers and elastosis of the corium. There was no leukocytoclastic vasculitis. These findings established the diagnosis of Sweet syndrome and erythroleukaemia. TREATMENT AND COURSE: The erythroleukaemia was treated symptomatically and the skin changes gradually receded under prednisone, 1 mg/kg, but new spots occurred when the prednisone dose was halved. Candida oesophagitis occurred as a complication of the erythroleukaemia. Chest radiogram showed diffuse infiltrates in both upper lobes of the lung. Despite intensive antimycotic and antibiotic treatment the patient died 10 days later from pulmonary aspergillosis. CONCLUSION: This case report describes the rare occurrence of Sweet syndrome during the transformation from a myelodysplastic Syndrome to erythroleukaemia.

[HIV-associated malignant lymphomas]. / HIV-assoziierte maligne Lymphome.

In a retrospective analysis of data from 35 cases with malignant lymphoma from a cohort of 2017 HIV-infected patients, the stage of HIV-disease, the CD4 counts at the time of diagnosis, and the use of antineoplastic agents or radiotherapy were correlated with outcome. 6 patients had Hodgkin's lymphoma (HL) and 29 non-Hodgkin-lymphoma (NHL). 11 of these lymphomas were classified according to the international working formulation (IWF) as high grade (H, I and J, respectively) and 8 as intermediate grade (G). 10 could not be classified. 22 patients with NHL had stage IV disease according to the Ann Arbor classification, all of whom had manifestations at extranodular sites. 23 patients with NHL were treated with multiagent chemotherapy (18 with m-BACOD or CHOP, 5 patients with various other regimens) and four of them had additional radiotherapy. One patient received radiotherapy only. Two of 24 treated patients showed complete and five a partial response. Median survival of patients without treatment (all of them in poor general condition at the time of diagnosis) was 1.8 months and treated patients survived a median of 5 months. The pretreatment CD4 count was the most important predictor of survival. Patients with prior Aids-diagnosis showed a tendency towards shorter survival. The observed remission rate indicates that HL in HIV-infected patients is better treatable than HIV-associated NHL. However, the overall outcome of HL in our patients was clearly less favorable compared to the course of HL usually seen in patients without HIV infection. The proportion of patients with HL among all patients with malignant lymphoma and HIV disease was unexpectedly larger in our cohort compared to others. Therefore, a possible association of HL and HIV infection, as addressed by several other authors, needs further clarification.

[Therapy of immune thrombopenia]. / Therapie der Immunthrombopenie.

Idiopathic thrombocytopenic purpura (ITP) belongs to the family of autoimmune diseases. The term "idiopathic", however, is no longer correct as it is in fact an immunologically-related thrombocytopenia. This is why nowadays it is referred to as immune thrombopenia. Clinically the acute and chronic forms of ITP can be distinguished. We discuss the different forms of treatment based upon data provided by various studies of ITP. If treatment with prednisone or with gammaglobulins fails, or after unsuccessful splenectomy, then alternative experimental therapies may have to be used. Some of these treatments are described with reference to their therapeutic benefit and their function.

[Malignant lymphoma: a study of an outpatient cohort]. / Das maligne Lymphom: eine Studie an einem poliklinischen Krankengut.

Data from 168 patients with malignant lymphoma were collected. 57 had Hodgkin's disease, 76 suffered from non Hodgkin's lymphoma and 35 presented with chronic lymphocytic leukemia. All patients were treated between January 1980 and December 1986 at the medical policlinic of the university of Zurich either as in- or outpatients. Presentation at the time of diagnosis, therapeutic regimen and treatment success as well as prognostic features of disease were evaluated. Overall the therapeutic results in this patient cohort were good and comparable with the results of large prospective studies. Complete remission rate (CRR) was 91% and overall survival rate (OSR) after 5 years was 72% for Hodgkin's disease. In Non Hodgkin's lymphoma of low malignancy OSR was 60% after 5 years and 39% in NHL of intermediate or high malignancy. In NHL CRR varied according to histologic subtype. In Hodgkin's disease staging according to the Ann Arbor classification and extranodal involvement including the spleen proved meaningful for prognosis. In NHL the international working formulation (IWF) was a useful prognostic tool. Anemias, higher age and relapses carried a poorer prognosis whereas induction of remission was a favorable prognostic sign. For chronic lymphocytic leukemia staging according to Binet was found a useful prognostic criterion.

[Combined GM-CSF and erythropoietin therapy in myelodysplastic syndrome]. / Kombinierte GM-CSF- und Erythropoietintherapie bei myelodysplastischem Syndrom.

A 60-year-old patient with a myelodysplastic syndrome (MDS) corresponding to refractory anemia with an increase in blast cells (RAEB) was treated with granulocyte-macrophage colony stimulating factor (GM-CSF) and erythropoietin (EPO) for severe symptomatic pancytopenia. During the GM-CSF treatment a distinct increase in granulocytes was observed, but the reticulocytes and thrombocytes decreased to the point where treatment had to be discontinued after eight days. After subsequent treatment with EPO the reticulocyte count rose from 0% to 2%. However, this rise alone was insufficient to decrease the number of blood transfusions required. The thrombocyte count rose to the original values after the cessation of GM-CSF therapy while continuing treatment with EPO. Bone marrow investigations were performed before and after GM-CSF treatment and indicated a distinct increase in the myeloid precursor cells after therapy, without an increase in blasts. On the other hand, an obvious decrease in erythro- and megakaryopoiesis was observed.

[Serum erythropoietin levels: a new diagnostic tool?]. / Serumerythropoietinwerte: ein neues diagnostisches Hilfsmittel?

The development of highly specific antibodies against recombinant human erythropoietin (EPO) has recently made the accurate radioimmunological measurement of serum levels of this hormone possible. In this study we determined the serum-EPO levels in 100 healthy volunteers, in 54 patients suffering from polycythemia vera and in 51 patients with secondary polyglobulia. The mean levels for the healthy group were found to be 11.3 +/- 3.4 mU/ml in females and 8.0 +/- 3.2 mU/ml in males. Patients with polycythemia vera had serum-EPO levels of 4.3 mU/ml, while those with secondary polyglobulia had significantly higher levels averaging 30.3 mU/ml (p less than 0.0001). However, an overlapping of serum-EPO values in the range between 10 and 20 mU/ml occasionally occurs. Our results show that measurement of the serum-EPO level can be useful in the differential diagnosis of polyglobulias. Additionally, sequential EPO level measurements after phlebotomy and after hemorrhage show a pronounced increase in serum-EPO in secondary polyglobulia, while in polycythemia vera the level only increases slightly.

[Serum erythropoietin levels in several diseases]. / Serumerythropoietinwerte bei verschiedenen Krankheitszuständen.

The accurate radioimmunological measurement of serum erythropoietin (EPO) levels has only been possible since the development of highly specific antibodies directed against recombinant human EPO. In the present study, we determined the serum EPO levels in 100 healthy volunteers and in over 300 patients with anemias and hyperglobulinemia of various causes. In the healthy group, the females had levels of 11.3 +/- 3.4 mU/ml, while the males had levels of 8 +/- 3.2 mU/ml. The serum EPO concentrations were inversely related to the degree of anemia in patients with nonrenal anemias, while predialysis patients with renal anemias showed only partially such a tendency. Hemodialysis patients exhibited EPO-levels that were inadequately low relative to the degree of anemia. Patients with hyperglobulinemia had significantly higher serum EPO-levels than healthy individuals and polycythemia vera patients, the latter having particularly low serum EPO levels. Our results show that the determination of serum EPO levels can be of value in the differential diagnosis of hyperglobulinemia. Finally, sequential measurements document fluctuating serum EPO-levels after gastrointestinal hemorrhages and in patients with iron deficiency anemias receiving iron substitution. The probable reason for this phenomenon seems to be the intermittent utilisation of the hormone by EPO-sensitive erythropoietic precursor cells.

[Plasma cell leukemia]. / Plasmazelleukämie.

The following article describes five patients with plasma cell leukemia treated during the last two years at a Medical University Polyclinic. Plasma cell leukemia is a disease which was seen extremely rarely in the past. The disease can develop in patients with multiple myeloma or, even more rarely, as a "de novo" disease. Generally patients with plasma cell leukemia are younger than the multiple myeloma patients and have a higher incidence of organomegaly. Despite the fact that patients with plasma cell leukemia received the same intensive chemotherapy as those with multiple myeloma, their prognosis was considerably worse, with a median survival time of only five month.