Treatment of advanced renal cell cancer with sequential intravenous recombinant interleukin-2 and subcutaneous alpha-interferon.

Starting from in vitro studies suggesting synergistic antitumour activity against renal cell cancer (RCC) of recombinant interleukin-2 (rIL-2) and alpha-interferon (IFN), a phase II trial was initiated to test the clinical activity of this combination. The two cytokines were administered sequentially, with the aim of reducing the risk of additive toxicity and enhancing the immunological reaction against the tumour. The original treatment schedule consisted of rIL-2 18 x 10(6) U/m2/day by continuous intravenous infusion for 120 h days 1-5, and alpha-IFN 2b, at a flat dose of 9 x 10(6) U by subcutaneous or intramuscular injection thrice in a week, from day 8 to 28. Treatment was planned to be continued for six or more 28-day cycles, depending on clinical response. 12 patients were treated according to this schedule; as some cardiovascular toxicity was experienced in this set of patients, 11 further patients were treated with half-dose rIL-2 (i.e. 9 x 10(6) U/m2/day). 17 out of 23 enrolled patients completed at least one cycle of treatment and were evaluated for response. We observed six major responses [one complete response (CR) + five partial responses (PR)] for an objective response rate of 35% [95% confidence interval (CI) 17-59%]. 5 additional patients achieved stabilisation of disease; one of them reached CR after surgical extirpation of a lung mass. Sites of response included lung, nodes and bone. Duration of response is 12+ months for CR; 17, 16, 12+, 9 and 9 months for PRs. Median survival is 16 months. Response was not significantly different between full-dose and half-dose rIL-2. Considering stable disease (SD) as responses, there seemed to be a higher chance of response for patients with smaller tumour burden (P = 0.032). The toxicity of rIL-2 treatment, mainly cardiovascular, was substantial; 9 patients experienced severe cardiotoxicity, consisting of major arrhythmias, myocardial ischaemia, reduction of ejection fraction measured with heart radionuclide scan, and were excluded from continuing treatment. Other rIL-2-related toxicities forcing exclusion from the study were severe thrombocytopenia (1 case), and generalised exfoliative dermatitis requiring steroids (1 case). Otherwise, treatment was well tolerated; rIL-2-related toxicities promptly recovered after rIL-2 discontinuation in the majority of cases, and no treatment-related deaths were reported. The half-dose rIL-2 regimen was significantly less toxic in terms of hypotension (P = 0.014), fever (P = 0.014), oliguria (P = 0.042), serum creatinine elevation (P = 0.009) and prothrombin time elongation (P = 0.038).(ABSTRACT TRUNCATED AT 400 WORDS)

Lack of TdT and immunoglobulin and T-cell receptor gene rearrangements in Hodgkin's disease.

To study the pathogenesis of Hodgkin's disease (HD), which today remains obscure, we have undertaken a combined experimental approach: determination of TdT and molecular analysis of rearrangements of immunoglobulin heavy chain (IgH), T-cell receptor (TCR) beta chain and the T-cell rearranging gamma (TRG) genes. TdT determination indicate would the presence of immature cells that are not detected in the normal lymphnode; molecular analysis of the rearrangements of these genes would reveal the presence of even a small monoclonal population of both T and B lineages in the lymphnodes. We believe that the combination of these two types of analysis can indicate whether an expanding lymphoid clone is responsible for this disease. TdT determination was negative in all 41 cases tested. Gene rearrangements were studied in 10 cases for IgH and TCR beta genes and in 5 cases for the TRG gene. No abnormal band beside the germ-line ones was detected in any of our cases, ruling out the presence of a minor neoplastic population. We can explain these results in at least three ways: first, the neoplastic population could represent less than 1% of the total, thus escaping detection by current techniques; second, the neoplastic population is not lymphoid in nature or is composed of mature cells that do not rearrange Ig and TCR genes and therefore belongs to a true non-B, non-T lineage; third, the pathogenesis of HD is completely different from that of non-Hodgkin's lymphomas (NHL) and does not involve the clonal expansion of a cell frozen at a particular maturative stage as is thought to happen in most NHL.

Primary antiphospholipid syndrome and neurologic events.

The occurrence of lupus anticoagulant and anticardiolipin antibodies was demonstrated in a girl affected by recurrent episodes of visual disturbances, with ophthalmologic evidence of visual impairment and sometimes accompanied by migraine. Systemic lupus erythematosus was excluded on the basis of both clinical and serologic criteria and the diagnosis of primary antiphospholipid syndrome was made. Vascular pathogenesis was suggested by the characteristic symptoms. The serologic demonstration of antiphospholipid antibodies made it possible to relate the illness to an immune-mediated thrombotic tendency. This patient demonstrated that the diagnosis of primary antiphospholipid syndrome must always be considered in focal cerebral or retinal ischemia in childhood.

Intrapleural administration of interleukin-2 and LAK cells in locally advanced non-small-cell lung cancer. A case report.

AIMS AND BACKGROUND: The systemic administration of recombinant interleukin-2 (rIL-2) and lymphokine-activated killer (LAK) cells is ineffective in non-small-cell lung cancer (NSCLC). However, there is some evidence that their intrapleural administration could be effective, since it increases the concentrations of the cytokine and the effector cells in the tumor area, thereby obtaining greater antitumor activity. STUDY DESIGN: We report the case of a patient affected by a locally advanced lung adenocarcinoma with pleural effusion (T4 N0 M0-stage IIIb) treated with repetitive courses consisting of a priming continuous i.v. infusion (48 h) of rIL-2 (18 MIU/m2/day) intraplural administration of LAK cells (3-9 x 10(9)/day), in a single daily bolus, for 3 consecutive days and concomitant administration of rIL-2 (1.8-7.2 x 10(6) IU/day), for 5 days. RESULTS: We observed early disappearance of neoplastic cells in the pleural effusion, progressive decrease until disappearance of the pleural effusion, cavitation of the primary lesion during the treatment, and its stabilization for 9 months until progression. Radiologic changes were accompanied by a marked eosinophilia (up to 50 x 10(9)/L), and the intrapleural route of administration of rIL-2 induced a relevant increase in eosinophil count in peripheral blood. Immunologic changes in lymphocyte subpopulation phenotypes were also observed. The performance status of the patient improved, and she was still alive and eupnoic 25 months from the diagnosis and 23 months from the start of treatment. CONCLUSIONS: This case suggests a therapeutic role for intrapleural rIL-2, and we believe that the relationship among intrapleural administration of rIL-2 and LAK cells, the development of peripheral eosinophilia, and clinical response should be further investigated.

Autoimmune thyroiditis following interleukin-2 and LAK cell therapy for metastatic renal cell carcinoma: correlation with tumor regression.

A 63-year-old woman receiving recombinant interleukin-2 (rIL-2) + lymphokine activated killer cells for metastatic renal cell carcinoma developed autoimmune thyroiditis with clinical hypothyroidism and high titer anti-thyroglobulin and anti-microsomal antibodies. The onset of thyroid dysfunction was associated with tumor regression and resulted in complete response at the end of the treatment. Cytologic and cytofluorimetric studies on thyroid tissue showed two distinct populations, mainly consisting of small lymphocytes and large thyrocytes, and the latter expressed MHC class II antigens. After completion of rIL-2 treatment, hypothyroidism gradually decreased until resolution; complete tumor remission lasted 18 months. Mechanisms underlying the association between autoimmune thyroiditis and cancer regression are discussed.

Specificity of the rearrangements of the T-cell receptor gamma gene in human lymphomas.

The structure and function of the human T-cell rearranging gamma gene are not completely understood. Several reports have suggested that this gene rearranges specifically in normal T cells, but the pattern of rearrangement in human lymphoid neoplasms is not clear. Some authors have described the rearrangements of this gene in unmanipulated leukemias as relatively specific for T-derived tumors, whereas others were unable to observe such specificity in malignant lymphomas. The present paper reports the analysis of the structure of the gamma gene in 32 lymphoid samples of different origin, with emphasis on non-T lymphomas. Four out of four T-cell lymphomas had this gene rearranged, whereas none of the 17 cases of B-cell lymphomas, 5 of Hodgkin's disease or 6 of nonneoplastic lesions showed any alterations of the gamma gene. Therefore, our data support the relative specificity of the gamma gene rearrangements in human T-cell malignant proliferations.

Interleukin-2, interferon-alpha and interleukin-2 plus interferon-alpha in renal cell carcinoma. A randomized phase II trial.

BACKGROUND: The purpose of the present study was to investigate the therapeutic effectiveness of interleukin-2 (IL-2) and interferon (IFN), either alone or in combination, in comparable groups of patients affected by advanced renal cell carcinoma (RCC). PATIENTS AND METHODS: In order to limit selection biases, treatment was allocated on a random basis. Patients randomized to IL-2 alone were scheduled to receive eight rlL-2 24-hour i.v. infusion cycles, days 1 to 4, at a daily dose of 18 x 10(6) lU/m2 for a total of 25 weeks. Patients randomized to IFN alone were scheduled to receive rIFN-alpha at a daily dose of 6 x 10(6) IU/m2, days 1, 3 and 5, every week for a total of 52 weeks. Patients randomized to the combination of IFN and IL-2 were given the same drugs at the same daily doses for a total of 24 weeks. Drug dose was modified according to toxicity. RESULTS: Twenty-three percent (95% CI:+/-17.5) of patients treated with IL-2 alone showed an objective response to treatment (9% CR). The corresponding figures in patients treated with IFN alone or IFN plus IL-2 were 9% (95% CI:+/-11.9) and 9% (95% CI:+/-11.9), respectively. Complete responses were observed only in patients treated with IL-2. The median duration of response in the IL-2 arm was 18 months (range, 9.5-24). The duration of the two responses achieved by IFN alone was seven and nine months, respectively. The corresponding figures in the two patients responding to the combination of IFN with IL-2 were 19 and 27 months, respectively. Total IL-2 dose appeared to be a major predictor of response. Only a minority of patients experienced grade 3-4 toxicity, the incidence being higher in those treated with IL-2 or IL-2 plus IFN. CONCLUSIONS: Neither IFN nor IL-2 or the combination of the two appear to be very active in patients with advanced RCC, even when trial entry was restricted to patients with relatively indolent disease. This stresses the need for the development of new approaches.

Dramatic development of severe SLE in a patient with an incomplete disease.

This case report describes the previously-unreported clinical course of a patient with a so-called incomplete systemic lupus erythematosus (SLE), i.e. symptoms related to one organ system only, together with the presence of ANA. He had an indolent course initially and developed, 6 months after the first symptoms, a severe disease with rapid appearance of major and unusual manifestations. The possibility of fast progression and a grave course of an incomplete SLE should be kept in mind. This report is meant to heighten awareness of such an atypical presentation so that prompt and aggressive immunosuppressive therapy may be instituted.

Meperidine in detoxification of hospitalized heroin addicts.

Forty-six heroin abusers were hospitalized and treated with meperidine either alone or in association with clonidine. Meperidine was given orally in rapidly decreasing doses according to three different schedules. The majority of patients (87%) successfully completed the detoxification program. The best meperidine starting posology was 200 mg four times daily, which allowed stoppage of the opioid treatment after gradual reduction of the daily dose in a mean time of 9.5 days. Association with clonidine was not proven to be useful. This study shows that meperidine can be effectively used in rapidly decreasing doses in the pharmacological detoxification treatment of hospitalized heroin addicts.

Chronic bilateral dacryo-adenitis in identical twins: a possible incomplete form of Sjögren syndrome.

We report an unusual case of chronic bilateral dacryo-adenitis in 10-year-old identical twin sisters. Both girls presented with bilateral lacrimal gland enlargement and developed moderate xerophthalmia and keratitis. Both the lacrimal and minor salivary gland biopsies showed a non-granulomatous inflammatory infiltration of mono-nuclear cells. All granulomatous diseases and neoplasms could therefore be ruled out and only Sjögren syndrome and very few other forms of chronic dacryo-adenitis remained as possible diagnoses. Both patients and their parents were evaluated for auto-antibodies. Very low titres of smooth muscle antibodies were found in one, antinuclear antibodies in two and anti-dsDNA antibodies in all four members of the family. Even though the titres of antinuclear and anti-dsDNA antibodies increased in one of the sisters, both patients did not develop any sign or symptom of a systemic connective tissue disease. During the 6 years' follow up, both patients showed persistent tarsal gland enlargement but no other symptoms apart from a moderate xerophthalmia and occasional mild keratitis.

Partial seizures associated with antiphospholipid antibodies in childhood.

We report antiphospholipid antibody positivity in three of a consecutive series of 23 children presenting partial epileptic seizures. There was no clinical or serological evidence of systemic lupus erythematosus or other connective-tissue disease. Neither computed tomography nor magnetic resonance imaging revealed ischemic alteration. The presence of antiphospholipid antibodies in 3/23 children may indicate that immune-mediated neuronal damage could be a pathogenetic mechanism for partial epilepsy.

Effects of short-term lithium treatment on peripheral blood lymphocytes and granulocytes in healthy volunteers.

The effects of a short-term treatment with lithium carbonate on lymphocytes and granulocytes were studied in six normal subjects. The lithium effects are related to a direct, immediate and quickly reversible action of the drug on the bone marrow, as demonstrated by the granulocyte number and variations in Arneth's index. Although lymphocyte and granulocyte functions do not seem to be affected by lithium when investigated by the usual methods, the ability of the drug to counteract the theophylline-induced inhibition of cellular functions would suggest that lithium acts mainly through the modulation of intracellular levels of cyclic nucleotides. This is confirmed by evaluation of cellular cyclic 3',5'-adenosine monophosphate (cAMP). The above hypothesis could explain the quick onset and loss of lithium action on granulopoiesis.

[Demonstration of a granulocyte defect in aged persons correlated with the presence of autoantibodies]. / Dimostrazione di un difetto granulocitario in soggetti anziani e correlazione con la presenza di auto-anticorpi

Assessment of PMN leukocyte function and search for autoantibodies were performed in 36 aged human subjects (more than 60 years of age) and in 15 younger controls (40 to 60 years of age). Autoantibodies were found in 15 of the 36 aged subjects, and in none of the controls. Leukocyte function defects were therefore correlated to old age and to markers of autoimmunity. Phagocytosis of bacteria was significantly impaired in both groups of old-aged subjects, irrespective to the presence or absence of autoimmunity. Intracellular killing of bacteria was shown to be normal in all the examined subjects. Nitroblue tetrazolium reduction by resting and latex-stimulated leukocytes was significantly impaired only in the group of old-aged subjects with autoimmunity. These leukocyte function defects are similar to those already described in human autoimmune diseases -- particularly S.I.E. -- and confirm the possible association between P.M.N. dysfunction and autoimmunity.

Immunological investigation and immunotherapy approaches in cancer patients.

The Authors report the preliminary results of a two-step far-reaching investigation carried out on cancer patients to study: 1) the immune conditions of the patients and establish, by a thorough immune monitoring, employing tests of humoral immunity (tetanus toxoid response), of delayed immunity (BCG test, PHA-lymphocyte blastogenesis, MIF release, skin window) and macrophage immunity (skin window), the chemotherapy effects on the immune conditions and the most suitable time to carry out immunotherapy; 2) the immunotherapeutic results which can be obtained with three different immunogens (BCG, C. parvum and ribonucleotides). The results obtained in the first part of the investigations pointed out the usefulness of the tests adopted to follow up the evolution of the immunological reactivity in patients submitted to chemotherapy, while the results of the immunotherapeutic trial show a preliminary character and, at present, do not allow definitive conclusions. Carefully planned and randomized studies are at present under way to establish, more thoroughly, the optimal modalities and the real possibilities of the immunotherapy performed with C. parvum and ribonucleotides in cancer patients.

Peripheral neuropathy associated with mycosis fungoides.

A 56 year old man with acute sensory-motor polyneuropathy associated with mycosis fungoides is described. EMG studies showed diffuse signs of muscle denervation. A skin biopsy specimen showed a lymphocyte infiltration in the dermis, composed of mycosis cells characterised by deep invaginations of the nuclear membrane, and small Pautrier's microabscesses in the epidermis. Sural nerve biopsy revealed endoneurial fibrosis, a decreased number of myelinated fibres and acute axonal degeneration.

Abnormal OKT4/OKT8 ratio and deranged capping in ataxia-telangiectasia.

Two sisters with ataxia-telangiectasia (A-T) and their parents were investigated for some parameters related to immunological functions. We found a decrease of total mature T lymphocytes, a decrease of OKT4+ helper-inducer T subset, and normal values of OKT8+ suppressor-cytotoxic T subset; a normal decrease of E rosette formation after incubation in vitro with theophylline, with a lowered E rosette capacity in one patient. The responses to phytohemagglutinin (PHA)and concanavalin A (ConA) were lowered. In addition we observed a reduction of basal capping of B lymphocytes in one patient and in her parents: this phenomenon could be related to cytoskeletal disorders, possibly involved in the pathogenesis of the disease.