Chronic recurrent aphthous stomatitis: oral treatment with low-dose interferon alpha

Recombinant human interferon alfa-2a (HuIFN alpha) was administered orally once daily in a low concentration (1,200 IU/day) to nine patients with chronic recurrent aphthous stomatitis (RAS), and a placebo solution was given to 10 control chronic RAS patients in a double-blind study. All HuIFN alpha-treated patients had total remission of their aphthae within a 2-week period, while placebo control patients had no change in their condition. The 10 placebo control patients were then treated with HuIFN alpha in a manner identical to that used for the initial principal group. Within a 2-week period, all original placebo patients had complete remission of their aphthae. Eleven of the patients did not have a recurrence of RAS during a subsequent 6-month observation period. Eight patients had recurring aphthae; however, the lesions were resolved by retreating with oral HuIFN alpha for less than 1 week.     

Self-inoculation with milk as a cause of recurrent cellulitis.

A 21-year-old patient had six admissions to hospital for recurrent cellulitis over a 6-month period. She underwent extensive investigations, which failed to reveal any underlying predisposing factors. On the final admission she admitted to injecting herself subcutaneously with milk to induce the lesion. Self-inoculation with foreign material must be considered in patients presenting with recurrent cellulitis.     

Alpha 1-adrenergic-induced airway obstruction in ponies with recurrent pulmonary disease

We examined the response of five ponies with recurrent airway obstruction (principals) and five age- and gender-matched controls to the aerosol alpha-adrenergic agonist phenylephrine after blockade with propranolol and atropine. Measurements were made with principal ponies in clinical remission (period A) and during acute airway obstruction (period B). The blockade had no effect on base-line pulmonary mechanics in control ponies during periods A and B or in the principal ponies during period A. However, in the principal ponies during period B, blockade increased dynamic compliance (Cdyn) and decreased pulmonary resistance (RL). Phenylephrine had no effect on the controls during either period. In the principals, phenylephrine decreased Cdyn and increased RL during both periods. The alpha 1-agonist aerosol prazosin shifted the phenylephrine dose-response curves to the right, but prasozin did not bronchodilate the principals during period B. This suggests that the role of alpha 1-adrenergic receptors in airway narrowing in ponies with recurrent airway obstruction is minimal. However, the response to phenylephrine in only the principal ponies suggests an increase in alpha-receptor numbers and/or activity in these animals compared with controls.     

Homology model of human interferon-alpha 8 and its receptor complex.

Human interferon-alpha 8 (HuIFN alpha 8), a type I interferon (IFN), is a cytokine belonging to the hematopoietic super-family that includes human growth hormone (HGH). Recent data identified two human type I IFN receptor components. One component (p40) was purified from human urine by its ability to bind to immobilized type I IFN. A second receptor component (IFNAR), consisting of two cytokine receptor-like domains (D200 and D200'), was identified by expression cloning. Murine cells transfected with a gene encoding this protein were able to produce an antiviral response to human IFN alpha 8. Both of these receptor proteins have been identified as members of the immunoglobulin superfamily of which HGH receptor is a member. The cytokine receptor-like structural motifs present in p40 and IFNAR were modeled based on the HGH receptor X-ray structure. Models of the complexes of HuIFN alpha 8 with the receptor subunits were built by superpositioning the conserved C alpha backbone of the HuIFN alpha 8 and receptor subunit models with HGH and its receptor complex. The HuIFN alpha 8 model was constructed from the C alpha coordinates of murine interferon-beta crystal structure. Electrostatic potentials and hydrophobic interactions appear to favor the model of HuIFN alpha 8 interacting with p40 at site 1 and the D200' domain of IFNAR at site 2 because there are regions of complementary electrostatic potential and hydrophobic interactions at both of the proposed binding interfaces. Some of the predicted receptor binding residues within HuIFN alpha 8 correspond to functionally important residues determined previously for human IFN alpha 1, IFN alpha 2, and IFN alpha 4 subtypes by site-directed mutagenesis studies. The models predict regions of interaction between HuIFN alpha 8 and each of the receptor proteins, and provide insights into interactions between other type I IFNs (IFN-alpha subtypes and IFN-beta) and their respective receptor components.     

Thyroid Function Outcomes after Pegylated Interferon-α and Ribavirin Therapy - For Chronic Hepatitis C

ObjectiveTo assess the frequency of new thyroid disease, in patients who did not develop thyroid disease during treatment with interferon-a in combination with ribavirin for hepatitis C, during the 6-month period after the end of therapy.MethodsA prospective study was performed in 190 patients who underwent a combination of interferon-a and ribavirin therapy for hepatitis C infection during the 36-month period between 2006 and 2008. Thyroid function tests were performed at the completion of treatment and at 4, 12, and 24 weeks of follow-up.ResultsDuring the 6 months after the completion of interferon-a and ribavirin therapy in the 190 study patients with hepatitis C infection, there were 2 cases of thyroid disease. One patient had the typical biphasic thyroiditis, and the other had primary hypothyroidism. Thus, the prevalence of thyroid disease in this setting was 2 of 190 patients (1.0%).ConclusionThe majority (99%) of patients had normal thyroid outcomes at 6-month follow-up. Only 1 patient had symptoms. This finding is reassuring and eliminates the need for ongoing thyroid surveillance during this time and probably longer. In the absence of symptoms, only a single thyroid-stimulating hormone measurement at 6-month review is recommended. (Endocr Pract. 2010;16:934-939)     

Leiomyosarcoma of the stomach and small intestine

Three cases of leiomyosarcoma are presented. The primary lesion to the stomach was seen in 2 patients while the small intestine in the remaining patient. Two patients underwent radical surgery. All patients were treated with multiple drug regimens. Radiotherapy was additionally carried out in one patient. One patient who underwent radical surgery and given maintaining chemotherapy is alive in the complete remission since 6 years while two remaining patients died within 3 and 6 years because of recurrence and haematopoietic proliferation.     

Modifying effects of interferon and puromycin on cytogenetic damage induced by alkylating drug phopurine in human lymphocytes.

The induction of sister chromatid exchanges (SCEs) by the bifunctional alkylating antineoplastic drug phopurine (2-dimethyl-amino-6-diethyleneiminophosphamido-7-methylpurine) and its modification by human recombinant interferons alpha 2, beta and gamma (HuIFN alpha 2, HuIFN beta and HuIFN gamma) and puromycin (PM) were studied in human lymphocytes. Results demonstrated a striking similarity in the modifying action of HuIFN alpha 2 and PM: 1) both modifiers reduced SCE values induced by phopurine, 2) at high and low doses of phopurine the effect of both modifiers was minimal, and 3) both agents were able to convert DNA lesions from short-term to long-term.     

Low dose oral alpha-interferon therapy for patients seropositive for human immunodeficiency virus type-1 (HIV-1)

Thirty eight symptomatic and two asymptomatic patients seropositive for human immunodeficiency virus type-1 (HIV-1) were treated with a natural human interferon alpha (HuIFN alpha). Patients were given 2 IU/kg HuIFN alpha orally once daily in powdered maltose held in the mouth to promote mucosal absorption. This oral immunomodulating HuIFN alpha therapy resulted in an increase in CD4+ lymphocytes, an increase in weight, and a dramatic alleviation of clinical symptoms related to HIV-1 infection.     

Recombinant human interferon-alpha induced cytoreduction in chronic myelogenous leukemia. Results of a multicenter study

Fourteen patients with Ph'-chromosome positive chronic myelogenous leukemia (CML) in first chronic phase were treated with recombinant interferon-alpha 2c. Interferon-alpha 2c 5 to 10 X 10(6) units s.c. was given for 12 weeks as an induction therapy. Maintenance treatment consisted of interferon-alpha 2c 5 X 10(6) units twice weekly s.c.. Two patients (14%) attained a complete clinical remission and 6 (43%) a partial remission, 3 of whom developed progressive disease during maintenance therapy. A complete disappearance of Ph'-chromosome was achieved in 1 patient. All patients had a more than 45% initial decline of the leukocyte count. Four out of ten patients with an initially enlarged spleen demonstrated reduction in spleen size. Influenza-like symptoms, anorexia, nausea, weight loss and fatigue were common side effects. Interferon-alpha is active in CML but additional clinical investigations are warranted to assess more precisely the therapeutic value of the interferons in this disease.     

Treatment of Cushing's disease with low dose radiation therapy.

Nineteen patients with Cushing''s disease were treated with low dose external pituitary irradiation (20 Gy (2000 rad) in eight fractions over 10 days). While awaiting the effects of pituitary irradiation all patients were treated with metyrapone. Seven patients had a complete remission of their disease within six to 12 months of irradiation. They did not require any further treatment and were followed up for a mean of three and a half (range one to eight) years. Another patient had a complete remission after a second course of pituitary irradiation. A further two patients showed a significant biochemical improvement after irradiation, although they were not rendered eucorticoid. There were no complications after this dose of irradiation. These results compare favourably with those reported after pituitary irradiation at conventional doses (40-50 Gy (4000-5000 rad) over four or five weeks) but were not associated with any complications. It is therefore recommended that low dose external pituitary irradiation be used as definitive first line treatment for Cushing''s disease.     

Characterization of human beta-interferon-binding sites on human cells

Radioiodinated recombinant human beta-interferon (rHuIFN beta Ser), with almost full (greater than 90%) biological activity, was used to study the binding of human beta-interferon to Daudi cells. Specific binding was not observed with less biologically active (less than or equal to 10%) radioiodinated interferon. The bound radioiodinated interferon was shown to compete with human beta-interferon (HuIFN beta), rHuIFN beta Ser, human alpha-interferon (HuIFN alpha) and with human gamma-interferon (HuIFN gamma). Scatchard plot analyses suggest the presence of about 10,000 binding sites for HuIFN beta/Daudi cell. About 6,600 of these sites can be blocked by HuIFN alpha and 3,700 sites can be blocked by HuIFN gamma. The apparent Kd for HuIFN beta is 2.7 nM. The apparent Kd values for HuIFN alpha and HuIFN gamma are 3.7 and 1.1 nM, respectively. It was possible to demonstrate the cross-linking of HuIFN beta to two macromolecular components of Mr = 128,000 and 103,000. We propose the existence of at least two binding sites for HuIFN beta in Daudi cells, one site recognizing both HuIFN beta and HuIFN gamma, the other site recognizing both HuIFN beta and HuIFN alpha. Each site is capable of recognizing only HuIFN gamma or HuIFN alpha.     

Effects of human interferon on cellular response to UV in UV-sensitive human cell strains

Cells of a human RSa cell line, with high sensitivity to UV killing and low capacity for DNA repair, when pretreated with 1-100 units/ml of human interferon (HuIFN) preparations for more than 12 h before irradiation, acquired an enhancement of UV-induced DNA-repair replication synthesis in association with recovery from inhibition of total cellular DNA synthesis and UV survival. Prompt and transient induction of plasminogen activator activities was also found within 5 min after UV irradiation in the cells pretreated with HuIFN but not in the cells non-pretreated with HuIFN. The enhancement and induction effects of HuIFN were observed, irrespective of the kind of HuIFN preparation used (alpha, beta or gamma, and natural or recombinant) and in other UV-sensitive fibroblast cells which were derived from Cockayne syndrome and xeroderma pigmentosum fibroblasts (XP1KY). However, all of the enhancement of DNA-repair synthesis and the induction of plasminogen activator activities by HuIFN was suppressed by treatment with cycloheximide immediately after UV irradiation.     

Prediction of recurrent disease by cytology and HPV testing after treatment of cervical intraepithelial neoplasia

Objective: To assess the role of human papillomavirus (HPV) testing and cytology as predictors of residual/recurrent disease after treatment of high‐grade cervical intraepithelial lesions. Methods: One hundred and thirty‐eight women with cervical intraepithelial neoplasia (CIN) grade 2/3 lesion on biopsy were included in a prospective follow‐up study in Belgium and Nicaragua. All women were treated with loop electrosurgical excision procedure (LEEP) and follow‐up visits took place at 6 weeks, 6 months, 1 year and 2 years. During these visits, a Papanicolaou (Pap) smear test was taken, colposcopy was performed and specimens were collected for HPV testing. Cytology, high‐risk (HR) HPV presence, persistent HR HPV infection and combinations of these tests at different time points during follow‐up were correlated with histologically confirmed residual/recurrent disease. Results: Thirteen patients (9%) developed residual/recurrent disease during follow‐up. Abnormal cytology at 6 weeks after treatment was significantly correlated with residual/recurrent disease. Nine of thirty‐seven patients with abnormal cytology at 6 weeks had recurrent disease versus three of seventy with a normal cytology [odds ratio (OR): 7.2; 95% confidence interval (CI): 1.8–28.5; P = 0.003). Sensitivity of this test was 75.0%, specificity 70.5%. Combining abnormal cytology and the presence of HR HPV within the first 6 months after treatment gave the best correlation with residual/recurrent disease: of the 54 women with abnormal cytology and/or HR HPV presence within the first 6 months, 11 developed residual/recurrent disease (OR 10.2; 95% CI: 2.2–48.3). Sensitivity of this combination was 84.6% and specificity 65.0%. Conclusion: Cytology remains the cornerstone in the early follow‐up after LEEP for CIN lesions of the cervix. HPV testing can add value as it increases the sensitivity of cytology in concomitant testing within the first 6 months.     

Acute Kidney Injury in Patients with Newly Diagnosed High-Grade Hematological Malignancies: Impact on Remission and Survival

Background

Optimal chemotherapy with minimal toxicity is the main determinant of complete remission in patients with newly diagnosed hematological malignancies. Acute organ dysfunctions may impair the patient’s ability to receive optimal chemotherapy.

Design and Methods

To compare 6-month complete remission rates in patients with and without acute kidney injury (AKI), we collected prospective data on 200 patients with newly diagnosed high-grade malignancies (non-Hodgkin lymphoma, 53.5%; acute myeloid leukemia, 29%; acute lymphoblastic leukemia, 11.5%; and Hodgkin disease, 6%).

Results

According to RIFLE criteria, 137 (68.5%) patients had AKI. Five causes of AKI accounted for 91.4% of cases: hypoperfusion, tumor lysis syndrome, tubular necrosis, nephrotoxic agents, and hemophagocytic lymphohistiocytosis. Half of the AKI patients received renal replacement therapy and 14.6% received suboptimal chemotherapy. AKI was associated with a lower 6-month complete remission rate (39.4% vs. 68.3%, P<0.01) and a higher mortality rate (47.4% vs. 30.2%, P<0.01) than patients without AKI. By multivariate analysis, independent determinants of 6-month complete remission were older age, poor performance status, number of organ dysfunctions, and AKI.

Conclusion

AKI is common in patients with newly diagnosed high-grade malignancies and is associated with lower complete remission rates and higher mortality.     

Myeloperoxidase-deficient polymorphonuclear leucocytes. Longitudinal study during the preremission--and the remission phase in acute myeloid leukaemia. Comparison to neutrophil alkaline phosphatase (NAP) activity

Serial determinations of MPO and NAP activities in granulocytes were performed during the preremission phase and the remission phase in patients with AML. Of 18 patients examined during the preremission period, 9 showed an increased number of MPO deficient PMN. Complete remission was attained in 4 of these, in 3 the number of abnormal granulocytes changed to normal 7, 7 and 14 days before and in 1 simultaneously with the attainment of complete remission. In the other patients no changes in granulocyte MPO activity occurred during the preremission period. All 20 patients examined during complete remission showed a normal MPO activity in granulocytes. Of eight patients, who at diagnosis had shown abnormal granulocyte MPO activity, three developed relapse. In two of these, an increased number of MPO deficient PMN reappeared two and eight months prior to and in one simultaneous with clinical and laboratory suspicion of relapse. A statistically significant relation between low NAP scores and an increased number of MPO deficient PMN was found (P = 0.011). Serial determinations of MPO activities in PMN, although restricted to cases of AML with initially abnormal values, may prove helpful in predicting achievement of complete remission and may furthermore prove to be useful as an indicator of early relapse.     

An analytical biomarker for treatment of patients with recurrent B-ALL after remission induced by infusion of anti-CD19 chimeric antigen receptor T (CAR-T) cells

Anti-CD19 chimeric antigen receptor-modified T (CAR-T-19) cells have emerged as a powerful targeted immunotherapy for B-cell lineage acute lymphoblastic leukemia with a remarkable clinical response in recent trials. Nonetheless, few data are available on the subsequent clinical monitoring and treatment of the patients, especially those with disease recurrence after CAR-T-19 cell infusion. Here, we analyzed three patients who survived after our phase I clinical trial and who were studied by means of biomarkers reflecting persistence of CAR-T-19 cells in vivo and predictive factors directing further treatment. One patient achieved 9-week sustained complete remission and subsequently received an allogeneic hematopoietic stem cell transplant. Another patient who showed relapse after 20 weeks without detectable leukemia in the cerebrospinal fluid after CAR-T-19 cell treatment was able to achieve a morphological remission under the influence of stand-alone low-dose chemotherapeutic agents. The third patient gradually developed extensive extramedullary involvement in tissues with scarce immune- cell infiltration during a long period of hematopoietic remission after CAR-T-19 cell therapy. Long-term and discontinuous increases in serum cytokines (mainly interleukin 6 and C-reactive protein) were identified in two patients (Nos. 1 and 6) even though only a low copy number of CAR molecules could be detected in their peripheral blood. This finding was suggestive of persistent functional activity of CAR-T-19 cells. Combined analyses of laboratory biomarkers with their clinical manifestations before and after salvage treatment showed that the persistent immunosurveillance mediated by CAR-T-19 cells would inevitably potentiate the leukemia-killing effectiveness of subsequent chemotherapy in patients who showed relapse after CAR-T-19-induced remission.     

Protective effect of an oral natural phytonutrient in recurrent vulvovaginal candidiasis: a 12-month study

The aim of the present study is to assess the clinical efficacy of a phytocompound with antimicotic properties (K-712, with the following 100 mg composition: 10 mg of oleoresin from Pseudowintera colorata at 30 percent concentration in Polygodial together with trace amounts of Olea europea) in recurrent vulvo-vaginal candidiasis (RVVC) as compared to an azole drug during a 12-month period: 6 months of treatment followed by 6 months of observation. This prospective randomized study involved 82 women (19-61 years) with complaints of abnormal vaginal discharge and with a history of at least four proven episodes of RVVC in the previous 12 months. Patients were divided into two groups of treatment of 41 patients each and were given: A) Itraconazole 200 mg orally daily for 4 days, then 200 mg once weekly for 6 months or B) 1 tablet twice a day of a K-712 for 4 weeks and then for the first 2 weeks of each month for a total of 6 months. Both groups were then followed-up for further 6 months. Each treatment schedule was well tolerated with only 4 patients in the azole group complaining of transient mild symptoms (nausea, abdominal discomfort, unpleasant taste). Itraconazole reached an earlier symptomatic relief during the first two weeks of observation as compared with K-712 (p<0.05) but both treatments enabled a comparable benefit during the entire treatment study period, afterwards with comparable symptom/sign score (itraconazole vs K-712: 9 vs 11). At 6-month observation, mycological cure was reached by 83 percent in the itraconazole group and in 78 percent of the K-712-treated patients. During the further 6-month observation period without treatment, the itraconazole group showed significantly more relapses (65.7 vs 34.2 in K-712, p<0.05) and at the end of the whole 12-month study period the mycological cure was significantly higher in the K-712-treated patients (65.8 vs 34.3 percent, p<0.05). There was a non- significant trend increase of less drug-susceptible species in the itraconazole group. From these preliminary data it would appear that a natural antifungal phytocompound proves to be as good as itraconazole in the maintenance treatment of RVVC. Moreover, this approach seems to maintain a higher mycological success rate afterwards by reducing the number of relapses and probably of the growth of azole-resistant species.     

Neurological effects of recombinant human interferon.

Ten women with advanced locally recurrent breast cancer who had failed to respond to radiation and hormonal and cytotoxic agents were given up to 12 weeks of recombinant leucocyte interferon 20 X 10(6) U/m2 daily or 50 X 10(6) U/m2 three times a week. Within one hour of administration influenza-like symptoms began, which one week later were superseded by lethargy, anorexia, and nausea, with a consequent loss of weight in most patients. Other side effects included profound somnolence, confusion, paraesthesia, and (in one patient) signs of an upper motor neurone lesion in the legs. All these effects together with increased slow wave activity in electroencephalograms from all patients during treatment disappeared when interferon was withdrawn and did not recur on reintroducing the drug at a lower dosage. Studies are continuing to determine the mechanisms of these effects.     

Human anti-lymphoma responses generated in vitro and in vivo following sensitization with allogeneic leukocytes

Peripheral blood lymphocytes (PBL) from a patient with poorly differentiated lymphocyte lymphoma (PDLL), after stimulation for 7 days with X-irradiated allogeneic lymphocytes pooled from three or ten donors (poolx), were cytotoxic for autologous lymphoma cells. Some clones lytic for autologous lymphoma cells, that were derived from this patient's pool-stimulated cells, resembled cytotoxic T lymphocytes (CTL), while other clones resembled natural killer (NK)-like cells in that they also lysed NK-sensitive HLA-negative K562 cells. In a second patient with more advanced PDLL, PDL cultured with T-cell growth factor (which is produced following stimulation with mitogens or alloantigens) lysed autologous lymphoma cells. On the basis of these in vitro findings, we asked whether IV transfusions with X-irradiated allogeneic leukocytes would result in anti-lymphoma responses in vivo. Ten days after transfusions with X-irradiated leukocytes from four unrelated donors, the first patient's two previously palpable nodes were no longer palpable and he remained in complete clinical remission for 6 months. The second patient had a temporary partial remission with dramatic reduction in size of multiple cervical and axillary nodes within 2 weeks after receiving the leukocyte transfusions.     

Combined reserpine and pituitary irradiation therapy for Cushing's disease patients following unsuccessful transsphenoidal microsurgery

The effectiveness of treatment with reserpine and pituitary irradiation, and with reserpine alone was evaluated in three female patients with Cushing's disease whose transsphenoidal pituitary microsurgery (TPM) had been unsuccessful. In these patients, endocrinological examination after the surgery demonstrated a recurrence of the disease although the microadenomas had apparently been curetted out from the pituitary in all patients. The first patient therefore received 1.0-2.0 mg/day of reserpine with 60 Gy x-ray irradiation, and there was complete remission within 3 months and the patient remained asymptomatic even when reserpine was reduced to 0.1 mg/day 10 years later. The second case was treated with low dose x-ray (20 Gy) and reserpine (0.5-2.0 mg/day), which were also effective. However, 2 weeks discontinuation of the drug caused urinary 17-hydroxycorticosteroids (17-OHCS) and serum cortisol to increase abnormally again, but these were finally re-normalized by an additional administration of reserpine. The third case was given reserpine alone (1.0-2.0 mg/day). She also had a remission in 3 months and the treatment was continued for one year, requiring no further treatment. These results suggest that additional treatment with reserpine and pituitary irradiation or with reserpine alone after unsuccessful TPM may be an effective alternative for patients with Cushing's disease.