Early reduction of serum TARC levels may predict for success of ABVD as frontline treatment in patients with Hodgkin Lymphoma.

BACKGROUND: Many efforts have been made to predict prognosis of newly diagnosed Hodgkin Lymphoma (HL) patients. Objective of this study was to investigate the association between early reduction of Thymus and Activation-Regulated Chemokine after the first ABVD cycle (TARC-1) and prognosis of HL patients. METHODS: Serum samples of 116 HL patients were collected at baseline, after every ABVD cycle and during follow-up. The 99th centile of TARC distribution in a group of 156 independent healthy subjects (800pg/ml) was considered as cut-off for discriminating between abnormal and normal TARC values. FINDINGS: 101 patients out of 116 had baseline TARC above 800pg/ml (median value 27515pg/ml (IQR, 11001-68139)) and were the object of this analysis. TARC-1 significantly decreased to a median value of 556pg/ml (IQR, 378-977pg/ml). TARC-1 values below 800pg/ml were associated with success of therapy (p=0.0003) and PET-2 negativity (p=0.001). TARC-1≤800pg/ml identified a population with a significantly higher 5-years PFS in the whole cohort (90.1% vs 55.6%; p<0.0001) and in both subgroups of advanced (p=0.003) and early stage patients (p=0.021). At multivariable analysis, TARC-1 was significant independent predictor of PFS (p=0.0035). INTERPRETATION: Early reduction of TARC serum levels can predict success of treatment, being associated with achievement of interim PET-2 negative and favorable long-term outcome in HL patients receiving ABVD as front-line therapy.

Results of a randomized trial comparing high-dose chemotherapy plus Auto-SCT and R-FC in CLL at diagnosis.

The importance of early therapy intensification in B-cell CLL (B-CLL) patients remains to be defined. Even though several studies have been published, no randomized trials comparing directly autologous stem cell transplant (ASCT) and the accepted conventional therapy (that is, rituximab, fludarabine and CY; R-FC) have been reported so far. To assess the benefit of a first-line aggressive therapy, we designed a multicenter, randomized, phase 3 trial comparing R-FC and high-dose chemotherapy supported by ASCT in patients under 65 years of age, with stage B(II) or C B-CLL. Primary end point was CR: 96 patients were enrolled (48 in each arm). On an intent-to-treat basis, the CR rates in the ASCT and R-FC arms were 62.5% and 58%, respectively. After 5 years of follow-up, PFS was 60.4% in the ASCT arm and 65.1% in the R-FC arm, time to progression 65.8 and 70.5%, and overall survival 88% vs 88.1%, respectively. Our trial demonstrates, for the first time in a randomized manner, that frontline ASCT does not translate into a survival advantage when compared with benchmark chemoimmunotherapy in B-CLL patients; the possibility of its clinical benefit in certain subgroups remains uncertain.

Perifosine and sorafenib combination induces mitochondrial cell death and antitumor effects in NOD/SCID mice with Hodgkin lymphoma cell line xenografts.

The effects of the Akt inhibitor perifosine and the RAF/MEK/ERK inhibitor sorafenib were investigated using two CD30(+)Hodgkin lymphoma cell lines (L-540 and HDLM-2) and the CD30(-)HD-MyZ histiocytic cell line. The combined perifosine/sorafenib treatment significantly inhibited mitogen-activated protein kinase and Akt phosphorylation in two of the three cell lines. Profiling of the responsive cell lines revealed that perifosine/sorafenib decreased the amplitude of transcriptional signatures that are associated with the cell cycle, DNA replication and cell death. Tribbles homolog 3 (TRIB3) was identified as the main mediator of the in vitro and in vivo antitumor activity of perifosine/sorafenib. Combined treatment compared with single agents significantly suppressed cell growth (40-80%, P<0.001), induced severe mitochondrial dysfunction and necroptotic cell death (up to 70%, P<0.0001) in a synergistic manner. Furthermore, in vivo xenograft studies demonstrated a significant reduction in tumor burden (P<0.0001), an increased survival time (81 vs 45 days, P<0.0001), an increased apoptosis (2- to 2.5-fold, P<0.0001) and necrosis (2- to 8-fold, P<0.0001) in perifosine/sorafenib-treated animals compared with mice receiving single agents. These data provide a rationale for clinical trials using perifosine/sorafenib combination.

Absorbed dose and biologically effective dose in patients with high-risk non-Hodgkin's lymphoma treated with high-activity myeloablative 90Y-ibritumomab tiuxetan (Zevalin).

PURPOSE: The aim of this study was to carry out two different dose estimation approaches in patients with non-Hodgkin's lymphoma (NHL) treated with a myeloablative amount of (90)Y-labelled ibritumomab tiuxetan (Zevalin(R)) in an open-label dose escalation study. METHODS: Twenty-seven patients with relapsed/refractory or de novo high-risk NHL receiving one myeloablative dose of (90)Y-ibritumomab tiuxetan followed by tandem stem cell reinfusion were evaluated for dose estimate. The injected activity was 30 MBq/kg in 12 patients and 45 MBq/kg in 15 patients. Dose estimation was performed 1 week prior to (90)Y-ibritumomab tiuxetan by injection of (111)In-ibritumomab tiuxetan (median activity: 200 MBq). The absorbed dose (D) and the biologically effective dose (BED) were calculated. RESULTS: The absorbed doses per unit activity (Gy/GBq) were [median (range)]: heart wall 4.6 (2.5-9.7), kidneys 5.1 (2.8-10.5), liver 6.1 (3.9-10.4), lungs 2.9 (1.5-6.8), red marrow 1.0 (0.5-1.7), spleen 7.0 (1.5-14.4) and testes 4.9 (2.9-16.7). The absorbed dose (Gy) for the 15 patients treated with 45 MBq/kg were: heart wall 17.0 (8.7-25.4), kidneys 17.1 (7.9-22.4), liver 20.8 (15.4-28.3), lungs 8.1 (5.4-11.4), red marrow 3.1 (2.0-4.0), spleen 26.2 (17.0-35.6) and testes 17.3 (9.0-28.4). At the highest activities the acute haematological toxicity was mild or moderate and of very short duration, and it was independent of the red marrow absorbed dose. No secondary malignancy or treatment-related myelodysplastic syndrome was observed. No non-haematological toxicity (liver, kidney, lung) was observed during a follow-up period of 24-48 months. CONCLUSION: The use of 45 MBq/kg of (90)Y-ibritumomab tiuxetan in association with stem cell autografting resulted in patients being free of toxicity in non-haematological organs. These clinical findings were in complete agreement with our dose estimations, considering both organ doses and BED values.

CD4 lymphocyte count and CD4/CD8 ratio in elderly long-term care patients with oropharyngeal dysphagia: comparison between oral and tube enteral feeding.

Many institutionalized elderly patients are at risk of undernutrition as a result of oropharyngeal dysphagia (OD) that possibly affects their immunological status. Tube enteral fed (TEF) patients on controlled intake of nutrients enables us to evaluate the effect of inadequate nutrition on the immune system in the orally fed elderly with OD. The aim of our study was to compare CD4 lymphocyte count and CD4/CD8 ratio between these two differently fed groups. Twenty-eight orally fed patients with OD in the Functional Outcome Swallowing Scale (FOSS) stage 2 (group A) and 17 TEF subjects (group B) were studied. CD4 and CD8 counts were determined by flow cytometry. Nutritional markers (albumin, hemoglobin, and basal metabolic index) were recorded for each group. The Charlson index was used for comparison of comorbidity between the two patient groups. The average count of CD4 lymphocytes was significantly lower in group A than in group B (754 +/- 365 vs. 1032 +/- 404 cells/ml, p < 0.01). Six patients in group A (21%) had a CD4 count of less than 400 cells/ml (lower threshold) while all the patients in group B had a CD4 count of over 500 cells/ml (p < 0.001). The CD4/CD8 average ratio was also significantly lower in group A (p < 0.008). Nutritional markers were within normal limits with no difference between the groups. These results confirm our presumption that a low CD4 lymphocyte count and a low CD4/CD8 ratio could prevail among elderly frail patients with dysphagia. This supports the view that under an apparently satisfactory nutritional profile these patients may be in a state of undernutrition that negatively influences their immunodefense.

Cytokine secretion associated with the clearance of apoptotic bodies in renal cell carcinoma patients.

The factors determining the outcome of immunotherapy in metastatic renal cell carcinoma (RCC) patients remain elusive. Macrophages from normal donors that phagocytose apoptotic cells secrete the immunosuppressive cytokine IL-10 in vitro. Conversely, IL-10 genetic deletion enhances the immunogenicity of apoptotic tumor cells in vivo. Elevated pre-treatment levels of IL-10 are associated with an unfavorable outcome of RCC. We examined whether the ability to release IL-10 by macrophages from RCC patients that phagocytosed apoptotic cells correlated with the outcome of immunotherapy. To this aim, we derived macrophages from 30 patients with metastatic RCC and from 21 healthy subjects (11 sex- and age-matched healthy controls and 10 younger donors). Patients either had a clinical response after immunotherapy, with a median survival after treatment of more than 18 months (n = 16), or were beginning immunotherapy after diagnosis of metastatic disease (n = 14). Macrophages from responding patients challenged with apoptotic cells released significantly less IL-10 than controls (p = 0.0075) and recently diagnosed patients (p = 0.0198), as ascertained by a 2-sided Student's t-test. This was not because macrophages from responding patients lost the ability to secrete IL-10, because antibody opsonization of apoptotic cells rescued IL-10 secretion. In contrast, macrophages from all groups of donors released similar amounts of TNF-alpha. The failure in IL-10 secretion by engulfing macrophages of responding subjects may exalt the immunogenicity of dying tumor cells, contributing to the success of immunotherapy.

[External radiotherapy in early stage squamous cell carcinoma of the supraglottic larynx. Report of 28 cases]. / Il trattamento radiante nel carcinoma iniziale (T1-T2N0) sopraglottico. Revisione di una casistica di 28 casi.

The Authors reviewed a group of 28 pts with early-stage supraglottic carcinoma (T1-T2N0), classified according to UICC (1987), and treated exclusively with radiotherapy (RT) between 1980 and 1991. Until 1990 RT was employed for such tumors when surgery was refused or controindicated, while since 1991 primary irradiation (with surgery in reserve) has been considered the treatment of choice. The total dose ranged from 66 to 70 Gy on the larynx and up to 50 Gy on neck nodes. RT was applied in a daily fraction of 2 Gy five times a week. No significant early complications were observed. Only 1 pt showed residual cronical oedema in the arytenoid region. In none of the pts was tracheostomy necessary. The local control rate obtained after 30 months was 85.7% (24/28). Salvage surgery (horizontal supraglottic laringectomy, HSL) was performed in 3 out of 4 pts with local failure and achieved complete control of the disease. In the last pt the surgery was controindicated because of poor general health conditions. The actuarial survival rate after 5 years is 86.2%. The present series was compared to a group of 152 pts with T1-T2N0 supraglottic cancer treated surgically (HSL) at the same Istitution. In these pts local control and the actuarial survival rates are 85.6% and 89% respectively. According to recent Literature data, the present findings confirm that RT may be administered for the treatment of selected early stage (T1-T2N0) supraglottic squamous cell carcinoma of the larynx with oncologic results equivalent to those obtained with radical surgery. The importance of imaging techniques (TC, MRI) in the correct staging of the tumor is emphasised.

[Radiotherapy of stage T1 carcinoma of the glottis. Analysis of prognostic factors in 154 patients]. / La radioterapia dei carcinomi della glottide nello stadio T1. Analisi dei fattori prognostici in 154 pazienti.

A retrospective study was carried out on a series of 154 patients affected with vocal cord cancer in stage T1 treated with definitive radiotherapy April, 1979, to November, 1991. According to the 1992 TNM classification (UICC), 121 patients were classified as stage T1a and 33 patients as stage T1b. All patients were treated using parallel opposed fields of a 60 cobalt unit. Field size ranged from 16 to 30 square centimeters and the dose from 4400 to 7000 cGy, but only 15 patients received less than 6400 cGy. All patients were treated with once-daily fractionation (200 cGy/day). Follow-up ranges from 25 to 123 months; the median is 63 months. We observed 14 local recurrences (9.0%), all but one within 36 months from the end of treatment. Ten of 14 patients (71.4%) were rescued by surgery (8 patients underwent total laryngectomy and 2 conservative surgery); 13 patients were lost for intercurrent deaths. The incidence of recurrences is 7.4% for T1a patients (9/121) and 15.1% for T1b patients (5/33). The total dose does not seem to be related to relapse rate since recurrences were found in 6.6% of patients after a dose < 6400 cGy and in 9.3% of patients who had received higher doses. In our experience, field size did not affect, treatment results (< 25 cm2: 7.5% recurrences, > 25 cm2: 10.7%). Besides lesion volume, the main prognostic factor was overall treatment time. The incidence of failure was 3 times lower (5.8%) in the patients who completed the treatment within 7 weeks than in the patients whose treatment lasted more than 8 weeks (16.6%).

[Poliomyelitis surveillance: seroepidemiologic study on a Piedmont population sample]. / Sorveglianza della poliomielite: indagine sieroepidemiologica su un campione di popolazione piemontese.

In order to assess the immunity/receptivity towards the three poliovirus strains, a sample representative of the sex and age composition of the resident population in Piedmont at census 1981, was examined. For each subject data were collected in order to identify the population from social-ambient point of view. For the evaluation of antibodie's title to poliovirus 1, 2, 3, the serums were analyzed with the neutralization method using the microtitolation plates and epithelial larynx cancer cells (HEp-2), like revealing system. The samples with > or = 2 title were considered positives for specific antibodies. To determine the relation between presence/absence of specific poliovirus antibodies and the other variables, a multiple logistic regression was fitted and the odds ratio was calculated. The results of our study show an immunity in all age groups, underlying a herd immunity condition. Furthermore the incomplete antibodies response to the three poliovirus strains seems to be influenced by age only.

Haemoptysis as the sole presenting symptom of dissection of the aorta.

A 75 year old man who had had haemoptysis for 24 hours was found to have his left lower lobe compressed by a dissection of the aorta, which was otherwise symptomless.