Weekly docetaxel versus CMF as adjuvant chemotherapy for older women with early breast cancer: final results of the randomized phase III ELDA trial.

BACKGROUND: Evidence on adjuvant chemotherapy in older women with breast cancer is poor. We tested whether weekly docetaxel is more effective than standard chemotherapy. PATIENTS AND METHODS: We carried out a multicenter, randomized phase III study. Women aged 65-79, operated for breast cancer, with average to high risk of recurrence, were allocated 1 : 1 to CMF (cyclophosphamide 600 mg/m², methotrexate 40 mg/m², fluorouracil 600 mg/m², days 1, 8) or docetaxel (35 mg/m(2) days 1, 8, 15) every 4 weeks, for four or six cycles according to hormone receptor status. Primary end point was disease-free survival (DFS). A geriatric assessment was carried out. Quality of life (QoL) was assessed with EORTC C-30 and BR-23 questionnaires. RESULTS: From July 2003 to April 2011, 302 patients were randomized and 299 (152 allocated CMF and 147 docetaxel) were eligible. After 70-month median follow-up, 109 DFS events were observed. Unadjusted hazard ratio (HR) of DFS for docetaxel versus CMF was 1.21 [95% confidence interval (CI) 0.83-1.76, P = 0.32]; DFS estimate at 5 years was 0.69 with CMF and 0.65 with docetaxel. HR of death was 1.34 (95% CI 0.80-2.22, P = 0.26). There was no interaction between treatment arms and geriatric scales measuring patients' ability or comorbidities. Hematological toxicity, mucositis and nausea were worse with CMF; allergy, fatigue, hair loss, onychopathy, dysgeusia, diarrhea, abdominal pain, neuropathy, cardiac and skin toxicity were worse with docetaxel. One death was attributed to CMF and two to docetaxel. Increasing age, impairment in instrumental daily living activities, number of comorbidities and docetaxel treatment were independently associated with severe nonhematological toxicity. QoL was worse with docetaxel for nausea-vomiting, appetite loss, diarrhea, body image, future perspective, treatment side-effects and hair loss items. CONCLUSIONS: Weekly docetaxel is not more effective than standard CMF as adjuvant treatment of older women with breast cancer and worsens QoL and toxicity. CLINICALTRIALSGOV: NCT00331097.

Preoperative weekly cisplatin, epirubicin, and paclitaxel (PET) improves prognosis in locally advanced breast cancer patients: an update of the Southern Italy Cooperative Oncology Group (SICOG) randomised trial 9908.

BACKGROUND: The present article reports the updated survival outcome of the 200 patients enrolled in the Southern Italy Cooperative Oncology Group 9908 trial, which compared 12 weekly cycles of cisplatin-epirubicin-paclitaxel (PET) with 4 triweekly (once every 3 weeks) cycles of epirubicin-paclitaxel (ET) in patients with locally advanced breast cancer (LABC). METHODS: The effects of treatment, pathologically documented response (pathological response), pre- and post-treatment biomarkers on relapse-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS) are analysed. RESULTS: At a median follow-up of 74 (range 48-105 months) months, the 5-year RFS, DMFS, and OS were 64 % versus 53% (P = 0.11), 73% versus 55% (P = 0.04), and 82% versus 69% (P = 0.07) in PET and ET, respectively. At multivariate analysis, after adjusting treatment effect for pretreatment biomarkers, PET independently predicted better DMFS (P = 0.018) and OS (P = 0.03), whereas the impact on RFS was of borderline significance (0.057). PET treatment was significantly better than ET treatment only in high-grade or highly proliferating tumours. The better outcome in PET arm was the results of both the higher rate of patients with optimal pathological response and the lower rate of patients with biologically aggressive residual tumour. CONCLUSIONS: The PET weekly regimen significantly improves both DMFS and OS in LABC patients, compared with the triweekly ET combination. The therapeutic advantage is limited to patients with highly aggressive tumours.

Comparison between filgrastim and lenograstim plus chemotherapy for mobilization of PBPCs.

Recombinant human (rHu) G-CSF has been widely used to treat neutropenia and mobilize PBPCs for their autologous and allogeneic transplantation. It shortens neutropenia and thus reduces the frequency of neutropenic fever. We compared the efficiency of glycosylated rHu and non-glycosylated Hu G-CSF in mobilizing hematopoietic progenitor cells (HPCs). In total, 86 patients were consecutively enrolled for mobilization with CY plus either glycosylated or non-glycosylated G-CSF, and underwent leukapheresis. The HPC content of each collection, toxicity, days of leukapheresis needed to reach the minimum HPC target and days to recover WBC (> or =500 and >1000/mm(3)) and plts (>50 000/mm(3)) were evaluated. Glycosylated G-CSF mobilized more CD34+ cells than did the non-glycosylated form. The ability to reach a collection target of >3 x 10(6) CD34+/kg body weight in two leukaphereses was higher for glycosylated G-CSF. No significant differences between the two regimens were observed with regard to toxicity and days to WBC and plt recovery. High-dose CY plus glycosylated G-CSF achieved adequate mobilization and the collection target more quickly and with fewer leukaphereses.

Preoperative weekly cisplatin-epirubicin-paclitaxel with G-CSF support in triple-negative large operable breast cancer.

BACKGROUND: Findings from our previously published phase II study showed a high pathologic complete remission (pCR) rate in patients with triple-negative large operable breast cancer after the administration of eight cisplatin-epirubicin-paclitaxel (PET) weekly cycles. The safety and efficacy data of the initial population were updated, with inclusion of additional experience with the same therapy. METHODS: Patients with triple-negative large operable breast cancer (T2-T3 N0-1; T > 3 cm) received eight preoperative weekly cycles of cisplatin 30 mg/m2, epirubicin 50 mg/m2, paclitaxel (Taxol) 120 mg/m2, with granulocyte colony-stimulating factor (5 microg/kg days 3-5) support. RESULTS: Overall 74 consecutive patients (T2/T3 = 35/39; N0/N+ = 26/48) were treated, from May 1999 to May 2008. At pathological assessment, 46 women (62%; 95% confidence interval 50-73) showed pCR in both breast and axilla. At a 41-month median follow-up (range 3-119), 13 events (nine distant metastases) had occurred, 5-year projected disease-free survival (DFS) and distant disease-free survival being 76% and 84%, respectively. Five-year DFS was 90% and 56% in pCRs and non-pCRs, respectively. Severe neutropenia and anemia occurred in 23 (31%) and eight (10.8%) patients, respectively. Severe non-hematological toxicity was recorded in <20% of patients. Peripheral neuropathy was quite frequent but never severe. CONCLUSIONS: Eight weekly PET cycles are a highly effective primary treatment in women with triple-negative large operable breast cancer. This approach results in a very promising long-term DFS in this poor prognosis population. This triplet regimen is worthy of evaluation in phase III trials.

Factors predicting complete necrosis rate after ultrasound-guided percutaneous laser thermoablation of small hepatocellular carcinoma tumors in cirrhotic patients: a multivariate analysis.

PURPOSE: To assess factors affecting the effectiveness of percutaneous laser ablation (PLA) under ultrasound (US) guidance in terms of complete ablation achievement. MATERIAL AND METHODS: The clinical records of 86 hepatocellular carcinoma (HCC) tumors (mean diameter 23.7 mm) in 60 cirrhotic patients (mean age 68.3 years; 36 males; 57 HCV+; 53 Child's class A, seven Child's class B) treated by means of PLA were reviewed. PLA was performed with a continuous-wave Nd:YAG laser by a single operator who positioned two to four 300-microm optic fibers advanced in 21-gauge needles into target lesions under US guidance. Triphasic computed tomography (CT) studies were used to verify treatment effectiveness 1 month after PLA completion. The association between characteristics of the lesion and outcome (complete or incomplete ablation) was evaluated by logistic regression, taking into account the following predictive factors: tumor size, pattern of growth (infiltrating or not) at imaging, location, first diagnosis of HCC (naïve tumors vs. non-naïve tumors), number of sessions (1/ > 1), total delivered energy, and years of treatment in 2001-2002 (first period) vs. 2003-2004 (second period). RESULTS: Complete ablation was obtained in 62 nodules (72%). Statistically significant predictors of incomplete ablation after the first PLA course at both univariate and multivariate analysis included: infiltrating growth pattern (odds ratio (OR) 12.3, P<0.002), non-naïve tumors (OR 8.7, P<0.001), and first period of treatment (OR 10.3, P<0.002). CONCLUSION: The effectiveness of US-guided PLA for HCC tumors < or =4 cm turned out to be negatively affected by both operator-related (the beginning of the operator's experience with the technique) and tumor-related factors (non-naïve, infiltrating HCC tumors).

Weekly cisplatin, epirubicin, and paclitaxel with granulocyte colony-stimulating factor support vs triweekly epirubicin and paclitaxel in locally advanced breast cancer: final analysis of a sicog phase III study.

The present study aimed at evaluating whether a weekly cisplatin, epirubicin, and paclitaxel (PET) regimen could increase the pathological complete response (pCR) rate in comparison with a tri-weekly epirubicin and paclitaxel administration in locally advanced breast cancer (LABC) patients. Patients with stage IIIB disease were randomised to receive either 12 weekly cycles of cisplatin 30 mg m(-2), epirubicin 50 mg m(-2), and paclitaxel 120 mg m(-2) (PET) plus granulocyte-colony stimulating factor support, or four cycles of epirubicin 90 mg m(-2)+paclitaxel 175 mg m(-2) (ET) every 3 weeks. Overall, 200 patients (PET/ET=100/100) were included in this study. A pCR in both breast and axilla occurred in 16 (16%) PET patients and in six (6%) ET patients (P=0.02). The higher activity of PET was evident only in ER negative (27.5 vs 5.4%; P=0.026), and in HER/neu positive (31 vs 5%; P=0.037) tumours. The two arms yielded similar pCR rate in ER positive (PET/ET=7.5/7.1%) and HER/neu negative (PET/ET=10/6%) patients. At a 39 months median follow-up, 70 patients showed a progression or relapses (PET, 32 vs ET, 38). Anaemia, mucositis, peripheral neuropathy, and gastrointestinal toxicity were substantially more frequent in the PET arm. The PET weekly regimen is superior to ET in terms of pCR rate in LABC patients with ER negative and/or HER2 positive tumours Mature data in terms of disease-free and overall survival are needed to ascertain whether this approach could improve the prognosis of these subsets of LABC patients.

Should we continue to study high-dose chemotherapy in metastatic breast cancer patients? A critical review of the published data.

Data from eight randomised trials on high-dose chemotherapy (HDC) for metastatic breast cancer (MBC) have been published, but only seven studies are evaluable after the Bezwoda trial was discredited. Moreover, overall survival (OS) has been evaluated in only four out of seven studies since three had a crossover design. OS was similar for the HDC and standard-dose chemotherapy (SDC) group in the four evaluable trials, while disease-free survival (DFS) was improved in the HDC group in six of the seven trials. The delay in relapse for patients with metastatic disease represents an important clinical outcome; furthermore, since none of the reported studies randomised more than 220 patients, their statistical power may have been too limited to detect meaningful survival differences. Finally, preliminary experiences have shown that HDC seems to be the ideal platform upon which to build novel therapies. In conclusion, HDC remains an important field of clinical research for breast cancer patients with stage IV disease and, from the studies reported in this article, there is some evidence for offering this therapeutic modality to selected patients who are interested in a medically aggressive approach.

[Diagnosis, therapy, and follow up in synchronous colorectal cancer of the colon]. / Diagnosi, terapia e follow-up dei cancri colorettali (CCR) sincroni del colon.

The authors report their experience with synchronous colorectal cancers (CRC). They underline the role of pre-operative diagnosis to improve surgical results and overall survival. The endoscopic surveillance allows the identification of neoplasms missed at previous examinations. In selected cases intraoperative colonoscopy may prove to be helpful.

Single-step treatment of gallbladder and bile duct stones: a combined endoscopic-laparoscopic technique.

BACKGROUND: The introduction of laparoscopic cholecystectomy has given rise to a debate as to whether endoscopic retrograde cholangiopancreatography (ERCP) should be performed before or after cholecystectomy in patients with bile duct stones. METHODS: This study evaluated the efficacy of treatment of cholecystocholedocholithiasis in a single step by performing ERCP during surgery in 52 patients (35 women, 17 men; mean age 57.0 years; age range 20 to 89 years). Laparoscopic intraoperative cholangiography via the cystic duct was carried out to confirm the presence of duct stones. A soft-tipped guidewire was passed through the cystic duct and papilla into the duodenum. A papillotome was inserted endoscopically over the guidewire. Endoscopic sphincterectomy was performed and the stones removed with balloon and basket catheters. RESULTS: Endoscopic stone removal was successful in 94% of cases without complications related to ERCP or surgery. Although operative time was lengthened by about 20 minutes, the hospital stay was as short and equal to that for simple laparoscopic cholecystectomy (3 days on average). CONCLUSIONS: The single-step combined endoscopic-laparoscopic technique is safe and effective for treatment of patients with gallbladder and bile duct stones.

Autocrine interleukin-6 production and highly malignant multiple myeloma: relation with resistance to drug-induced apoptosis.

In this study, flow cytometry was used to evaluate interleukin-6 (IL-6) production by bone marrow mononuclear cells from 47 patients with multiple myeloma (MM) in different clinical stages and 15 patients with monoclonal gammopathy of undetermined significance. In patients with MM, autocrine IL-6 production paralleled the clinical disease stage. The largest proportion of syndecan-1(+)/IL-6(+) cells was detected in patients with resistant relapse or primary refractory disease, suggesting that tumor progression involves expansion of myeloma cells producing IL-6. The authors assessed autocrine IL-6 production and in vitro proliferation and apoptosis of myeloma cells in 6 myeloma cell clones (MCCs) and in 2 myeloma cell lines, namely IM-9 and U-266-1970, which showed different sensitivities to the addition of exogenous IL-6. Autocrine IL-6 production was observed in IL-6-independent MCC-2, MCC-3, and MCC-5 cloned from patients with aggressive disease and in the IM-9 cell line. In contrast, IL-6-dependent MCC-1, MCC-4, and MCC-6 were syndecan-1(+) and IL-6(-). Blocking experiments with anti-IL-6 monoclonal antibody from clone AH65, which binds IL-6-IL-6Ralpha complexes, prevented cell proliferation of IL-6(+) MCCs. Flow cytometry evaluations after propidium iodide staining revealed different susceptibilities of MCCs to cell death. IL-6-producing MCCs showed minimal spontaneous and dexamethasone-induced apoptosis, whereas a regular amplitude of apoptosis occurred in the IL-6(-) MCCs. These data provide evidence that autocrine IL-6 reflects a highly malignant phenotype of myeloma cells. In fact, autocrine IL-6 production and deregulated apoptosis may induce expansion of selective IL-6(+) myeloma cells resistant to spontaneous and drug-induced cell death.

Fas/Fas ligand (FasL)-deregulated apoptosis and IL-6 insensitivity in highly malignant myeloma cells.

IL-6 is a growth factor which interferes in the apoptosis of malignant plasma cells. Here we explore its role in the spontaneous and Fas/FasL-regulated apoptosis of seven myeloma cell clones (MCC). MCC-2 and -7 were constitutively defective in Fas antigen in the presence of large membrane exposure of FasL, and showed a high rate of cell proliferation irrespective of the presence of IL-6. Cytofluorimetric analysis following propidium iodide (PI) staining revealed a minimal extent of spontaneous apoptosis, as in other IL-6-insensitive, though Fas-positive MCC, namely MCC-3 and -5. By contrast, a regular amplitude of apoptosis occurred in the remaining IL-6-dependent clones. Their propensity to cell death, as well as their FasL membrane expression, were promptly down-modulated by the cytokine, whereas no substantial effect was detected in IL-6-independent MCC. Furthermore, we investigated the quantitative secretion of FasL. Both [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT) cytotoxicity assay and PI staining of WC8 lymphoblasts from a Fas-transfected mouse lymphoma, incubated with supernatants from MCC, showed a variable cytocidal property, thus confirming the cellular release of FasL. However, a significant elevation of FasL secretion occurred in both Fas- MCC, whereas molecular cloning and sequencing of Fas revealed the presence of a splicing variant, namely Fas Exo4,6Del, in the cDNA from both MCC-3 and -5, which were previously demonstrated to be unresponsive to Fas stimulation. Taken together, these data provide evidence that concurrence of IL-6 insensitivity and deregulation of apoptosis in myeloma cells reflects a high malignancy grade. It is suggested that the secretion of Fas splicing variants in Fas+ plasma cells, as well as the over-production of FasL in Fas- myelomas, are differential mechanisms by which myeloma cells escape host immune surveillance.

Hepatitis C virus infection involves CD34(+) hematopoietic progenitor cells in hepatitis C virus chronic carriers.

Although hepatitis C virus (HCV) mainly affects hepatocytes, infection is widespread and involves immunologically privileged sites. Whether lymphoid cells represent further targets of early HCV infection, or whether other cells in the hematopoietic microenvironment may serve as a potential virus reservoir, is still unclear. We studied whether pluripotent hematopoietic CD34(+) cells support productive HCV infection and can be used to establish an in vitro infection system for HCV. Six patients were selected as part of a cohort of HCV chronic carriers who developed a neoplastic disease. Reverse transcriptase-polymerase chain reaction (RT-PCR) and branched DNA signal amplification assays were used to detect and quantitate HCV RNA in extracted nucleic acids from purified bone marrow and peripheral blood CD34(+) cells. Direct in situ RT-PCR, flow cytometry analysis, and immunocytochemistry were applied to demonstrate specific viral genomic sequences and structural and nonstructural virus-related proteins in intact cells. Results indicated that both positive and negative HCV RNA strands and viral proteins were present in CD34(+) cells from all HCV-positive patients and in none of the controls. Additional experiments showed that a complete viral cycle took place in CD34(+) cells in vitro. Spontaneous increases in viral titers indicated that virions were produced by infected hematopoietic progenitor cells. To further define the cellular tropism, we attempted to infect CD34(+) cells in vitro. We were unable to demonstrate viral uptake by cells. These findings suggest that HCV replication can occur in the early differentiation stages of hematopoietic progenitor cells, and that they may be an important source of virus production.

[Echo-guided radiofrequency percutaneous ablation of hepatocellular carcinoma in cirrhosis using a cooled needle]. / Ablazione percutanea ecoguidata del carcinoma epatocellulare su cirrosi mediante radiofrequenza con "ago freddo".

INTRODUCTION: Radiofrequency hyperthermia using the newly-developed "cooled-tip" needle is one of the latest US-guided percutaneous treatments of hepatocellular carcinoma arising in cirrhosis. The continuous cooling of the needle tip allows tissue heating and necrosis far from the electrode without tissue charring, which was the major drawback of the old monopolar technique. Herein we report our preliminary results on feasibility and effectiveness of the thermoablation of mono- or paucifocal hepatocellular carcinoma with the cooled-tip needle. MATERIAL AND METHODS: November, 1996, to January, 1998, we treated thirteen cirrhotic patients (mean age 69.5 yrs, 10 men, 12 HCV-positive; 11 in Child's Class A and 2 in Class B) with 19 hepatocellular carcinoma nodules (mean diameter: 27 mm; range: 10-41 mm; 6 with diameter > 3 cm). None of the patients had portal thrombosis and/or extrahepatic spread. We used a radiofrequency generator (100 W power) connected to an 18 G perfusion electrode needle with an exposed tip of 2-3 cm. The circuit is closed through a dispersive electrode positioned under the patient's thighs. A peristaltic pump infuses a chilled (2-5 degrees C) saline solution to guarantee the continuous cooling of the needle tip. The needle was placed into target lesions under US guidance. The interventional procedure was carried out under general anesthesia using Propofol without intubation. Dynamic CT (more recently with the helical technique) was carried out 15-20 days after thermoablation to assess treatment efficacy. RESULTS: In all, 31 thermal injuries (at 1000-1200 mA for 10-15 minutes) were caused in 21 sessions in the 19 hepatocellular carcinoma nodules (mean: 1.5 lesions per nodule and 1.6 sessions per patient). Complete necrosis as assessed at dynamic CT (no enhancement during the arteriographic phase) was achieved in 16 of 19 nodules (84%). No side-effects occurred. During the follow-up (median: 11 months) no death occurred and five patients had recurrent hepatocellular carcinoma appearing either as single nodule or as multinodular liver involvement. CONCLUSIONS: In our experience radiofrequency hyperthermia with the cooled-tip needle permits effective and safe percutaneous ablation of HCC in cirrhosis. In addition, treatment time is short and lesions > 3 cm can be treated. Further experience is needed to better define the role of percutaneous thermoablation in the treatment strategy of hepatocellular carcinoma.

Increased prevalence of colonic polyps and altered lymphocyte subset pattern in the colonic lamina propria in acromegaly.

OBJECTIVE: The balance of evidence suggests that acromegaly is a risk factor for colonic neoplasia. We have evaluated the prevalence of colonic polyps in acromegalics from Southern Italy and characterized the lymphocyte subsets in the colonic lamina propria in order to analyze differences in the colonic immunological environment. DESIGN: All the patients and controls were submitted to pancolonoscopy. Ten per-endoscopic biopsies of the intestinal mucosa surrounding polyps were carried out to evaluate lymphocyte subsets. PATIENTS: Fifty acromegalics and 318 sex- and age-matched controls entered this study. Colonic lamina propria lymphocyte subsets were studied in 34 patients and 34 controls. RESULTS: Colonic polyps were resected in 23 acromegalics (46%) and 42 controls (13.2%; P < 0.0001); hyperplastic polyps were found in 24% and 6.3%, adenomatous polyps in 22 and 6.9%, (P < 0.01), adenocarcinoma in 2 and 1.2% while synchronous polyps occurred in 18% and 2.5% (P < 0.01), respectively. The number of polyps was significantly correlated with age both in acromegalics (r = 0.422, P < 0.005) and in controls (r = 0.865, P < 0.001). However, polyp prevalence was greater in patients aged below 40 yrs (r.r = 1.9) and in patients with two or more skin tags (r.r = 1.2). A significant decrease of CD20, CD19, CD16, gamma/delta, CD4@leu8- and increase of CD3 and CD4+/leu8+ was found in the lamina propria lymphocyte subsets. CONCLUSIONS: The results of this study confirm that acromegalics are at increased risk of colonic polyps compared to the healthy population. The increased prevalence of premalignant polyps, namely the adenomatous type, suggests that acromegalics should undergo a careful screening and follow-up by pancolonoscopy. An impairment of mucosal immune surveillance seems to exist in acromegaly although a causal effect in the polyp formation cannot be ruled out.

Relapsing neoplastic seeding after percutaneous ethanol injection for hepatocellular carcinoma. Clinical and ultrasonographic findings in a cirrhotic patient.

A case of neoplastic implant after percutaneous ethanol injection (PEI) therapy for hepatocellular carcinoma (HCC) occurring in two steps is described. A 74-year-old male cirrhotic patient underwent PEI for a 5-cm HCC nodule. To obtain complete tumoral necrosis, 80 ml were injected under sonographic guidance in four sessions. Ten months after the completion of PEI a subcutaneous nodule was palpated in the abdominal wall within the area of needle punctures. Histologic examination of the excised nodule confirmed the sonographic and Power Doppler diagnosis of metastatic HCC. At the US exam scheduled three months later a non-palpable subcutaneous nodule of 16 mm was appreciated near the surgical wound. Once again metastatic HCC was demonstrated at pathological examination. Copyright 1997 Elsevier Science Ireland Ltd.

Detection of hepatitis C virus (HCV) proteins by immunofluorescence and HCV RNA genomic sequences by non-isotopic in situ hybridization in bone marrow and peripheral blood mononuclear cells of chronically HCV-infected patients.

Immunofluorescence (IF) to detect HCV antigens and non-isotopic in situ hybridization (NISH) to detect HCV RNA genome were carried out on bone marrow (BM) and peripheral blood (PB) mononuclear cells (MC) of 11 chronically HCV-infected patients. In four patients (36.4%) HCV antigens were detected in monocytes/macrophages as well as in B lymphocytes in both BMMC and PBMC. Positive T lymphocytes in BMMC were found in three of them, but only one patient showed positive T cells in PBMC. NISH invariably demonstrated minus and plus HCV RNA genomic strands either in monocytes/macrophages or B and T lymphocytes in BMMC and PBMC in the four HCV antigen-positive patients and in two further patients not expressing viral proteins in blood MC. IF signals appeared diffusely distributed within the cytoplasm, or as brilliant granules in distinct submembrane areas or else in cytoplasm membrane. Nuclei never stained. Similarly, NISH displayed HCV RNA accumulation restricted to MC cytoplasm only, nuclei being persistently negative. NISH, however, was unable to detect cell membrane signal. Infection of blood MC is a common event in naturally acquired HCV infection, since none of these patients was conditioned by immunomodulating or immunosuppressive therapies. No difference was found in terms of age, length of disease, anti-HCV immune response, type and severity of chronic liver damage between patients with HCV-infected MC and patients without cell infection. These results demonstrate that HCV can infect BMMC and PBMC that represent important extrahepatic sites of virus replication, and may help to explain the immunological abnormalities observed in chronic HCV carriers.

Langerhans cell histiocytosis, diabetes insipidus, hyperprolactinemia and empty sella: a four-fold association. Report of two cases.

Two cases of Langerhans cell histiocytosis (LCH) expressing as Hand-Schuller-Christian syndrome with diabetes insipidus, hyperprolactinemia and empty sella are here reported. Up-to-date this four-fold association is lacking in world literature and it is here discussed in the light if LCH is a cancer or the clinical expression of an immunologic disorder.

Bone marrow of patients with active multiple myeloma: angiogenesis and plasma cell adhesion molecules LFA-1, VLA-4, LAM-1, and CD44.

Bone marrow plasma cells and stromal cells in multiple myeloma (MM) have been shown to be capable of releasing cytokines with angiogenic properties. Plasma cells can also express adhesion molecules controlling their adhesive interactions with endothelial cells. In the present study, we have evaluated by immunohistochemistry the extent of angiogenesis in the bone marrow of: a) 51 patients with active and non-active MM; b) 25 patients with monoclonal gammopathy of undetermined significance (MGUS). Plasma cells were investigated by flow cytometry for the expression of the adhesion molecules LFA-1, VLA-4, LAM-1, and CD44. The results showed that, while angiogenesis was very low or absent in patients with MGUS and non-active MM, it increased markedly in those with active MM. The highest detectability of plasma cell adhesion molecules, except LAM-1, was also found in these patients. The functional significance of these findings is unknown. Their consistent occurrence in the bone marrow of active myeloma patients, however, strongly suggests that more frequent adhesive interactions between plasma cells and their microvasculature underlie tumor dissemination.

[Idiopathic CD4+ lymphocytopenia: a case report]. / Linfocitopenia CD4+ idiopatica: descrizione di un caso.

We present the case of a 47-year-old patient who was seen for recurrent opportunistic infections. Immunophenotypic analyses disclosed severe reduction of CD4+ T cells. Repeated Elisa, Western blot and polymerase chain reaction tests for HIV were negative. The low CD4+ T lymphocyte count unaccompanied by increased CD8+ T lymphocytes and hypergammaglobulinemia, along with negativity for HIV infection, suggested the diagnosis of idiopathic CD4+ lymphocytopenia (ICL). The patient's clinical manifestations and laboratory results conformed with the case definition of ICL established in 1992 by the Centers for Disease Control of Atlanta, i.e., CD4+ T cells < 300/mm3 on two occasions and no evidence of HIV infection. In vitro analyses evidenced depressed lymphoproliferative responses to mitogens such as concanavalin A and pokeweed mitogen, while the expression of Fas antigen on peripheral lymphocytes and the percentage of apoptotic cells after propidium iodide staining were increased. Since in vitro concanavalin A stimulation inhibits T cell proliferation and induces apoptosis, these results suggest that the patient's lymphocytes are susceptible, in vivo, to an apoptotic signal.

Intermediate and high grade malignant non-Hodgkin's lymphomas: preliminary results using a new combination regimen (EVE-COPEM).

Between 1988 and 1992, 60 patients with intermediate and high-grade non-Hodgkin's lymphomas (NHL) were treated with a new multidrug combination chemotherapy including 4'epidoxorubicin (25 mg/m2), etoposide (60 mg/m2), cyclophosphamide (400 mg/m2), administered intravenously (i.v.) on the 1st, 2nd and 3rd day every 4 weeks, prednisone (40 mg/m2) orally for 6 days every 4 weeks, vincristine (1 mg/m2) i.v. and methotrexate (400 mg/m2) i.v. on the 8th day every 4 weeks, vindesine (2.5 mg/m2) and cytarabine (200 mg/m2) on the 15th day every 4 weeks. Patients achieving apparent complete remission (CR) or good partial response (PR) after the 1st cycle of therapy were submitted to three other cycles of the same therapy. Patients failing to respond to the 1st cycle or whose disease progressed despite therapy, were treated with an alternative 2nd line therapy. Seventeen patients (28%) had stage II-II E, 15 (25%) stage III and 28 (47%) stage IV disease. Tumoral mass > 10 cm was found in 28 cases, the presence of extranodal sites (ES) in 32 cases, serum lactate dehydrogenase (LDH) > 240 IU/l in 34 cases, performance status (PS) > or = 2 in 12 cases. CR was obtained in 46 (76.4%) out of the 60 patients. Relapse-free survival (RFS) was 82, 64 and 61% with a median follow-up of 12, 24 and 36 months respectively. No relapse occurred later than 26 months after achievement with CR thus far. Overall survival (OS) was 77% at 12 months and calculated to be 62% and 59% at 24 and 36 months, respectively. Two patients died as a result of the treatment. Reversible myelosuppression was the main toxic effect. One hundred and ten out of the 221 cycles of chemotherapy were delayed because of therapy toxicity. Negative prognostic factors on the RFS and OS were the presence of an advanced stage of disease, a mass larger than 10 cm, the presence of ES, the elevated LDH, the PS > or = 2, the delay of therapy. In conclusion, results obtained using our protocol overlap those from other third generation regimens. Toxicity was also similar. The influence of clinical conditions such as stage of disease, the presence of ES, high LDH level and tumoral mass > 10 cm on the RFS and OS were significant. Principal variables influencing prognosis must be unified to compare results of similar treatments from different institutions.