Cellular and humoral immune alterations in thymectomized patients for thymoma.

The aim of this study was to analyze the impact of thymectomy on kinetics of the immune reconstitution in thymoma patients. Nine consecutive patients with completely resected thymoma were enrolled. Immunophenotype analysis (total lymphocytes, CD3, CD4, CD8, CD19, NK subsets) and detection of autoantibodies at 6, 12, 18, and 24 months after thymectomy were planned. A prolonged inversion of CD4/CD8 ratio was present, due to a diminished number of CD4+ cells; CD8+ cell numbers remaining constantly normal at different time points; CD19+ cells remained for a long time understatement, achieving almost normal levels at 24 months; and NK cells always showed a normal amount. Autoantibodies against the muscle acetylcholine receptor were detected in four patients (44.4%) at the time of diagnosis, while antinuclear antibody were detected in eight patients (88.8%) at different time points during postthymectomy. A high incidence of multiple primary neoplasms was observed (66.6% of cases). Our study showed that cellular and humoral immune alterations are a common sequelae of postthymectomy. Further studies, a longer surveillance and a cooperative approach, due to the rarity of the disease, are necessary to define eventual implications of immune alterations on patient's outcome.

Laparoscopic resection of sporadic synchronous gastric and jejunal gastrointestinal stromal tumors: report of a case.

Multicentricity of gastrointestinal stromal tumors (GISTs) has been described only in patients with neurofibromatosis type 1 (NF1) or within the small intestine, and different pathogenetic mechanisms are involved. We report a case of synchronous sporadic gastric and jejunal GISTs, which were resected laparoscopically in a 67-year-old man. Immunohistochemical analysis revealed that both lesions were KIT (CD117)-positive, but that the gastric lesion was CD34-positive, whereas the jejunal one was Vimentin-, S-100-, and SMA-positive. Molecular analysis of mutations in KIT exons 9, 11, 13, and 17, and in PDGFRA exons 12 and 18 revealed the presence of a gastric sporadic GIST with a KIT mutation of the exon 11 and a jejunal sporadic GIST without KIT or PDGFRA mutations. To our knowledge, this is the first report of laparoscopically resected synchronous sporadic gastric and jejunal GISTs.

Impact of five prophylactic filgrastim schedules on hematologic toxicity in early breast cancer patients treated with epirubicin and cyclophosphamide.

PURPOSE: To evaluate the comparative efficacy of varying intensity schedules of recombinant human granulocyte colony-stimulating factor (G-CSF; filgrastim) support in preventing febrile neutropenia in early breast cancer patients treated with relatively high-dose epirubicin plus cyclophosphamide (EC). PATIENTS AND METHODS: From October 1991 to April 1994, 506 stage I and II breast cancer patients were randomly assigned to receive, in a factorial 2 x 2 design, epirubicin 120 mg/m2 and cyclophosphamide 600 mg/m2 intravenously on day 1 every 21 days for 4 cycles +/- lonidamine +/- G-CSF. The following five consecutive G-CSF schedules were tested every 100 randomly assigned patients: (1) 480 microg/d subcutaneously days 8 to 14; (2) 480 microg/d days 8, 10, 12, and 14; (3) 300 microg/d days 8 to 14; (4) 300 microg/d days 8, 10, 12, and 14; and (5) 300 microg/d days 8 and 12. RESULTS: All of the G-CSF schedules covered the neutrophil nadir time. Schedule 5 was equivalent to the daily schedules (schedules 1 and 3) and to the alternate day schedules (schedules 2 and 4) with respect to incidence of grade 3 and 4 neutropenia (P = .79 and P = .89, respectively), rate of fever episodes (P = .84 and P = .77, respectively), incidence of neutropenic fever (P = .74 and P = .56, respectively), need of antibiotics (P = .77 and P = .88, respectively), and percentage of delayed cycles (P = .43 and P = .42, respectively). G-CSF had no significant impact on the delivered dose-intensity compared with the non-G-CSF arms. CONCLUSION: In the adjuvant setting, the frequency of prophylactic G-CSF administration during EC could be curtailed to only two administrations (days 8 and 12) without altering outcome. This nonrandomized trial design provides support for evaluating alternative, less intense G-CSF schedules for women with early breast cancer.

Addition of either lonidamine or granulocyte colony-stimulating factor does not improve survival in early breast cancer patients treated with high-dose epirubicin and cyclophosphamide.

PURPOSE: Lonidamine (LND) can enhance the activity of anthracyclines in patients with metastatic breast cancer. A multicenter, prospective, randomized trial was designed to determine whether the association of LND with high-dose epirubicin plus cyclophosphamide (EC) could improve disease-free survival (DFS) in patients with early breast cancer (BC) compared with EC alone. Granulocyte colony-stimulating factor (G-CSF) was added to maintain the EC dose-intensity. PATIENTS AND METHODS: From October 1991 to April 1994, 506 patients with stage I/II BC were randomly assigned to four groups: (A) epirubicin 120 mg/m2 and cyclophosphamide 600 mg/m2 administered intravenously on day 1 every 21 days for four cycles (124 patients); (B) EC plus LND 450 mg/d administered orally (125 patients); (C) EC plus G-CSF administered subcutaneously (129 patients); (D) EC plus LND plus G-CSF (128 patients). RESULTS: Median follow-up was 55 months. Five-year DFS rate was similar for LND (B+D groups; 69.6%) versus non-LND arms (A+C groups; 70.3%) and G-CSF (C+D groups; 67.2%) versus non-G-CSF arms (A+B groups; 72.9%). Five-year overall survival (OS) was comparable in LND (79.1%) versus non-LND arms (81.3%) and in G-CSF (80.6%) versus non-G-CSF arms (79.6%). DFS and OS distributions in LND and G-CSF arms did not change according to tumor size, node, receptor, and menopausal status. G-CSF dramatically reduced hematologic toxicity without having a significant impact on dose-intensity (98.1% v 95.5% for C+D and A+B groups, respectively). CONCLUSION: EC is active and well tolerated in patients with early breast cancer. The addition of LND or G-CSF does not improve DFS or OS.

Cigarette smoking habit does not reduce the benefit from first line trastuzumab-based treatment in advanced breast cancer patients.

Many ErbB2-positive cancers may show intrinsic resistance, and the frequent development of acquired resistance to ErbB-targeted agents represents a substantial clinical problem. The constitutive NF-κB activation in some HER-2/neu positive breast cancer may represent a potential cause of resistance to trastuzumab therapy. Preclinical data revealed that 4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the tobacco-specific nitrosamine is able to enhance NF-κB DNA binding activity and theoretically to increase the resistance to trastuzumab. Two hundred and forty-eight women with pathologically confirmed, uni- or bidimensionally measurable, HER-2-positive metastatic breast cancer (MBC) treated with trastuzumab-based therapy as first line combination for metastatic disease were considered eligible. For all included patients data on smoking habit were detectable from medical records. We retrospectively analysed the smoking habits of 248 MBC patients and correlated these habits with activity and efficacy of trastuzumab-based therapy. No statistically significant difference in terms of response rate (RR), time to progression (TTP) and overall survival (OS) was identified between smokers (former plus active smokers) and never smokers. Moreover, no statistically significant difference in terms of RR, TTP and OS was identified either comparing active smokers and former smokers. Moreover, we did not observed any significant statistical difference in terms of TTP and OS between smokers ≥10 cigarettes/day and <10 cigarettes/day. This study clearly showed lack of any correlation between cigarette smoking habit and both activity and efficacy of trastuzumab-based first line therapy in metastatic HER2/neu positive breast cancer patients.

Does granulocyte colony-stimulating factor worsen anemia in early breast cancer patients treated with epirubicin and cyclophosphamide?

PURPOSE: We report on the effects of granulocyte colony-stimulating factor (G-CSF) on hemoglobin (Hb) value in early breast cancer patients receiving high-dose epirubicin and cyclophosphamide (EC) adjuvant treatment. METHODS: Five hundred and six stage I or stage II female breast cancer patients were treated with E 120 mg/m2 and C 600 mg/m2 with or without G-CSF and randomly assigned to receive in a factorial 2 x 2 design: EC; EC + lonidamine; EC + G-CSF; EC + lonidamine + G-CSF. Five consecutive G-CSF schedules tested 100 randomly assigned patients each: (1) 480 microg subcutaneously on days 8 to 14; (2) 480 microg on days 8, 10, 12, 14; (3) 300 microg on days 8 to 14; (4) 300 microg on days 8, 10, 12, and 14; and (5) 300 microg on days 8 and 12. The mean Hb level of 246 patients receiving EC plus G-CSF was compared with that of 240 patients receiving EC alone. The data presented are derived from an exploratory hypothesis-generating analysis. RESULTS: The EC dose intensity did not statistically differ between the G-CSF and the control arm. From the third cycle onward, the mean Hb value resulted significantly lower in G-CSF arm compared with control at each time point of each cycle (P < .0001). No statistically significant difference in the mean Hb level was observed between schedule 5 and control. Of interest, from the second course onward, the mean Hb level tended to be lower in patients receiving seven or four G-CSF injections compared with those patients who received only two injections. CONCLUSION: Our data suggest that a G-CSF dose-related effect may play a role in worsening anemia in patients receiving adjuvant EC.

Prolonged gemcitabine infusion in advanced non-small cell lung carcinoma: a randomized phase II study of two different schedules in combination with cisplatin.

BACKGROUND: Preclinical and clinical evidence suggests that a fixed infusion rate of 10 mg/m2 per minute may be more effective than the standard 30-minute infusion of gemcitabine. To investigate the activity and toxicity of the cisplatin plus gemcitabine combination with gemcitabine at a fixed infusion rate in patients with advanced non-small cell lung carcinoma (NSCLC), the authors conducted a randomized Phase II trial of cisplatin plus gemcitabine at the 30-minute standard infusion (calibration arm) or cisplatin plus gemcitabine at a fixed infusion rate (experimental arm). METHODS: A total of 112 chemonaive patients with advanced NSCLC entered the study: 57 patients in Arm A and 55 patients in Arm B. The patients were randomly assigned to receive gemcitabine at a dose of 1000 mg/m2 on Days 1, 8, and 15 over 30 minutes (Arm A) or at a rate of 10 mg/m2 per minute (Arm B). In both treatment arms, cisplatin at a dose of 80 mg/m2 was administered on Day 15 every 28 days. RESULTS: The overall response rates in Arms A and B were 26% (95% confidence interval [95% CI], 10-42%) and 34% (95% CI, 17-52%) (intent-to-treat-analysis), respectively. The median time to disease progression was 6 months (range, 1-26 months) and 8 months (range, 2-21 months), respectively, for Arms A and B and the median overall survival was 13 months (range, 2-26 months) for each arm. It is interesting to note that a high response rate (67%) of brain metastases was noted in the experimental arm. Toxicity was tolerable and comparable in the two arms. CONCLUSIONS: The results of this randomized Phase II trial demonstrated that cisplatin plus gemcitabine with gemcitabine at fixed infusion rate (10 mg/m2 per minute) is active and well tolerated in patients with advanced NSCLC.