Distinct DC subsets regulate adaptive Th1 and 2 responses during Trichuris muris infection.

Low- and high-dose infections with the murine large intestinal nematode Trichuris muris are associated with induction of adaptive Th1 and Th2 responses, respectively, in mesenteric lymph nodes (MLN). Classical dendritic cells (cDC) accumulate in the large intestinal mucosa and MLN upon T. muris infection, yet their role in driving adaptive responses to infection remains largely unknown. We performed low- and high-dose T. muris infections of mice deficient in defined cDC subsets to investigate their role in induction of adaptive immune responses. Mice lacking IRF4-dependent cDC failed to clear a high-dose infection and displayed impaired Th2 responses. Conversely, mice lacking IRF8-dependent cDC cleared a low-dose infection and displayed an impaired Th1 response while increased production of Th2 cytokines. Finally, mice lacking both IRF4- and IRF8-dependent cDC were able to generate a Th2 response and clear a low-dose infection. Collectively, these results suggest that IRF4- and IRF8-dependent cDC act antagonistically during T. muris infection, and demonstrate that intestinal Th2 responses can be generated towards T. muris in the absence of IRF4-dependent cDC.

First-line chemotherapy with docetaxel and cisplatin in metastatic breast cancer.

The purpose of this study was to evaluate the efficacy and tolerance of combined treatment with docetaxel-cisplatin as first-line chemotherapy in patients with metastatic breast cancer (MBC). Consecutive eligible chemonaive patients received docetaxel 75 mg/m(2) on day 1 and cisplatin 75 mg/m(2) on day 2 every 3 weeks for 6 cycles, with prophylactic recombinant human granulocyte colony-stimulating factor (rHuG-CSF) on days 4-11. Thirty-two patients (64%) had received prior adjuvant chemotherapy; these included 16 (32%) who had received anthracyclines. In 50 evaluable patients with a median age (range) of 56 (31-72) years, the overall response rate was 68% (95% CI, 55-81%), with 7 (14%) complete and 27 (54%) partial responses. Stable and progressive disease was observed in 10 (20%), and 6 (12%) patients, respectively. The median duration of response was 10 months, and the median time to progression was 39 weeks. Grade 3/4 hematological toxicity included--neutropenia in 9 patients (18%), anemia in 2 (4%) and thrombocytopenia in 1 (2%). One patient (2%) with febrile neutropenia required hospitalization. Grade 3/4 nonhematological toxicities included nausea/vomiting in 18%, nephrotoxicity in 14%, asthenia (4%), and neurotoxicity (2%). Toxicity was common in older patients (>56 years). There were no treatment-related deaths. A combination of docetaxel-cisplatin with rHuG-CSF support is well tolerated and effective as first-line chemotherapy in MBC.

Vinorelbine and cisplatin for metastatic breast cancer: a salvage regimen in patients progressing after docetaxel and anthracycline treatment.

PURPOSE: To assess the antitumor efficacy and safety of a combination of vinorelbine (VNR) and cisplatin in patients with metastatic breast cancer previously treated with anthracyclines and docetaxel. PATIENTS AND METHODS: Thirty-six patients with assessable metastatic breast cancer previously treated with anthracyclines and docetaxel (adjuvant n = 1, palliative n = 20, both n = 15) were studied. Cisplatin was given at 75 mg/m2 on day 1 followed by 25 mg/m2 VNR on days 1 + 8 in a 5-minute i.v. infusion. Courses were repeated every 3 weeks. Treatment was continued until disease progression, excess toxicity, or patient refusal. Patients were classified according to their response to anthracyclines according to criteria published previously: 1) Anthracycline and/or docetaxel resistant were patients who progressed during treatment with anthracyclines and docetaxel or within 4 months after cessation of treatment (metastatic). In addition, adjuvant patients who progressed within 6 months after completion of chemotherapy belong to this group. 2) Anthracycline and/or docetaxel relapsed were either metastatic patients who responded initially and then progressed after 4 months of completing an anthracycline- and docetaxel-based chemotherapy or patients who progressed after 6 months from completion of anthracycline/docetaxel-based adjuvant chemotherapy. RESULTS: Two patients (5.6%) achieved a complete response (CR) and 15 patients (41.6%) achieved a partial response (PR), for an overall response rate (OR) of 47.2% (95% confidence interval, 31-63). Of 18 patients relapsed to anthracycline/docetaxel, 2 had a CR (11%) and 8 a PR (44.4%), giving an objective response of 55.5%. Stable disease (SD) was observed in one patient (5.5%); seven patients had progressive disease (PD) (39%). Among the 18 resistant patients, 7 PRs (39%) were observed (p = 0.5), one patient (5.5%) had stable disease, 10 patients (55.5%) progressed. The median time to progression (TTP) was 16 weeks and median overall survival 36 weeks. Relapsed patients had a longer TTP than resistant patients (24 vs. 8 weeks, p = 0.05) but similar survival (48 vs. 24 weeks, p = 0.173). All patients were assessed for toxicity. The main toxicity was neutropenia grade 3 and 4 in 47% of patients. Febrile neutropenia requiring hospitalization was absent. There were no treatment-related deaths. Thrombocytopenia grade 3 and 4 occurred in four patients (11%). Phlebitis, orthostatic hypotension, and asthenia, all reversible, were observed in 3% of patients, respectively. CONCLUSION: This cisplatin/VNR regimen is well tolerated and active in patients who failed anthracyclines and docetaxel treatment. The response rate, TTP, and survival data are high and indicate that cisplatin/VNR may have a place as salvage treatment in this group of patients. If these results can be verified in multi-institutional trials, this combination of drugs would merit investigation as part of a first-line therapy in breast cancer.

Vinorelbine and docetaxel as first-line chemotherapy in metastatic breast cancer.

PURPOSE: To evaluate the efficacy and tolerability of a combination of vinorelbine (VNR) and docetaxel (DOC) as first-line chemotherapy in patients with metastatic breast cancer. PATIENTS AND METHODS: The study group comprised 40 women with untreated metastatic breast cancer with visceral (85%) and bone (70%) metastases. Of the 40 patients, 24 (60%) had previously received adjuvant chemotherapy, which had included anthracyclines in 12 patients (30%). Treatment consisted of VNR 25 mg/m(2) on days 1 and 5, and DOC 75 mg/m(2) on day 1 every 3 weeks. Depending on the neutrophil nadir (grade 3 or 4 neutropenia by WHO criteria) recombinant human granulocyte colony-stimulating factor (G-CSF) 5 micro g/kg on days 2-4 and 6-13 was given for all subsequent treatment cycles. RESULTS: The overall response rate (ORR) was 40% (95% confidence interval, CI 15-65). Six patients (15%) achieved a complete response (CR) and ten patients (25%) achieved a partial response (PR). Stable disease (SD) was observed in six patients (15%), and 18 patients (45%) had progressive disease (PD). The median duration of response was 8 months and the median predictive time to progression (TTP) was 6 months. The main toxicity was neutropenia grade 3 and 4 in 28 patients (70%). Febrile neutropenia requiring hospitalization occurred in 12 patients (30%). Grade 3 or 4 anemia was seen in two patients (5%) and grade 3 or 4 thrombocytopenia was seen in one patient (2.5%). Severe nonhematologic toxicity, except alopecia, was uncommon and included stomatitis in two patients (5%), vomiting in two (5%) and diarrhea in one (2.5%). There were no treatment-related deaths. CONCLUSIONS: The combination of VNR and DOC at the doses used in this study showed moderate activity as first-line chemotherapy in metastatic breast cancer. Neutropenia was considerable despite G-CSF administration.

Control of irinotecan-induced diarrhea by octreotide after loperamide failure.

Diarrhea is a well-recognized side effect of chemotherapy, which affects the quality of life and when refractory is potentially life threatening. Irinotecan (CPT-11) is associated with an elevated incidence of chemotherapy-induced diarrhea and subsequent morbidity. Standard antidiarrheal treatment is based on high-dose loperamide, but this agent is associated with a significant failure rate. Octreotide is active against chemotherapy-induced diarrhea caused by fluoropyrimidines and irinotecan, with a distinct mechanism of action. We administered octreotide in a phase I trial in 37 patients who received irinotecan and experienced loperamide-refractory diarrhea, 23 of whom experienced grade III-IV diarrhea and were treated with loperamide. The 13 patients in whom to loperamide failed to control diarrhea received octreotide, with a high response rate (92%). We conclude that octreotide is effective against loperamide-refractory diarrhea resulting from irinotecan-based chemotherapy.

Altered apolipoprotein D expression in the brain of patients with Alzheimer disease.

The etiology of late-onset Alzheimer disease is poorly understood. Predisposing factors such as the apolipoprotein E4 allele, as well as protective factors (e.g., antioxidants) have been proposed to play a role in the disease's process. A search for predisposing factors contributing to sporadic late-onset Alzheimer disease was initiated using the differential display technique. RNA expression profiles of the entorhinal cortex and the cerebellum of Alzheimer-diseased and normal patients were compared. The entorhinal cortex is the first brain region to accumulate neurofibrillary tangles during disease progression, whereas the cerebellum is spared. In the Alzheimer cases of this study, one signal showing preferential expression in the entorhinal cortex corresponded to the apolipoprotein D gene. This preferential expression might be genuine at the RNA level as suggested by the in situ hybridization method used. In addition, immunohistochemical experiments showed higher percentages of Apolipoprotein D reactive pyramidal neurons in the entorhinal cortex and region 1 of Ammon's horn in diseased patients. This increase correlated with the number of neurofibrillary tangles in Alzheimer as well as in normal patients. Colocalization of Apolipoprotein D proteins and neurofibrillary tangles in the same neuron was rare. Thus, these results suggest that in Alzheimer disease and aging, apolipoprotein D gene expression is increased in stressed cortical neurons before they possibly accumulate neurofibrillary tangles.

Vinorelbine and cisplatin in metastatic breast cancer patients previously treated with anthracyclines.

PURPOSE: To assess the antitumor efficacy and safety of a vinorelbine and cisplatin combination in patients with metastatic breast cancer previously treated with anthracyclines. PATIENTS AND METHODS: Fifty-three patients with assessable metastatic breast cancer with previous exposure to anthracyclines (adjuvant n = 6, palliative n = 47) were studied. Cisplatin 75 mg/m2 on day 1 was given followed by 25 mg/m2 vinorelbine (VNR) on days 1 + 8, in a five-min i.v. infusion. Courses were repeated every three weeks on an outpatient basis. Treatment continued until disease progression, excess toxicity or patient refusal. Patients were classified according to their response to anthracyclines: anthracycline refractory patients were patients who had never responded under an anthracycline regimen. Anthracycline resistant patients were either metastatic patients who progressed within four months of completing anthracycline-based chemotherapy or patients who progressed within six months of completion of an anthracycline adjuvant treatment. Patients who progressed four months after the end of an anthracycline regimen in metastatic setting or six months after the end of an anthracycline regimen in adjuvant setting were considered as patients previously treated with anthracyclines and were called 'relapsed'. RESULTS: Four patients (8%) achieved a complete response (CR) and twenty-two patients (41%) achieved a partial response (PR) with an overall response rate (OR) of 49% (95% confidence interval (CI): 35-63). Stable disease (SD) was observed in five patients (9%), twenty-two patients had progressive disease (PD). Responses according to previous sensitivity to anthracycline were as follow: 5 refractory patients achieved a PR from 14 patients (36%). Seven of sixteen resistant patients responded (44%), six with PR and one with CR. Among 23 'relapsed' patients, 14 responses were observed (61%), with 3 CR and 11 PR. There was no statistical difference in RR among the three groups. The median duration of response for all patients was 7 months, the median time to progression (TTP) 5 months and median overall survival 12 months. All patients were assessed for toxicity. The main toxicity was neutropenia grade 3 and 4 in 49% of patients. Febrile neutropenia requiring hospitalization was uncommon (2 patients). There were no treatment related deaths. Despite potential overlapping neurologic toxicities of the two drugs, only eight patients (15%) developed neuropathy, which was, however, mild (grades 1 and 2). CONCLUSIONS: This cisplatin VNR regimen is well tolerated and active in patients who failed anthracyclines. The response rate, TTP and survival data are encouraging and indicate that cisplatin VNR may have a place as second-line treatment alternative to taxanes or other less active regimens. If these results can be verified in multi-institution trials, this combination of drugs would merit investigation as first-line therapy in this patient population.