Phase I study of weekly nab-paclitaxel + weekly cetuximab + intensity-modulated radiation therapy (IMRT) in patients with stage III-IVB head and neck squamous cell carcinoma (HNSCC).

BACKGROUND: There is a clinical need to improve the efficacy of standard cetuximab + concurrent intensity-modulated radiation therapy (IMRT) for patients with locally and/or regionally advanced HNSCC. Taxanes have radiosensitizing activity against HNSCC, and nab-paclitaxel may offer therapeutic advantage in comparison with other taxanes. PATIENTS AND METHODS: This was a single-institution phase I study with a modified 3 + 3 design. Four dose levels (DLs) of weekly nab-paclitaxel were explored (30, 45, 60, and 80 mg/m(2)), given with standard weekly cetuximab (450 mg/m(2) loading dose followed by 250 mg/m(2) weekly) and concurrent IMRT (total dose, 70 Gy). RESULTS: Twenty-five eligible patients (20 M, 5 F) enrolled, with median age 58 years (range, 46-84 years). Primary tumor sites were oropharynx, 19 (10 human papillomavirus [HPV] pos, 8 HPV neg, 1 not done); neck node with unknown primary, 2; larynx 2; and oral cavity and maxillary sinus, 1 each. Seven patients had received prior induction chemotherapy. Maximum tolerated dose (MTD) was exceeded at DL4 (nab-paclitaxel, 80 mg/m(2)) with three dose-limiting toxicities (DLTs) (grade 3 neuropathy, grade 3 dehydration, with grade 3 mucositis grade 3 anemia) among five assessable patients. There was only one DLT (grade 3 supraventricular tachycardia) among six patients at DL3 (nab-paclitaxel, 60 mg/m(2)), and this was deemed the MTD. Among 23 assessable patients, the most common ≥ g3 AEs were lymphopenia 100%, functional mucositis 65%, and pain in throat/oral cavity 52%. At a median follow-up of 33 months, 2-year failure-free survival (FFS) is 65% [95% confidence interval (CI) 42% to 81%] and 2-year overall survival (OS) is 91% (95% CI 69-97). CONCLUSION: The recommended phase II dose for nab-paclitaxel is 60 mg/m(2) weekly when given standard weekly cetuximab and concurrent IMRT. This regimen merits further study as a nonplatinum alternative to IMRT + cetuximab alone. CLINICALTRIALSGOV ID: NCT00736619.

Bluetongue infection rate in mithun (Bos frontalis) in the north-eastern upland region of India.

Studies conducted on 106 mithun at the National Research Centre on Mithun and 66 free-ranging mithun in Nagaland, India, revealed an infection rate with bluetongue virus of 86%, using a commercially available competitive enzyme-linked immunosorbent assay. Animals were grouped according to their age: 36 of 1 to 2 years of age, 50 of 2 to 4 years of age and 86 aged 4 years and over. The highest infection rate (98%) was found in mithun > 4 years old and the lowest (58%) in those 1 to 2 years old. No statistically significant difference was observed between infection rates of males (89%) and females (85%). The infection rate was higher (95%) in free-ranging mithun than in mithun kept under a semi-intensive system (80%). This is the first report of serological evidence of antibodies to bluetongue virus in mithun. The possible role of vectors in the epidemiology of bluetongue virus infection in mithun is discussed briefly.

Serological evidence of Neospora caninum infection in mithun (Bos frontalis) from India.

Studies conducted on mithuns maintained at National Research Centre on mithun, Indian Council of Agricultural Research (ICAR), Nagaland, India and mithuns found in free-ranging condition of Nagaland revealed that the overall prevalence of antibodies to Neospora caninum in mithun was 10% (95% CI=5-15) when detected by a commercially available competitive enzyme-linked immunosorbent assay test. Highest (prevalence rate=16, 95% CI=8-24) seroprevalence was found in mithuns above 3 years of age and lowest (prevalence rate=2, 95% CI=0-6) in mithuns of 2-12 months old. No statistically significant difference was observed between male (prevalence rate=7, 95% CI=0-14) and female (prevalence rate=12, 95% CI=6-18) seroprevalences. The seroprevalence was found to be higher (prevalence rate=20, 95% CI=9-31) in mithuns found in free-ranging condition in comparison to mithuns kept in semi-intensive system (prevalence rate=5, 95% CI=1-9). This is probably the first report on serological evidence of N. caninum infection in mithun. The possible role of sylvatic fauna in the epidemiology of N. caninum infection mithun is also discussed in brief.

In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. V. Affinity maturation develops in two stages of clonal selection.

To examine the role of germinal centers (GCs) in the generation and selection of high affinity antibody-forming cells (AFCs), we have analyzed the average affinity of (4-hydroxy-3-nitrophenyl)acetyl (NP)-specific AFCs and serum antibodies both during and after the GC phase of the immune response. In addition, the genetics of NP-binding AFCs were followed to monitor the generation and selection of high affinity AFCs at the clonal level. NP-binding AFCs gradually accumulate in bone marrow (BM) after immunization and BM becomes the predominant locale of specific AFCs in the late primary response. Although the average affinity of NP-specific BM AFCs rapidly increased while GCs were present (GC phase), the affinity of both BM AFCs and serum antibodies continued to increase even after GCs waned (post-GC phase). Affinity maturation in the post-GC phase was also reflected in a shift in the distribution of somatic mutations as well as in the CDR3 sequences of BM AFC antibody heavy chain genes. Disruption of GCs by injection of antibody specific for CD154 (CD40 ligand) decreased the average affinity of subsequent BM AFCs, suggesting that GCs generate the precursors of high affinity BM AFCs; inhibition of CD154-dependent cellular interactions after the GC reaction was complete had no effect on high affinity BM AFCs. Interestingly, limited affinity maturation in the BM AFC compartment still occurs during the late primary response even after treatment with anti-CD154 antibody. Thus, GCs are necessary for the generation of high affinity AFC precursors but are not the only sites for the affinity-driven clonal selection responsible for the maturation of humoral immune responses.