IgE is an ancient and conserved immunoglobulin isotype with potent immunological function. Nevertheless, the regulation of IgE responses remains an enigma, and evidence of a role for IgE in host defense is limited. Here we report that topical exposure to a common environmental DNA-damaging xenobiotic initiated stress surveillance by γδTCR intraepithelial lymphocytes that resulted in class switching to IgE in B cells and the accumulation of autoreactive IgE. High-throughput antibody sequencing revealed that γδ T cells shaped the IgE repertoire by supporting specific variable-diversity-joining (VDJ) rearrangements with unique characteristics of the complementarity-determining region CDRH3. This endogenous IgE response, via the IgE receptor FcεRI, provided protection against epithelial carcinogenesis, and expression of the gene encoding FcεRI in human squamous-cell carcinoma correlated with good disease prognosis. These data indicate a joint role for immunosurveillance by T cells and by B cells in epithelial tissues and suggest that IgE is part of the host defense against epithelial damage and tumor development.

Objective To establish the prognostic value of knowledge of sentinel node status in melanoma. Design Single centre prospective observational study, with sentinel nodes identified by lymphoscintigraphy, probe, and intraoperative blue dye and examined by both conventional histopathology and immunopathology. Setting Specialist surgical service in west of Scotland. Participants 482 patients with melanoma who consented to sentinel node biopsy in 1996-2003. Main outcome measure Time to recurrence of or death from melanoma. Results Of 472 patients who consented to sentinel node biopsy and in whom at least one sentinel node was identified, 367 (78%) had no tumour in the sentinel node. At mean follow-up of 42 months, 299 (82%) of this group were alive and free from disease, 24 were alive with melanoma recurrence, and 31 had died of melanoma. Of 105 patients with a positive sentinel node biopsy, 44 (42%) were alive and disease free, 12 were alive with recurrence, and 46 had died of melanoma. The survival difference between patients who were negative and those who were positive for tumour in the sentinel node was highly significant at all thickness levels over 1.0 mm (P < 0.001). Multivariate analysis showed that sentinel node status was independent of tumour thickness and ulceration. 71/105 (68%) patients with a positive sentinel node had a negative completion lymphadenectomy, and 44/71 (62%) were alive and disease free at follow-up; 34 patients with a positive sentinel node had further nodes involved, and only 4 (12%) were disease free (P < 0.001). 16 patients (13 sentinel node biopsy positive; 3 negative) died of other causes.

Lysophosphatidic acid (LPA) stimulated the transport of deoxyglucose into oocytes isolated from Xenopus laevis. This stimulation was accounted for entirely by an increase in the Vmax for transport. Various LPAs with different acyl groups in the sn-1 position and phosphatidic acid stimulated deoxyglucose (deGlc) transport in these cells with a rank order potency of 1-oleoyl-LPA > 1-palmitoyl-LPA > phosphatidic acid = 1-stearoyl-LPA > 1-myristoyl-LPA. The phosphatidylinositol 3'-kinase inhibitor LY294002 completely blocked LPA-stimulated deoxyglucose uptake (IC50 approximately 2 microM). In marked contrast, wortmannin, which can completely block both insulin-like growth factor-I (IGF-I)-stimulated deGlc uptake in oocytes and phosphatidylinositol 3'-kinase activation at concentrations as low as 20 nM [Gould, Jess, Andrews, Herbst, Plevin and Gibbs (1994) J. Biol. Chem. 269, 26622-26625], was a relatively poor inhibitor of LPA-stimulated deGlc transport, even at concentrations as high as 100 nM. We further show that LPA stimulates phosphatidylinositol 3'-kinase activity(s) that can phosphorylate both phosphatidylinositol and phosphatidylinositol 4,5-bisphosphate, and that this stimulation is inhibited by LY294002 but is relatively insensitive to wortmannin, again in marked contrast to IGF-I-stimulated phosphatidylinositol 3'-kinase activity. Antibodies against the p85 regulatory subunit of phosphatidylinositol 3'-kinase or antiphosphotyrosine antibodies immunoprecipitated IGF-I-stimulated but not LPA-stimulated phosphatidylinositol 3'-kinase activity. We conclude that LPA stimulates glucose uptake in Xenopus oocytes by a mechanism that may involve activation of a form of phosphatidylinositol 3'-kinase that is distinguished from other isoforms by its resistance to wortmannin and by its substrate specificity. Since the LPA-activated form of phosphatidylinositol 3'-kinase is pharmacologically and immunologically distinct from that which is involved in IGF-I-stimulated glucose transport in these cells, we suggest that distinct isoforms of this enzyme are able to function with the same biological effect, at least in the regulation of sugar transport.

Definitive immediate diagnosis in breast fine needle aspiration cytology (FNAC) remains the aim for cytopathologists. We reviewed 72 consecutive equivocal (C3 and C4) aspirates with respect to 16 cytomorphological criteria. We assessed the power of each criterion at predicting either a malignant [positive predictive value (PPV)] or a benign [negative predictive value (NPV)] diagnosis by correlation with follow-up histology. Blind review led to 34% of cases being correctly definitively diagnosed. Eccentrically placed epithelial cell nuclei (PPV = 88%, sensitivity = 67%, specificity = 87%) and coarse nuclear chromatin (PPV = 81%, sensitivity = 72%, specificity = 83%) are the features that are most useful in predicting malignancy in this selected series. The presence of myoepithelial cells within epithelial groups is not a good indicator of a benign diagnosis (NPV = 24%, sensitivity = 80%, specificity = 53%).

Endoscopic CO(2) laser excision for T(1a) glottic cancer is a recognized treatment modality producing equivalent disease-free and voice results to external beam radiotherapy. On reviewing a series of 15 patients who had undergone endoscopic resection of a T(1a) glottic squamous cancer, it was noted that five patients had negative excisional pathology following the initial biopsy of an invasive squamous carcinoma. The histopathology of each patient's resected specimen was reviewed by a second pathologist who confirmed the accuracy of the results in all cases. We conclude that a significant number of early squamous carcinomas of the glottis present with very small localized, minimally invasive disease and that a proportion may be treated by biopsy alone.