© Oxford University Press 2006.
IN THIS ISSUE
Delayed Versus Immediate Prostate Cancer SurgeryWarlick et al. (p. 355) assessed outcome for two groups of patients with small, lower-grade prostate cancer tumors treated with surgical intervention—one group was treated a median of 3 months after diagnosis and the other group a median of 26.5 months after diagnosis. Noncurable prostate cancer was defined as adverse pathology associated with a less than 75% chance of remaining disease-free for 10 years after surgery. After adjusting for age and prostate-specific antigen (PSA) density (i.e., PSA value divided by prostate volume), the risks of developing noncurable cancer associated with delayed and immediate surgery were not statistically significantly different. The authors conclude that delayed prostate cancer surgery for patients with small, lower-grade prostate cancers does not appear to compromise curability.
Human Papillomavirus and Cervical Adenocarcinoma
The incidence of squamous cell carcinoma (SCC), the most common cancer of the uterine cervix, has decreased in recent years, while that of cervical adenocarcinoma has risen—even in countries with widespread cervical cancer screening. Castellsagué et al. (p. 303) conducted a pooled analysis of eight case–control studies of cervical adenocarcinoma from three continents. HPV-positive women had more than 80 times the cervical adenocarcinoma risk of HPV-negative women. More than 80% of patients were infected with HPV 16 or 18, the most common HPV types in patients with SCC. Several sexual behavior–associated variables, poor hygiene, long-term use of hormonal contraceptives, and HSV-2 seropositivity were associated with increased risk of cervical adenocarcinoma among HPV-positive women.
In an editorial, Hildesheim and Berrington (p. 292) note that, although some cofactors for the development of cervical adenocarcinoma and SCC are similar, others may be different. They also point out that, given the relative inaccessibility of cervical adenocarcinoma lesions—which often occur deep within the endocervical canal—to sampling for Pap screening, HPV testing may be especially beneficial in improving detection of this form of cervical cancer. Finally, they note that the relative impact of HPV vaccination on rates of cervical adenocarcinoma may be higher than for SCC, because a larger fraction of cervical adenocarcinomas are accounted for by the two HPV types (HPV types 16 and 18) included in the vaccines undergoing evaluation in large-scale efficacy trials.
Modeling the Angiogenic Switch
The progression of a tumor from a microscopic, dormant state to a rapidly growing, vascularized state involves multiple events. One is the angiogenic switch, in which tumor cells develop the ability to induce neovascularization, i.e., become angiogenic. In this issue, Naumov et al. (p. 316) were able to establish separate populations of angiogenic and nonangiogenic tumor cells in vivo. They did so by injecting mice with nonangiogenic tumor cells, waiting many months until occasional tumors grew, and obtaining cells from those angiogenic tumors. When re-injected into mice, these cells underwent rapid tumor growth and angiogenesis. Nonangiogenic and angiogenic cells had similar proliferation rates in vitro, but the time to tumor development in vivo was distinct and characteristic for nonangiogenic and angiogenic cells of each tumor type. In addition, tumors that developed from angiogenic cells produced higher levels of proangiogenic factors and lower levels of an antiangiogenic factor than tumors that developed from nonangiogenic cells.
In an editorial, Narazaki and Tosato (p. 294) note that it will be interesting to extend these observations to examine the expression of other known regulators of angiogenesis in both angiogenic and nonangiogenic tumor cell subsets. They note that better understanding of the angiogenic switch may make it possible to devise strategies to prevent it or turn it off early, before tumors become highly vascularized.
Inhibition of Oncogenic RET mutants by BAY 43-9006
Medullary and papillary thyroid carcinomas often carry oncogenic RET tyrosine kinase mutants that are constitutively active. To determine whether the tyrosine kinase inhibitor BAY 43-9006 could inhibit the activity of these oncogenic RET mutants, including those known to be resistant to chemotherapy, Carlomagno et al. (p. 326) treated fibroblasts, thyroid carcinoma cells, and mice carrying xenograft tumors derived from thyroid carcinoma cells harboring oncogenic RET mutants with BAY 43-9006 and measured RET phosphorylation and cell growth. They observed that RET phosphorylation and growth of treated cells and tumors were lower than those of untreated controls. The authors conclude that BAY 43-9006 is a potent inhibitor of oncogenic RET mutants.
Tumor accumulation of Macromolecular Drug Carriers
Macromolecular drug carriers are attractive because they appear to target solid tumors and have limited toxicity in normal tissues. Dreher et al. (p. 335) investigated how molecular weight influences the accumulation of a model macromolecular drug carrier, dextran, in mice carrying human FaDu squamous cell carcinoma tumors. They found that increasing the molecular weight of dextran (from 3.3 kDa to 2 MDa) reduced its vascular permeability by two orders of magnitude but increased its plasma half-life. Tumor accumulation was maximal for dextrans of 40–70 kDa (which is in the range of clinically available macromolecular drug carriers), but such dextrans penetrated only 15 µm into tumor tissue, whereas smaller dextrans penetrated more than 35 µm. However, the authors note that shallower penetration may be an advantage because it would concentrate these molecules near the vascular surface, where cancer cells proliferate most rapidly.
Meat Consumption and Gastric and Esophageal Cancer
Dietary factors are thought to have an important role in gastric and esophageal carcinogenesis, but evidence from cohort studies for such a role is lacking. González et al. (p. 345) examined risks of cardia and noncardia gastric cancer and esophageal adenocarcinoma associated with meat consumption among 521,457 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Risks of noncardia gastric cancer, but not of gastric cardia cancer, were statistically significantly associated with intakes of total meat, red meat, and processed meat. In a nested case–control study, the association between noncardia gastric cancer and total meat intake was especially large in Helicobacter pylori–infected subjects.
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