Citations

Purpose The primary goal of this multicenter phase III trial was to determine whether overall survival (OS) of fluorouracil (FU) -refractory patients was noninferior when treated with second-line infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4; arm B) versus irinotecan (arm A). Cross-over to the other treatment on disease progression was mandated. Patients and Methods Patients who experienced treatment failure with one prior FU-based therapy and had not received prior irinotecan or oxaliplatin, either for metastatic disease or within 6 months of adjuvant FU therapy, were randomly assigned to arm A (irinotecan 350 or 300 mg/m2 every 3 weeks) or arm B (FOLFOX4). Results A total of 491 patients were randomly assigned (arm A, n = 245; arm B, n = 246); 288 (59%) had experienced treatment failure with FU for metastatic colorectal cancer. Two hundred twenty-seven patients (46%) received protocol-mandated third-line therapy (arm A, 43%; arm B, 57%). Median survival was 13.8 months (95% CI, 12.2 to 15.0 months) for initial treatment with FOLFOX4 and 14.3 months (95% CI, 12.0 to 15.9 months) for irinotecan (P = .38; hazard ratio = 0.92; 95% CI, 0.8 to 1.1). Response rates (RR; 28% v 15.5%; P = .0009) and time to progression (TTP; 6.2 v 4.4 months; P = .0009) were significantly superior with FOLFOX4. In the nonrandom subset of patients who crossed over, RR and TTP improvements with FOLFOX4 continued into third-line treatment. Irinotecan therapy was associated with more grade 3 nausea, vomiting, diarrhea, and febrile neutropenia; FOLFOX4 was associated with more neutropenia and paresthesias. Conclusion In patients who experienced treatment failure with front-line FU therapy, OS does not significantly differ whether second-line therapy begins with irinotecan or FOLFOX4. FOLFOX4 produces higher RR and longer TTP. Both arms had notable OS in patients who experienced treatment failure with first-line FU therapy.

Recently the World Health Organization (WHO), in collaboration with the European Association for Haematopathology and the Society for Hematopathology, published a revised and updated edition of the WHO Classification of Tumors of the Hematopoietic and Lymphoid Tissues. The 4th edition of the WHO classification incorporates new information that has emerged from scientific and clinical studies in the interval since the publication of the 3rd edition in 2001, and includes new criteria for the recognition of some previously described neoplasms as well as clarification and refinement of the defining criteria for others. It also adds entities—some defined principally by genetic features—that have only recently been characterized. In this paper, the classification of myeloid neoplasms and acute leukemia is highlighted with the aim of familiarizing hematologists, clinical scientists, and hematopathologists not only with the major changes in the classification but also with the rationale for those changes.

MODERN ORTHOPEDIC SURGERY HAS become complex and technically sophisticated. Orthopedic surgeons and basic scientists have translated recent advances in chemistry, molecular biology, physiology, and biomaterials science into novel management options for their patients. In particular, the development of new synthetic bone graft substitutes (BGS) represents a rapidly evolving area. These synthetic biomaterials may be used alone, as scaffold, or as carrier for bioactive agents (proteins, antibiotics, blood derived or bone marrow derived agents, and cells). To date, most BGS materials available on the market have been classified as Bone Void Fillers (BVF) “intended to be gently packed into bone voids or gaps that are not intrinsic to the stability of the bony structure” [12]. These graft alternatives are subjected to varying degrees of regulatory scrutiny, and thus their true safety and effectiveness in patients may not be known prior to their clinical use [22]. Continuous innovation and the development of new implants raise important issues for technology testing, clinical performance, risk assessment and regulation. It is therefore not surprising that the development of standards for these implants represents an issue that increasingly confronts the professionals from industrial and health care sectors.

This column discusses the prevalence, symptoms, and treatment of Crohn's disease and ulcerative colitis and the role nurses play for these patients. J Contin Educ Nurs 2008;39(4):151–152.

Abstract Family history is a strong predictor of colorectal cancer risk; however, a diagnosis of colorectal cancer among first-degree relatives has not been systematically investigated as a function of the colorectal cancer molecular subtypes related to tumor microsatellite instability (MSI) status. We investigated whether the observable familial colorectal cancer risks differed according to tumor MSI subtypes, stratified as MSI-High (>30% instability), MSI-Low (<30% instability), and MSS (no instability). Data from 3,143 population-based colorectal cancer cases from five institutions were assessed for family history according to the Amsterdam criteria and the Bethesda guidelines, age at diagnosis, sex, tumor location, and MSI status. The distribution of patient characteristics by MSI status was compared using polytomous logistic regression. Overall, 2.8% colorectal cancer cases met the Amsterdam criteria and 37% met the Bethesda guidelines. There were 14% MSI-High, 13% MSI-Low, and 73% MSS colorectal cancers. MSI-High (P < 0.0001) and MSI-Low tumors (P = 0.01) were more proximally located than MSS tumors. MSI-High tumors were more common among females (P < 0.001). The highest proportion of MSI-High tumors occurred in cases <40 years of age whereas the age-dependent distribution of MSI-Low tumors was unchanged. MSI-High tumors showed a statistically significant association with increasing numbers of first-degree relatives with colorectal cancer (P = 0.002); this association disappeared, however, when MSI-High cases meeting Amsterdam criteria were removed from the analysis. MSI-Low tumors did not show a similar association with family history of colorectal cancer. Familial risk associated with MSI-High tumors is primarily driven by the Amsterdam-criteria patients. MSI-Low tumors may represent a distinct subtype of colorectal cancer with respect to certain epidemiologic variables studied here. (Cancer Epidemiol Biomarkers Prev 2009;18(3):967–75)

Abstract Anaplastic thyroid carcinoma (ATC) is a highly aggressive form of the disease for which new therapeutic options are desperately needed. Previously, we showed that the high-affinity peroxisome proliferator–activated receptor γ (PPARγ) agonist, RS5444, inhibits cell proliferation of ATC cells via induction of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 (p21). We show here that up-regulation of RhoB is a critical step in PPARγ-mediated activation of p21-induced cell stasis. Using multiple independently derived ATC cell lines, we found that treatment with RS5444 leads to the up-regulation of RhoB and subsequent activation of p21, and that silencing of RhoB by RNAi blocks the ability of RS5444 to induce p21 and to inhibit cell proliferation. Our results show that transcriptional regulation of RhoB by the nuclear transcription factor PPARγ is responsible for the induction of p21 mRNA and protein. We further implicate RhoB as a key signaling effector for the growth inhibition of ATC, as treatment with a histone deacetylase inhibitor shown to increase RhoB expression in lung cancer cells caused the up-regulation of RhoB in ATC cells accompanied by increased expression of p21 and inhibition of cell proliferation; this effect occurred even in ATC cells that were unresponsive to RS5444 due to a lack of expression of PPARγ. Our results implicate RhoB as a novel intermediate in critical signaling pathways and as an additional target for therapeutic intervention in ATC. [Cancer Res 2009;69(4):1536–44]

Abstract Resistance to temozolomide and radiotherapy is a major problem for patients with glioblastoma but may be overcome using the poly(ADP-ribose) polymerase inhibitor ABT-888. Using two primary glioblastoma xenografts, the efficacy of ABT-888 combined with radiotherapy and/or temozolomide was evaluated. Treatment with ABT-888 combined with temozolomide resulted in significant survival prolongation (GBM12: 55.1%, P = 0.005; GBM22: 54.4%, P = 0.043). ABT-888 had no effect with radiotherapy alone but significantly enhanced survival in GBM12 when combined with concurrent radiotherapy/temozolomide. With multicycle therapy, ABT-888 further extended the survival benefit of temozolomide in the inherently sensitive GBM12 and GBM22 xenograft lines. However, after in vivo selection for temozolomide resistance, the derivative GBM12TMZ and GBM22TMZ lines were no longer sensitized by ABT-888 in combination with temozolomide, and a similar lack of efficacy was observed in two other temozolomide-resistant tumor lines. Thus, the sensitizing effects of ABT-888 were limited to tumor lines that have not been previously exposed to temozolomide, and these results suggest that patients with newly diagnosed glioblastoma may be more likely to respond to combined temozolomide/poly(ADP-ribose) polymerase inhibitor therapy than patients with recurrent disease. [Mol Cancer Ther 2009;8(2):OF407–8]

Object Although nontraumatic spinal arteriovenous malformations and fistulas (AVMs and AVFs) restricted to the epidural space are rare, they can lead to significant neurological morbidity. Careful diagnostic imaging is essential to their detection and the delineation of the pathological anatomy. Aggressive endovascular and open operative treatment can provide arrest and reversal of neurological deficits. Methods The authors report on 6 cases of extradural AVMs/AVFs causing progressive myelopathy. Clinical findings, diagnostic evaluation, treatment, and outcome are discussed. Special consideration is given to the anatomy of the lesions and the operative techniques used to treat them. A review of the literature concerning extradural vascular malformations is also presented. Results All 6 cases of extradural AVMs had an extradural fistulous location with intradural medullary venous drainage. These cases illustrate progressive myelopathy through cord venous congestion (hypertension) that can be caused by an extradural nidus or fistula. In 4 cases, a large epidural lake was identified on angiography. At surgery, the epidural lake was obliterated and medullary drainage interrupted. All patients had stabilization of their neurological deficits and successful obliteration of the AVM/AVF was obtained. Conclusions Extradural AVMs and AVFs are a poorly described entity with published clinical experience limited to sporadic case reports and small series. Although these lesions have a purely extradural location of arteriovenous shunting and early venous drainage, they can be responsible for acute and progressive neurological symptoms similar to those caused by their dural-based intradural counterparts. With careful imaging recognition of the pathological anatomy, surgical and endovascular techniques can be used for the treatment of extradural AVMs affording effective and durable obliteration with stabilization or reversal of neurological symptoms. Venous drainage directly correlates the pathologic mechanisms of presentation. Specific attention must be paid intraoperatively to the epidural lake common to both variants so that recurrence is avoided.