Citations

Purpose An increasing serum prostate-specific antigen (PSA) level is the initial sign of recurrent prostate cancer among patients treated with radical prostatectomy. Salvage radiation therapy (SRT) may eradicate locally recurrent cancer, but studies to distinguish local from systemic recurrence lack adequate sensitivity and specificity. We developed a nomogram to predict the probability of cancer control at 6 years after SRT for PSA-defined recurrence. Patients and Methods Using multivariable Cox regression analysis, we constructed a model to predict the probability of disease progression after SRT in a multi-institutional cohort of 1,540 patients. Results The 6-year progression-free probability was 32% (95% CI, 28% to 35%) overall. Forty-eight percent (95% CI, 40% to 56%) of patients treated with SRT alone at PSA levels of 0.50 ng/mL or lower were disease free at 6 years, including 41% (95% CI, 31% to 51%) who also had a PSA doubling time of 10 months or less or poorly differentiated (Gleason grade 8 to 10) cancer. Significant variables in the model were PSA level before SRT (P < .001), prostatectomy Gleason grade (P < .001), PSA doubling time (P < .001), surgical margins (P < .001), androgen-deprivation therapy before or during SRT (P < .001), and lymph node metastasis (P = .019). The resultant nomogram was internally validated and had a concordance index of 0.69. Conclusion Nearly half of patients with recurrent prostate cancer after radical prostatectomy have a long-term PSA response to SRT when treatment is administered at the earliest sign of recurrence. The nomogram we developed predicts the outcome of SRT and should prove valuable for medical decision making for patients with a rising PSA level.

Abstract The use of tyrosine kinase inhibitors (TKI) has yielded great success in treatment of lung adenocarcinomas. However, patients who develop resistance to TKI treatment often acquire a somatic resistance mutation (T790M) located in the catalytic cleft of the epidermal growth factor receptor (EGFR) enzyme. Recently, a report describing EGFR-T790M as a germ-line mutation suggested that this mutation may be associated with inherited susceptibility to lung cancer. Contrary to previous reports, our analysis indicates that the T790M mutation confers increased Y992 and Y1068 phosphorylation levels. In a human bronchial epithelial cell line, overexpression of EGFR-T790M displayed a growth advantage over wild-type (WT) EGFR. We also screened 237 lung cancer family probands, in addition to 45 bronchoalveolar tumors, and found that none of them contained the EGFR-T790M mutation. Our observations show that EGFR-T790M provides a proliferative advantage with respect to WT EGFR and suggest that the enhanced kinase activity of this mutant is the basis for rare cases of inherited susceptibility to lung cancer. [Cancer Res 2007;67(10):4665–70]

Abstract The Janus kinase 2 mutation, JAK2617V>F, is myeloid neoplasm-specific; its presence excludes secondary polycythemia, thrombocytosis, or bone marrow fibrosis from other causes. Furthermore, JAK2617V>F or a JAK2 exon 12 mutation is present in virtually all patients with polycythemia vera (PV), whereas JAK2617V>F also occurs in approximately half of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). Therefore, JAK2 mutation screening holds the promise of a decisive diagnostic test in PV while being complementary to histology for the diagnosis of ET and PMF; the combination of molecular testing and histologic review should also facilitate diagnosis of ET associated with borderline thrombocytosis. Accordingly, revision of the current World Health Organization (WHO) diagnostic criteria for PV, ET, and PMF is warranted; JAK2 mutation analysis should be listed as a major criterion for PV diagnosis, and the platelet count threshold for ET diagnosis can be lowered from 600 to 450 × 109/L. The current document was prepared by an international expert panel of pathologists and clinical investigators in myeloproliferative disorders; it was subsequently presented to members of the Clinical Advisory Committee for the revision of the WHO Classification of Myeloid Neoplasms, who endorsed the document and recommended its adoption by the WHO.

Abstract To better understand the molecular changes that occur in Waldenstrom macroglobulinemia (WM), we employed antibody-based protein microarrays to compare patterns of protein expression between untreated WM and normal bone marrow controls. Protein expression was defined as a &gt;2-fold or 1.3-fold change in at least 67% of the tumor samples. Proteins up-regulated by &gt;2-fold included Ras family proteins, such as Rab-4 and p62DOK, and Rho family proteins, such as CDC42GAP and ROKα. Other proteins up-regulated by &gt;1.3-fold included cyclin-dependent kinases, apoptosis regulators, and histone deacetylases (HDAC). We then compared the samples of patients with symptomatic and asymptomatic WM and showed similar protein expression signatures, indicating that the dysregulation of signaling pathways occurs early in the disease course. Three proteins were different by &gt;2-fold in symptomatic versus asymptomatic, including the heat shock protein HSP90. Elevated protein expression was confirmed by immunohistochemistry and immunoblotting. Functional significance was validated by the induction of apoptosis and inhibition of proliferation using specific HDAC and HSP90 inhibitors. This study, therefore, identifies, for the first time, multiple novel proteins that are dysregulated in WM, which both enhance our understanding of disease pathogenesis and represent targets of novel therapeutics. [Cancer Res 2007;67(8):3777–8]

AbstractProperly performed clinical trials provide a foundation for evidence‐based medical practice. The surgeon plays a central role in the management of patients with malignant solid tumors, including thyroid cancer, because operative extirpation of the malignancy is the essential first step in effective therapy. This article discusses the role of the surgeon in the clinical research of thyroid cancer and also reviews the important clinical trials that have influenced the treatment of patients with thyroid cancer. Recent discoveries defining the genetic mutations underlying the various types of thyroid cancers have led to the development of targeted therapies. These chemical compounds, which are now being evaluated in clinical trials, hold great promise for the treatment of patients with locally advanced and distant metastatic disease. The surgical investigator also plays an important role in procuring tumor tissue from patients in clinical trials. The molecular analysis of these tissues is of critical importance in selecting specific therapies and predicting patient response and prognosis.

The fitting of mathematical models to physiological sys tems can be tedious and difficult, whether one uses analog or digital computer methods. Both methods have their pros and cons depending on the available hardware and software and on the type of modeling. In recent years many digital simulation languages have been written com bining analog-like and digital features to facilitate model ing, but, for a variety of reasons, none of these was suit able for our applications. We, therefore, designed a new digital simulation control system, SIMCON, which is de scribed in this paper. The primary objectives were to provide: (1) Maximum man-machine interaction at run-time, in cluding visual displays, digital control, and both con tinuous analog and digital parameter adjustment (2) The ability to generate solutions and to fit them to experimental data or other theoretical curves with a minimum of computer memory (3) The option to use a mathematically oriented language, FORTRAN, and block operators with variable input/ output. The result is a relatively general and simple simulation system which is easy to use and has wide versatility.

The changes in health care reimbursement have the potential to affect the availability of quality medical physicist service in patient care. A survey was conducted by the AAPM Professional Council and the ACMP to collect cost information for special medical physics consultation, CPT4‐77370 and continuing medical physics, CPT4‐77336. The data collected from the survey was compared to current reimbursement schemes for a number of special procedures. Under varying reimbursement schemes, the costs of the medical physics services provided cannot be recaptured by the institution. It remains important for medical physicists to assess our utilization of resources and allocation to each of the services we provide and to understand the implications of policy changes at the federal and local levels. PACS number(s): 87.90.+y, 87.53.–j

AbstractBackgroundSince the human genome has been sequenced many mysteries of cell biology have been unravelled, thereby clarifying the pathogenesis of several diseases, particularly cancer. In members of kindreds with certain hereditary diseases, it is now possible early in life to predict with great certainty whether or not a family member has inherited the mutated allele causing the disease. In hereditary malignancies this has been particularly important, because in affected family members there is the possibility of removing the organ destined to develop cancer before malignancy develops or while it is in situ. At first consideration, it would appear that “prophylactic surgery” would have a place in many hereditary malignancies; however, the procedure has applicability only if certain criteria are met: (1) the genetic mutation causing the hereditary malignancy must have a very high penetrance and be expressed regardless of environmental factors; (2) there must be a highly reliable test to identify patients who have inherited the mutated gene; (3) the organ must be removed with minimal morbidity and virtually no mortality; (4) there must be a suitable replacement for the function of the removed organ; and (5) there must be a reliable method of determining over time that the patient has been cured by “prophylactic surgery.”ConclusionsIn this monograph we review several hereditary malignancies and consider those where prophylactic surgery might be useful. As we learn, there are various barriers to performing the procedure in many common hereditary cancer syndromes. The archetype disease syndromes, which meet each of the five criteria mentioned above and where prophylactic surgery is most useful, are the type 2 multiple endocrine neoplasia (MEN) syndromes: MEN2A, MEN2B, and the related familial medullary thyroid carcinoma. An additional benefit of the Human Genome Project, has been the development of pharmacologic and biologic compounds that block the metabolic pathway(s) activated by specific genetic mutations. Many of these compounds have shown efficacy in patients with locally advanced or metastatic cancers, and there is the likelihood that they will prove beneficial in preventing the outgrowth of malignant cells in patients destined to develop a hereditary cancer.

AbstractWaldenström macroglobulinemia (WM) is an incurable lymphoplasmacytic lymphoma with limited options of therapy. Protein kinase Cβ (PKCβ) regulates cell survival and growth in many B-cell malignancies. In this study, we demonstrate up-regulation of PKCβ protein in WM using protein array techniques and immunohistochemistry. Enzastaurin, a PKCβ inhibitor, blocked PKCβ activity and induced a significant decrease of proliferation at 48 hours in WM cell lines (IC50, 2.5-10 μM). Similar effects were demonstrated in primary CD19+ WM cells, without cytotoxicity on peripheral blood mononuclear cells. In addition, enzastaurin overcame tumor cell growth induced by coculture of WM cells with bone marrow stromal cells. Enzastaurin induced dose-dependent apoptosis at 48 hours mediated via induction of caspase-3, caspase-8, caspase-9, and PARP cleavage. Enzastaurin inhibited Akt phosphorylation and Akt kinase activity, as well as downstream p-MARCKS and ribosomal p-S6. Furthermore, enzastaurin demonstrated additive cytotoxicity in combination with bortezomib, and synergistic cytotoxicity in combination with fludarabine. Finally, in an in vivo xenograft model of human WM, significant inhibition of tumor growth was observed in the enzastaurin-treated mice (P = .028). Our studies therefore show that enzastaurin has significant antitumor activity in WM both in vitro and in vivo, providing the framework for clinical trials to improve patient outcome in WM.