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Therapeutic progress in acute myeloid leukemia (AML) is generally acknowledged to have been slower than that in the other commonly occurring types of leukemia. To a very large extent this reflects a relative lack of understanding of AML "biology" and in particular an inability to identify genetic and/or molecular aberrations not found in normal myeloid precursors ("targets"). Here, however, I also point out that the pace of development/acceptance of new therapies may be retarded by continued adherence to past practices, although these may lack empirical support. Among these practices are reliance on preclinical models that do not accurately represent clinical AML, delay in combining targeted therapies with each other or with "chemotherapy," and limitation of eligibility for clinical trials to patients with relapsed/refractory AML or unfit patients with newly diagnosed disease, and the stereotyped use of single-arm phase II trials followed by very large randomized phase III trials. Finally, I question whether improvement in survival should be the sole or even principal criterion for approval of new drugs in AML.

Aim: To provide a multi-institutional description of current practices of stereotactic body radiotherapy (SBRT) for head and neck cancer. Materials & methods: 15 international institutions with significant experience in head and neck SBRT were asked to complete a questionnaire covering clinical and technical factors. Results: SBRT is used 10–100% of the time for recurrent primary head and neck cancer, and 0–10% of the time in newly diagnosed disease. Five centers use a constraint for primary disease of 3–5 cm and 25–30 cc. Nine institutions apply a clinical target volume expansion of 1–10 mm and 14 use a planning target volume margin of 1–5 mm. Fractionation regimens vary between 15 and 22 Gy in 1 fraction to 30–50 Gy in 5 or 6 fractions. The risk of carotid blowout quoted in the re-irradiation setting ranges from 3 to 20%. Conclusion: There is considerable heterogeneity in patient selection and techniques in head and neck SBRT practice among experienced centers.

TPS2071 Background: GBM is the most aggressive primary brain tumor in adults and is extremely difficult to treat. Patients with GBM tend to progress rapidly within weeks or months. Median overall survival is only 12–15 months despite aggressive treatment, and less than 5% of patients survive 5 years. GBM also severely impacts quality of life and cognitive function. Approximately 50% of GBM tumors test positive for amplification or mutation of the epidermal growth factor receptor (EGFR), the most common of which is the EGFRvIII gain-of-function mutation. AMG 596 is a bispecific T cell engager (BiTE®) antibody construct designed to crosslink and engage CD3-positive T cells to EGFRvIII-positive tumor cells, inducing tumor cell lysis and T cell proliferation. A clinical trial is being conducted for this novel immunotherapy agent in patients with EGFRvIII-positive GBM. Methods: NCT03296696 is a phase 1, first-in-human, open-label, sequential dose-escalation and dose-expansion study evaluating the safety, tolerability, and pharmacokinetics and pharmacodynamics (PK/PD) of AMG 596 in patients with EGFRvIII-positive GBM. AMG 596 is administered via continuous intravenous infusion. The study is expected to enroll approximately 82 patients total and comprises two groups (Group 1: patients with recurrent GBM; Group 2: patients with newly diagnosed GBM in the maintenance treatment phase after standard of care). Key inclusion criteria include: male or female; ≥ 18 years of age; with pathologically documented and diagnosed grade IV GBM; Eastern Cooperative Oncology Group performance status ≤ 1; life expectancy ≥ 3 months per study investigator; and acceptable renal, hematological, and hepatic function. The primary endpoint evaluates the safety and tolerability of AMG 596 via collection of treatment-emergent adverse events. Additional endpoints include objective response rate per modified Response Assessment in Neuro-Oncology Criteria and PK/PD analyses of AMG 596 in serum. The study began enrolling patients in April 2018 and enrollment is ongoing. For more information, please contact Amgen Medical Information: medinfo@amgen.com. Clinical trial information: NCT03296696.

The use of imatinib in chronic myelogenous leukemia (CML) transformed the disease, rapidly changing the median survival from 4 years to at least 20 years. In this review, we outline the causes of this revolution, including the identification of a critical driving molecular aberration, BCR-ABL , and the development of a potent and specific inhibitor, imatinib. Equally important was the timing of the targeted therapy, specifically its administration to patients with newly diagnosed disease. In solid tumors, targeted therapies are often both developed and used in metastatic malignancies after conventional approaches have failed. We postulate that this strategy is similar to using imatinib in blast-crisis CML, in which response rates are less than 15%, all patients relapse, and median survival remains only about 1 year. We hypothesize that the imatinib-led revolution in CML, including the critically important factor of timing, may be applicable to other cancers as well. Therefore, it will be important to use promising targeted therapies in the earliest phases of biomarker-defined solid tumors, before metastatic progression, to determine if outcomes can be significantly improved and, thus, establish if the success of imatinib in CML is an anomaly or a paradigm. Mol Cancer Ther; 11(12); 2549–55. ©2012 AACR . This article is featured in Highlights of This Issue, [p. 2547][1] [1]: /lookup/volpage/11/2547?iss=12

Background - Objective measures of physical activity and function with a diverse cohort of UK adults in their 70s and 80s were used to investigate relative risk of all-cause mortality and diagnoses of new diseases over a 4-year period.Participants - Two hundred and forty older adults were randomly recruited from 12 general practices in urban and suburban areas of a city in the United Kingdom. Follow-up included 213 of the baseline sample.Methods - Socio-demographic variables, height and weight, and self-reported diagnosed diseases were recorded at baseline. Seven-day accelerometry was used to assess total physical activity, moderate-to-vigorous activity and sedentary time. A log recorded trips from home. Lower limb function was assessed using the Short Physical Performance Battery. Medical records were accessed on average 50 months post baseline, when new diseases and deaths were recorded.Analyses - ANOVAs were used to assess socio-demographic, physical activity and lower limb function group differences in diseases at baseline and new diseases during follow-up. Regression models were constructed to assess the prospective associations between physical activity and function with mortality and new disease.Results - For every 1,000 steps walked per day, the risk of mortality was 36% lower (hazard ratios 0.64, 95% confidence interval (CI) 0.44–0.91, P = 0.013). Low levels of moderate-to-vigorous physical activity (incident rate ratio (IRR) 1.67, 95% CI 1.04–2.68, P = 0.030) and low frequency of trips from home (IRR 1.41, 95% CI 0.98–2.05, P = 0.045) were associated with diagnoses of more new diseases.Conclusion - Physical activity should be supported for adults in their 70s and 80s, as it is associated with reduced risk of mortality and new disease development.

Beta-thalassemia is a hereditary anemia that is quite prevalent in Lebanon. Most patients with beta-Thalassemia are treated and followed up mostly at a multidisciplinary center, located in the suburban area of Beirut: the Chronic Care Center (CCC), operational since 1994. We will review the experience with beta-Thalassemia accumulated through this institution. Four hundred and twenty five patients, aged 2 to 68 years are followed up at the CCC. Sixty four percent have thalassemia major (TM) while 36% have thalassemia intermedia (TI). Lebanese patients with TM receive periodic packed red cell transfusions to maintain a pre-transfusional hemoglobin level of 10 gm/dl at all times and desferrioxamine is the standard iron chelator in use. Since 1994, 12 patients with TM have died from complications of their disease, with heart failure being responsible for the majority of deaths. The incidence of cardiac, endocrinologic, and infectious complications will be reviewed. Finally, both current and prospective preventive measures will be discussed, specifically educational campaigns and premarital screening. The effects of prevention are starting to show as the number of newly diagnosed disease is diminishing.

The Internet is a repository of information unparalleled in history. The abundance of published material about prostate cancer has never been greater. Couple this with burgeoning pharmaceutical public-relations budgets and the result is a bewildering maze of hundreds of thousands of prostate cancer–oriented Internet pages. Our purposes are to help practitioners understand the profound handicap that patients are faced with when they attempt to search the Internet for information about their newly diagnosed disease and to succinctly evaluate the presence or absence of key aspects of prostate cancer on some of the most easily accessible sites. Part two of this paper will then discuss 4 of the most valuable Web sites for the prostate cancer specialist. Surfing the World Wide Web can be frustrating and timeconsuming, but it can also be rewarding and informative.

Overview: Although chronic myelogenous leukemia (CML) is rare, with approximately 5000 new cases in the United States annually, it may be the poster child for the future of oncology. Imatinib mesylate, a selective Bcr-Abl tyrosine kinase inhibitor (TKI), transformed the course of CML from a rapidly fatal disease (median survival, 3 to 6 years) to a functionally curable, indolent disease with an estimated median survival of more than 25 years. This transformation can be attributed to several key factors: the identification of a causal and actionable molecular aberration— BCR-ABL; the development of a potent and selective Bcr-Abl TKI—imatinib; and, importantly the application of imatinib in the earliest phase of CML. In contrast, imatinib, if used in CML blastic phase, improves median survival to only about 1 year. Similar to CML blastic phase, metastatic solid malignancies have undergone genetic evolution, and their molecular aberrations are complex. As a result, resistance is common and eradication is difficult. The key to the dramatic improvement in the survival of patients with CML involved using imatinib in newly diagnosed disease, before blastic transformation. We hypothesize that metastatic solid tumors are analogous to CML blastic phase, and that to achieve improvements in solid tumor outcomes similar to those seen in CML, application of targeted agents to newly diagnosed disease may be required to prevent disease transformation (i.e., metastases). Targeting driver mutations at the time of diagnosis may be critical to the goal of markedly changing the outlook for patients with cancer.

In this review, the historical and modern classification schemes of non-Hodgkin's lymphoma (NHL) will be briefly summarized, with a critical review of the evolution and current state of treatment strategies for diffuse large-cell lymphoma (DLCL). We provide current treatment recommendations for newly diagnosed disease and indicate the areas of active clinical investigation. In the past, many of the promising phase II studies in DLCL have appeared beneficial based on patient selection criteria and not the therapeutic result. Lessons learned in clinical trials in NHL may serve as a paradigm for other cancer investigations.

For elderly patients, risks associated with a newly diagnosed disease may be less than competing risks of death and disability from other causes. Treatment benefits should be viewed in the context of normal life expectancy and quality of life.

The treatment of multiple myeloma has changed dramatically in the past decade. The increase in the number of active agents has generated numerous possible drug combinations that can be used in the first-line and relapsed settings. As a result, there is considerable confusion about the choice of regimens for initial therapy, role of transplantation in the era of new drugs, end points for therapy, and the role of maintenance therapy. A hotly debated area is whether treatment approaches should achieve cure or disease control, which impacts greatly on the treatment strategy employed. This article provides an update on the treatment of multiple myeloma, with a focus on recent advances, newly diagnosed disease, role of transplantation and maintenance therapy. A synthesized approach to the treatment of myeloma is presented, along with a discussion of key paradigms that need to be challenged.

The treatment of human lymphomas over the last two decades has been sub-stancially influenced by the availability of several active drugs combined in different chemotherapy (CT) regimens. However, only 45 % to 50 % of patients with aggressive non-Hodgkin’s lymphomas (NHL) achieve a long-term disease-free survival or cure [1, 2]. Similarly, relapsed patients, or those with newly diagnosed disease but displaying poor prognostic factors, have a cure rate of < 50 %. The introduction of the international prognostic index [3] has led to a major advance in the prognostic grouping of NHL patients and in the identification of high-risk patients not likely to be cured by standard CHOP or CHOPlike regimes. In addition, early relapses of Hodgkins disease (HD) [4], patients with intermediate- and low-grade NHLs [5], those relapsing following high-dose chemotherapy (HDT) and, in general, those with primary refractory lymphoma can rarely be cured with conventional combination CT.

6506 Background: Dasatinib, a potent BCR-ABL inhibitor, is approved for use as 1st- and 2nd-line therapy for CML pts with newly diagnosed disease or resistance/intolerance to imatinib. This ongoing study in pts with imatinib-resistant/-intolerant CML provides the longest follow-up of a second-generation BCR-ABL inhibitor. Methods: Study design has been described (Shah, J Clin Oncol 2008). Pts with imatinib-resistant/-intolerant CML (N=670) were randomized to dasatinib 100 mg once daily (QD), 50 mg twice daily (BID), 140 mg QD, or 70 mg BID. Results: Five-yr data are reported here; 6-yr data will be presented. After a minimum of 5 yrs, 151 pts (74%) remain on QD dosing, 85 of whom (56%) are on ≥100 mg QD dosing. Overall, 205 pts (31%) remain on study therapy with 55 pts (53%) originally randomized to BID dosing having switched to QD dosing. For pts randomized to the 100 mg QD arm (n=167), progression-free survival (PFS) at 5 yrs is 57%, overall survival (OS) is 78% with an overall 5% rate of transformation to advanced disease. In exploratory analyses, 42% and 60% of pts had BCR-ABL levels ≤10% (International Scale) at 1 and 3 months (mos), respectively. In a landmark analysis, BCR-ABL ≤10% at 1 or 3 mos was associated with higher 5-yr PFS. For dasatinib 100 mg QD, nonhematologic adverse events (AEs; all grades) generally first occurred in

17082 Background: mTC is relatively rare and little is known about treatment patterns or HC costs in patients with newly diagnosed disease. Methods: Retrospective longitudinal cohort study. Using a large (∼14 million covered lives) US health-insurance claims database, we identified a cohort of pts with diagnoses of thyroid cancer (ICD-9-CM diagnosis codes 193.XX) and distant metastatic disease (197.XX-198.XX) between 1/1/2003 and 12/31/2005 (“study period”); the date of first mention of metastatic disease was designated the “index date”. All pts were required to be =18 years of age as of their index date and to have been continuously enrolled in the database for =6 months prior to this date. Pts were followed from their index date until health plan disenrollment (for any reason) or end of the study period, whichever occurred first. Utilization of HC services and costs (total reimbursed amount including pt liability) were then examined during each quarter of follow-up (eg, first 3 months of follow-up=Q1). Results: 183 pts met all study entry criteria. Mean (±SD) age was 51.5 (11.8) years; mean duration of follow-up was 344 days (median=275 days). Most common management/treatment strategies during Q1 included: imaging [eg, US/CT of the neck (49.7%)], thyroglobulin/thyroglobulin antibody testing (25.7%); radiation therapy (23.0%); I131 therapy (19.1%); thyroid surgery (12.6%); chemotherapy (10.9%); lymphadenectomy (8.7%); and bisphosphonate therapy (3.8%). In addition, during Q1, pts averaged 9.5 office visits (95% CI, 8.2, 10.9) and 0.6 hospitalizations (95% CI, 0.5, 0.7); for pts hospitalized during Q1, average length of stay was 6.6 (95% CI, 4.9, 8.4). Costs during the first 2 years of follow-up are presented in the table ; inpt care represented 43% of total HC costs. Conclusions: Many different treatment modalities are used in pts with newly diagnosed mTC; the cost of such care is substantial. [Table: see text] [Table: see text]

The recommended dose of intravenous IgG for idiopathic thrombocytopenic purpura has been 0.4 g/kg on 5 consecutive days. A simplified approach, giving a single infusion of 0.8-1.0 g/kg over 8 hours, has been tried in a series of 11 children with newly diagnosed disease. In 8 cases the infusion produced a prompt platelet response culminating at 128-502 X 10(9)/l after 3-13 days, and 4 of these cases required no further treatment while 2 needed a booster infusion due to an early relapse and 2 followed a chronic course. In 3 cases platelet responses were poor in spite of supplementary doses to a total of 1.4-2.0 g/kg: 2 infants failed to achieve normal platelet counts and 1 case with fulminant bleeding manifestations proved completely resistant. Significant side effects were not observed. These results indicate that IgG-therapy practically may be initiated with a single infusion, the resulting platelet response indicating the need for further infusions.

In 17 patients with coeliac disease the 5-hydroxytryptamine (5-HT) concentration was measured in platelet-poor plasma (PPP) and in whole blood and compared with that of a control group of 30 healthy persons. The 5-HT level was determined by high-pressure liquid chromatography and electrochemical detection. In patients with coeliac disease the concentration of 5-HT in whole blood was elevated compared with the control group (p less than 0.001). The 5-HT level in PPP was significantly increased in patients with coeliac disease in whom the disease was untreated or treated with gluten-free diet for less than a year (p less than 0.01) but also compared with the patients with coeliac disease treated with a gluten-free diet for more than a year (p less than 0.01). In some untreated patients with newly diagnosed disease the 5-HT levels in PPP were markedly elevated and exceeded the levels ordinarily found in PPP in patients with carcinoid tumours. In these patients with coeliac disease the 5-HT concentration in PPP was reduced when the enteropathy was healed. There was no significant correlation between the 5-HT concentration in PPP versus whole blood in the different groups.

Intravenous tolbutamide was administered to three groups of children with diabetes mellitus: (A) those with newly diagnosed disease, (B) those diabetic for less than two and one-half years, and (C) those diabetic for more than three years. Children in Groups A and B were found to respond to tolbutamide with a drop in blood glucose which differed from the response of normal children in that it was slow in onset and persisted throughout a three-hour period of observation. Children in Group C were unresponsive to tolbutamide. Children in Groups A and B showed an interference with the expected starvation-induced rise in nonesterified fatty acids over the period of observation, while children in Group C showed gradually increasing levels. The effect of tolbutamide on nonesterified fatty acids was less striking and showed more individual variation than did the effect on blood glucose. A few children with early diabetes mellitus developed hypoglycemia which appeared resistant to the usual counter-regulatory mechanisms. The fall in blood glucose was not accompanied by increased levels of insulin in peripheral blood.

The 13-year-old boy described herein had an acute psychotic episode as an emotional response to the diagnosis of acute lymphocytic leukemia. Although the final psychiatric diagnosis was brief psychotic reaction, this term does not convey the deep existential dilemma experienced by this child, who had not emotionally dealt with his newly diagnosed disease. The choice of symptoms, the Rubik's Cube, served as a metaphor and an easily understood symbol for his distress. The psychosis allowed this boy to deal with and adjust to his illness.