Citations

AL amyloidosis (AL) is rare and frequently remains undiagnosed until organ function is compromised, even among patients with known pre‐existing untreated plasma cell dyscrasias (PCD). We identified 168 patients with AL amyloidosis who had a prior untreated PCD. The earliest symptom or sign (s/s) was defined as the first symptom reported by the patient that could be attributed to organ dysfunction caused by AL. The interval from the time of development of s/s to the establishment of diagnosis of AL (Interval‐SA) was calculated. PCD diagnosis preceded recorded onset of s/s in 75% (114/152) of patients, with a median interval‐SA for this group of 10 months. PCD was diagnosed after s/s in 25% (38/152) of patients, with a median interval‐SA of 20 months. Overall survival (OS) from diagnosis of AL was not different between the two groups. AL amyloidosis patients with an identified pre‐existing PCD had less advanced cardiac disease at AL diagnosis when compared to a control group of AL patients without preidentified PCD. Long‐term OS was not significantly superior among patients with a pre‐identified PCD. In patients with “asymptomatic” PCD, symptoms and signs of AL amyloidosis should be solicited, since timely diagnosis is important in AL amyloidosis. Am. J. Hematol. 89:1051–1054, 2014. © 2014 Wiley Periodicals, Inc.

Despite successful treatment of the clonal plasma cell implicated in its pathogenesis, patients with AL amyloidosis (AL) experience significant morbidity related to underlying amyloid mediated organ dysfunction. While normalization of the serum free light chain measurements [normal ratio of involved and uninvolved free light chains (nFLCr)] is the goal of therapy and centerpiece of hematologic response criteria, achieving (or not achieving) meaningful organ response (OR) is clinically significant for its implications on long‐term symptomatology as well as overall survival (OS), and remains the ultimate goal of treatment. Expectations for organ recovery following successful therapy leading to nFLCr in AL remain poorly described. We evaluated the timeframe and predictive factors for OR, and long‐term outcome, in 313 AL patients who achieved nFLCr following therapy initiation. OR was seen in 80% of surviving AL patients within 1‐year of nFLCr. Patients achieving early OR within 1 year of nFLCr had superior OS compared with those who despite obtaining nFLCr did not achieve early OR. We further evaluated factors predicting OR and OS among patients achieving nFLCr. Higher values of dFLC (involved–uninvolved) at diagnosis predict OR, and early OR predicts improved OS following successful hematologic therapy in AL. Am. J. Hematol. 90:181–186, 2015. © 2014 Wiley Periodicals, Inc.

Abstract RATIONALE: The inability to deliver viruses homogeneously throughout solid tumors is a universal obstacle encountered in oncolytic virotherapy. The initial intratumoral viral dispersion volume is a critical determinant of virotherapy efficacy, and depends not only on the number of infected cells, but also on the spatial distribution of the infected cells. In this study, we determined the feasibility and usefulness of monitoring the initial intratumoral delivery of oncolytic viruses to solid tumors using contrast-enhanced computed tomography (CT). EXPERIMENTAL PROCEDURES: Human BxPC-3 pancreatic tumor xenografts were established in nude mice. An engineered oncolytic measles virus expressing the sodium iodide symporter reporter (MV-NIS) was mixed with a 1:10 dilution of Omnipaque-300 contrast material and injected directly into mouse tumors. Mice were imaged with micro-CT immediately pre and post-injection of the virus + Omnipaque solution and on day 3 post-injection with 99mTcO4 micro-SPECT/CT. Tumors were harvested immediately after micro-SPECT/CT imaging for autoradiography and immunistochemistry analysis of radioactivity uptake and viral infection. Linear regression and Spearman correlation analyses were performed to determine the relationship between intratumoral contrast enhancement and subsequent intratumoral viral infection. RESULTS: This dilution of Omnipaque was found to have no effect on viral infectivity or cell viability in vitro, yet was more than adequate for CT imaging of the virus + Omnipaque injectate distribution following intratumoral injection. Ex vivo autoradiography and immunohistochemistry confirmed a strong correlation between intratumoral CT contrast enhancement, SPECT activity, viral infection, and sodium iodide symporter activity. CONCLUSIONS: This injection method is translatable to the clinic and should allow optimization of intratumoral injection in humans. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4145. doi:10.1158/1538-7445.AM2011-4145

Abstract Many tumors are believed to be maintained by a small number of cancer stem–like cells, where cure is thought to require eradication of this cell population. In this study, we investigated the dynamics of acute promyelocytic leukemia (APL) before and during therapy with regard to disease initiation, progression, and therapeutic response. This investigation used a mathematical model of hematopoiesis and a dataset derived from the North American Intergroup Study INT0129. The known phenotypic constraints of APL could be explained by a combination of differentiation blockade of PML–RARα–positive cells and suppression of normal hematopoiesis. All-trans retinoic acid (ATRA) neutralizes the differentiation block and decreases the proliferation rate of leukemic stem cells in vivo. Prolonged ATRA treatment after chemotherapy can cure patients with APL by eliminating the stem-like cell population over the course of approximately one year. To our knowledge, this study offers the first estimate of the average duration of therapy that is required to eliminate stem-like cancer cells from a human tumor, with the potential for the refinement of treatment strategies to better manage human malignancy. Cancer Res; 74(19); 5386–96. ©2014 AACR.

AbstractAn estimated 22 350 patients had multiple myeloma diagnosed in 2013, representing 1.3% of all new cancers; 10 710 deaths are projected, representing 1.8% of cancer deaths. Approximately 0.7% of US men and women will have a myeloma diagnosis in their lifetime, and with advances in therapy, 77 600 US patients are living with myeloma. The 5-year survival rate was 25.6% in 1989 and was 44.9% in 2005. The median age at diagnosis is 69 years, with 62.4% of patients aged 65 or older at diagnosis. Median age at death is 75 years. The rate of new myeloma cases has been rising 0.7% per year during the past decade. The most common indication for autologous stem cell transplantation in the United States is multiple myeloma, and this article is designed to provide the specifics of organizing a transplant program for multiple myeloma. We review the data justifying use of stem cell transplantation as initial management in myeloma patients. We provide selection criteria that minimize the risks of transplantation. Specific guidelines on mobilization and supportive care through the transplant course, as done at Mayo Clinic, are given. A review of the data on tandem vs sequential autologous transplants is provided.

Key Points Survival of patients with primary plasma cell leukemia has improved in recent years, but is still inferior to those patients with multiple myeloma. This survival benefit appears to be mainly in patients older than 65 years of age.

The accumulation of somatic mutations, to which the cellular genome is permanently exposed, often leads to cancer. Analysis of any tumour shows that, besides the malignant cells, one finds other ‘supporting’ cells such as fibroblasts, immune cells of various types and even blood vessels. Together, these cells generate the microenvironment that enables the malignant cell population to grow and ultimately lead to disease. Therefore, understanding the dynamics of tumour growth and response to therapy is incomplete unless the interactions between the malignant cells and normal cells are investigated in the environment in which they take place. The complex interactions between cells in such an ecosystem result from the exchange of information in the form of cytokines- and adhesion-dependent interactions. Such processes impose costs and benefits to the participating cells that may be conveniently recast in the form of a game pay-off matrix. As a result, tumour progression and dynamics can be described in terms of evolutionary game theory (EGT), which provides a convenient framework in which to capture the frequency-dependent nature of ecosystem dynamics. Here, we provide a tutorial review of the central aspects of EGT, establishing a relation with the problem of cancer. Along the way, we also digress on fitness and of ways to compute it. Subsequently, we show how EGT can be applied to the study of the various manifestations and dynamics of multiple myeloma bone disease and its preceding condition known as monoclonal gammopathy of undetermined significance. We translate the complex biochemical signals into costs and benefits of different cell types, thus defining a game pay-off matrix. Then we use the well-known properties of the EGT equations to reduce the number of core parameters that characterize disease evolution. Finally, we provide an interpretation of these core parameters in terms of what their function is in the ecosystem we are describing and generate predictions on the type and timing of interventions that can alter the natural history of these two conditions.

AbstractImmunoglobulin light chain (AL) Amyloidosis is a condition whereby misfolded proteins generated by plasma cells deposit in tissues causing organ dysfunction. Chemotherapy and autologous stem cell transplant when eligible are standard treatment options. Several studies report long‐term outcomes of patients post‐transplant. However, there is a paucity of literature describing outcomes of relapsed patients post‐transplant. We performed a retrospective study to assess outcomes and therapies employed upon relapse after transplant. Between 1996 and 2009, 410 patients received transplant at the Mayo Clinic as first‐line therapy. Of those patients, 42 (10%) died within 3 months of transplant, 64 (16%) died without documented relapse, 158 (38%) were alive without documented progression, and 146 (36%) had documented progression. Those 146 patients are the subject of our study, and their median time to hematologic relapse/progression was 23.6 months (95%CI 18.3, 26.3 months). Their median overall survival and 5‐yrs overall survival from post‐transplant relapse/progression was 51.7 months (95%CI 34.1–62.3) and 39%, respectively. The most common first regimen for treatment after relapse was lenalidomide or thalidomide. In conclusion, our study indicates that patients with AL amyloidosis fare well post‐transplant relapse/progression. Additionally, it provides a yardstick to design clinical trials to determine best treatment options.

Objectives To define whether the high sensitivity cardiac troponin T (hs-cTnT) assay in patients with immunoglobulin light chain amyloidosis (AL) improves risk prediction. Background Cardiac involvement is the major cause of death in patients with AL amyloidosis. Risk stratification is facilitated by cardiac biomarkers such as cardiac troponin T (cTnT) and N-terminal pro B-type natriuretic peptide (NT-proBNP). Methods Stored serum from patients with newly diagnosed AL was used to measure hs-cTnT, cTnT, and NT-proBNP. Survival modelling was performed. Results The direct numeric result from hs-cTnT measurement cannot merely be substituted for a cTnT measurement in the Mayo AL staging system. The performance of the receiver operator curve derived an hs-cTnT cut-point of 54 ng/L which improves on the value of 35 ng/L validated with the prior iteration of the assay. An alternate staging option using hs-cTnT alone—using the two thresholds 14 ng/L and 54 ng/L—performs as well as either the original Mayo AL staging system or other systems incorporating hs-cTnT. On multivariate analysis, an hs-cTnT alone staging system was independent of period of diagnosis, type of therapy, and NT-proBNP value, the last of which dropped out of the model. Alternate models were explored, but none performed better than the original system or the new hs-cTnT system. Thus, hs-cTnT can be used alone for the staging of disease prognosis. Conclusions A survival model based on hs-cTnT improves the prognostic staging of patients with AL amyloidosis, relegating NT-proBNP to a measure of cardiac response.