Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease.

Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic disorder with heterogeneous presentations ranging from moderate constitutional symptoms to life-threatening multiorgan system involvement. There are vastly different clinical subtypes, with some patients demonstrating thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin fibrosis/renal failure, and organomegaly (TAFRO) and others having milder/more moderate symptoms with potential for severe disease (not otherwise specified, NOS). Due to its rarity and heterogeneity, the natural history and long-term burden of iMCD are poorly understood. We investigated real-world medical data from ACCELERATE, a large natural history registry of patients with Castleman disease, to better characterize the long-term disease burden experienced by these patients. We found that iMCD-TAFRO patients face a significant hospitalization burden, requiring more time in the hospital than iMCDNOS patients during the year surrounding diagnosis (median [interquartile range]: 36 [18-61] days vs. 0 [0-4] days; P<0.001). In addition, we found life-sustaining interventions, such as mechanical ventilation (17%) and dialysis (27%), were required among iMCD patients, predominantly those with iMCD-TAFRO. iMCD-NOS patients, however, spent a significantly greater proportion of time following disease onset in a state of disease flare (median 52.3% vs. 18.9%; P=0.004). Lastly, we observed severe iMCD-related morbidities, such as acute renal failure, sepsis and pneumonia, among others, arising after iMCD diagnosis, impairing the patients' quality of life. These data demonstrate a substantial disease burden experienced by iMCD patients and emphasize the importance of ongoing research into iMCD to aid disease control.

The disease course of Castleman disease patients with fatal outcomes in the ACCELERATE registry.

Castleman disease (CD) describes a group of rare, potentially fatal lymphoproliferative disorders. To determine factors associated with mortality in CD, we analysed data from deceased patients in the ACCELERATE registry and compared them with matched controls. We analysed demographic, treatment and laboratory data from all deceased CD patients, matched controls and a subgroup of idiopathic multicentric Castleman disease (iMCD) patients. Of the 140 patients in ACCELERATE with a confirmed CD diagnosis, 10 had died. There were 72 patients with confirmed iMCD; six were deceased. The deceased CD cohort had more hospitalisations per year, higher overall hospitalisations and more days hospitalised per month, and received more treatment regimens per year than the matched-control group. Analysis of laboratory values showed a significantly decreased absolute lymphocyte count at months 3 and 6 in the deceased cohort compared with controls. Among iMCD patients, there was a higher proportion of iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction and organomegaly) cases in the deceased group. The deceased iMCD group had significantly lower immunoglobulin M, international normalised ratio and platelet count. These data demonstrate that there may be differences between patients who have fatal and non-fatal outcomes, and provide preliminary suggestions for parameters to evaluate further.

International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease.

Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8-negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti-interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.

MammaPrint guides treatment decisions in breast Cancer: results of the IMPACt trial.

BACKGROUND: Increased usage of genomic risk assessment assays suggests increased reliance on data provided by these assays to guide therapy decisions. The current study aimed to assess the change in treatment decision and physician confidence based on the 70-gene risk of recurrence signature (70-GS, MammaPrint) and the 80-gene molecular subtype signature (80-GS, BluePrint) in early stage breast cancer patients. METHODS: IMPACt, a prospective, case-only study, enrolled 452 patients between November 2015 and August 2017. The primary objective population included 358 patients with stage I-II, hormone receptor-positive, HER2-negative breast cancer. The recommended treatment plan and physician confidence were captured before and after receiving results for 70-GS and 80-GS. Treatment was started after obtaining results. The distribution of 70-GS High Risk (HR) and Low Risk (LR) patients was evaluated, in addition to the distribution of 80-GS compared to IHC status. RESULTS: The 70-GS classified 62.5% (n = 224/358) of patients as LR and 37.5% (n = 134/358) as HR. Treatment decisions were changed for 24.0% (n = 86/358) of patients after receiving 70-GS and 80-GS results. Of the LR patients initially prescribed CT, 71.0% (44/62) had CT removed from their treatment recommendation. Of the HR patients not initially prescribed CT, 65.1% (41/63) had CT added. After receiving 70-GS results, CT was included in 83.6% (n = 112/134) of 70-GS HR patient treatment plans, and 91.5% (n = 205/224) of 70-GS LR patient treatment plans did not include CT. For patients who disagreed with the treatment recommended by their physicians, most (94.1%, n = 16/17) elected not to receive CT when it was recommended. For patients whose physician-recommended treatment plan was discordant with 70-GS results, discordance was significantly associated with age and lymph node status. CONCLUSIONS: The IMPACt trial showed that treatment plans were 88.5% (n = 317/358) in agreement with 70-GS results, indicating that physicians make treatment decisions in clinical practice based on the 70-GS result. In clinically high risk, 70-GS Low Risk patients, there was a 60.0% reduction in treatment recommendations that include CT. Additionally, physicians reported having greater confidence in treatment decisions for their patients in 72% (n = 258/358) of cases after receiving 70-GS results. TRIAL REGISTRATION: "Measuring the Impact of MammaPrint on Adjuvant and Neoadjuvant Treatment in Breast Cancer Patients: A Prospective Registry" (NCT02670577) retrospectively registered on Jan 27, 2016.

Insufficient evidence exists to use histopathologic subtype to guide treatment of idiopathic multicentric Castleman disease.

Idiopathic multicentric Castleman disease (iMCD) is a rare immunologic disorder characterized by systemic inflammation, multicentric lymphadenopathy, and organ dysfunction. Enlarged lymph nodes demonstrate a spectrum of characteristic but variable histopathologic features historically categorized into hyaline vascular (HV) (or hypervascular [HyperV] more recently), plasmacytic, or "mixed." Though the etiology is unknown, a pro-inflammatory cytokine storm, often involving interleukin-6 (IL-6), contributes to pathogenesis. Anti-IL-6 therapy with siltuximab is the only FDA- or EMA-approved treatment based on efficacy and safety in multiple studies. Importantly, no patients considered to have HV histopathology achieved the primary endpoint in the Phase II study. NCCN currently recommends siltuximab first-line for iMCD, except for patients considered to have HV histopathology. We investigated whether histopathologic subtype should guide siltuximab treatment decisions. Secondary analyses of clinical trial and real-world data revealed similar clinical benefit across histopathologic subtypes. Notably, only 18 of 79 patients in the Phase II study were consistently classified into histopathologic subtype by three independent review panels, demonstrating limited reliability to guide treatment decisions. Real-world data further demonstrate siltuximab's effectiveness in patients considered to have HV (or HyperV). Though histopathology is a critical component for diagnosis, there is insufficient evidence to guide treatment based solely on lymph node histopathologic subtype.

International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease.

Human herpesvirus-8 (HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving systemic inflammatory symptoms, polyclonal lymphoproliferation, cytopenias, and multiple organ system dysfunction caused by a cytokine storm often including interleukin-6. iMCD accounts for one third to one half of all cases of MCD and can occur in individuals of any age. Accurate diagnosis is challenging, because no standard diagnostic criteria or diagnostic biomarkers currently exist, and there is significant overlap with malignant, autoimmune, and infectious disorders. An international working group comprising 34 pediatric and adult pathology and clinical experts in iMCD and related disorders from 8 countries, including 2 physicians that are also iMCD patients, was convened to establish iMCD diagnostic criteria. The working group reviewed data from 244 cases, met twice, and refined criteria over 15 months (June 2015 to September 2016). The proposed consensus criteria require both Major Criteria (characteristic lymph node histopathology and multicentric lymphadenopathy), at least 2 of 11 Minor Criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. Characteristic histopathologic features may include a constellation of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, hypervascularization, and polytypic plasmacytosis. Laboratory and clinical Minor Criteria include elevated C-reactive protein or erythrocyte sedimentation rate, anemia, thrombocytopenia or thrombocytosis, hypoalbuminemia, renal dysfunction or proteinuria, polyclonal hypergammaglobulinemia, constitutional symptoms, hepatosplenomegaly, effusions or edema, eruptive cherry hemangiomatosis or violaceous papules, and lymphocytic interstitial pneumonitis. iMCD consensus diagnostic criteria will facilitate consistent diagnosis, appropriate treatment, and collaborative research.

Pentostatin, Cyclophosphamide, and Rituximab Followed by Alemtuzumab for Relapsed or Refractory Chronic Lymphocytic Leukemia: A Phase 2 Trial of the ECOG-Acrin Cancer Research Group (E2903).

Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) may benefit from salvage chemoimmunotherapy (CIT). To explore further the use of CIT in the pre-novel agent era, ECOG-ACRIN undertook a phase 2 trial (E2903) for R/R CLL utilizing pentostatin, cyclophosphamide, and rituximab (PCR) followed by a consolidation course of alemtuzumab. This trial enrolled 102 patients with a median age of 64 years. Treatment consisted of 6 cycles of PCR followed by alemtuzumab for either 4 or 18 weeks depending on the initial response to PCR. The overall response after PCR (complete remission, CR, nodular partial remission, nPR, and partial remission, PR) was 55%. Major responses (CR or nPR) were achieved in 6%. The median overall survival (OS) and the median progression-free survival were 28 and 12 months, respectively. The most serious nonlethal adverse events were myelosuppression, febrile neutropenia, fatigue, nausea, and hyponatremia. PCR is an effective and well-tolerated nucleoside-based regimen for heavily pretreated CLL patients with R/R disease. The addition of alemtuzumab to CLL patients with a minor response (PR) or stable disease did not result in a significant number of higher responses (CR or nPR) nor an improvement in OS.

Chemotherapy interruptions in relation to symptom severity in advanced breast cancer.

PURPOSE: Interruptions in medical treatment such as dose delays, reductions, or stoppages can lead to suboptimal treatment of cancer. Knowing how and for whom symptom severity and symptom interference with activities of daily living (ADL) are associated with treatment interruptions can guide behavioral interventions for supportive care. The purpose of this analysis is to inform research and clinical practice by bringing attention to specific patient symptoms that may hinder dose completion. METHODS: A secondary analysis of data collected in a randomized clinical trial (RCT) of reflexology for symptom management was performed. The trial enrolled women with advanced breast cancer undergoing treatment (N = 385). Outcome data were collected at baseline, weeks 5 and 11 using valid and reliable measures. Medical records provided data on treatment interruptions and metastasis. The association between alterations in medical treatment during the study period with symptom severity, symptom interference with ADLs, and metastatic status were tested using generalized estimating equation (GEE) models. RESULTS: The relationship between dose delays and dose reductions and symptom severity was differential according to metastatic status, with the higher strength of association among women with distant metastasis compared to those with loco-regional disease (p = 0.02). The interaction of symptom interference and metastatic status was also significantly related to dose delays and reductions (p = 0.04). Severity of pain was a stronger predictor of dose delays or reductions among patients with distant metastasis compared to those with loco-regional disease (p < 0.01). CONCLUSION: The analysis highlights the importance of understanding symptom outcomes that impact research, practice, and treatment decisions.

Mature results of MM-011: a phase I/II trial of liposomal doxorubicin, vincristine, dexamethasone, and lenalidomide combination therapy followed by lenalidomide maintenance for relapsed/refractory multiple myeloma.

A previous interim report of MM-011, the first study that combined lenalidomide with anthracycline-based chemotherapy followed by lenalidomide maintenance for relapsed and/or refractory multiple myeloma (RRMM), showed promising safety and activity. We report the long-term outcomes of all 76 treated patients with follow-up ≥ 5 years. This single-center phase I/II study administered lenalidomide (10 mg on days 1-21 of every 28-day cycle), intravenous liposomal doxorubicin (40 mg/m(2) on day 1), dexamethasone (40 mg on days 1-4), and intravenous vincristine (2 mg on day 1). After 4-6 planned induction cycles, lenalidomide maintenance therapy was given at the last tolerated dose until progression, with or without 50 mg prednisone every other day. The median number of previous therapies was 3 (range, 1-7); 49 (64.5%) patients had refractory disease. Forty-three (56.6%) patients received maintenance therapy. Grade 3/4 adverse events occurred during induction and maintenance therapy in 48.7% and 25.6% of patients, respectively. Four (5.3%) treatment-related deaths occurred during induction. Responses were seen in 53.0% (at least partial response) and 71.2% (at least minor response) of patients. Overall, median progression-free survival and overall survival were 10.5 and 19.0 months, respectively; in patients with refractory disease these values were 7.5 and 11.3 months, respectively. Lenalidomide with anthracycline-based chemotherapy followed by maintenance lenalidomide provided durable control in patients with RRMM (ClinicalTrials.gov number, NCT00091624).

Increase in Vascular Endothelial Growth Factor (VEGF) Expression and the Pathogenesis of iMCD-TAFRO.

TAFRO (thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (F/R), renal failure (R), and organomegaly (O)) is a heterogeneous clinical subtype of idiopathic multicentric Castleman disease (iMCD) associated with a significantly poorer prognosis than other subtypes of iMCD. TAFRO symptomatology can also be seen in pathological contexts outside of iMCD, but it is unclear if those cases should be considered representative of a different disease entity or simply a severe presentation of other infectious, malignant, and rheumatological diseases. While interleukin-6 (IL-6) is an established driver of iMCD-TAFRO pathogenesis in a subset of patients, the etiology is unknown. Recent case reports and literature reviews on TAFRO patients suggest that vascular endothelial growth factor (VEGF), and the interplay of VEGF and IL-6 in concert, rather than IL-6 as a single cytokine, may be drivers for iMCD-TAFRO pathophysiology, especially renal injury. In this review, we discuss the possible role of VEGF in the pathophysiology and clinical manifestations of iMCD-TAFRO. In particular, VEGF may be involved in iMCD-TAFRO pathology through its ability to activate RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways. Further elucidating a role for the VEGF-IL-6 axis and additional disease drivers may shed light on therapeutic options for the treatment of TAFRO patients who do not respond to, or otherwise relapse following, treatment with IL-6 targeting drugs. This review investigates the potential role of VEGF in the pathophysiology of iMCD-TAFRO and the potential for targeting related signaling pathways in the future.

Talazoparib in Patients With Solid Tumors With BRCA1/2 Mutation: Results From the Targeted Agent and Profiling Utilization Registry Study.

PURPOSE: The Targeted Agent and Profiling Utilization Registry Study is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. Results of a cohort of patients with various solid tumors with germline or somatic BRCA1/2 mutations treated with talazoparib are reported. METHODS: Eligible patients had advanced solid tumors, measurable disease (RECIST), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. Patients with germline BRCA-mutated human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer were not eligible for this study. Primary end point was disease control (DC) determined by investigator assessment of objective response (OR) or stable disease (SD) of at least 16 weeks duration (SD16+). The results were evaluated on the basis of a one-sided exact binomial test with a null DC rate of 15% versus 35% (power = 0.82; α = .10). Secondary end points were OR, progression-free survival, overall survival, duration of response, duration of SD, and safety. RESULTS: Twenty-eight patients (20 cancer types) with BRCA1/2 mutations were enrolled from December 2019 to September 2021 and collapsed into a single histology pooled cohort for analysis. All patients were evaluable for efficacy. One complete response, nine partial response, and six SD16+ were observed for DC and OR rates of 57% (one-sided 90% CI, 43 to 100) and 36% (95% CI, 19 to 56), respectively. The null hypothesis of a 15% DC rate was rejected (P < .001). Patients with OR had the following tumor types: breast (2), nonmelanoma skin, mesothelioma, stomach, uterus, non-small cell lung cancer, ovary, hepatocellular carcinoma, and pancreas. Thirteen patients had at least one grade 3-5 adverse event (AE) or serious AE at least possibly related to talazoparib. All were consistent with the drug label except bilirubin increase and hyponatremia (both grade 3 AEs). CONCLUSION: Talazoparib demonstrated antitumor activity in patients with advanced solid tumors and BRCA1/2 mutations, including cancer types for which poly ADP-ribose polymerase inhibitors are not yet US Food and Drug Administration-approved.

Treatment consistent with idiopathic multicentric Castleman disease guidelines is associated with improved outcomes.

Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic disorder with an unknown etiology. Clinical presentation is heterogeneous, ranging from mild constitutional symptoms with lymphadenopathy to life-threatening multiorgan dysfunction. International, consensus treatment guidelines developed in 2018 relied upon a limited number of clinical trials and small case series; however, to our knowledge, real-world performance of these recommendations has not been subsequently studied. Siltuximab, a monoclonal antibody against interleukin 6 (IL6), is approved for the treatment of iMCD and recommended first-line, and tocilizumab, a monoclonal antibody directed against the IL6 receptor, is recommended when siltuximab is unavailable. Chemotherapy, rituximab, and immunomodulators are recommended as second- and third-line treatments based on limited evidence. Corticosteroid monotherapy is used by clinicians, although not recommended. Here, we draw upon the ACCELERATE Natural History Registry to inventory regimens and evaluate regimen response for 102 expert-confirmed iMCD cases. Siltuximab with/without (w/wo) corticosteroids was associated with a 52% response, whereas corticosteroid monotherapy was associated with a 3% response. Anti-IL6-directed therapy with siltuximab or tocilizumab demonstrated better response and more durability than was observed with rituximab w/wo corticosteroids. Cytotoxic chemotherapy was associated with a 52% response and was predominantly administered in patients characterized by thrombocytopenia, anasarca, fever, renal failure/reticulin fibrosis, and organomegaly. Our results provide evidence in support of current recommendations to administer anti-IL6 as first-line treatment, to administer cytotoxic chemotherapy in patients with severe refractory disease, and to limit corticosteroid monotherapy. Evidence remains limited for effective agents for patients who are refractory to anti-IL6-directed therapy. This trial was registered at www.clinicaltrials.gov as #NCT02817997.

Patient with Lobular Carcinoma of the Breast and Activating AKT1 E17K Variant.

OBJECTIVE: To present the characteristics of the AKT1E117K gene variant and a description of the clinical application in a patient with metastatic breast cancer. RESULTS: 63 y/o woman with Stage IV Invasive lobular carcinoma at diagnosis was treated with Palbociclib and aromatase inhibitors (AI). At progression, tissue was sent for comprehensive genomic profiling to Foundation Medicine (FM) which revealed AKT1E17K mutation. In lieu of available clinical data within the patient's tumor type (HR+ HER2- breast cancer), extrapolated data from the Flatiron Health-FM (FH-FMI) Clinico-genomic Database (CGDB) was discussed at our Molecular Tumor Board (MTB). After multidisciplinary discussion, the consensus recommendation was to start treatment with the combination of mTOR inhibitor everolimus, and AI, exemestane. Patient tolerated treatment without major side effects. By the second clinical visit the patient's breast showed signs of improvement. PET/CT showed diminished left axillary uptake, decreased right paratracheal lymph node PET avidity, and stable bone disease consistent with a partial response. The most recent office visit in January 2021, breast exam revealed a normal-appearing skin with only faint erythema. All other skin lesions have resolved. Although, the role of AKT1 variant described here is not well defined and therapeutic significance of M-Tor inhibitors not established in metastatic breast cancers, comprehensive approach to this case unraveled new and successful therapeutic option in this patient. CONCLUSION: This demonstrates that applying available Precision Medicine tools like MTB and real world data sets from patient populations with similar clinical and genomic profiles may provide more options for treatment.

Patient-reported tolerability of veliparib combined with cisplatin and etoposide for treatment of extensive stage small cell lung cancer: Neurotoxicity and adherence data from the ECOG ACRIN cancer research group E2511 phase II randomized trial.

OBJECTIVES: The ECOG-ACRIN Cancer Research Group trial E2511 recently demonstrated a potential benefit for the addition of veliparib to cisplatin-etoposide (CE) in patients with extensive stage small cell lung cancer (ES-SCLC) in a phase II randomized controlled trial. Secondary trial endpoints included comparison of the incidence and severity of neurotoxicity, hypothesized to be lower in the veliparib arm, and tolerability of the addition of veliparib to CE. Physician-rated and patient-reported neurotoxicity was also compared. MATERIALS AND METHODS: Patients randomized to veliparib plus CE (n = 64) or placebo plus CE (n = 64) completed the 11-item Functional Assessment of Cancer Therapy Gynecologic Oncology Group Neurotoxicity (questionnaire pre-treatment, end of cycle 4 [ie 3 months after randomization] and 3 months post-treatment [ie 6-months]). Adherence analysis was based on treatment forms. RESULTS AND CONCLUSION: No significant differences in mean or magnitude of change in neurotoxicity scores were observed between treatment arms at any time point. However, patients in the placebo arm reported worsening neurotoxicity from baseline to 3-months (M difference = -1.5, P = .045), compared to stable neurotoxicity in the veliparib arm (M difference = -0.2, P = .778). Weakness was the most common treatment-emergent (>50%) and moderate to severe (>16%) symptom reported, but did not differ between treatment arms. The proportion of adherence to oral therapy in the overall sample was 75%. Three percent of patients reported clinically significant neurotoxicity that was not captured by physician assessment. Neurotoxicity scores were not different between treatment arms. The addition of veliparib to CE appeared tolerable, though weakness should be monitored. CLINICALTRIALS. GOV IDENTIFIER: NCT01642251.

ACCELERATE: A Patient-Powered Natural History Study Design Enabling Clinical and Therapeutic Discoveries in a Rare Disorder.

Geographically dispersed patients, inconsistent treatment tracking, and limited infrastructure slow research for many orphan diseases. We assess the feasibility of a patient-powered study design to overcome these challenges for Castleman disease, a rare hematologic disorder. Here, we report initial results from the ACCELERATE natural history registry. ACCELERATE includes a traditional physician-reported arm and a patient-powered arm, which enables patients to directly contribute medical data and biospecimens. This study design enables successful enrollment, with the 5-year minimum enrollment goal being met in 2 years. A median of 683 clinical, laboratory, and imaging data elements are captured per patient in the patient-powered arm compared with 37 in the physician-reported arm. These data reveal subgrouping characteristics, identify off-label treatments, support treatment guidelines, and are used in 17 clinical and translational studies. This feasibility study demonstrates that the direct-to-patient design is effective for collecting natural history data and biospecimens, tracking therapies, and providing critical research infrastructure.

International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease.

Castleman disease (CD) includes a group of rare and heterogeneous disorders with characteristic lymph node histopathological abnormalities. CD can occur in a single lymph node station, which is referred to as unicentric CD (UCD). CD can also involve multicentric lymphadenopathy and inflammatory symptoms (multicentric CD [MCD]). MCD includes human herpesvirus-8 (HHV-8)-associated MCD, POEMS-associated MCD, and HHV-8-/idiopathic MCD (iMCD). The first-ever diagnostic and treatment guidelines were recently developed for iMCD by an international expert consortium convened by the Castleman Disease Collaborative Network (CDCN). The focus of this report is to establish similar guidelines for the management of UCD. To this purpose, an international working group of 42 experts from 10 countries was convened to establish consensus recommendations based on review of treatment in published cases of UCD, the CDCN ACCELERATE registry, and expert opinion. Complete surgical resection is often curative and is therefore the preferred first-line therapy, if possible. The management of unresectable UCD is more challenging. Existing evidence supports that asymptomatic unresectable UCD may be observed. The anti-interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome. Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization. Further research is needed in UCD patients with persisting constitutional symptoms despite complete excision and normal laboratory markers. We hope that these guidelines will improve outcomes in UCD and help treating physicians decide the best therapeutic approach for their patients.

Immunomodulatory compounds (IMiDs) in the treatment of multiple myeloma.

The design of innovative, more effective, less toxic therapy of multiple myeloma (MM) is emerging in parallel to a better understanding of the underlying pathophysiology of this common hematologic malignancy. Thalidomide has changed the treatment paradigm of patients with MM. Its efficacy, however, has been compromised by significant side effects. IMiDs (immunodulatory compounds) are structural and functional analogs of thalidomide that were specifically designed to create new agents with enhanced immunomodulatory and anticancer properties and better tolerability profiles. In this article, we review the clinical trial development of the second-generation IMiDs, lenalidomide and pomalidomide. Both agents demonstrate potent activity and are highly effective and well tolerated treatment options for patients with MM.

Prospective Validation of a Genomic Assay in Breast Cancer: The 70-gene MammaPrint Assay and the MINDACT Trial.

MammaPrint was the first genomic assay in breast cancer to be validated with a prospective randomized trial, the MINDACT trial. The 70 gene MammaPrint assay was developed to determine the risk of distant metastasis in early stage breast cancer through gene expression analysis and was the first FDA cleared genomic assay for breast cancer. The assay identifies primary breast cancers likely to metastasize within the first five years of diagnosis and has clinical utility for helping to determine the expected benefit from adjuvant chemotherapy. The MINDACT Trial was the first trial of a genomic assay in breast cancer to provide prospective, randomized evidence of clinical utility for this important clinical question, identifying a significant proportion of patients who could safely forgo chemotherapy within a cohort of patients with high risk clinical characteristics. Nearly half of all patients (46%) who would have been advised chemotherapy according to clinical guidelines were identified genomically by MammaPrint as being low risk and found to have equivalent rates of freedom from metastasis at 5 years with or without chemotherapy. Based upon the MINDACT trial, the ASCO Biomarker Guidelines now approve the use of MammaPrint to inform decisions regarding chemotherapy for women with clinically high-risk ER+ breast cancer, and as the only approved assay for use in women with 1-3 involved lymph nodes. Recent studies suggest information obtained from the 70-gene assay may also help inform decisions regarding endocrine therapy, as well as chemotherapy, targeted therapy and immunotherapy. CONCLUSION: The power of gene expression analysis in breast cancer, effectively illustrated with MammaPrint in the MINDACT trial, is now being explored through examination of the full transcriptome in breast cancer.

Changing Landscape of Clinical-Genomic Oncology Practice.

The current paper discusses the use of genomics in the context of the changing landscape of clinical practice and modern medicine. Medical practice has shifted considerably over the past few decades, from empirical to evidence-based to personalized medicine, and the transition from reliance on observation to measureable parameters. Scientific innovation is required to collect an ever-increasing number and variety of data points and sophisticated analyses capable of distilling vast datasets into meaningful information. The next phase of innovation seeks to personalize disease management, in particular through genomics in oncology. With expanding use of genomics in medicine, and several initiatives collecting genomic data at the population level, education of patients and physicians is critical for data utility. By combining genomic and clinical data, bioinformatics approaches can be applied to developing individualized or targeted therapies. Breast cancer provides an example through which to understand the evolution of genomic data from pure science to clinical utility. From intrinsic subtype classification to development of multigene panels estimating recurrence risk, new studies, such as the FLEX trial, will expand to evaluate the whole transcriptome of tumours. This approach will enable discovery of novel gene signatures and ultimately pave the way toward a personalized approach to breast cancer management. CONCLUSION: Despite the potential for genomics to personalize treatments, a number of challenges remain to fully integrate these types of large datasets in a manner that provides clinicians and patients with meaningful, actionable information. However, if challenges are addressed, precision medicine has the capacity to transform patient care.