Jackie Szymonifka

BACKGROUND: Extramedullary disease is an uncommon manifestation in multiple myeloma and can either accompany newly diagnosed disease or develop with disease progression or relapse. We evaluated the impact of this disease feature on patients' outcome in the context of novel agents. DESIGN AND METHODS: We analyzed clinical and biological features of extramedullary disease in 936 patients with multiple myeloma enrolled in Total Therapy protocols, 240 patients in non-Total Therapy protocols, and 789 non-protocol patients, all of whom had baseline positron emission tomography scans to document extramedullary disease at diagnosis and its subsequent development at the time of disease progression or relapse. RESULTS: The most common sites for extramedullary disease at diagnosis were skin and soft tissue whereas liver involvement was the striking feature in extramedullary disease at disease relapse or progression. Regardless of therapy, extramedullary disease was associated with shorter progression-free and overall survival, as well as the presence of anemia, thrombocytopenia, elevated serum lactate dehydrogenase, cytogenetic abnormalities, and high-risk features in 70-and 80-gene risk models in univariate analysis. Multivariate analysis with logistic regression revealed that this disease feature was more prevalent in patients with an elevated centrosome index, as determined by gene expression profiling, as well as in myeloma molecular subtypes that are more prone to relapse. These include the MF subtype (also called the "MAF" subtype, associated with over-expression of the MAF gene seen with chromosome translocation 14;16 or 14;20) and the PR subtype (also called the "Proliferation" subtype, associated with overexpression of pro-proliferative genes). CONCLUSIONS: These data show that extramedullary disease is more prevalent in genomically defined high-risk multiple myeloma and is associated with shorter progression-free survival and overall survival, even in the era of novel agents. All clinical trials included in the analyses were registered with www.clinicaltrials.gov (NCT00083551, NCT00083876, NCT00081939, NCT00572169, NCT00644228,NCT00002548,NCT00734877).

Aims: The aim of this study was to determine the diagnostic performance of single-photon emission computed tomography (SPECT), stress echocardiography (SE), invasive coronary angiography (ICA), coronary computed tomography angiography (CCTA), fractional flow reserve (FFR) derived from CCTA (FFRCT), and cardiac magnetic resonance (MRI) imaging when directly compared with an FFR reference standard. Method and results: PubMed and Web of Knowledge were searched for investigations published between 1 January 2002 and 28 February 2015. Studies performing FFR in at least 75% of coronary vessels for the diagnosis of ischaemic coronary artery disease (CAD) were included. Twenty-three articles reporting on 3788 patients and 5323 vessels were identified. Meta-analysis was performed for pooled sensitivity, specificity, likelihood ratios (LR), diagnostic odds ratio, and summary receiver operating characteristic curves. In contrast to ICA, CCTA, and FFRCT reports, studies evaluating SPECT, SE, and MRI were largely retrospective, single-centre and with generally smaller study samples. On a per-patient basis, the sensitivity of CCTA (90%, 95% CI: 86-93), FFRCT (90%, 95% CI: 85-93), and MRI (90%, 95% CI: 75-97) were higher than for SPECT (70%, 95% CI: 59-80), SE (77%, 95% CI: 61-88), and ICA (69%, 95% CI: 65-75). The highest and lowest per-patient specificity was observed for MRI (94%, 95% CI: 79-99) and for CCTA (39%, 95% CI: 34-44), respectively. Similar specificities were noted for SPECT (78%, 95% CI: 68-87), SE (75%, 95% CI: 63-85), FFRCT (71%, 95% CI: 65-75%), and ICA (67%, 95% CI: 63-71). On a per-vessel basis, the highest sensitivity was for CCTA (pooled sensitivity, 91%: 88-93), MRI (91%: 84-95), and FFRCT (83%, 78-87), with lower sensitivities for ICA (71%, 69-74), and SPECT (57%: 49-64). Per-vessel specificity was highest for MRI (85%, 79-89), FFRCT (78%: 78-81), and SPECT (75%: 69-80), whereas ICA (66%: 64-68) and CCTA (58%: 55-61) yielded a lower specificity. Conclusions: In this meta-analysis comparing cardiac imaging methods directly to FFR, MRI had the highest performance for diagnosis of ischaemia-causing CAD, with lower performance for SPECT and SE. Anatomic methods of CCTA and ICA yielded lower specificity, with functional assessment of coronary atherosclerosis by SE, SPECT, and FFRCT improving accuracy.

The objective of our retrospective institutional experience is to report the overall response rate, R0 resection rate, progression-free survival, and safety/toxicity of neoadjuvant FOLFIRINOX (5-fluorouracil [5-FU], oxaliplatin, irinotecan, and leucovorin) and chemoradiation in patients with locally advanced pancreatic cancer (LAPC). Patients with LAPC treated with FOLFIRINOX were identified via the Massachusetts General Hospital Cancer Center pharmacy database. Demographic information, clinical characteristics, and safety/tolerability data were compiled. Formal radiographic review was performed to determine overall response rates (ORRs). Twenty-two patients with LAPC began treatment with FOLFIRINOX between July 2010 and February 2012. The ORR was 27.3%, and the median progression-free survival was 11.7 months. Five of 22 patients were able to undergo R0 resections following neoadjuvant FOLFIRINOX and chemoradiation. Three of the five patients have experienced distant recurrence within 5 months. Thirty-two percent of patients required at least one emergency department visit or hospitalization while being treated with FOLFIRINOX. FOLFIRINOX possesses substantial activity in patients with LAPC. The use of FOLFIRINOX was associated with conversion to resectability in >20% of patients. However, the recurrences following R0 resection in three of five patients and the toxicities observed with the use of this regimen raise important questions about how to best treat patients with LAPC.

BACKGROUND: Biomarkers to optimize extended adjuvant endocrine therapy for women with estrogen receptor (ER)-positive breast cancer are limited. The HOXB13/IL17BR (H/I) biomarker predicts recurrence risk in ER-positive, lymph node-negative breast cancer patients. H/I was evaluated in MA.17 trial for prognostic performance for late recurrence and treatment benefit from extended adjuvant letrozole. METHODS: A prospective-retrospective, nested case-control design of 83 recurrences matched to 166 nonrecurrences from letrozole- and placebo-treated patients within MA.17 was conducted. Expression of H/I within primary tumors was determined by reverse-transcription polymerase chain reaction with a prespecified cutpoint. The predictive ability of H/I for ascertaining benefit from letrozole was determined using multivariable conditional logistic regression including standard clinicopathological factors as covariates. All statistical tests were two-sided. RESULTS: High H/I was statistically significantly associated with a decrease in late recurrence in patients receiving extended letrozole therapy (odds ratio [OR] = 0.35; 95% confidence interval [CI] = 0.16 to 0.75; P = .007). In an adjusted model with standard clinicopathological factors, high H/I remained statistically significantly associated with patient benefit from letrozole (OR = 0.33; 95% CI = 0.15 to 0.73; P = .006). Reduction in the absolute risk of recurrence at 5 years was 16.5% for patients with high H/I (P = .007). The interaction between H/I and letrozole treatment was statistically significant (P = .03). CONCLUSIONS: In the absence of extended letrozole therapy, high H/I identifies a subgroup of ER-positive patients disease-free after 5 years of tamoxifen who are at risk for late recurrence. When extended endocrine therapy with letrozole is prescribed, high H/I predicts benefit from therapy and a decreased probability of late disease recurrence.