Chromosomal copy number alterations for associations of ductal carcinoma in situ with invasive breast cancer

Introduction

Screening mammography has contributed to a significant increase in the diagnosis of ductal carcinoma in situ (DCIS), raising concerns about overdiagnosis and overtreatment. Building on prior observations from lineage evolution analysis, we examined whether measuring genomic features of DCIS would predict association with invasive breast carcinoma (IBC). The long-term goal is to enhance standard clinicopathologic measures of low- versus high-risk DCIS and to enable risk-appropriate treatment.

Methods

We studied three common chromosomal copy number alterations (CNA) in IBC and designed fluorescence in situ hybridization-based assay to measure copy number at these loci in DCIS samples. Clinicopathologic data were extracted from the electronic medical records of Stanford Cancer Institute and linked to demographic data from the population-based California Cancer Registry; results were integrated with data from tissue microarrays of specimens containing DCIS that did not develop IBC versus DCIS with concurrent IBC. Multivariable logistic regression analysis was performed to describe associations of CNAs with these two groups of DCIS.

Results

We examined 271 patients with DCIS (120 that did not develop IBC and 151 with concurrent IBC) for the presence of 1q, 8q24 and 11q13 copy number gains. Compared to DCIS-only patients, patients with concurrent IBC had higher frequencies of CNAs in their DCIS samples. On multivariable analysis with conventional clinicopathologic features, the copy number gains were significantly associated with concurrent IBC. The state of two of the three copy number gains in DCIS was associated with a risk of IBC that was 9.07 times that of no copy number gains, and the presence of gains at all three genomic loci in DCIS was associated with a more than 17-fold risk (P = 0.0013).

Conclusions

CNAs have the potential to improve the identification of high-risk DCIS, defined by presence of concurrent IBC. Expanding and validating this approach in both additional cross-sectional and longitudinal cohorts may enable improved risk stratification and risk-appropriate treatment in DCIS.

Electronic supplementary material

The online version of this article (doi:10.1186/s13058-015-0623-y) contains supplementary material, which is available to authorized users.     

Myelomatous Pleural Effusion Presenting with Extreme Hyperferritinemia and Severe Inflammatory Response

Myelomatous involvement of pleural effusions developing in patients with multiple myeloma is extremely rare and only a few cases have been reported so far. It is thought to represent an aggressive clinical progression of disease and is usually associated with severe complications, poor prognosis and high mortality. Ferritin is a marker of inflammatory pathways that plays a significant role in plasma cell malignancies and has been studied as a prognostic factor for multiple myeloma. In severe inflammatory states such as septic shock or hemophagocytic lymphohistiocytosis, extreme levels of ferritin are thought to precipitate a cytokine storm associated with poor clinical outcomes. We present a case of myelomatous pleural effusion associated with extreme levels of ferritin and explore the possibility of a connection between this rare entity and other severe inflammatory states, which could account for its ominous outcomes and poor prognosis.Key Words: Multiple myeloma, Pleural effusion, Hyperferritinemia     

Improved Mycobacterium tuberculosis clearance after the restoration of IFN-γ+TNF-α+CD4+T cells: Impact of PD-1 inhibition in active tuberculosis patients

Prolonged therapy, drug toxicity, noncompliance, immune suppression, and alarming emergence of drug resistance necessitate the search for therapeutic vaccine strategies for tuberculosis (TB). Such strategies ought to elicit not only IFN-γ, but polyfunctional response including TNF-α, which is essential for protective granuloma formation. Here, we investigated the impact of PD-1 inhibition in facilitating protective polyfunctional T cells (PFTs), bacillary clearance, and disease resolution. We have observed PD-1 inhibition preferentially rescued the suppressed PFTs in active tuberculosis patients. In addition, polyfunctional cytokine milieu favored apoptosis of infected MDMs over necrosis with markedly reduced bacillary growth (≪CFU) in our in vitro monocyte-derived macrophages (MDMs) infection model. Furthermore, the animal study revealed a significant decline in the bacterial burden in the lungs and spleen of infected mice after in vivo administration of α-PD-1 along with antitubercular treatment. Our findings suggest that rescuing polyfunctional immune response by PD-1 inhibition works synergistically with antituberculosis chemotherapy to confer improved control over bacillary growth and dissemination. In summary, our data strongly indicate the therapeutic potential of α-PD-1 as adjunct immunotherapy that can rejuvenate suppressed host immunity and enhance the efficacy of candidate therapeutic vaccine(s).     

Medial collateral ligament of the knee: anatomy,management and surgical techniques for reconstruction

The medial collateral ligament (MCL) is the most commonly injured ligament in the knee. The incidence is reported to be 0.24 per 1000 per year, and twice as high in males. The majority of MCL injuries are isolated, occurring in young sportsmen and women. However, they can occur in association with other injuries of the knee, most commonly the anterior cruciate ligament. Most injuries to the medial supporting structures occur as a result of valgus forces; but in sports, these can be a result of skiing injuries or ‘cutting’ manoeuvres. The majority of MCL injuries heal well with non-operative management and rarely require surgery; but if acute injuries are insufficiently treated or missed, the result can be chronic laxity. This chapter reviews the existing literature on common history and examination findings in MCL injuries. There are a number of classification systems designed to grade the severity of injury, which are based on the amount of laxity and the ability of the assessor to feel an end-point. There has been significant advancement in the understanding of the anatomy and biomechanics of the different components of the MCL. The anatomical landmarks of the superficial and deep MCL as well as the posterior oblique ligament are discussed along with the function of these individual structures. Although most MCL injuries heal well with non-operative management, there are a number of indications for operative intervention. These include open and multi-ligament knee injuries, as well as chronic instability. Broadly these are divide into repair or reconstruction categories. Repair is best performed in acute cases, where surgery is indicated for other reasons such as a meniscal tear; whereas reconstruction is best reserved for chronic instability. The reconstruction techniques including the Lind and LaPrade are described.     

Use of acupuncture in the management of chronic haemophilia pain

Persons with haemophilia experience persistent pain resulting in chronic arthritic symptoms. The older person with haemophilia who did not benefit from primary prophylaxis are particularly at risk for persistent pain in multiple target joints as a result of repeated joint bleeding with delayed treatment received. The National Pain Study, Ref. [11] identified over 700 persons with haemophilia who rated daily persistent pain as 4.22/10 (SD ± 2.05) using a visual analogue scale. The study suggests that persons are continually seeking additional resources to relieve pain. This study seeks to identify: (i) effects of acupuncture use for persons with haemophilia who experience persistent joint pain as a result of repeated haemarthrosis and (ii) document no reported increased bleeding risk as a result of acupuncture use. End points include the subjects reported perception of reduction in pain via the 10-point visual analogue pain scale and bleeding. Nine subjects participated in the study, some who received a factor replacement to 15% correction and others who did not receive factor prior to any acupuncture sessions totaling 14 acupuncture treatments. No one of the subjects experienced bleeding or bruising. Six of the nine subjects reported an improvement in pain scores by at least 50%. Seven of the nine quality of life (QOL) domains within the QOL SF-36 questionnaire improved, suggesting a perception by subjects of improvement. This study suggests that acupuncture therapy can be a safe additional modality for pain management therapies in persons with haemophilia, although larger randomized studies are needed for further validation.