Management of Newly Diagnosed Multiple Myeloma Today, and in the Future.

Treatment options have expanded rapidly and widely in the past two decades for patients with multiple myeloma. Triplet novel agent-based induction regimens have been accepted as the standard practice wordwide over the last decade both for transplant-eligible and non-eligible patients. The addition of anti-CD38 monoclonal antibodies as part of quadruplet regimens has led to even deeper and longer-lasting responses. The impressive results shown by the quadruplets havebeen practice-changing where accessible in recent years. Chimeric antigen receptor T cell therapy and bispecific antibodies are being tested in the upfront setting and have the potential to once again shift the paradigm of treatment of newly diagnosed MM.

B cell profiles, antibody repertoire and reactivity reveal dysregulated responses with autoimmune features in melanoma.

B cells are known to contribute to the anti-tumor immune response, especially in immunogenic tumors such as melanoma, yet humoral immunity has not been characterized in these cancers to detail. Here we show comprehensive phenotyping in samples of circulating and tumor-resident B cells as well as serum antibodies in melanoma patients. Memory B cells are enriched in tumors compared to blood in paired samples and feature distinct antibody repertoires, linked to specific isotypes. Tumor-associated B cells undergo clonal expansion, class switch recombination, somatic hypermutation and receptor revision. Compared with blood, tumor-associated B cells produce antibodies with proportionally higher levels of unproductive sequences and distinct complementarity determining region 3 properties. The observed features are signs of affinity maturation and polyreactivity and suggest an active and aberrant autoimmune-like reaction in the tumor microenvironment. Consistent with this, tumor-derived antibodies are polyreactive and characterized by autoantigen recognition. Serum antibodies show reactivity to antigens attributed to autoimmune diseases and cancer, and their levels are higher in patients with active disease compared to post-resection state. Our findings thus reveal B cell lineage dysregulation with distinct antibody repertoire and specificity, alongside clonally-expanded tumor-infiltrating B cells with autoimmune-like features, shaping the humoral immune response in melanoma.

Disease and outcome disparities in multiple myeloma: exploring the role of race/ethnicity in the Cooperative Group clinical trials.

Multiple myeloma (MM) is an incurable hematologic malignancy with disparities in outcomes noted among racial-ethnic subgroups, likely due to disparities in access to effective treatment modalities. Clinical trials can provide access to evidence-based medicine but representation of minorities on therapeutic clinical trials has been dismal. We evaluated the impact of patient race-ethnicity in pooled data from nine large national cooperative group clinical trials in newly diagnosed MM. Among 2896 patients enrolled over more than two decades, only 18% were non-White and enrollment of minorities actually decreased in most recent years (2002-2011). African-Americans were younger and had more frequent poor-risk markers, including anemia and increased lactate dehydrogenase. Hispanics had the smallest proportion of patients on trials utilizing novel therapeutic agents. While adverse demographic (increased age) and clinical (performance status, stage, anemia, kidney dysfunction) factors were associated with inferior survival, patient race-ethnicity did not have an effect on objective response rates, progression-free, or overall survival. While there are significant disparities in MM incidence and outcomes among patients of different racial-ethnic groups, this disparity seems to be mitigated by access to appropriate therapeutic options, for example, as offered by clinical trials. Improved minority accrual in therapeutic clinical trials needs to be a priority.

Protocol for M3P: A Comprehensive and Clinical Oriented Targeted Sequencing Panel for Routine Molecular Analysis in Multiple Myeloma.

Over the past 10 years next generation sequencing (NGS) approaches deciphered a large number of genomes from a wide variety of tumor types. However, despite most relevant findings, this technology has not yet been implemented into standard diagnostic workflows. Broad access to NGS technology is still limited, sequencing/analysis times exceed clinically relevant timeframes and despite huge cuts, costs remain significant. We proposed a custom-tailored gene panel, which focuses on a selected number of relevant genes and developed a clinically oriented NGS targeted sequencing approach for the molecular characterization of Multiple Myeloma (MM) tumors, allowing the description of the tumor genetic heterogeneity and its changes under selective pressure of antitumor therapy, in a more cost effective and faster turnaround timeframe.

Facial trauma caused by electronic cigarette explosion.

Electronic cigarettes are increasingly popular as a supposed safer alternative to tobacco cigarettes or a smoking cessation tool. Research and debate have focused primarily on possible adverse effects caused by the inhaled aerosol produced by electronic cigarettes and on smoking cessation efficacy. Few reports in the medical literature describe injuries secondary to device malfunction. We present a case of electronic cigarette explosion, with a projectile fracturing the patient's right naso-orbital-ethmoid complex and anterior and posterior frontal sinus tables, with frontal sinus outflow tract involvement. The patient underwent combined open and endoscopic repair, including open reduction internal fixation, with reconstitution and preservation of the frontal sinus and frontal sinus outflow tract. Additionally, we review the available data on electronic cigarette malfunction-including fires, explosions, associated injuries, and possible reasons for device malfunction-and discuss new 2016 U.S. Food and Drug Administration regulations pertaining to electronic cigarettes.

Multiple myeloma: genome sequencing, drug development and the future outlook.

Keith Stewart is the Dean for Research at Mayo Clinic (AZ, USA). He holds the Vasek and Anna Maria Polak Endowed Professorship in Cancer Research. He received his medical degree at Aberdeen University Medical School and trained in internal medicine and hematology in Glasgow, Kingston, Toronto and Boston. He was a consultant at the Toronto General and Princess Margaret Hospitals from 1992 to 2005 and a Professor in the Faculty of Medicine at the University of Toronto. He joined Mayo Clinic in Arizona in 2005. His lab-based research has focused on the genomics and developmental therapeutics of multiple myeloma. He has led numerous clinical trials from 'first in man', through to large international Phase III studies. Funding for his research includes the National Cancer Institute, the Leukemia and Lymphoma Society (LLS) and the Multiple Myeloma Research Foundation (MMRF). In addition, he is an associate editor of Blood, the journal of the American Society of Hematology (ASH).

An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib.

Carfilzomib is a next-generation proteasome inhibitor that selectively and irreversibly binds to its target. In clinical studies, carfilzomib has shown efficacy in patients with relapsed and/or refractory multiple myeloma (MM) and has demonstrated a tolerable safety profile. In this phase 2, open-label, multicentre clinical trial, 35 patients with relapsed and/or refractory MM following 1-3 prior therapies, including at least one bortezomib-based regimen, received carfilzomib 20 mg/m(2) in a twice-weekly, consecutive-day dosing schedule for ≤12 monthly cycles. The best overall response rate (ORR) was 17·1% and the clinical benefit response rate (ORR + minimal response) was 31·4%. The median duration of response was >10·6 months and the median time to progression was 4·6 months. The most common adverse events were fatigue (62·9%), nausea (60·0%), and vomiting (42·9%). No exacerbation of baseline peripheral neuropathy was observed. Single-agent carfilzomib was generally well tolerated for up to 12 treatment cycles and showed activity in patients with relapsed and/or refractory MM who had received prior treatment with bortezomib. These data, combined with an acceptable toxicity profile, support the potential use of carfilzomib in patients with relapsed and/or refractory MM and warrant continued investigation of carfilzomib as single agent or in combination with other agents.

Monoclonal gammopathy of undetermined significance does not affect outcomes in patients undergoing solid organ transplants.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic plasma cell proliferative disorder with a lifelong risk of progression to multiple myeloma or another plasma cell dyscrasia. Despite a high incidence in the general population and an increased relative risk for later malignancy, there are few reports about the clinical course of MGUS or risk profile in long-term immunosuppressed patients. METHODS: We reviewed 1593 solid organ transplant patients and reported the frequency and outcomes of patients with MGUS identified pretransplant. RESULTS: Polyclonal gammopathy pretransplant is common with 17% of all patients and as many as 75% of liver transplant candidates having increased globulins.However, a monoclonal immunoglobulin was identified in only 3% of all solid organ transplant patients pretransplant (n=34). Importantly, in these 34 patients, no cases of progression to multiple myeloma, amyloid, or lymphoma were observed during immune suppression, and there was no association between posttransplant lymphoproliferative disorders and pretransplant MGUS. Death in MGUS patients was not associated with progression of the monoclonal clone or development of posttransplant lymphoproliferative disorders or other malignancy. CONCLUSION: In conclusion, routine testing for MGUS before transplantation is not prognostic nor a contraindication to transplant, and therefore, it is not recommended.

Variability of radiation exposure with in-office sinus computed tomography examinations.

BACKGROUND: An increasing number of patients seeking care by an otolaryngologist are undergoing computed tomography (CT) examinations via in-office CT scanners. Many otolaryngologists and patients are not fully aware of the radiation dosages and the associated risks. A recent study of common CT examinations demonstrated significant variability in radiation dosages for similar studies. Despite the relatively low doses associated with sinus scans, widely publicized studies and events have generated a renewal of physician, public, and regulatory agency awareness and concern regarding medical radiation exposure. METHODS: Phantom measurements and/or radiation dosage reports from CT scanners utilized by a large otolaryngology group in California were reviewed and compared. Different types of CT scanners from multiple manufacturers were included. RESULTS: There was nearly a 10-fold difference (0.15-1.45 mSv) in radiation between scans obtained from in-office, hospital-based, and outpatient imaging facility CT scanners. CONCLUSION: Significant relative variability can exist in radiation dosages associated with routine sinus CT scans obtained in different locations. There is a need for increased awareness and understanding among otolaryngologists and their patients regarding medical radiation exposure. All otolaryngologists should constantly consider the principle of "as low as reasonably achievable" (ALARA). Shielding, pediatric protocols, and other dosage reduction measures should be utilized whenever possible.

Balloon sinuplasty versus surgical management of chronic rhinosinusitis.

The first US Food and Drug Administration-approved dilating balloon catheter system for obstructed paranasal sinus drainage pathways was introduced in September 2005. It was discussed as an alternative treatment option for traditional endoscopic sinus surgery for those suffering from chronic rhinosinusitis. Widespread patient interest has ensued, although controversy regarding application of this device continues. Many otolaryngologists have been trained to use the device, and more than 88,000 patients have had surgery using this device. Like similar dilating catheters used in other specialties to relieve obstruction, it is a minimally invasive tool for mucosal-sparing dilation of sinus ostia or sinus outflow tracts. Although studies have been completed that demonstrate feasibility, safety, and long-term patency of dilated sinuses, the evolving indications for its use remain controversial. Referring physicians and patients can expect a range of opinions on the role of these devices in the treatment of rhinosinusitis for the foreseeable future.

High-resolution genomic analysis in Waldenström's macroglobulinemia identifies disease-specific and common abnormalities with marginal zone lymphomas.

Cytogenetic analyses have been historically limited in Waldenström's macroglobulinemia (WM) by the difficulty to obtain tumor metaphases. Thus, few recurrent karyotypic abnormalities have been reported and the molecular consequences of these imbalances are largely unknown. We used an array-based comparative genomic hybridization approach to better characterize the recurrent chromosome abnormalities associated with WM pathogenesis and to compare them with the publicly available findings in other B-cell neoplasias. The majority of the recurrent chromosome abnormalities identified in WM were shared with marginal zone lymphomas (MZL), as deletions of 6q23 and 13q14 and gains of 3q13-q28, 6p and 18q. On the other hand, gains of 4q and 8q were recurrently identified in WM but have not been described as being common abnormalities in MZL. The genetic consequences of these specific abnormalities remain elusive and further studies are critical to refine the search and to precise the molecular pathways affected by these abnormalities.

Mean glandular dose estimation using MCNPX for a digital breast tomosynthesis system with tungsten/aluminum and tungsten/aluminum+silver x-ray anode-filter combinations.

Breast cancer screening with x-ray mammography, using one or two projection images of the breast, is an indispensible tool in the early detection of breast cancer in women. Digital breast tomosynthesis (DBT) is a 3D imaging technique that promises higher sensitivity and specificity in breast cancer screening at a similar radiation dose to conventional two-view screening mammography. In DBT a 3D volume is reconstructed with anisotropic voxels from a limited number of x-ray projection images acquired over a limited angle. Although the benefit of early cancer detection through screening mammography outweighs the potential risks associated with radiation, the radiation dosage to women in terms of mean glandular dose (MGD) is carefully monitored. This work studies the MGD arising from a prototype DBT system under various parameters. Two anode/filter combinations (W/Al and W/Al+Ag) were investigated; the tube potential ranges from 20 to 50 kVp; and the breast size varied between 4 and 10 cm chest wall-to-nipple distance and between 3 and 7 cm compressed breast thickness. The dosimetric effect of breast positioning with respect to the imaging detector was also reviewed. It was found that the position of the breast can affect the MGD by as much as 5% to 13% depending on the breast size.

Subcutaneous emphysema and pneumomediastinum complicating tonsillectomy.

BACKGROUND: Subcutaneous emphysema and pneumomediastinum are very rare complications of tonsillectomy. OBJECTIVES: To report on a case study and a literature review of these conditions; to discuss the management and controversial causes. DESIGN: Case study and literature review. METHODS: A case is presented of subcutaneous emphysema and pneumomediastinum complicating tonsillectomy. All published reports of these complications dating back to 1910 are reviewed. RESULTS: An additional 30 cases of subcutaneous emphysema and 9 of pneumomediastinum have been reported following tonsillectomy. This group of 32 patients with emphysematous complications included 17 male patients, 14 female, and a child of unknown sex. The mean age was 18.6 years (range, 2-65 years). All tonsillectomies were performed with a cold technique except our case. Subcutaneous emphysema was first noted intraoperatively in 8 patients (25%) a mean of 3.5 hours (range, 10 minutes to 14 hours) after the procedure in 18 patients (56%) and not until the next morning in 6 patients (19%). Most cases resolved without specific treatment or significant sequelae. Some cases were life-threatening and required urgent intervention. Others were misdiagnosed, which resulted in unnecessary surgery. CONCLUSION: Subcutaneous emphysema and pneumomediastinum are rare occurrences following tonsillectomy that should alert one to the possibility of more serious complications.

Tomographic mammography using a limited number of low-dose cone-beam projection images.

A method is described for using a limited number (typically 10-50) of low-dose radiographs to reconstruct the three-dimensional (3D) distribution of x-ray attenuation in the breast. The method uses x-ray cone-beam imaging, an electronic digital detector, and constrained nonlinear iterative computational techniques. Images are reconstructed with high resolution in two dimensions and lower resolution in the third dimension. The 3D distribution of attenuation that is projected into one image in conventional mammography can be separated into many layers (typically 30-80 1-mm-thick layers, depending on breast thickness), increasing the conspicuity of features that are often obscured by overlapping structure in a single-projection view. Schemes that record breast images at nonuniform angular increments, nonuniform image exposure, and nonuniform detector resolution are investigated in order to reduce the total x-ray exposure necessary to obtain diagnostically useful 3D reconstructions, and to improve the quality of the reconstructed images for a given exposure. The total patient radiation dose can be comparable to that used for a standard two-view mammogram. The method is illustrated with images from mastectomy specimens, a phantom, and human volunteers. The results show how image quality is affected by various data-collection protocols.

Fungus-specific IgG and IgE in allergic fungal rhinosinusitis.

OBJECTIVE: Our study goal was to study fungus-specific immunoglobulins G (sIgG) and E (sIgE) in polypoid rhinosinusitis with and without evidence of allergic fungal rhinosinusitis (AFS). STUDY DESIGN AND SETTING: A prospective analysis was conducted of fungal sIgG and sIgE using a 9-mold RAST panel in 13 AFS, 11 AFS-like, and 27 non-AFS polypoid rhinosinusitis patients. Nonpolyp controls included 17 volunteers with allergic rhinitis and 11 with no atopic history. RESULTS: All groups had elevated fungal sIgG levels. Polyps, increasing polyp severity, and AFS were associated with elevated fungal sIgG to a greater number of molds. The AFS group had sIgE elevations (>or=class II) to an average of 5 molds versus only 0.1 in the non-AFS polyp group. Total IgE was 971 U/mL versus 64 U/mL, respectively. CONCLUSIONS: Multiple elevations of fungal sIgE are adequate diagnostic evidence of these fungi when fungal cultures and histologic examinations are negative in diagnosing AFS. The significance of increased fungal sIgG remains unclear. SIGNIFICANCE: Early recognition of AFS may be facilitated by screening polypoid rhinosinusitis patients with total serum IgE and RAST testing.

High-sensitivity CCD-based X-ray detector.

The detector is designed for imaging measurements requiring relatively high sensitivity and high spatial resolution. The detector can discriminate single X-ray photons, yet has the wide dynamic range ( approximately 10000:1) associated with integrating detectors. A GdO2S2 phosphor screen converts the incoming X-ray image into an optical image. The optical image is coupled (without demagnification) to the CCD image sensor using a fiber optic faceplate. The CCD (Philips Semiconductors) has an area of 4.9 x 8.6 cm with 4000 x 7000 12 microm pixels. A single 12 keV X-ray photon produces a signal of 100 e-. With 2 x 2 pixel binning, the total noise per 24 microm pixel in a 100 s image is approximately 30 e- the detective quantum efficiency is >0.6 at 1 X-ray photon per pixel, and the full image can be read out in <4 s. The spatial resolution is 50 microm. The CCD readout system is fully computer-controlled, allowing flexible operation in time-resolved experiments. The detector has been characterized using visible-light images, X-ray images and time-resolved muscle diffraction measurements.