Advances in next-generation sequencing and emerging technologies for hematologic malignancies.

Innovations in molecular diagnostics have often evolved through the study of hematologic malignancies. Examples include the pioneering characterization of the Philadelphia chromosome by cytogenetics in the 1970s, the implementation of polymerase chain reaction for high-sensitivity detection and monitoring of mutations and, most recently, targeted next- generation sequencing to drive the prognostic and therapeutic assessment of leukemia. Hematologists and hematopath- ologists have continued to advance in the past decade with new innovations improving the type, amount, and quality of data generated for each molecule of nucleic acid. In this review article, we touch on these new developments and discuss their implications for diagnostics in hematopoietic malignancies. We review advances in sequencing platforms and library preparation chemistry that can lead to faster turnaround times, novel sequencing techniques, the development of mobile laboratories with implications for worldwide benefits, the current status of sample types, improvements to quality and reference materials, bioinformatic pipelines, and the integration of machine learning and artificial intelligence into mol- ecular diagnostic tools for hematologic malignancies.

Tumor Mutational Burden Testing in Solid Tumors.

A 58-year-old man with diabetes, chronic kidney disease, and JAK2-positive myeloproliferative neoplasm is referred for newly diagnosed oligometastatic prostate cancer with substantial urinary symptoms. What would you do next?

Comparison of Cervical Cancer Screen Results on Female-to-Male Transgender Patients With Female Patients.

OBJECTIVES: There are limited data on cervical screen results from female-to-male (FTM) transgender patients. Herein, we compiled demographic information and cervical screen testing on FTM transgender patients and compared with age-appropriate controls. METHODS: A search of our previous and current databases was performed for Papanicolaou (Pap) tests from patients taking testosterone and/or with a diagnosis of gender dysphoria, transsexualism, or transvestism. Patient data were reviewed. Relative risks of abnormal Pap smear and human papillomavirus (HPV) infection were calculated against age-matched controls. RESULTS: Eighty-nine Pap tests from FTM transgender individuals were identified, with a mean age of 31.3 years (range, 21-60 years). The Pap test diagnoses were distributed as follows: negative for intraepithelial lesion (n = 84, 94.4%), atypical squamous cells of undetermined significance (n = 0), low-grade intraepithelial lesion (n = 4, 4.5%), and high-grade squamous intraepithelial lesion (n = 1, 1.1%). Fifty (56.2%) patients had concurrent high-risk HPV testing with four (8%) positive results. Relative risk was 0.625 (95% confidence interval [CI], 0.25-1.59; P = .32) for an abnormal Pap test and 0.55 (95% CI, 0.19-1.52; P = .24) for HPV compared with 267 age-matched controls. Of note, 13.5% of patients older than 21 years had documentation of never having a prior Pap test in our medical record. CONCLUSIONS: In our study, FTM transgender individuals were not at a higher or lower risk of HPV infection or abnormal Pap test result compared with women. However, larger studies are needed to support our findings.

A Novel NIPBL-NACC1 Gene Fusion Is Characteristic of the Cholangioblastic Variant of Intrahepatic Cholangiocarcinoma.

We report a novel NIPBL-NACC1 gene fusion in a rare primary hepatic neoplasm previously described as the "cholangioblastic variant of intrahepatic cholangiocarcinoma." The 2 index cases were identified within our consultation files as morphologically distinctive primary hepatic neoplasms in a 24-year-old female and a 54-year-old male. The neoplasms each demonstrated varied architecture, including trabecular, organoid, microcystic/follicular, and infiltrative glandular patterns, and biphasic cytology with large, polygonal eosinophilic cells and smaller basophilic cells. The neoplasms had a distinctive immunoprofile characterized by diffuse labeling for inhibin, and patchy labeling for neuroendocrine markers (chromogranin and synaptophysin) and biliary marker cytokeratin 19. RNA sequencing of both cases demonstrated an identical fusion of NIBPL exon 8 to NACC1 exon 2, which was further confirmed by break-apart fluorescence in situ hybridization assay for each gene. Review of a tissue microarray including 123 cases originally diagnosed as well-differentiated neuroendocrine neoplasm at one of our hospitals resulted in identification of a third case with similar morphology and immunophenotype in a 52-year-old male, and break-apart fluorescence in situ hybridization probes confirmed rearrangement of both NIPBL and NACC1. Review of The Cancer Genome Atlas (TCGA) sequencing data and digital images from 36 intrahepatic cholangiocarcinomas (www.cbioportal.org) revealed one additional case with the same gene fusion and the same characteristic solid, trabecular, and follicular/microcystic architectures and biphasic cytology as seen in our genetically confirmed cases. The NIPBL-NACC1 fusion represents the third type of gene fusion identified in intrahepatic cholangiocarcinoma, and correlates with a distinctive morphology described herein.

Contemporary Characterization and Recategorization of Adult Unclassified Renal Cell Carcinoma.

Our recent study of early-onset unclassified eosinophilic renal cell carcinoma (RCC) demonstrated that two third of cases could be reclassified by performing a limited number of immunohistochemistry stains. Following the same approach, we aimed to investigate what proportion of adult unclassified RCC could be reclassified. We identified 79 cases. The mean age at presentation was 58 years (range, 29 to 84 y). Tumors were grouped based on their predominant morphologic features as oncocytic (n=23); papillary (n=22); clear cell (n=22); mucinous tubular and spindle cell (MTSC; n=5); rhabdoid (n=4); or lacking a dominant pattern (n=3). By reviewing the morphologic features and performing ancillary studies, we were able to reclassify 10 cases (13%). Four cases were positive for CK20 and showed morphologic features consistent with eosinophilic solid and cystic RCC. Four cases were reclassified as MTSC based on VSTM2A expression by RNA in situ hybridization. One case was negative for SDHB and reclassified as succinate dehydrogenase-deficient RCC. None of the cases showed loss of expression of fumarate hydratase. One case was diffusely positive for CK7 and negative for CD117 and reclassified as a low-grade oncocytic tumor. Four cases were positive for both cathepsin-K and TFE3 by immunohistochemistry, although fluorescence in situ hybridization failed to identify rearrangement in either TFE3 or TFEB genes. Of the tumors that remained unclassified, those with oncocytic features were less likely to be a high grade (odds ratio [OR]=0.22, P=0.013) or advanced stage (OR=0.19, P=0.039) and were more common in women (OR=3.4, P=0.05) compared with those without oncocytic features. Tumors with rhabdoid morphology were associated with advanced stage (relative risk=3.6, P=0.009), while tumors with clear cell or papillary features had a wide range of grades and stages at presentation. In summary, the most frequent reclassified entity is eosinophilic solid and cystic RCC. Investigation of expression of succinate dehydrogenase or fumarate hydratase in individuals older than 35 years with unclassifiable tumors is low yield in the absence of specific morphologic features. A subset of MTSC without well-developed morphologic features can be reclassified by using RNA-ISH for VSTM2A. Recognition of more-recently described RCC subtypes allows for their distinction from the unclassified subtype and improves the prognostic information provided.

Pediatric Idiopathic Basal Ganglia Calcification and Spherocytosis With Chromosome 8p11 Deletion.

Idiopathic basal ganglia calcification (IBGC), also known as Fahr disease, is a rare neurodegenerative disorder characterized by the accumulation of extensive parenchymal and vascular calcifications in the basal ganglia, with variable calcifications elsewhere in the brain. Typically, IBGC presents with neurologic and psychiatric symptoms in middle-aged adults. Recent genetic studies have identified alterations in 4 genes causing IBGC, including alterations in SLC20A2 on chromosome 8p11.2. Currently, there are no clinical descriptions of patients with IBGC occurring within the context of a complex genetic syndrome. Here, we present a case of pediatric 8p11 deletion with IBGC, hereditary spherocytosis, vitreoretinopathy, and focal cortical dysplasia. We review multiple cases of IBGC with pediatric onset due to SLC20A2 deletion in the literature, and raise the consideration of IBGC in the evaluation of pediatric patients with 8p11.2 deletion syndromes.

The Effect of Total Cost Information on Consumer Treatment Decisions: An Experimental Survey.

BACKGROUND: Unrestrained use of expensive, high-risk interventions runs counter to the idea of a limited medical commons. OBJECTIVE: To examine the effect of displaying the total first-year cost of implanting a left ventricular assist device (LVAD) on a hypothetical treatment decision and whether this effect differs when choosing for oneself versus for another person. DESIGN: We conducted an online survey in February 2016. The survey described the clinical course of end-stage heart failure and the risks and benefits of an LVAD. Participants were randomized to 1 of 4 scenarios, which varied by patient identity (oneself versus another person) and description of total cost. MEASUREMENTS: This study measured acceptance of LVAD implantation. Reasoning and attitudes were secondarily explored. RESULTS: We received 1211 valid responses. The mean age was 38.3 y (±12.8); 53.5% were female and 84.4% were white. Participants were more likely to accept an LVAD when shown the total cost (66.2% v. 58.0%, P = 0.003) or when choosing for another (68.0 % v. 56.4%, P < 0.001). Open-ended responses indicated that acceptors wanted to extend survival while decliners feared poor quality of life with LVAD therapy. Acceptors and decliners agreed that consumers can help lower the cost of health care, but decliners were more likely to consider cost when making health care decisions ( P < 0.001). LIMITATIONS: Limitations include the use of a hypothetical scenario, the use of paid participants, and differences between the respondents and the typical patient facing an LVAD decision. CONCLUSIONS: In this sample, being shown the total cost increased the likelihood of accepting an expensive, high-risk treatment. The results question how well consumers understand the relationship between expensive treatments and the commons.

Lung cancer: current therapies and new targeted treatments.

Lung cancer is the most frequent cause of cancer-related deaths worldwide. Every year, 1·8 million people are diagnosed with lung cancer, and 1·6 million people die as a result of the disease. 5-year survival rates vary from 4-17% depending on stage and regional differences. In this Seminar, we discuss existing treatment for patients with lung cancer and the promise of precision medicine, with special emphasis on new targeted therapies. Some subgroups, eg-patients with poor performance status and elderly patients-are not specifically addressed, because these groups require special treatment considerations and no frameworks have been established in terms of new targeted therapies. We discuss prevention and early detection of lung cancer with an emphasis on lung cancer screening. Although we acknowledge the importance of smoking prevention and cessation, this is a large topic beyond the scope of this Seminar.

The Potential of Gaming in Rehabilitation of the Burn-Injured Patient.

The use of videogames for non-entertainment purposes has interested educational and behavioral researchers for decades. Recent technology advances have increased the interactivity of games while maintaining reasonable costs, leading rehabilitation therapists to investigate gaming consoles as an adjunct to traditional techniques. Obstacles to large-scale trials exist, but the transformative potential of gaming consoles should motivate developers and healthcare professionals to find solutions.

Use of Nintendo(®) Wii(™) in Physical Therapy of an Adult with Lower Extremity Burns.

OBJECTIVE: The purpose of this exploratory case study is to describe differences in rehabilitation outcomes for a 47-year-old male with bilateral lower extremity burns when using conventional therapy techniques alone versus such techniques in combination with Nintendo(®) Wii™ (Nintendo of America, Inc., Redmond, WA) videogames. MATERIALS AND METHODS: The patient received three series of rehabilitation therapy over 2 weeks. During the second series, the Wii was introduced for a portion of the otherwise conventional therapy. Under standardized conditions and upon completion of each series, the Limits of Stability test with a SMART Balance Master(®) (NeuroCom(®), Clackamas, OR) was used to measure reaction time (RT), maximum excursion (MXE), endpoint excursion (EPE), movement velocity, and directional control. The Timed Up and Go (TUG) test for functional mobility and a questionnaire assessing level of motivation and interest were administered at the end of each day; these results formed mean scores for each series. RESULTS: The patient performed better on RT and MXE during the series that combined conventional therapy with the Wii than during the two series using conventional therapy alone. Improvement on EPE was greater for combined therapy than for conventional therapy alone and continued to improve after combined therapy. The patient completed the TUG test faster during the combined Wii series. Additionally, the patient reported increased motivation and interest levels for the series using combined therapy. CONCLUSIONS: The Wii may be a feasible and valuable adjunct to traditional therapy. Improvements during the series with Wii were demonstrated for areas of balance and functional mobility. Trends toward improvement in motivation and interest with the Wii suggest its use may elicit increased patient engagement during burn rehabilitation.