Citations

Abstract The FKBP5 gene encodes the FKBP51 immunophilin, a negative regulator of AKT. Variability in level of FKBP5 expression is a major factor contributing to variation in response to several classes of chemotherapeutic agents including gemcitabine, first line treatment for pancreatic cancer. Genetic variation of FKBP5 could influence its expression, function, and, ultimately, treatment response of pancreatic cancer. We set out to comprehensively study the role of genetic variation in FKBP5 identified by Next Generation DNA resequencing in response to gemcitabine treatment of pancreatic cancer by utilizing both tumor and germline DNA samples from 43 pancreatic cancer patients, including 19 paired tumor-normal samples. Genotype-phenotype association studies with overall survival (in tumor only) as well as with FKBP5 gene expression were performed using the same samples in which Next Generation DNA resequencing had been performed, followed by functional genomic studies of top selected single nucleotide polymorphisms (SNPs). In-depth resequencing identified 404 FKBP5 SNPs in both normal and tumor DNA patient samples. SNPs with the smallest p-values for association with FKBP5 survival or expression were subjected to functional genomic studies. Electromobility shift assay (EMSA) showed that the rs73748206 “T” allele altered DNA-protein binding patterns, consistent with a significantly increased reporter gene activity. The effect of rs73748206 was also confirmed by mRNA expression studies using lymphoblastoid cell lines (LCL) derived from the same patients from whom DNA used for resequencing had been obtained. This comprehensive FKBP5 resequencing study provides insight into the role of inheritance in variation in response to gemcitabine therapy of pancreatic cancer. Citation Format: Katarzyna A. Ellsworth, Bruce W. Eckloff, Liang Li, Irene Moon, Brooke L. Fridley, Greg D. Jenkins, Erin Carlson, Abra Brisbin, Ryan Abo, William Bamlet, Gloria Petersen, Eric D. Wieben, Liewei Wang. Contribution of FKBP5 genetic variation to gemcitabine treatment and survival in pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2209. doi:10.1158/1538-7445.AM2013-2209

Abstract Background: Cutaneous T-cell neoplasms display markedly heterogeneous clinical behavior despite often similar pathologic features. For example, transformed mycosis fungoides (tMF) has a poor prognosis and requires intensive therapy whereas lymphomatoid papulosis (LyP) is an indolent lymphoproliferative disorder with spontaneously resolving lesions. These entities have overlapping histologic features and no molecular tools currently exist to aid in subclassification. Methods: We identified 11 T-cell neoplasms with histologic appearances distinct from previously described cutaneous T-cell neoplasms but with features overlapping those of both tMF and LyP. The phenotypic and genetic characteristics of the tumors were studied using immunohistochemistry and fluorescence in situ hybridization, respectively. Clinical data on presentation, treatment, evolution of the lesions, and follow-up were obtained. Results: All patients were older adults (mean age, 75 yr; range, 67-88 yr; 9M:2F). Clinical presentations were similar, with papulonodular skin lesions (0.3-1.0 cm) restricted to a single body area in all but two patients. Histologically there was an extensive atypical lymphoid infiltrate in the epidermis and a dermal tumor containing large transformed cells with numerous mitotic figures and apoptotic bodies. All tumors had a T-cell phenotype and expressed CD30 in both dermal and epidermal components. No case expressed ALK. Most cases had a high proliferative rate (>80%) by Ki67 staining. FISH analysis demonstrated rearrangements of the DUSP22-IRF4 locus on 6p25.3 in all cases. No patient had evidence of systemic disease on imaging studies. In 4 untreated patients, papules began to regress spontaneously a few weeks after presentation, with complete resolution within a month or two. Seven patients were treated with local excision (with or without cryotherapy) or radiotherapy. All non-excised lesions ultimately regressed. All patients were alive at last follow-up (median, 21 mo; range, 7-150 mo). Cutaneous recurrences occurred in 5 patients. At last follow-up only 1 patient had active lesions, which were confined to the presenting site. The remaining 10 patients had been disease-free from 2 to 32 months. Conclusions: Despite pathologic features mimicking an aggressive lymphoma, the benign clinical course observed in all 11 patients suggests these cases represent a newly recognized subtype of LyP. These neoplasms are characterized by 6p25.3 rearrangements, representing the first recurrent genetic abnormality identified in LyP. In contrast, we previously have shown absence of these rearrangements in tMF. Distinction of LyP from tMF is critical in this older patient population unlikely to tolerate intensive therapy. Thus, detection of 6p25.3 rearrangements represents a new tool for molecular classification of cutaneous T-cell neoplasms. Citation Format: Andrew L. Feldman, Laszlo J. Karai, Marshall E. Kadin, Eric D. Hsi, Jason C. Sluzevich, Rhett P. Ketterling, Ryan A. Knudson. Discovery of a previously undescribed cutaneous T-cell neoplasm with chromosomal rearrangements of 6p25.3. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1208. doi:10.1158/1538-7445.AM2013-1208

Abstract Background: Preplanned combined analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial and North Central Cancer Treatment Group (NCCTG) (Alliance) N9831 Trial compared adjuvant chemotherapy with or without trastuzumab in women with HER2-positive breast cancer. The initial results were reported in 2005 and updated in early 2011 Methods: 4045 patients with HER2-positive operable breast cancer were enrolled to receive doxorubicin plus cyclophosphamide followed by paclitaxel with or without trastuzumab in both trials. The definitive analysis for OS will occur when 710 events have been reported. Results: Median time on study is 8 years. The required number of events have occurred for the definitive analysis for OS to be conducted by the end of September 2012. Updated analyses of disease free survival and related subgroups will also be presented. Supported by NCI grants U10-CA-12027, -69651, -37377, -69974, -44066, U24-CA-114732, CA25224; Breast Cancer Research Foundation; Genentech 35–03 Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S5-5.

Background— Massively parallel, high-throughput sequencing technology is helping to generate new insights into the genetic basis of human diseases. We used whole exome sequencing to identify the mutation underlying a syndrome affecting 2 siblings with aortic hypoplasia, calcific atherosclerosis, systolic hypertension, and premature cataract. Methods and Results— Exonic regions were captured and sequenced using a next-generation sequencing platform to generate 100 bases paired-end reads. A computational genomic data analysis pipeline was used to perform quality control, align reads to a reference genome, and identify genetic variants; findings were confirmed using a different exome analyses pipeline. The 2 siblings were homozygous for a rare missense mutation (Ser818Cys) in INO80D , a subunit of the human INO80 chromatin remodeling complex. Homozygosity mapping and Sanger sequencing confirmed that the mutation is located in one of the runs of homozygosity on chromosome 2. INO80D encodes a key subunit of the human IN080 complex, a multiprotein complex involved in DNA binding, chromatin modification, organization of chromosome structure, and ATP-dependent nucleosome sliding. By introducing a new disulphide-bond in the protein product and also disrupting the composition of low-complexity regions, the Ser818Cys mutation may affect INO80D function, protein–protein interactions, and chromatin remodeling. Conclusions— Our findings suggest a link between the Ser818Cys mutation in INO80D , a subunit of the human INO80 chromatin remodeling complex, and accelerated arterial aging.

Pulmonary arterial hypertension (PAH) is a chronic, symptomatic, life‐threatening illness; however, it is complex, with variable expression regarding impact on quality of life (QOL). This study investigated attitudes and comfort of physicians regarding palliative care (PC) for patients with PAH and explored potential barriers to PC in PAH. An internet‐based, mixed‐methods survey was distributed to Pulmonary Hypertension Clinicians and Researchers, a professional organization within the Pulmonary Hypertension Association. Only responses from physicians involved in clinical care of patients with PAH were analyzed. Of 355 clinicians/researchers, 79 (22%) returned surveys, including 76 (21%) providers involved in clinical care. Responding physicians were mainly pulmonologists (67%), practiced in university/academic medical centers (89%), had been in practice a mean of 12 ± 7 years, cared for a median of 100 PAH patients per year, and reported a high level of confidence in managing PAH (87%), advanced PAH‐specific pharmacologic interventions (95%), and end‐of‐life care (88%). Smaller proportions were comfortable managing pain (62%) and QOL issues (78%). Most physicians (91%) reported utilizing PC consultation at least once in the prior year, primarily in the setting of end‐of‐life/active dying (59%), hospice referral (46%), or symptomatic dyspnea/impaired QOL (40%). The most frequent reasons for not referring patients to PC included nonapproval by the patient/family (51%) and concern that PC is “giving up hope” (43%). PAH may result in symptoms that impair QOL despite optimal PAH therapy; however, PC awareness and utilization for PAH providers is low. Opportunities may exist to integrate PC into care for PAH patients.

Several groups have reported cases of rectal cancer with carcinomatous involvement of the lumbosacral plexus and sciatic, obturator, pudendal, or spinal nerves. To our best knowledge, clear examples of perineural tumor spread in rectal carcinoma have not yet been described. We retrospectively reviewed clinical data and imaging studies of three patients with primary or recurrent rectal cancer involving the lumbosacral plexus. Imaging studies included MRI and 18FDG PET/CT scans in all (n = 3) patients, histological samples were available in two (n = 2). Imaging studies demonstrated distinct features of tumor spread from the organ to the plexus and beyond in all cases (n = 3), histological specimens demonstrated perineural involvement thus supporting our theory (n = 2). We present these three cases of perineural tumor spread in rectal cancer as a proof of concept. We hypothesize that not only our cases, but other similar reported cases can be explained anatomically by extension of the rectal cancer to the inferior hypogastric plexus with perineural tumor spread to the lumbosacral plexus using the pelvic and sacral splanchnic nerves as conduits. Once the tumor reaches the lumbosacral plexus, it can continue to spread proximally or distally. We believe that perineural spread of colon cancer represents an important, under‐recognized mechanism of recurrence to neighboring major nerves in the pelvis. Clin. Anat. 28:136–143, 2015. © 2014 Wiley Periodicals, Inc.

Abstract Previous studies have analyzed patterns of transcription, transcription factor (TF) binding or mapped nucleosome occupancy across the genome. These suggest that the three aspects are genetically connected but the cause and effect relationships are still unknown. For example, physiologic TF binding studies involve many TFs, consequently, it is difficult to assign nucleosome reorganization to the binding site occupancy of any particular TF. Therefore, several aspects remain unclear: does TF binding influence nucleosome (re)organizations locally or impact the chromatin landscape at a more global level; are all or only a fraction of TF binding a result of reorganization in nucleosome occupancy and do all TF binding and associated changes in nucleosome occupancy result in altered gene expression? With these in mind, following characterization of two states (before and after induction of a single TF of choice) we determined: (i) genomic binding sites of the TF, (ii) promoter nucleosome occupancy and (iii) transcriptome profiles. Results demonstrated that promoter-proximal TF binding influenced expression of the target gene when it was coupled to nucleosome repositioning at or close to its binding site in most cases. In contrast, only in few cases change in target gene expression was found when TF binding occurred without local nucleosome reorganization.

Objective To assess the occurrence of acute coronary syndrome (ACS) in patients with giant cell arteritis (GCA) compared to subjects without GCA. Methods We retrospectively reviewed a population‐based incidence cohort of Olmsted County, Minnesota residents with GCA diagnosed in 1950–2009. We compared this cohort with a cohort of patients without GCA of similar age, sex, and calendar year from the same population. Results The study included 245 patients with GCA and 245 non‐GCA subjects. The mean ± SD Framingham cardiovascular risk score was 30% ± 19% in GCA patients and 34% ± 23% in non‐GCA subjects ( P = 0.096) at the incidence/index date. Diabetes mellitus was significantly less common in GCA patients than non‐GCA subjects at the index date. The mean high‐density lipoprotein was higher and triglycerides were lower, with fewer patients taking lipid‐lowering medications in the GCA cohort compared to the non‐GCA cohort at the index date. During followup, no difference between the 2 cohorts was noted in the overall rate of ACS events (hazard ratio 0.74, 95% confidence interval 0.44–1.26). Overall thrombosis in myocardial infarction scores were similar in both cohorts. Revascularization procedures were done less frequently in GCA than in non‐GCA subjects (19% versus 50%; P = 0.015). Post‐ACS hospital length of stays and complications were similar in both cohorts. Conclusion Multiple cardiovascular risk factors are less atherogenic at incidence of GCA. There is no overall increased risk of ACS in patients with GCA.