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Denis L. Jardim Sherri Z. Millis Jeffrey S. Ross Michelle SueAnn Woo Siraj M. Ali Razelle Kurzrock 《The oncologist》2021,26(1):e78-e89
BackgroundWe describe the landscape of cyclin and interactive gene pathway alterations in 190,247 solid tumors.MethodsUsing comprehensive genomic profiling (315 genes, >500× coverage), samples were analyzed for alterations in activating/sensitizing cyclin genes (CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B [loss], CDKN2A [loss], SMARCB1), hormone genes (estrogen receptor 1 [ESR1], androgen receptor [AR]), and co‐alterations in genes leading to cyclin inhibitor therapeutic resistance (RB1 and CCNE1).ResultsAlterations in at least one cyclin activating/sensitizing gene occurred in 24% of malignancies. Tumors that frequently harbored at least one cyclin alteration were brain gliomas (47.1%), esophageal (40.3%) and bladder cancer (37.9%), and mesotheliomas (37.9%). The most frequent alterations included CDKN2A (13.9%) and CDKN2B loss (12.5%). Examples of unique patterns of alterations included CCND1 amplification in breast cancer (17.3%); CDK4 alterations in sarcomas (12%); CCND2 in testicular cancer (23.4%), and SMARCB1 mutations in kidney cancer (3% overall, 90% in malignant rhabdoid tumors). Alterations in resistance genes RB1 and CCNE1 affected 7.2% and 3.6% of samples. Co‐occurrence analysis demonstrated a lower likelihood of concomitant versus isolated alterations in cyclin activating/sensitizing and resistance genes (odds ratio [OR], 0.35; p < .001), except in colorectal, cervical, and small intestine cancers. AR and cyclin activating/sensitizing alterations in prostate cancer co‐occurred more frequently (vs. AR alterations and wild‐type cyclin activating/sensitizing alterations) (OR, 1.79; p < .001) as did ESR1 and cyclin activating/sensitizing alterations in breast (OR, 1.62; p < .001) and cervical cancer (OR, 4.08; p = .04) (vs. ESR1 and cyclin wild‐type activating/sensitizing alterations).ConclusionCyclin pathway alterations vary according to tumor type/histology, informing opportunities for targeted therapy, including for rare cancers.Implications for PracticeCyclin pathway genomic abnormalities are frequent in human solid tumors, with substantial variation according to tumor site and histology. Opportunities for targeted therapy emerge with comprehensive profiling of this pathway. 相似文献
104.
Muna A. Al Dhaibani Ayman W. El-Hattab Kathryn B. Holroyd Jennifer Orthmann-Murphy Valerie A. Larson Khurram A. Siddiqui 《Journal of neurogenetics》2018,32(1):1-5
We report a consanguineous family with three affected siblings with novel mutation in the KCNJ10 gene. All three presented with central nervous system symptoms in the form of infantile focal seizures, ataxia, slurred speech with early developmental delay and intellectual disability in two siblings. None had any associated electrolyte abnormalities and no symptomatic hearing deficits were observed. 相似文献
105.
Ersilia M. DeFilippis Avinainder Singh Sanjay Divakaran Ankur Gupta Bradley L. Collins David Biery Arman Qamar Amber Fatima Mattheus Ramsis Daniel Pipilas Roxanna Rajabi Monica Eng Jon Hainer Josh Klein James L. Januzzi Khurram Nasir Marcelo F. Di Carli Deepak L. Bhatt Ron Blankstein 《Journal of the American College of Cardiology》2018,71(22):2540-2551
Background
Substance abuse is increasingly prevalent among young adults, but data on cardiovascular outcomes remain limited.Objectives
The objectives of this study were to assess the prevalence of cocaine and marijuana use in adults with their first myocardial infarction (MI) at ≤50 years and to determine its association with long-term outcomes.Methods
The study retrospectively analyzed records of patients presenting with a type 1 MI at ≤50 years at 2 academic hospitals from 2000 to 2016. Substance abuse was determined by review of records for either patient-reported substance abuse during the week before MI or substance detection on toxicology screen. Vital status was identified by the Social Security Administration’s Death Master File. Cause of death was adjudicated using electronic health records and death certificates. Cox modeling was performed for survival free from all-cause and cardiovascular death.Results
A total of 2,097 patients had type 1 MI (mean age 44.0 ± 5.1 years, 19.3% female, 73% white), with median follow-up of 11.2 years (interquartile range: 7.3 to 14.2 years). Use of cocaine and/or marijuana was present in 224 (10.7%) patients; cocaine in 99 (4.7%) patients, and marijuana in 125 (6.0%). Individuals with substance use had significantly lower rates of diabetes (14.7% vs. 20.4%; p = 0.05) and hyperlipidemia (45.7% vs. 60.8%; p < 0.001), but they were significantly more likely to use tobacco (70.3% vs. 49.1%; p < 0.001). The use of cocaine and/or marijuana was associated with significantly higher cardiovascular mortality (hazard ratio: 2.22; 95% confidence interval: 1.27 to 3.70; p = 0.005) and all-cause mortality (hazard ratio: 1.99; 95% confidence interval: 1.35 to 2.97; p = 0.001) after adjusting for baseline covariates.Conclusions
Cocaine and/or marijuana use is present in 10% of patients with an MI at age ≤50 years and is associated with worse all-cause and cardiovascular mortality. These findings reinforce current recommendations for substance use screening among young adults with an MI, and they highlight the need for counseling to prevent future adverse events. 相似文献106.
John W. Nance Jr Irfan M. Khurram Saman Nazarian Jane DeWire Hugh Calkins Stefan L. Zimmerman 《Medicine》2015,94(37)
Cardiac magnetic resonance (CMR) imaging is increasingly used to evaluate patients with atrial fibrillation (AF) before pulmonary vein antral isolation (PVAI). The purpose of this study was to assess the incidence and pattern of left ventricular (LV) late gadolinium enhancement (LGE) in patients undergoing CMR before PVAI and compare the clinical and demographic differences of patients with and without LV LGE.Clinical and demographic data on 62 patients (mean age 61 ± 7.9, 69% male) undergoing CMR before PVAI for AF were collected. Two observers, masked to clinical histories, independently recorded the prevalence, extent (number of myocardial segments), and pattern (subendocardial, midmyocardial, or subepicardial) of LV LGE in each patient. Clinical and demographic predictors of LV LGE were determined using logistic regression.Twenty-three patients (37%) demonstrated LV LGE affecting a mean of 3.0 ± 2.1 myocardial segments. There was no difference in LV ejection fraction between patients with and without LGE, and most (65%) patients with LGE had normal wall motion. Only age (P = 0.04) and a history of congestive heart failure (P = .03) were statistically significant independent predictors of LGE. The most common LGE pattern was midmyocardial, seen in 17 of 23 (74%) patients. Only 4 of 23 (17%) patients had LGE in an “expected” pattern based on clinical history. Of the remaining 19 patients, 4 had known congestive heart failure, 5 nonischemic cardiomyopathy, 4 known coronary artery disease, and 2 prior aortic valve replacement. Six of 23 (26%) patients had no known coronary artery, valvular, or myocardial disease.There is a high prevalence of unexpected LV scar in patients undergoing CMR before PVAI for AF, with most patients demonstrating a nonischemic pattern of LV LGE and no wall motion abnormalities (ie, subclinical disease). The high prevalence of unexpected LGE in these patients may argue for CMR as the modality of choice for imaging integration before PVAI, especially given the demonstrated prognostic value of LGE in this and other patient populations. 相似文献
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108.
Jeeyun Lee Hee Cheol Kim Jung Yong Hong Kai Wang Sun Young Kim Jiryeon Jang Seung Tae Kim Joon Oh Park Ho Yeong Lim Won Ki Kang Young Suk Park Jiyun Lee Woo Yong Lee Yoon Ah Park Jung Wook Huh Seong Hyeon Yun In-Gu Do Seok Hyung Kim Sohail Balasubramanian Philip J. Stephens Jeffrey S. Ross Gang Gary Li Zachary Hornby Siraj M. Ali Vincent A. Miller Kyoung-Mee Kim Sai-Hong Ignatius Ou 《Oncotarget》2015,6(27):24320-24332
Purpose
Anaplastic lymphoma kinase (ALK) rearrangement has been detected in colorectal carcinoma (CRC) using advanced molecular diagnostics tests including exon scanning, fluorescence in situ hybridization (FISH), and next generation sequencing (NGS). We investigated if immunohistochemistry (IHC) can be used to detect ALK rearrangement in gastrointestinal malignancies.Experimental designs
Tissue microarrays (TMAs) from consecutive gastric carcinoma (GC) and CRC patients who underwent surgical resection at Samsung Medical Center, Seoul, Korea were screened by IHC using ALK monoclonal antibody 5A4. IHC positive cases were confirmed by FISH, nCounter assays, and NGS-based comprehensive genomic profiling (CGP). ALK IHC was further applied to CRC patients enrolled in a pathway-directed therapeutic trial.Results
Four hundred thirty-two GC and 172 CRC cases were screened by IHC. No GC sample was ALK IHC positive. One CRC (0.6%) was ALK IHC positive (3+) that was confirmed by ALK FISH and a novel CAD-ALK (C35; A20) fusion variant that resulted from a paracentric inversion event inv(2)(p22–21p23) was identified by CGP. One out of 50 CRC patients enrolled in a pathway-directed therapeutic trial was ALK IHC positive (3+) confirmed by ALK FISH and found to harbor the EML4-ALK (E21, A20) fusion variant by CGP. Growth of a tumor cell line derived from this EML4-ALK CRC patient was inhibited by ALK inhibitors crizotinib and entrectinib.Conclusions
ALK IHC is a viable screening strategy for identifying ALK rearrangement in CRC. ALK rearrangement is a potential actionable driver mutation in CRC based on survival inhibition of patient tumor-derived cell line by potent ALK inhibitors. 相似文献109.
110.
Jamil AZ Iqbal K Gondal TM Iqbal W Fawad-ur-Rahman Mirza KA 《Journal of the College of Physicians and Surgeons--Pakistan : JCPSP》2012,22(7):464-465
We report a case of bilateral loss of pupillary light reflex and accommodation following 360° peripheral retinal laser therapy. A 24 years old male underwent prophylactic laser barrage for peripheral retinal lattice degenerations. Soon after the procedure, he developed bilateral loss of pupillary light reflex and accommodation. The patient faced difficulty while doing near work. On instillation of 0.125% pilocarpine, both pupils demonstrated the phenomenon of denervation supersensitivity. Damage to the short ciliary nerves was the most likely mechanism responsible for this adverse outcome. 相似文献