Genomic landscape of circulating tumor (ct)-DNA alterations in patients with penile cancer.

6 Background: Penile cancer is a rare disease associated with HPV infection and harbors recurrent somatic genomic alterations in the ERBB (HER)-family, CDKN2A, TP53, NOTCH1 and PIK3CA. ctDNA assay allows the noninvasive genomic profiling of malignancies and may assist with understanding molecular evolution. To our knowledge, the genomic alterations observed in ctDNA for penile cancer have not been described before. We report ctDNA profiling of patients with advanced penile cancer. Methods: Sixteen pts with metastatic penile cancer from multiple institutions in the United States that underwent ctDNA analysis using the Guardant360 platform were eligible. Three patients had at least one serial ctDNA sample. De-identified demographic data were collected. Guardant 360 is CLIA-certified ctDNA panel that assesses single nucleotide variants and copy number alterations in 68 to 73 genes for potentially actionable genomic alterations. Variants seen at least 3 times in the Catalogue of Somatic Mutations in Cancer (COSMIC) database or reported in OncoKB were considered pathogenic. Results: The median age was 64 years (range 40-77). 4 pts (25%) were documented to be post platinum-based chemotherapy. Among the entire cohort, 51 ctDNA alterations were detected (median=2, range 0-6) in 15/16 patients (94%) across 21 genes (table). Of the 51 alterations, 24 (47%) were actionable and had approved targeted therapies in other cancers. Alterations were most frequently detected in TP53 (9/16, 56%), CDKN2A (5/16, 31%), and TERT promoter (5/16, 31%) (table). In 3 patients with serial samples, 9 novel pathogenic alterations were detected in the second sample including ATM, CDKN2A, ARID1A, CCND1, CDK6, EGFR, PDGFRA, PIK3CA, and SMAD4. Conclusions: ctDNA alterations in patients with advanced penile cancer were frequently detected and appeared similar to previously described tumor tissue analyses. New alterations found on serial ctDNA assays shed light on patterns of tumor evolution and may inform drug development for this challenging orphan malignancy.[Table: see text]

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Genomic landscape of circulating tumor (ct)-DNA alterations in patients with penile cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e16027 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e16027-e16027

Author(s):

Archana Agarwal ◽

Amin Nassar ◽

Rebecca Nagy ◽

Catherine Curran ◽

Sarah Abou Alaiwi ◽

...

Keyword(s):

Penile Cancer ◽

Demographic Data ◽

Tumor Biology ◽

The United States ◽

Median Number ◽

Hpv Infection ◽

Single Nucleotide Variants ◽

Genomic Alterations ◽

Her Family ◽

Platinum Based Chemotherapy

e16027 Background: Penile cancer is a rare disease associated with HPV infection and is known to harbor recurrent somatic genomic alterations in the ERBB (HER)-family, CDKN2A, TP53, NOTCH1 and PIK3CA. ctDNA assay allows the noninvasive genomic profiling of malignancies and may assist with understanding molecular evolution of resistance. To our knowledge, the genomic alterations observed in ctDNA for penile cancer have not been described before. We report ctDNA profiling of patients with advanced penile cancer. Methods: Sixteen pts with metastatic penile cancer from multiple institutions in the United States that underwent ctDNA analysis using the Guardant360 platform were eligible. Three patients had at least one serial ctDNA sample. De-identified demographic data were collected. Guardant 360 is CLIA-certified ctDNA panel that assesses single nucleotide variants and copy number alterations in 68 to 73 genes for potentially actionable genomic alterations. Variants seen at least 3 times in the Catalogue of Somatic Mutations in Cancer (COSMIC) database or reported in OncoKB were considered pathogenic. Results: The median age was 64 years (range 40-77). 4 pts (25%) were documented to be post platinum-based chemotherapy. The median number of ctDNA alterations detected per sample was 2 (range 0-6). Overall, genomic alterations were detected in 15/16 patients (94%) across 21 genes (table 1). Alterations were most frequently detected in TP53 (9/16, 56%), CDKN2A (5/16, 31%), TERT promoter (5/16, 31%), PIK3CA (3/16, 19%) and ERBB2 (3/16, 19%). In 3 patients with serial samples, 9 novel pathogenic alterations were detected in the second sample including ATM, CDKN2A, ARID1A, CCND1, CDK6, EGFR, PDGFRA, PIK3CA, and SMAD4. Conclusions: ctDNA alterations in patients with advanced penile cancer were frequently detected with similar prevalences to previously described tumor tissue analyses. New alterations observed on serial ctDNA assays may provide insights regarding tumor biology and inform drug development. [Table: see text]

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Circulating tumor (ct)-DNA alterations in patients with testicular germ tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e16063 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e16063-e16063 ◽

Cited By ~ 1

Author(s):

Amin Nassar ◽

Archana Agarwal ◽

Rebecca Nagy ◽

Catherine Curran ◽

Sarah Abou Alaiwi ◽

...

Keyword(s):

Somatic Mutations ◽

Demographic Data ◽

Germ Cell Tumors ◽

The United States ◽

Median Number ◽

Genomic Alterations ◽

Testicular Germ Cell ◽

Dna Alterations ◽

Ctdna Analysis ◽

Serial Samples

e16063 Background: Testicular germ cell tumors (GCT) infrequently harbor somatic mutations. ctDNA assay allows the noninvasive genomic profiling of malignancies and may assist with understanding molecular evolution of resistance. To our knowledge, ctDNA genomic alterations observed in in testicular GCTs have not been heretofore described. We report ctDNA profiling of patients (pts) with testicular GCTs. Methods: 31 Pts with testicular GCTs from multiple institutions in the United States that underwent ctDNA analysis using the Guardant360 platform were eligible. Two patients had one serial ctDNA sample. De-identified demographic data were collected in addition to data for ctDNA alterations. Guardant360 is a CLIA-certified ctDNA panel that assesses single nucleotide variant and copy number alterations in 68 to 73 genes for potentially actionable genomic alterations. Variants reported at least 3 times in the Catalogue of Somatic Mutations in Cancer (COSMIC) database or found in OncoKB were considered pathogenic. Results: Of 31 patients with testicular GCTs, 162 ctDNA alterations were detected in 26 patients (84%) across 41 genes (Table). A median number of 3 alterations (range 1-19) was detected per sample. Among the 162 alterations, 88 were believed to be pathogenic and detectable in 20 patients (65%). 12/31 pts (39%) were documented to be post systemic therapy. The median age was 38 years (range 20-61). The most common pathogenic somatic alterations were KRAS (n = 12/88, 14%), CCND2 (n = 8/88, 9%), MET (n = 8/88, 9%), CDK6 (n = 7/88, 8%), TP53 (n = 6/88, 7%), and RAF1 (n = 5/88, 6%). In 2 patients with serial samples, 5 novel pathogenic alterations were detected in the second sample including FGFR2, APC, CDK6, RAF1, and MAPK1. Conclusions: ctDNA alterations were frequently detected in resistant testicular GCTs and appear similar to alterations previously described in tumor tissue analyses of testicular GCTs. Given that ctDNA offers a non-invasive means of profiling tumor DNA, further development of this promising modality is warranted to determine it's relevance in clinical practice. [Table: see text]

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Insights From Targeted Genetic Analysis of 364 Adrenocortical Carcinomas

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.339 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A168-A168

Author(s):

Nikita Pozdeyev ◽

Lauren Michelle Fishbein ◽

Laurie M Gay ◽

Ethan S Sokol ◽

Ryan Hartmaier ◽

...

Keyword(s):

Demographic Data ◽

Genomic Analysis ◽

Enrichment Analysis ◽

Median Number ◽

Therapeutic Modality ◽

Pathway Enrichment Analysis ◽

Single Nucleotide Variants ◽

Genomic Alterations ◽

Dna Mismatch ◽

Adrenocortical Carcinomas

Abstract Adrenocortical carcinoma (ACC) is a rare endocrine malignancy affecting individuals across a broad age spectrum. Disease rarity, scarcity of pre-clinical models, lack of effective targeted therapy and limited clinical trials have contributed to poor prognosis for patients with ACC. Identifying targetable genetic drivers and pathways to guide precision medicine approaches is therefore critical to improve outcomes. The purpose of this study was to analyze the genomic profile of a large cohort of ACC to identify potential therapeutic targets. FoundationOne (Foundation Medicine Inc.; FMI, Cambridge, MA) is a next-generation sequencing-based platform for somatic genetic testing in solid tumors. The FoundationOne genomic data and limited demographic data through 2018 for 364 unique ACC specimens were analyzed. The cohort of 364 tumors were from 222 females and 141 males (1 gender unknown). The mean age (SD) was 48.6 (13.6) for females and 50.6 (12.20) for males with overall median age of 52 years. A total of 3117 genomic alterations were identified impacting 457 genes. The median number of genomic alterations per tumor was 7 (range 1–56), with single nucleotide variants and indels being the most common alterations (median=4), followed by copy number alterations (median=1) and rearrangements (median=0). The most frequently altered genes were TP53 (38%), CTNNB1 (28%), ZNRF3 (17%), CDKN2A (13%), ATRX (11%), TERT promoter (10%). Several novel recurrent alterations were identified including IL7R (6%), LRP1B (8%), FRS2 (4%), PTCH1 (4%) and KRAS (3%). Pathway enrichment analysis confirmed that tumor suppressor genes (51%) and Wnt signaling pathways (51%) are the most commonly dysregulated in ACC tumors. Epigenetic alterations, including histone modification (38%), SWI/SNF (21%) and DNA methylation (8%), affected upwards of one third of ACC tumors. Mutation signature analysis identified tumors with signatures 6, 15 and 26 associated with defective DNA mismatch repair (MMR), which was not reported previously. In addition, fifty ACCs (13.7%) exhibited 60 genomic alterations in MMR genes, MLH1, MSH2, MSH6 and PMS2, which included 49 SNVs/indels, 10 CNAs and one truncating rearrangement. In addition to MMR gene alterations, potentially actionable (www.oncokb.org) genomic alterations were found in 46 genes in 213 (58.5%) ACCs. In summary, this study represents the largest to date genomic analysis of ACC that showed that over 50% of ACC tumors had potentially actionable genomic alterations. Approximately 13% of tumors had an alteration in MMR pathway, suggesting that immunotherapy is a relevant therapeutic modality in a significant subset of patients with ACC.

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Operation of a hyperbaric oxygen therapy center in Korea: Report of our experience from a setting in its nascent stages

Undersea and Hyperbaric Medicine ◽

10.22462/04.06.2019.6 ◽

2019 ◽

pp. 135-143

Author(s):

Yoon Seop Kim ◽

Yoonsuk Lee ◽

Sun Ju Kim ◽

Sung Oh Hwang ◽

Yong Sung Cha ◽

...

Keyword(s):

Critically Ill ◽

Hyperbaric Oxygen ◽

Critically Ill Patients ◽

Demographic Data ◽

Developed Countries ◽

The United States ◽

Medical Society ◽

Hyperbaric Medicine ◽

Therapy Center ◽

Hbo2 Therapy

Purpose: Hyperbaric medicine is nascent in Korea when compared to other developed countries, such as the United States and Japan. Our facility has been managed by physicians with certifications from the Undersea and Hyperbaric Medical Society (UHMS) and National Oceanic and Atmospheric Administration in diving and clinical diseases since October 2016. This study was conducted to share similar issues that are encountered during the establishment of a program in a new area through our experiences in the operation of a hyperbaric oxygen (HBO2) therapy center. Methods: In this retrospective observational study we collected data on HBO2 patients treated at our center between October 2016 and June 2018 after HBO2 was conducted by HBO2-certified physicians. We then compared demographic data of patients with data from January 2011 to September 2015 – before HBO2 operations were conducted by HBO2-certified physicians. Result: A total of 692 patients received 5,130 treatments. Twelve indicated diseases were treated using HBO2 therapy. Fifty-six critically ill patients with intubation received HBO2. Although two patients experienced seizure due to oxygen toxicity during the study period, certified physicians and inside attendant took immediate corrective action. Conclusion: After the establishment of the HBO2 center operated by physicians with certification, more patients, including critically ill patients, received HBO2 safely for various diseases. In order to improve the practice of hyperbaric medicine in Korea, the Korean Academy of Undersea and Hyperbaric Medicine (KAUHM), an advanced and well-organized academic society, should communicate often with HBO2 centers, with the aim to set Korean education programs at UHMS course levels and increase reimbursement for HBO2 therapy.

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Examining the Economic and Environmental Impacts of COVID-19 Using Earth Observation Data

Remote Sensing ◽

10.3390/rs13010005 ◽

2020 ◽

Vol 13 (1) ◽

pp. 5

Author(s):

William Straka ◽

Shobha Kondragunta ◽

Zigang Wei ◽

Hai Zhang ◽

Steven D. Miller ◽

...

Keyword(s):

Air Quality ◽

Los Angeles ◽

Environmental Impacts ◽

Demographic Data ◽

The United States ◽

Earth Observation ◽

Observation Data ◽

Washington Dc ◽

Mobility Data ◽

Earth Observation Data

The COVID-19 pandemic has infected almost 73 million people and is responsible for over 1.63 million fatalities worldwide since early December 2019, when it was first reported in Wuhan, China. In the early stages of the pandemic, social distancing measures, such as lockdown restrictions, were applied in a non-uniform way across the world to reduce the spread of the virus. While such restrictions contributed to flattening the curve in places like Italy, Germany, and South Korea, it plunged the economy in the United States to a level of recession not seen since WWII, while also improving air quality due to the reduced mobility. Using daily Earth observation data (Day/Night Band (DNB) from the National Oceanic and Atmospheric Administration Suomi-NPP and NO2 measurements from the TROPOspheric Monitoring Instrument TROPOMI) along with monthly averaged cell phone derived mobility data, we examined the economic and environmental impacts of lockdowns in Los Angeles, California; Chicago, Illinois; Washington DC from February to April 2020—encompassing the most profound shutdown measures taken in the U.S. The preliminary analysis revealed that the reduction in mobility involved two major observable impacts: (i) improved air quality (a reduction in NO2 and PM2.5 concentration), but (ii) reduced economic activity (a decrease in energy consumption as measured by the radiance from the DNB data) that impacted on gross domestic product, poverty levels, and the unemployment rate. With the continuing rise of COVID-19 cases and declining economic conditions, such knowledge can be combined with unemployment and demographic data to develop policies and strategies for the safe reopening of the economy while preserving our environment and protecting vulnerable populations susceptible to COVID-19 infection.

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Experimental Models for Studying HPV-Positive and HPV-Negative Penile Cancer: New Tools for An Old Disease

Cancers ◽

10.3390/cancers13030460 ◽

2021 ◽

Vol 13 (3) ◽

pp. 460

Author(s):

Beatriz Medeiros-Fonseca ◽

Antonio Cubilla ◽

Haissa Brito ◽

Tânia Martins ◽

Rui Medeiros ◽

...

Keyword(s):

Mouse Models ◽

Cell Lines ◽

Penile Cancer ◽

Hpv Infection ◽

Experimental Models ◽

In Vivo Models ◽

Recent Developments ◽

Key Aspects

Penile cancer is an uncommon malignancy that occurs most frequently in developing countries. Two pathways for penile carcinogenesis are currently recognized: one driven by human papillomavirus (HPV) infection and another HPV-independent route, associated with chronic inflammation. Progress on the clinical management of this disease has been slow, partly due to the lack of preclinical models for translational research. However, exciting recent developments are changing this landscape, with new in vitro and in vivo models becoming available. These include mouse models for HPV+ and HPV− penile cancer and multiple cell lines representing HPV− lesions. The present review addresses these new advances, summarizing available models, comparing their characteristics and potential uses and discussing areas that require further improvement. Recent breakthroughs achieved using these models are also discussed, particularly those developments pertaining to HPV-driven cancer. Two key aspects that still require improvement are the establishment of cell lines that can represent HPV+ penile carcinomas and the development of mouse models to study metastatic disease. Overall, the growing array of in vitro and in vivo models for penile cancer provides new and useful tools for researchers in the field and is expected to accelerate pre-clinical research on this disease.

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Diagnostic Stewardship Effectively Reduces Healthcare-Onset Clostridioides difficile Infections and Concurrent Laxative Use

Infection Control and Hospital Epidemiology ◽

10.1017/ice.2020.730 ◽

2020 ◽

Vol 41 (S1) ◽

pp. s189-s191

Author(s):

Dipesh Solanky ◽

Ian Drobish ◽

Derek Juang ◽

Scott Johns ◽

Sanjay Mehta ◽

...

Keyword(s):

Enteral Feeding ◽

Demographic Data ◽

Healthcare Facility ◽

The United States ◽

Nucleic Acid Amplification ◽

Fiscal Year ◽

Medication Cost ◽

Laxative Use ◽

Clostridioides Difficile ◽

Test Ordering

Background:Clostridioides difficile infection (CDI) accounts for >500,000 community-, nursing-, and hospital-acquired infections (HAIs), as well as 15,000–30,000 deaths, and =$4.8 billion in the United States annually. C. difficile toxin B gene nucleic acid amplification testing (NAAT) cannot distinguish between active CDI and colonization, particularly in the setting of laxative use or enteral feeding. Lack of judicious testing can result in the incorrect diagnosis of CDI, unnecessary CDI treatment, increased costs, and falsely augmented HAI rates. Like many healthcare facilities, the VA San Diego Healthcare System (VASDHS) solely utilizes C. difficile NAAT for CDI diagnosis. The aim of this study was to implement and evaluate a facility-wide initiative at the VASDHS to reduce healthcare onset, healthcare facility associated CDI (HO-HCFA CDI), including the use of a test ordering algorithm. Methods: From fiscal year (FY) 2015–2018, various measures were implemented including a hand hygiene initiative, reduction in fluoroquinolone usage, prompt isolation of patients with CDI, thorough terminal cleaning of rooms, and, lastly, a test-ordering algorithm starting FY2018. A retrospective study was performed to assess VASDHS HO-HCFA CDI case incidence, risk factors for infection, laxative or enteral feeding use at the time of testing, and CDI treatment. Results: Patient demographic data, medical history, CDI history, laxative use, treatment, and cost of CDI treatment were reviewed. From 2015 to 2018, 127 cases of HO-HCFA CDI were identified. The total number of HO-HCFA CDI cases and medication cost for CDI treatment were dramatically reduced from 2017 to 2018 following implementation of the test-ordering algorithm (Table 1, Fig. 1). This trend corresponded to a significant reduction in median HO-HCFA CDI cases per month (P = .02), medication cost of CDI treatment (P = .02), and proton pump inhibitor (PPI) use at the time of testing (P = .01). The number of positive HO-HCFA CDI cases associated with laxative use or escalation at the time of CDI testing (accounting for those on chronic laxatives) also decreased across the study period—most dramatically from 2015 vs 2016 (20 vs 14) and 2017 vs 2018 (11 vs 4) (Table 1). Conclusions: At the VASDHS, diagnostic stewardship of C. difficile NAAT with the use of a test-ordering algorithm significantly reduced HO-HCFA CDI incidence and treatment cost. This trend also corresponded with significantly less PPI use at the time of testing and reduced detection of colonization among patients with laxative-induced diarrhea. Diagnostic stewardship may serve as an effective tool to correctly diagnose and treat HO-HCFA CDI, while significantly reducing treatment costs.Funding: NoneDisclosures: None

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The Mother Working Outside the Home

PEDIATRICS ◽

10.1542/peds.73.6.874 ◽

1984 ◽

Vol 73 (6) ◽

pp. 874-875 ◽

Cited By ~ 1

Author(s):

Keyword(s):

Young Infant ◽

The United States ◽

Child Rearing ◽

Care Giver ◽

Older Children ◽

Group Setting ◽

Her Family ◽

Substitute Care ◽

Care Giving ◽

Sociocultural Background

Sixty percent of women (35% of mothers of children less than 18 years of age and 45% of mothers with preschool-aged children) in the United States work outside the home either of necessity or by choice. The pediatrician, who has an important role in helping such women find the best way of dealing with their multiple and demanding roles as workers, wives, and mothers, is often asked to address some of the questions posed below. 1. Is my working harmful to my child? The answer to this question depends upon (a) the provision of a safe, caring environment for the child; and (b) the mother's satisfaction in her outside work, the support and help of her family, and her vitality at the end of the day to nurture her children. 2. How do I evaluate a substitute care-giving situation? In addition to safety, sanitation, and the provision of proper nutrition, the kind of care giver to whom a young infant or young child is entrusted is the overriding consideration. This person must be warm, caring, responsible, and able to provide the child the stimulation of new learning experiences. In all cases, parents should talk frequently with the care giver about the child-rearing practices they desire, especially if the substitute mother is inexperienced or comes from a different sociocultural background. Although the needs of each child in a group setting vary with his or her age and personality, a ratio of one adult to three infants less than 2 years of age is advised, with the desired ratio increasing to 1 to 4 or 1 to 5 for older children.

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