Use of HER2 score correction for putative chromosome 17 (Chr-17) aneusomy to increase eligibility for anti-HER2 therapy.

620 Background: HER2 amplification or overexpression status directs therapy choice in breast carcinoma. HER2/Chr-17 ratio is commonly assessed by fluorescence in-situ hybridization (FISH) using a CEP17 centromeric reference probe and ASCO/CAP scoring criteria. However, α-centromeric reference probes may underestimate true HER2 status in cases with para-centromeric amplification. Here we present comprehensive algorithmic testing of an alternative Chr-17 reference locus for resolution of putative CEP17-aneusomic cases in a consecutive series, within a single health system. Methods: 150 of 1256 consecutive breast carcinoma cases accessioned in 2011 within the Cleveland Clinic Health System displayed a mean CEP17 copy number greater than 3.0 by FISH (aneusomy). The patients were reflex-HER2 tested by FISH with a reference probe for the D17S122 locus (17p12) and a corrected HER2/Chr-17 ratio was calculated. Cases with equivocal HER2/D17S122 ratio (1.8-2.2) were further reflex tested for HER2 overexpression by immunohistochemistry (IHC). Results: Of 117 initially non-amplified cases by HER2/CEP17, 20 (17%) were revised to amplified and 18 (15.3%) to equivocal by HER2/D17S122. Of 3 initially equivocal cases, 1 was revised to amplified and 1 remained equivocal. Of the 19 equivocal cases by HER2/D17S122, 3 were revised to positive by IHC. Overall, for CEP17 aneusomic cases tested using this algorithmic approach, 24 of 120 (20%) patients with initial non-amplified or equivocal HER2 status became eligible for anti-HER2-based therapy, which was also considered in 10 equivocal cases with a HER2/D17S122 ratio of 2.0 - 2.2. A significantly lower proportion of initially amplified cases was revised as non-amplified by HER2/D17S122 (1 of 30, 3.3%, p<0.05). Conclusions: Our data, collected within a single health system for a consecutive case series, underscores the clinical limitations of commonly used FISH probes for HER2 testing and demonstrates that algorithmic use of a non-centromeric Chr-17 reference probe alters HER2 status and increases eligibility for anti-HER2 based therapy in a significant proportion of patients.

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The INFORM HER2 Dual ISH assay compared with FISH to determine HER2 gene status in invasive breast carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.27_suppl.25 ◽

2011 ◽

Vol 29 (27_suppl) ◽

pp. 25-25

Author(s):

I. R. Loftin ◽

A. McElhinny ◽

R. Miller ◽

C. Garcia ◽

I. Bai ◽

...

Keyword(s):

Breast Carcinoma ◽

Light Microscopy ◽

Method Comparison ◽

Invasive Breast Carcinoma ◽

Chromosome 17 ◽

Her2 Status ◽

Her2 Overexpression ◽

Central Laboratory ◽

Her2 Gene ◽

Reproducibility Study

25 Background: The HER2 gene, located on chromosome 17 (Chr17), is amplified in 15-25% of patients with invasive breast carcinoma. Amplification and/or HER2 overexpression is associated with poor clinical outcome for these patients; however prognosis is improved if HER2 status indicates eligibility of patients for trastuzumab therapy. Thus, accurate diagnosis of HER2 status through a companion diagnostic is essential. Here we validated the INFORM HER2 Dual ISH Probe Cocktail (Dual ISH) assay as an alternative to FISH, the current gold standard for HER2 testing. The Dual ISH assay is fully automated and is scored using light microscopy. Methods: A multi-site method comparison and inter-laboratory reproducibility study were performed. 5 sites were used to compare Dual ISH results with FISH (Vysis PathVysion). 510 invasive breast carcinoma cases were stained at 3 clinical sites, FISH staining was performed at a fourth site (central laboratory). IHC status was determined at a fifth site (second central laboratory). In addition, 6 cases were evaluated for inter-site (3 sites), inter-reader (6 readers), inter-run (15 runs) and intra-run (duplicate slides) reproducibility. All assay steps were fully automated on a VENTANA BenchMark XT automated slide stainer, using a HER2 repeat-reduced, dinitrophenyl-labeled probe targeting the HER2 gene, detected with silver metallographic detection, and a digoxigenin-labeled Chr 17 probe, detected by an alkaline phosphatase-driven red chromogenic detection. HER2 and CHR17 signals were enumerated using conventional light microscopy allowing interpretation within the morphological context of the specimen. HER2 status was determined as the ratio of HER2/Chr17, where a ratio <2 is non-amplified and a ratio ≥2 is amplified. Results: The positive and negative agreement rates with FISH (95% CI) were 96% (92.6-97.9) and 92.3% (88.6-94.8), respectively. The HER2 Dual ISH assay also was highly reproducible in determining HER2/Chr17 ratio across sites, days, readers and runs. Conclusions: The fully automated INFORM HER2 Dual ISH assay is reproducible and concordant with the manual FISH assay in determining HER2 status in invasive breast carcinoma.

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Pulmonary Sequestration: Case Series Review of 29 Patients in the Cleveland Clinic Health System

CHEST Journal ◽

10.1378/chest.1983679 ◽

2014 ◽

Vol 146 (4) ◽

pp. 92A ◽

Cited By ~ 1

Author(s):

Basheer Tashtoush ◽

Roya Memarpour ◽

Jose Gonzalez ◽

Anas Hadeh ◽

Gustavo Ferrer ◽

...

Keyword(s):

Health System ◽

Cleveland Clinic ◽

Case Series ◽

Pulmonary Sequestration

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Utility of Alternate, Noncentromeric Chromosome 17 Reference Probe for Human Epidermal Growth Factor Receptor Fluorescence In Situ Hybridization Testing in Breast Cancer Cases

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2017-0252-oa ◽

2018 ◽

Vol 142 (5) ◽

pp. 626-633 ◽

Cited By ~ 2

Author(s):

Trupti Pai ◽

Tanuja Shet ◽

Asawari Patil ◽

Omshree Shetty ◽

Angad Singh ◽

...

Keyword(s):

Epidermal Growth Factor Receptor ◽

In Situ Hybridization ◽

Growth Factor ◽

Growth Factor Receptor ◽

Chromosome 17 ◽

Her2 Status ◽

Breast Cancers ◽

Reference Probe ◽

Epidermal Growth

Context PathVysion—a US Food and Drug Administration–approved dual-probe human epidermal growth factor receptor (HER2) fluorescence in situ hybridization (FISH) assay—provides the HER2:CEP17 ratio, a centromeric enumeration probe ratio for determining HER2 status in breast cancers. However, pericentromeric amplifications might then skew the HER2:CEP17 ratio, underestimating the HER2 status, which calls into question the use of CEP17 as the reference probe. Objective To analyze the utility of a noncentromeric chromosome 17 reference locus (D17S122) to assess HER2 gene status in cases showing “nonclassical” FISH patterns with the CEP17 probe. Design The HER2 status of breast cancers accessioned in the years 2015–2017, displaying “nonclassical” or “equivocal” results by the PathVysion (Abbott Molecular Inc, Des Plaines, Illinois) HER2 DNA Probe Kit were reflex tested using an alternate FISH probe (ZytoLight SPEC/D17S122, ZytoVision, Bremerhaven, Germany) and interpreted with American Society of Clinical Oncology/College of American Pathologists 2013 guidelines. Results Of 37 cases, 17 were FISH equivocal. With the alternate D17S122 probe, 13 (76.4%) were reclassified as amplified, 3 (17.6%) as nonamplified, and a single case retained an equivocal result. Of the 17 cases with a chromosome 17 polysomy pattern, disomy, polysomy, and monosomy patterns were seen with 14 cases, 2 cases, and 1 case, respectively. Within the 17 cases with polysomy pattern, 3 (17.6%) demonstrated an unusual colocalization pattern of HER2 and CEP17, which was not observed with the alternate probe. Conclusions The denominator-stable alternate probe is a useful adjunct in the diagnostic armamentarium to analyze HER2 status in cases with FISH equivocal and complex patterns.

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Double-Equivocal HER2 Invasive Breast Carcinomas: Institutional Experience and Review of Literature

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2017-0265-ra ◽

2018 ◽

Vol 142 (12) ◽

pp. 1511-1516 ◽

Cited By ~ 2

Author(s):

Brannan B. Griffin ◽

Jennifer L. Pincus ◽

Kalliopi P. Siziopikou ◽

Luis Z. Blanco

Keyword(s):

Chromosome 17 ◽

Her2 Status ◽

Breast Carcinomas ◽

Her2 Positive ◽

Close Proximity ◽

Reference Probe ◽

Institutional Experience ◽

Reflex Testing ◽

Invasive Breast Carcinomas ◽

American Society

Context.— HER2 status is a prognostic factor and therapeutic target in invasive breast carcinomas. Reflex testing using an alternate method is recommended on equivocal cases via immunohistochemistry or fluorescence in situ hybridization (FISH). Therapeutic dilemmas arise when both tests are equivocal. The standard chromosome 17 centromere reference probe (CEP17) is in close proximity to the HER2 locus and may be coamplified, leading to equivocal results. Alternate chromosome 17 reference probes may aid in establishing the true HER2 status. Objective.— To describe our institutional experience using D17S122 probe for reflex FISH testing on double-equivocal invasive breast carcinomas and review the literature on alternate reference probes. Data Sources.— Twenty-two patients with double-equivocal invasive breast carcinomas, defined as HER2 immunohistochemistry score 2+ and FISH equivocal per the 2013 guidelines, were reviewed. Reflex FISH was performed with alternate probe D17S122 and the HER2 status classified for 11 cases by using a revised HER2:D17S122 ratio. Seven of 11 cases (63.6%) were ultimately classified as HER2 positive, while 4 cases (36.4%) remained equivocal. The 7 positive cases showed a HER2:D17S122 greater than 2.0. Conclusions.— Alternate probe D17S122 reclassified more than half of our cases as HER2 positive. Alternate probes may establish true HER2 status and direct proper management, as evidenced by our experience and the literature. Additional investigation is needed to determine which alternate probe(s) is(are) best for reflex testing. Finally, the American Society of Clinical Oncology/College of American Pathologists guidelines may need to be updated to reflect more specific recommendations for the utilization of appropriate probes in double-equivocal HER2 cases.

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63 Chronic Femoral Osteomyelitis Case Series: Outcomes and Economic Impact at A United Kingdom Based Tertiary Centre

British Journal of Surgery ◽

10.1093/bjs/znab134.222 ◽

2021 ◽

Vol 108 (Supplement_2) ◽

Author(s):

E Lau ◽

Z Arshad ◽

A Aslam ◽

A Thahir ◽

M Krkovic

Keyword(s):

Economic Impact ◽

Treatment Protocol ◽

Case Series ◽

Consecutive Series ◽

Financial Loss ◽

Patient Demographics ◽

Tertiary Centre ◽

The Mean ◽

Eq Vas

Abstract Introduction Osteomyelitis refers to an inflammatory process affecting bone and bone marrow. This study reviews chronic femoral osteomyelitis treatment and outcomes, including economic impact. Method We retrospectively collected data from a consecutive series of 14 chronic femoral osteomyelitis patients treated between January 2013 and January 2020. Data collected include patient demographics, comorbidities, pathogens, complications, treatment protocol and costs. Functional outcome was assessed using EuroQOL five-dimensional interview administration questionnaire (EQ-5D-5L™) and EuroQOL Visual Analogue Scale (EQ-VAS™). Results Of these, 92.9% had one or more osteomyelitis risk factor, including smoking and diabetes. Samples from 78.6% grew at least one pathogen. Only 42.9% achieved remission after initial treatment, but 85.7% were in remission at final follow-up, with no signs of recurrence throughout the follow-up period (mean: 21.4 months). The average treatment cost was £39,249.50 with a net mean loss of £19,080.10 when funding was considered. The mean-derived EQ-5D score was 0.360 and the mean EQ-VAS score was 61.7, lower than their values for United Kingdom’s general population, p = 0.0018 and p = 0.013 respectively. Conclusions Chronic femoral osteomyelitis treatment is difficult, resulting in significant economic burden. With previous studies showing cheaper osteomyelitis treatment at specialist centres, our net financial loss incurred suggests the need for management at specialised centres.

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Abstract 12933: Myocardial Dysfunction After In-Hospital Cardiac Arrest in COVID-19 Patients

Circulation ◽

10.1161/circ.144.suppl_2.12933 ◽

2021 ◽

Vol 144 (Suppl_2) ◽

Author(s):

Abhishek Bhardwaj ◽

Mahmoud Alwakeel ◽

Siddharth Dugar ◽

sudhir krishnan ◽

Xiaofeng Wang ◽

...

Keyword(s):

Cardiac Arrest ◽

Median Time ◽

Systolic Function ◽

Myocardial Dysfunction ◽

Systolic Dysfunction ◽

Cleveland Clinic ◽

Case Series ◽

Apache Ii Score ◽

Lv Function ◽

Hospital Cardiac Arrest

Introduction: Post resuscitation myocardial dysfunction (PRMD) is common after out-of-hospital cardiac arrest. While PRMD is a known cause of post-resuscitation circulatory failure, few studies have reported associations between PRMD and neurologic outcome or survival. Further, little is known about PRMD after in-hospital cardiac arrest (IHCA) nor on the incidence and prognosis of PRMD in COVID-19 IHCA. We sought to evaluate the incidence of PRMD in a multicenter cohort of resuscitated COVID-19 IHCA patients. Study Population and Methods: We included adult patients (≥18 y) admitted to multiple hospitals of Cleveland Clinic Health System. Patients who attained ROSC with an initial echocardiogram (EC) in the 72 hours post-arrest were included. Data were extracted from a data registry and electronic medical records. Results: From 03/2020-10/2020, 58 patients with COVID-19 had IHCA. ROSC was noted in 35 patients (60.3%), 27 (46.6%) were alive at 24 h and 13 patients (22.4%) survived to hospital discharge. Of the 35 patients who had ROSC, 14 patients (40%) had an EC within 72 h. The median age of this cohort was 67 y (IQR 47 - 73); 71% were male, and median BMI of 28 (IQR 27 - 34), and admission APACHE II score was 13 (IQR 11 - 19). One third of the patients (36%) were mechanically ventilated before arrest and 43% were on vasopressors. Initial arrest rhythms were: PEA/Asystole, 79%; and VF/VT, 21%. Most patients (93%) received manual chest compression with median CPR duration of 5 min (IQR 2 - 10). The median time of obtaining first EC post-ROSC in these 14 patients was 22 hours (IQR 6 - 62). 7/14 (50%) of the patient had systolic dysfunction on initial EC (6 had global dysfunction, 1 with regional wall motion abnormality, and 4/7 had combined LV and RV systolic dysfunction). 5/14 patients had a follow up EC with a median time of 43 days. 2/5 had normal initial EC and 3 out of these 5 patients who initially had PMRD showed complete recovery in their LV and RV systolic function. Conclusion: We report a case series of PRMD in COVID-19 patients who experienced IHCA. We found that PMRD is seen in half of the patients. Most patients with PMRD recovered to normal RV and LV function, consistent with prior studies of non-COVID-19 arrest EC.

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Case Series about the Changed Antiplatelet Protocol for Carotid Endarterectomy in a Teaching Hospital: More Patients with Complications?

The Surgery Journal ◽

10.1055/s-0038-1675566 ◽

2018 ◽

Vol 04 (04) ◽

pp. e220-e225

Author(s):

Martijn Marsman ◽

Denise Özdemir- van Brunschot ◽

Abdelkarime Jahrome ◽

Nic Veeger ◽

Wouter Schuiling ◽

...

Keyword(s):

Acetylsalicylic Acid ◽

Carotid Endarterectomy ◽

Extended Release ◽

Case Series ◽

Daily Practice ◽

Postoperative Hemorrhage ◽

Consecutive Series ◽

Cerebrovascular Event ◽

First Choice ◽

Ischemic Complications

Introduction In the Netherlands, clopidogrel monotherapy increasingly replaces acetylsalicylic acid and extended release dipyridamole as the first-choice antiplatelet therapy after ischemic stroke. It is unknown whether the risk of peri- and postoperative hemorrhage in carotid artery surgery is higher in patients using clopidogrel monotherapy compared with acetylsalicylic acid and extended release dipyridamole. We therefore retrospectively compared occurrence of perioperative major and (clinical relevant) minor bleedings during and after carotid endarterectomy of two groups using different types of platelet aggregation inhibition after changing our daily practice protocol in our center. Material and Methods A consecutive series of the most recent 80 carotid endarterectomy patients (November 2015–August 2017) treated with the new regime (clopidogrel monotherapy) were compared with the last 80 (January 2012–November 2015) consecutive patients treated according to the old protocol (acetylsalicylic acid and dipyridamole). The primary endpoint was any major bleeding during surgery or in the first 24 to 72 hours postoperatively. Secondary outcomes within 30 days after surgery included minor (re)bleeding postoperative stroke with persistent or transient neurological deficit, persisting or transient neuropraxia, asymptomatic restenosis or occlusion, (transient) headache. Reporting of this study is in line with the ‘Strengthening the Reporting of Observational Studies in Epidemiology’ statement. Results Although statistical differences were observed, from a clinical perspective both patients groups were comparable. Postoperative hemorrhage requiring reexploration for hemostasis occurred in none of the 80 patients in the group of the clopidogrel monotherapy (new protocol) and it occurred in one of the 80 patients (1%) who was using acetylsalicylic acid and dipyridamole (old protocol). In three patients (4%) in the clopidogrel monotherapy and one patient (1%) in the acetylsalicylic acid and extended release dipyridamole protocol an ipsilateral stroke was diagnosed. Conclusion In this retrospective consecutive series the incidence of postoperative ischemic complications and perioperative hemorrhage after carotid endarterectomy (CEA) seemed to be comparable in patients using clopidogrel monotherapy versus acetylsalicylic acid and extended release dipyridamole for secondary prevention after a cerebrovascular event. This study fuels the hypothesis that short- and midterm complications of clopidogrel and the combination acetylsalicylic acid and extended release dipyridamole are comparable.

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Clinical array-based karyotyping of breast cancer with equivocal HER2 status resolves gene copy number and reveals chromosome 17 complexity

BMC Cancer ◽

10.1186/1471-2407-10-396 ◽

2010 ◽

Vol 10 (1) ◽

Cited By ~ 35

Author(s):

Shelly Gunn ◽

I-Tien Yeh ◽

Irina Lytvak ◽

Budi Tirtorahardjo ◽

Natasha Dzidic ◽

...

Keyword(s):

Breast Cancer ◽

Copy Number ◽

Gene Copy Number ◽

Chromosome 17 ◽

Gene Copy ◽

Her2 Status

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Case series and review of Ayurvedic medication induced liver injury

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-021-03251-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Christopher M. Karousatos ◽

Justin K. Lee ◽

David R. Braxton ◽

Tse-Ling Fong

Keyword(s):

Liver Injury ◽

Plant Extracts ◽

Significant Proportion ◽

Case Series ◽

The United States ◽

Tinospora Cordifolia ◽

Individual Plant ◽

Medicine Use ◽

Drug Induced ◽

Drug Induced Liver Injury

Abstract Background Complementary and alternative medicine use among Americans is prevalent. Originating in India, Ayurvedic medicine use in the United States has grown 57% since 2002. CAM accounts for a significant proportion of drug induced liver injury in India and China, but there have been only three reports of drug induced liver injury from Ayurvedic medications in the U.S. We report three cases of suspected Ayurvedic medication associated liver injury seen at a Southern California community hospital and review literature of Ayurvedic medication induced liver injury. Case presentations Three patients presented with acute hepatocellular injury and jaundice after taking Ayurvedic supplements for 90–120 days. First patient took Giloy Kwath consisting solely of Tinospora cordifolia. Second patient took Manjishthadi Kwatham and Aragwadhi Kwatham, which contained 52 and 10 individual plant extracts, respectively. Third patient took Kanchnar Guggulu, containing 10 individual plant extracts. Aminotransferase activities decreased 50% in < 30 days and all 3 patients made a full recovery. Roussel Uclaf Causality Assessment Method (RUCAM) scores were 7–8, indicating probable causality. These products all contained ingredients in other Ayurvedic and traditional Chinese medicines with previously reported associations with drug induced liver injury. Conclusions These patients highlight the risk of drug induced liver injury from Ayurvedic medications and the complexity of determining causality. There is a need for a platform like LiverTox.gov to catalog Ayurvedic ingredients causing liver damage.

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Emerging challenges in the health systems of Kerala, India: qualitative analysis of literature reviews

Journal of Health Research ◽

10.1108/jhr-04-2020-0091 ◽

2021 ◽

Vol ahead-of-print (ahead-of-print) ◽

Author(s):

Manesh Muraleedharan ◽

Alaka Omprakash Chandak

Keyword(s):

Health Care ◽

Health Economic ◽

Health System ◽

Health Systems ◽

Significant Proportion ◽

Vital Statistics ◽

The State ◽

Future Research ◽

Health Seeking ◽

Content Type

PurposeThe substantial increase in non-communicable diseases (NCDs) is considered a major threat to developing countries. According to various international organizations and researchers, Kerala is reputed to have the best health system in India. However, many economists and health-care experts have discussed the risks embedded in the asymmetrical developmental pattern of the state, considering its high health-care and human development index and low economic growth. This study, a scoping review, aims to explore four major health economic issues related to the Kerala health system.Design/methodology/approachA systematic review of the literature was performed using PRISMA to facilitate selection, sampling and analysis. Qualitative data were collected for thematic content analysis.FindingsChronic diseases in a significant proportion of the population, low compliance with emergency medical systems, high health-care costs and poor health insurance coverage were observed in the Kerala community.Research limitations/implicationsThe present study was undertaken to determine the scope for future research on Kerala's health system. Based on the study findings, a structured health economic survey is being conducted and is scheduled to be completed by 2021. In addition, the scope for future research on Kerala's health system includes: (1) research on pathways to address root causes of NCDs in the state, (2) determine socio-economic and health system factors that shape health-seeking behavior of the Kerala community, (3) evaluation of regional differences in health system performance within the state, (4) causes of high out-of-pocket expenditure within the state.Originality/valueGiven the internationally recognized standard of Kerala's vital statistics and health system, this review paper highlights some of the challenges encountered to elicit future research that contributes to the continuous development of health systems in Kerala.

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