Disclaimer
This information collection is a core HTA, i.e. an extensive analysis of one or more health technologies using all nine domains of the HTA Core Model. The core HTA is intended to be used as an information base for local (e.g. national or regional) HTAs.

Prognostic tests for breast cancer recurrence (uPA/PAI-1 [FEMTELLE], MammaPrint, Oncotype DX )

UPA/PAI-1 (FEMTELLE), MammaPrint, Oncotype DX compared to Standard of care in selecting treatment for Breast cancer recurrence in females

(See detailed scope below)

HTA Core Model Application for Diagnostic Technologies (1.1)
Core HTA
Published
Tom Jefferson (age.na.s, Italy), Nicola Vicari (age.na.s, Italy), Heike Raatz (SNHTA, Switzerland)
Sarah Baggaley, NICE (Health problem and current use); Antonio Migliore, Agenas (Description and technical characteristics); Iris Pasternack, THL-FINOHTA (Safety); Mirjana Huic, AAZ (Clinical effectiveness), Isaura Vieira, INFARMED (Costs and economic evaluation); Dario Sacchini, A.Gemelli (Ethical analysis); Jennifer Butt, NICE (Organisational aspects); Marco Marchetti, A.Gemelli (Social and Legal aspects)
Agenzia nationale per i servizi sanitari regionali (age.na.s), Italy
A. Gemelli (Italy), AAZ (Croatia), Agenas (Italy), AHTAPol (Poland), AVALIA-t (Spain), INFARMED (Portugal), IPH-RS (Slovenia), NICE (United Kingdom), Regione Veneto (Italy), SNHTA (Switzerland), THL (Finland), UMIT (Austria)
13.6.2011 14.00.00
31.1.2013 18.05.00
Jefferson T, Vicari N, Raatz H [eds.]. Prognostic tests for breast cancer recurrence (uPA/PAI-1 [FEMTELLE], MammaPrint, Oncotype DX ) [Core HTA], Agenzia nationale per i servizi sanitari regionali (age.na.s), Italy ; 2013. [cited 24 October 2021]. Available from: http://corehta.info/ViewCover.aspx?id=113

Prognostic tests for breast cancer recurrence (uPA/PAI-1 [FEMTELLE], MammaPrint, Oncotype DX )

<< Description and technical characteristics of technologyClinical Effectiveness >>

Safety

Authors: Iris Pasternack, Emilio Chiarolla, Narine Sahakyan, Leonor Varela

Summary

The three tests under evaluation share general safety concerns of surgical pathology practice such as sample contamination, delays in transfer, incorrect labelling and other features which may affect the reliability of the result and thus patient safety. Formalin fixation is required for Oncotype DX® and optional for MammaPrint®, and this implies occupational and environment precautions. There is insufficient evidence of possible anxiety or other psychosocial harms to patients caused by the tests.

Introduction

The safety of the prognostic tests for breast cancer, uPA/PAI-1 [FEMTELLE®],  Oncotype DX® and MammaPrint®, covers the possible harms of the testing procedure itself, and the psychological effects and possible over- or under-treatment due to false positive or false negative test results, or incidental findings. Personnel and the environment may be affected by potentially harmful constituents and properties of the test itself or products consumed during the testing procedure.

Tissue samples for the three tests are taken during the surgery from the breast tissue removed, or sometimes from the diagnostic core biopsy. As the tests do not require a separate invasive tissue sampling procedure in addition to routine management, we did not consider the safety of biopsies and tissue sampling as part of this health technology assessment (HTA).

The objective of the three tests is not only to provide information on the prognosis of breast cancer but most importantly to guide the physician in treatment selection. Since the tests are part of the diagnostic and treatment pathway, we assumed that they are considered as necessary or unavoidable by patients, which means that they are likely to be considered more acceptable than genetic tests for predicting disease susceptibility.

Samples are analysed and test results determined in manufacturers’ laboratories or in laboratories recommended by the manufacturers. We do not intend to cover the occupational and environmental issues in those laboratories but to focus only on the safety of the hospitals’ surgical and pathological processes.

Methodology

Frame

A modified collection scope is used in this domain.

TechnologyuPA/PAI-1 (FEMTELLE), MammaPrint, Oncotype DX
Description (modified from collection scope)

Very likely we need to include evidence for eg psychological harms to gene tests for other cancers or even gene tests in general

Intended use of the technologyDefining an existing health condition in further detail to assist selection of appropriate or optimal treatment

Assessment of risk of breast cancer recurrence

Target condition
Breast cancer recurrence
Target condition description

Assessment of risk of breast cancer recurrence and likelihood of benefit from adjuvant treatment (particularly chemotherapy).

As testing for oestrogen receptor positivity is already considered to be part of the standard of care using these tests to decide on adjunctive treatment with Tamoxifen will not be considered part of the study question.

Target population

Target population sex: Female. Target population age: Any age except fetuses. Target population group: Patients who have the target condition.

Target population description

Women with invasive breast cancer in whom adjunctive treatment might be indicated

ComparisonStandard of care
Description

Standard care without any of the three index tests (uPA/PAI-1, MammaPrint, Oncotype DX).

Depending on manpower and time resources the three index tests may also be compared with each other.

Assessment elements

TopicIssue RelevantResearch questions or rationale for irrelevance
C0001Patient safetyWhat kind of harms can use of the technology cause to the patient and what is the incidence, severity and duration of harms?yesWhat are the incidence, severity and duration of direct harms to the patient related to the testing and sampling with uPA/PAI-1, Oncotype DX, or MammaPrint®?
What are the incidence, severity and duration of psychological harms to the patient related to the testing and with uPA/PAI-1, Oncotype DX, or MammaPrint®?
C0002Patient safetyWhat is the dose relatedness of the harms to patients?noThere is no dose relatedness
C0003Patient safetyWhat is the timing of onset of harms to patients: immediate, early or late?noNo obvious changes expected.
C0004Patient safetyIs the incidence of the harms to patients likely to change over time?noPsychological consequencies could in principle change over time when awareness increases and processes evolve. The same could be with possible direct harms and accuracy related harms.
C0005Patient safetyAre there susceptible patient groups that are more likely to be harmed through use of the technology?noNo obvious risk groups for harms.
C0006Patient safetyWhat are the consequences of false positive, false negative and incidental findings brought about using the technology to the patients from the viewpoint of patient safety?noThe aim was to look at the prognostic value of the tests and not their effectiveness in the test-treatment intervention.
C0007Patient safetyWhat are the special features in using (applying/interpreting/maintaining) the technology that may increase the risk of patient safety?noUnspecific question.
C0008Patient safetyWhat is the safety of the technology in comparison to alternative technologies used for the same purpose?noThese three index tests represent well enough all genetic tests for breast cancer. We don't assume there is fundamnetally different tests that have different safety profile.
C0020Occupational safetyWhat kind of occupational harms may exist through using the technology?yesWhat kind of occupational harms are there when applying uPA/PAI-1, Oncotype DX, or MammaPrint®?
C0040Environmental safetyWhat kind of environmental risks may use of the technology cause?yesWhat kind of environmental risks are there when using uPA/PAI-1, Oncotype DX, or MammaPrint®?
C0062Safety risk managementHow can one reduce safety risks for patients (including technology-, user-, and patient-dependent aspects)?yesHow can one increase safety of patients tested with uPA/PAI-1, Oncotype DX, or MammaPrint® (including technology-, user-, and patient-dependent aspects)?
C0063Safety risk managementHow can one reduce safety risks for professionals (including technology-, user-, and patient-dependent aspects)?yesHow can one increase safety of professionals applying uPA/PAI-1, Oncotype DX or MammaPrint® (including technology-, user-, and patient-dependent aspects)?
C0060Safety risk managementHow does the safety profile of the technology vary between different generations, versions or products?noThe technologies are in their early developmental phase.
C0061Safety risk managementIs there evidence that harms increase or decrease in different organizational settings?noHowever, there could be differences between specialized breast cancer care centers versus regular oncology hospitals
C0064Safety risk managementHow can one reduce safety risks for environment (including technology-, user-, and patient-dependent aspects)?noLargely same as occupational safety procedures. Will be handeled in C0063.

Methodology description

Domain frame

In questions dealing with psychological harm we considered studies related to all similar testing situations in all cancers. In questions dealing with occupational harms related to formalin fixation we considered studies and guidance related to formalin fixation of histological samples in general.

Information sources

Out of the 616 references in the basic search we included 45 articles for full text reading by reading the title and abstract. We included reviews and studies which looked at change in management with the idea that they might provide information on safe patient selection and on the consequences of false positive/negative findings. We excluded all studies that were purely on prognostic value. After full text reading 12 articles from the basic search were included {SAF-1}.

Additional searches were made for occupational and environmental hazards and risk management. Their sources, search strategies and yields are described in the result cards of SAF1, SAF7, SAF8, SAF11 and SAF12.

Quality assessment tools or criteria

No established criteria were used.

Analysis and synthesis

Results are reported descriptively, with added qualitative synthesis. Study card templates proposed by the Core Model were used to collect data from some studies {SAF-2}.

Result cards

Patient safety

Result card for SAF1: "What are the incidence, severity and duration of direct harms to the patient related to the testing and sampling with uPA/PAI-1, Oncotype DX, or MammaPrint&#174;? " and SAF14: "What are the incidence, severity and duration of psychological harms to the patient related to the testing and with uPA/PAI-1, Oncotype DX, or MammaPrint&#174;?"

View full card
SAF1: What are the incidence, severity and duration of direct harms to the patient related to the testing and sampling with uPA/PAI-1, Oncotype DX, or MammaPrint&#174;?
Method
Frame
Result

Importance: Important

Transferability: Completely

SAF14: What are the incidence, severity and duration of psychological harms to the patient related to the testing and with uPA/PAI-1, Oncotype DX, or MammaPrint&#174;?
Method
Result

Importance: Important

Transferability: Partially

Occupational safety

Result card for SAF7: "What kind of occupational harms are there when applying uPA/PAI-1, Oncotype DX, or MammaPrint&#174;? "

View full card
SAF7: What kind of occupational harms are there when applying uPA/PAI-1, Oncotype DX, or MammaPrint&#174;?
Method
Frame
Result
Comment

Importance: Important

Transferability: Partially

Environmental safety

Result card for SAF8: "What kind of environmental risks are there when using uPA/PAI-1, Oncotype DX, or MammaPrint&#174;?"

View full card
SAF8: What kind of environmental risks are there when using uPA/PAI-1, Oncotype DX, or MammaPrint&#174;?
Method
Frame
Result

Importance: Optional

Transferability: Completely

Safety risk management

Result card for SAF11: "How can one increase safety of patients tested with uPA/PAI-1, Oncotype DX, or MammaPrint&#174; (including technology-, user-, and patient-dependent aspects)?"

View full card
SAF11: How can one increase safety of patients tested with uPA/PAI-1, Oncotype DX, or MammaPrint&#174; (including technology-, user-, and patient-dependent aspects)?
Method
Frame
Result

Importance: Important

Transferability: Partially

Result card for SAF12: "How can one increase safety of professionals applying uPA/PAI-1, Oncotype DX or MammaPrint&#174; (including technology-, user-, and patient-dependent aspects)?"

View full card
SAF12: How can one increase safety of professionals applying uPA/PAI-1, Oncotype DX or MammaPrint&#174; (including technology-, user-, and patient-dependent aspects)?
Method
Frame
Result

Importance: Important

Transferability: Partially

Discussion

Because of a lack of methodological expertise we had to leave out issue SAF5 “Does implementing of uPA/PAI-1, Oncotype DX or MammaPrint® reduce undertreatment and overtreatment compared to management pathway without it?”, the original issue of which is “What are the consequences of false positive, false negative and incidental findings brought about using the technology to the patients from the viewpoint of patient safety?”. We had planned to produce a qualitative estimate on this, based on the predictive values of each of the tests to identify good prognosis and the evidence on changes in physicians’ treatment decisions, but this appeared to be too complex a task for the present team in the available time frame. As a consequence, the information in this domain is dominated by the risk of laboratory errors and occupational safety issues.

References

  1. Raab SS, Grzybicki DM. Quality in Cancer Diagnosis. CA: A Cancer Journal for Clinicians 2010;60(3):139-165.
  2. Valenstein P. Promoting Patient Safety through Risk Reduction and Continuous Improvement. Northfield, IL: College of American Pathologists 2005.
  3. Meier FA, Varney RC, Zarbo RJ. Study of amended reports to evaluate and improve surgical pathology processes. Adv Anat Pathol 2011 Sep;18(5):406-413.
  4. Valenstein PN, Sirota RL. Identification errors in pathology and laboratory medicine. Clin Lab Med 2004 12;24(4):979-996.
  5. Nakhleh RE, Idowu MO, Souers RJ, Meier FA, Bekeris LG. Mislabeling of cases, specimens, blocks, and slides: a college of american pathologists study of 136 institutions. Arch Pathol Lab Med 2011 Aug;135(8):969-974.
  6. Layfield LJ, Anderson GM. Specimen labeling errors in surgical pathology: an 18-month experience. Am J Clin Pathol 2010 Sep;134(3):466-470.
  7. Makary MA, Epstein J, Pronovost PJ, Millman EA, Hartmann EC, Freischlag JA. Surgical specimen identification errors: A new measure of quality in surgical care. Surgery 2007 4;141(4):450-455.
  8. Longo MS, O'Neill MJ, O'Neill RJ. Abundant human DNA contamination identified in non-primate genome databases. PLoS One 2011 Feb 16;6(2):e16410.
  9. Richman AR, Tzeng JP, Carey LA, Retèl VP, Brewer NT. Knowledge of genomic testing among early-stage breast cancer patients. Psychooncology 2011;20(1):28-35.
  10. Retel VP, Bueno-de-Mesquita JM, Hummel MJ, van de Vijver MJ, Douma KF, Karsenberg K, et al. Constructive Technology Assessment (CTA) as a tool in coverage with evidence development: the case of the 70-gene prognosis signature for breast cancer diagnostics. Int J Technol Assess Health Care 2009 Jan;25(1):73-83.
  11. Oncotype DX web site: ordering the Oncotype DX test. Available at: http://www.oncotypedx.com/en-US/Breast/HealthcareProfessionalsDCIS/Ordering/OrderingTest. Accessed June 20, 2012.
  12. Agendia web site: How to order tests with Agendia. Available at: http://www.agendia.com/pages/ordering_symphony/38.php. Accessed June 20, 2012.
  13. National Toxicology Program. Final Report on Carcinogens: Background Document for Formaldehyde. Rep Carcinog Backgr Doc 2010 Jan;10-5981:1-521.
  14. Dimenstein IB. A pragmatic approach to formalin safety in anatomical pathology. LABMEDICINE 2009;40(12):740-746.
  15. International Agency for Research on Cancer (IARC). Formaldehyde. 2006; Available at: http://monographs.iarc.fr/ENG/Monographs/vol88/mono88-6A.pdf). Accessed June 20, 2012.
  16. Donnay C, Denis M, Magis R, Fevotte J, Massin N, Dumas O, et al. Under-estimation of self-reported occupational exposure by questionnaire in hospital workers. Occupational and Environmental Medicine 2011 August 01;68(8):611-617.
  17. Wilhelmsson B, Holmström M. POSITIVE FORMALDEHYDE-RAST AFTER PROLONGED FORMALDEHYDE EXPOSURE BY INHALATION. The Lancet 1987 7/18;330(8551):164.
  18. Dapson JC, Dapson RW. Hazardous Materials in the Histopathology laboratory: regulations, risks, handling and disposal. 4th ed. Battle Creek, MI: Anatech LTD; 2005.
  19. Arif AA, Delclos GL. Association between cleaning-related chemicals and work-related asthma and asthma symptoms among healthcare professionals. Occupational and Environmental Medicine 2012 January 01;69(1):35-40.
  20. Kilburn KH, Warshaw R, Thornton JC. Pulmonary function in histology technicians compared with women from Michigan: effects of chronic low dose formaldehyde on a national sample of women. Br J Ind Med 1989 Jul;46(7):468-472.
  21. Paustenbach D, Alarie Y, Kulle T, Schachter N, Smith R, Swenberg J, et al. A recommended occupational exposure limit for formaldehyde based on irritation. J Toxicol Environ Health 1997 Feb 21;50(3):217-263.
  22. Saurel-Cubizolles MJ, Hays M, Estryn-Behar M. Work in operating rooms and pregnancy outcome among nurses. Int Arch Occup Environ Health 1994;66(4):235-241.
  23. Titford ME, Horenstein MG. Histomorphologic assessment of formalin substitute fixatives for diagnostic surgical pathology. Arch Pathol Lab Med 2005 Apr;129(4):502-506.
  24. Di Novi C, Minniti D, Barbaro S, Zampirolo MG, Cimino A, Bussolati G. Vacuum-based preservation of surgical specimens: An environmentally-safe step towards a formalin-free hospital. Sci Total Environ 2010 7/15;408(16):3092-3095.
  25. Berton F, Novi CD. Occupational hazards of hospital personnel: assessment of a safe alternative to formaldehyde. J Occup Health 2012;54(1):74-78.

Appendices

APPENDIX SAF-1. Selecting studies for safety domain

Going through possibly relevant articles, updated 3.2.2012/ip

2011 Ademuyiwa. About change in management. We should receive this information from eff-domain. |Exclude

2011 Albanell. About change in management. We should receive this information from eff-domain. Exclude.

2011 Bedard, Can some patients avoid…: non-systematic but recent review on topic, not directly relevant to us but worthwhile looking. Exclude

2011 Bedard. Review discussing the unnecessary chemotherapies. Useful for C0006

2011 Oratz: change-in management survey. We should receive this information from eff-domain. Exclude

2011 O´Toole: objective in HER2 test, looks also at Oncotype and mammaprint but compares them to other tests, not clinical risk assessment. Exclude

2011 Richman: on test knowledge, mentions concerns but very briefly. Not relevant for us. Exclude

2011 Vanerlaan Cost model, includes AEs on page 457. Include

2010 Bighin; editorial on tumor characteristics. Exclude

2010 Brauchli: a letter commenting Lo 2010,2010 Kelly: case series using Oncotype, examining prognosis. Exclude

2010 Klang: abstract about Oncotype and amount of therapies. Exclude

2010 Lo. using test result in management decision reduced anxiety. Use in C0001

2010 Ontario HTA: about OncotypeDX, not directly relevant for our questions. Exclude

2010 Retel, Cost effectiveness of…: simulation model studying survival and qol, Exclude

2010 Tzeng: 25% of women reported test related distress. Use in C0001

2009 Albain review on test utility, we should get this info from eff-domain. Exclude

2009 Berg: editorial of EGAPP guideline. Exclude

2009 Brewer: about understanding and interpretation, not anxiety etc. Exclude

2009 Brewer examines how women use the test info for decision making. Exclude

2009 EGAPP. Guideline. Include

2009 Henry: change in management. We should receive this information from eff-domain. Exclude

2009 Holzik: abstract about gene test results in the diagnostic phase. Exclude

2009 Lau: abstract on prognosis in time, not relevant. Exclude

2009 Retel, Constructive HTA examines psychological impact. Include C0001

2009 Teutsch: describes the methods of EGAPP guideline. Interesting methods issues. Exclude

2008 Asad about change in management. Exclude

2008 Duffy a review collecting info also of toxicity. Include

2008 Haas: inflammation of the biopsy channel causing things. Include at least C0001

2008 Koscielny. Methodological discussion which we can use when estimating the reliability of the figures,

2008 Leyland-Jones. Gives guidelines for sampling. This can be used to identify search terms for possible occupational harms

2008 Loi: predicting tamoxiphene response. Exclude

2008 Marchionni: Systematic review (AHRQ), not directly relevant to us. Exclude

2008 Mayordomo: abstract of MammaPrint used in core needle biopsies. Exclude

2008 Ross: properties of several tests. Not relevant to us. Exclude

2008 Wittner: mamma print predicting distant metsatsis in post menopausal. Exclude

2007 Ach: Reproducibility of the tests. Exclude

2007 ANZHSN; HTA which estimates the number of unnecessary chemotherapies. Include. Useful for C0006

2007 Bueno de Mesquita examines test that are not in our review. Exclude

2007 Kaklamani: Descriptive review. Exclude

2007 Lillie. About understanding. Exclude.

2007 O Neill about how women perceive the tests, concern mentioned only. Exclude

2007 Oratz: Change in management. Exclude

2006 Paik revieweing tets. Exclude

2000 LeGoff: neural networks. Exclude

APPENDIX SAF-2 Study cards for safety domain

Article

Full reference

Layfield LJ, Anderson GM. Specimen labeling errors in surgical pathology: an 18-month experience. Am J Clin Pathol. 2010 Sep;134(3):466-70.

DOI

PMID:20716804

Articles that belong to the same study

 

EUnetHTA project details

Name of the person who reviewed the article

Iris Pasternack

Date of review

15 March 2012

EUnetHTA project name

3 gene tests for breast cancer, result cards SAF1

EUnetHTA project ID

 

Study type

Study objective

To quantify the mislabelled cases, specimens, blocks, and slides and to identify the sources of error.

Study method

Retrospective review of quality control records for an 18 month period.

Place of study

Country (area): USA

Technology and comparison

Intervention:

How and where were participants selected (including setting of care)[free text]

Intervention

How was the intervention conducted and interpreted? e.g. technical details, presentation, who delivered the intervention, frequency and duration of sessions

Quality assurance records documenting all labelling errors were reviewed for an 18 month period

Co-intervention description

  

Drop-offs and withdrawals (number, reason)

  

Previous interventions/tests

  

Description of patients and target condition

Patient characteristics

Intervention group

Control group

Number of institution

1

Country

US

 

Sex

  

confounder 1 [Changeable title]

  

confounder 2...[add rows if needed]

  
      

Disease/condition

Intervention group

Control group

Duration

 

Severity

 

Excluded conditions

 

...... [add rows if needed]

 

Endpoints

Endpoint measures (all)

 

Patient relevant endpoint measures

 
   
 

Internal validity

Select: +, -, ? or NR “Not relevant or of minor relevance in this study”

Add free text to explain

Selection

Was the sequence generation adequate?

NR

Was allocation concealment adequate?

NR

Was a consecutive or random sample of patients enrolled? (applies to non randomised studies)

NR

Did the study avoid inappropriate exclusions?

+

Were the baseline characteristics similar? (applies to non randomised studies)

NR

Could the selection of patients have introduced bias?

NO

Conduct

Were participants and personnel blinded?

NR

Were the co-interventions identical?

NR

Was the number of withdrawals or uncompleted measurements appropriately low?

NR

Could the conduct of the intervention have introduced bias?

NO

Interpretation

Were outcome assessors blinded?

NR

Could the interpretation of the intervention have introduced bias?

NO

Analysis and reporting

Was data analysed appropriately?

+

Was incomplete outcome data addressed?

NR

Was the study free from selective reporting?

+

Other

Was the study funding independent from manufacturer?

+

Free of other bias? Which?

+

   
 

External validity

 
 

Relevant patient group

+

 

Relevant intervention

+

 

Relevant comparator

NR

 

Relevant endpoint measures

+

Results

 

29 479 cases accessioned, with 109354 blocks and 248 013 slides. 75 labelling errors were identified (0.25% of cases, 0.068% of blocks and 0.03 % of slides)

Article

Full reference

Nakhleh RE, Idowu MO, Souers RJ, Meier FA, Bekeris LG. Mislabeling of cases, specimens, blocks, and slides: a College of American Pathologists study of 136 institutions. Arch Pathol Lab Med. 2011 Aug;135(8):969-74.

DOI

PMID:21809987

Articles that belong to the same study

 

EUnetHTA project details

Name of the person who reviewed the article

Iris Pasternack

Date of review

15 March 2012

EUnetHTA project name

3 gene tests for breast cancer, result cards SAF1 and SAF11

EUnetHTA project ID

 

Study type

Study objective

To quantify the mislabelled cases, specimens, blocks, and slides, and to identify the sources of error and the ways the in which errors were detected

Study method

Prospective multicentre study. Review of cases until 8 weeks elapsed or 30 error incidents were identified. Mislabelling rates per 1000 were calculated and corrected by regression analysis. Associations between the rates and the demographic and practice variables were investigated using regression analysis for continuous independent variables after independency testing. Variables with significant associations were taken into multivariate regression model.

Place of study

Country (area): USA (127 of the participating 136 institutions), Saudi Arabia (6), Canada (2), Lebanon (1)

Years: autumn 2009

Technology and comparison

Intervention:

How and where were participants selected (including setting of care)[free text]

Subscription-based quality assurance study

Intervention

How was the intervention conducted and interpreted? E.g. technical details, presentation, who delivered the intervention, frequency and duration of sessions

Subscribers prospectively reviewed surgical pathology cases until 8 weeks had elapsed or 30 error incidents were identified related to mislabelling cases, specimens, blocks or slides. The participants counted the total numbers of cases, specimens, blocks and slides reviewed. They also recorded the instances of mislabelling and consequences.

Co-intervention description

  

Drop-offs and withdrawals (number, reason)

  

Previous interventions/tests

  

Description of patients and target condition

Patient characteristics

Intervention group

Control group

Number of institutions

136 laboratories

Country

United States (127 of the participating 136 institutions), Saudi Arabia (6), Canada (2), Lebanon (1)

 

Sex

  

confounder 1 [Changeable title]

  

confounder 2...[add rows if needed]

  

Disease/condition

Intervention group

Control group

Duration

 

Severity

 

Excluded conditions

 

......[add rows if needed]

 

Endpoints

Endpoint measures (all)

 

Patient relevant endpoint measures

 
 

Internal validity

Select: +, -, ? or NR “Not relevant or of minor relevance in this study”

Add free text to explain

Selection

Was the sequence generation adequate?

NR

Was allocation concealment adequate?

NR

Was a consecutive or random sample of patients enrolled? (applies to non randomised studies)

NR

Did the study avoid inappropriate exclusions?

+

Were the baseline characteristics similar? (applies to non randomised studies)

NR

Could the selection of patients have introduced bias?

NO

Conduct

Were participants and personnel blinded?

NR

Were the co-interventions identical?

NR

Was the number of withdrawals or incomplete measurements appropriately low?

NR

Could the conduct of the intervention have introduced bias?

NO

Interpretation

Were outcome assessors blinded?

NR

Could the interpretation of the intervention have introduced bias?

NO

Analysis and reporting

Was data analysed appropriately?

+

Was incomplete outcome data addressed?

NR

Was the study free from selective reporting?

+

Other

Was the study funding independent of the manufacturer?

+

Free of other bias? Which?

+

   
 

External validity

 
 

Relevant patient group

+

 

Relevant intervention

+

 

Relevant comparator

NR

 

Relevant endpoint measures

+

Results

 

There were 427 255 reviewed cases. Of them 1811 cases had some type of mislabelling (0.4%). The entire case was mislabelled in 1.1/1000 (490). Specimens were mislabelled 1/1000 (796 specimens of 358 cases). Blocks were mislabelled in 1.7/1000 (2172 blocks in 461 cases). Slides were mislabelled in 1/1000 (2509 slides in 502 cases). Misidentification of cases and specimens occurred most often at collection or at accessioning (i.e. when specimens are received, sorted, and entered in the laboratory). In 1751 of the 1811 mislabelled cases (97%) the mislabelling was corrected without any additional consequences. In 59 cases (3%) a correction report was issued, and in 24 cases (1%) patient care was affected some way.

Mislabelling occurred significantly less in laboratories with continuous individual-case (one by one) accessioning and in laboratories with formal, documented quality checks at accessioning.

Article

Full reference

Berton F, Novi CD. Occupational hazards of hospital personnel: assessment of a safe alternative to formaldehyde. J Occup Health. 2012 Mar 5;54(1):74-8. Epub 2011 Dec 16.

DOI

PMID 22186296

Articles that belong to the same study

Di Novi C, Minniti D, Barbaro S, Zampirolo MG, Cimino A, Bussolati G. Vacuum-based preservation of surgical specimens: an environmentally-safe step towards a formalin-free hospital. Sci Total Environ. 2010 Jul 15;408(16):3092-5. Epub 2010 May 4. PMID:20444497

EUnetHTA project details

Name of the person who reviewed the article

Iris Pasternack

Date of review

10 March 2012

EUnetHTA project name

3 gene tests in the management of breast cancer

EUnetHTA project ID

 

Study type

Study objective

To assess the effect of substituting formalin with under-vacuum sealing in the respiratory symptoms of staff working in a surgical theatre handling tissue samples.

Study method

Prospective study. Multivariate analysis

Place of study

Country (area): Italy, Turin

Years: Data collected December 2008-April 2009

Technology and comparison

Intervention:

How and where were patients selected (including setting of care)[free text]

Random sample of personnel of surgical theatre and pathology laboratory was educated to use the new vacuum sealing.

Intervention

Comparison

How was the intervention conducted and interpreted? E.g. technical details, presentation, who delivered the intervention, frequency and duration of sessions

Tissue specimens are sealed into plastic bags immediately after removal from human bodies; the bags are labelled with identification data and kept in refrigerator at 4ºC inside the premises of the surgical theatre until they are transferred to pathology. The tissue is routinely processed first in the pathology lab.

?

Co-intervention description

It was unclear whether the same person participated in several operations a day, some of which used the pressure sealing and some of which did not.

 

Drop-offs and withdrawals (number, reason)

171 interviewed, final sample includes 156 individuals. 15 drop-offs, i.e. 9%. Reason missing values.

Previous interventions/tests

  

Description of patients and target condition

Patient characteristics

Intervention group

Control group

Difference

 

Number of patients

70

86

Age, mean/years

40.3

40.0

not given

Sex: Women

72.9%

75.6%

not given

existing respiratory conditions, symptoms

30.0%

29.1%

not given

living in metropolitan area

78.6%

80.2%

not given

level of experience in tissue sample preparation/years

(measured of 115 only!)

18.4

18.7

not given

Occupation/physicians

27.1%

25.6%

not given

Occupation/ laboratory technicians

38.6%

37.2%

not given

Education/ tertiary degree or more

54.3%

47.7%

not given

Personal perception of difficulties in handling the tissue sampling procedure

10.0%

23.3%

not given, authors say this is the only relevantly different

      

Disease/condition

NA (healthy personnel)

Intervention group

Control group

Duration

 

Severity

 

Excluded conditions

 

......[add rows if needed]

 

Endpoints

Endpoint measures (all)

Respiratory symptoms: cough, chest pain, shortness of breath and wheezing

Patient relevant endpoint measures

Respiratory symptoms: cough, chest pain, shortness of breath and wheezing

   
 

Internal validity

Select: +, -, ? or NR “Not relevant or of minor relevance in this study”

Add free text to explain

Selection

Was the sequence generation adequate?

?

Was allocation concealment adequate?

NR

Was a consecutive or random sample of patients enrolled? (applies to non randomised studies)

+

Did the study avoid inappropriate exclusions?

?

Were the baseline characteristics similar? (applies to non randomised studies)

Could the selection of patients have introduced bias?

NO

Conduct

Were participants and personnel blinded?

NR

Were the co-interventions identical?

NR

Was the number of withdrawals or uncompleted measurements appropriately low?

+ It was 9%, and after controlling for the missing data some analyses were performed with the whole population, n = 156.

Could the conduct of the intervention have introduced bias?

YES NO ?

Interpretation

Were outcome assessors blinded?

Could the interpretation of the intervention have introduced bias?

YES It was not explicitly stated that the individuals who worked with the new sealing method did that all the time. If they occasionally did formalin preparations this could blur the results.

Analysis and reporting

Was data analysed appropriately?

? Mantel Haenszel test is used as a repeated test of independence in situations. There were quite a lot of possible confounders in relation to the small sample size.

Was incomplete outcome data addressed?

+ Multiple independence testing

Was the study free from selective reporting?

+

Other

Was the study funding independent from manufacturer?

?

Free of other bias? Which?

NR

   
 

External validity

 
 

Relevant patient group

+

 

Relevant intervention

?

 

Relevant comparator

?

 

Relevant endpoint measures

+

Results

 

4.3% of the individuals using the pressure sealing system experienced respiratory symptoms. The same figure was 34.9% for formalin users (confidence interval [CI] not given). There were however some differences in the groups’ baseline characteristics: mainly in the level of the perceived difference of using the method. The overall odds ratio for having respiratory symptoms if using formalin was about 12

     

Results

APPENDIX SAF-3. Search for SAF7 and SAF12

21 March 2012 search by Iris Pasternack in PubMed

Search strategy

  • 23 Add Search (#22) AND #21 35 04:45:29 > 35 hits listed below
  • 22 Add Search hospital[Title/Abstract] 550947 04:43:16
  • 21 Add Search (#20) AND #17 1505 04:42:46
  • 20 Add Search (#19) OR #18 546515 04:42:22
  • 19 Add Search work[Title/Abstract] 483270 04:41:54
  • 18 Add Search occupational[Title/Abstract] 79830 04:41:35
  • 17 Add Search (#16) OR #15 39041 04:41:15
  • 16 Add Search formaldehyde[Title/Abstract] 14641 04:40:39
  • 15 Add Search formalin[Title/Abstract] 24748 04:40:15
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  2. Donnay C, Denis MA, Magis R, Fevotte J, Massin N, Dumas O, Pin I, Choudat D, Kauffmann F, Le Moual N. Under-estimation of self-reported occupational exposure by questionnaire in hospital workers. Occup Environ Med. 2011 Aug;68(8):611-7. Epub 2011 Apr 21. PubMed PMID: 21515550.
  3. Persoons R, Maitre A, Bicout DJ. Modelling the time profiles of organic solvent concentrations for occupational exposure assessment purposes. Ann Occup Hyg. 2011 May;55(4):421-35. Epub 2011 Feb 14. PubMed PMID: 21320948.
  4. Tanca A, Addis MF, Pagnozzi D, Cossu-Rocca P, Tonelli R, Falchi G, Eccher A, Roggio T, Fanciulli G, Uzzau S. Proteomic analysis of formalin-fixed, paraffin-embedded lung neuroendocrine tumor samples from hospital archives. J Proteomics. 2011 Mar 1;74(3):359-70. Epub 2010 Dec 13. PubMed PMID: 21147281.
  5. National Toxicology Program. Final Report on Carcinogens Background Document for Formaldehyde. Rep Carcinog Backgr Doc. 2010 Jan;(10-5981):i-512. PubMed PMID: 20737003.
  6. Petrescu A, Berdan G, Hulea I, Gaitanidis R, Ambert V, Jinga V, Popescu M, Andrei F, Niculescu L. Renal inflammatory myofibroblastic tumor - a new case report. Rom J Morphol Embryol. 2007;48(4):437-42. PubMed PMID: 18060198.
  7. Deng JH, Yao KH, Hu HL, Yu SJ, Gao W, Fu LB, He LJ, Dmitriev A, Yang YH. [Detection of group B streptococcus in the cases died of neonatal pneumonia]. Zhonghua Er Ke Za Zhi. 2006 Nov;44(11):850-4. Chinese. PubMed PMID: 17274877.
  8. Tompa A, Jakab M, Biró A, Magyar B, Fodor Z, Klupp T, Major J. Chemical safety and health conditions among Hungarian hospital nurses. Ann N Y Acad Sci. 2006 Sep;1076:635-48. PubMed PMID: 17119241.
  9. Shangina O, Brennan P, Szeszenia-Dabrowska N, Mates D, Fabiánová E, Fletcher T, t'Mannetje A, Boffetta P, Zaridze D. Occupational exposure and laryngeal and hypopharyngeal cancer risk in central and eastern Europe. Am J Epidemiol. 2006 Aug 15;164(4):367-75. Epub 2006 Jun 26. PubMed PMID: 16801374.
  10. Quinn MM, Fuller TP, Bello A, Galligan CJ. Pollution prevention--occupational safety and health in hospitals: alternatives and interventions. J Occup Environ Hyg. 2006 Apr;3(4):182-93; quiz D45. PubMed PMID: 16531291.
  11. De Stefani E, Boffetta P, Brennan P, Deneo-Pellegrini H, Ronco A, Gutiérrez LP. Occupational exposures and risk of adenocarcinoma of the lung in Uruguay. Cancer Causes Control. 2005 Sep;16(7):851-6. PubMed PMID: 16132795.
  12. Takigawa T, Horike T, Ohashi Y, Kataoka H, Wang DH, Kira S. Were volatile organic compounds the inducing factors for subjective symptoms of employees working in newly constructed hospitals? Environ Toxicol. 2004 Aug;19(4):280-90. PubMed PMID: 15269897.
  13. Bovenzi M, Barbone F, Pisa FE, Della Vedova A, Betta A, Romeo L, Tonello A, Biasi D, Caramaschi P. [Scleroderma and occupational risk factors: a case-control study]. G Ital Med Lav Ergon. 2003 Jul-Sep;25 Suppl(3):46-7. Italian. PubMed PMID: 14979077.
  14. Elci OC, Akpinar-Elci M, Blair A, Dosemeci M. Risk of laryngeal cancer by occupational chemical exposure in Turkey. J Occup Environ Med. 2003 Oct;45(10):1100-6. PubMed PMID: 14534452.
  15. Sijercić N, Hadzigrahić N, Kamberović S, Suljagić E. Frequency of standard and occupational contact allergens in Tuzla area, Bosnia and Herzegovina: retrospective study. Acta Dermatovenerol Croat. 2003;11(2):75-9. PubMed PMID: 12773263.
  16. Leikauf GD. Hazardous air pollutants and asthma. Environ Health Perspect. 2002 Aug;110 Suppl 4:505-26. Review. PubMed PMID: 12194881; PubMed Central PMCID: PMC1241200.
  17. Penagos HG. Contact dermatitis caused by pesticides among banana plantation workers in Panama. Int J Occup Environ Health. 2002 Jan-Mar;8(1):14-8. PubMed PMID: 11843435.
  18. Vyas A, Pickering CA, Oldham LA, Francis HC, Fletcher AM, Merrett T, Niven RM. Survey of symptoms, respiratory function, and immunology and their relation to glutaraldehyde and other occupational exposures among endoscopy nursing staff. Occup Environ Med. 2000 Nov;57(11):752-9. PubMed PMID: 11024199; PubMed Central PMCID: PMC1739887.
  19. Roy DR. Histology and pathology laboratories. Chemical hazard prevention and medical/health surveillance. AAOHN J. 1999 May;47(5):199-205. Review. PubMed PMID: 10639940.
  20. Koda S, Kumagai S, Ohara H. Environmental monitoring and assessment of short-term exposures to hazardous chemicals of a sterilization process in hospital working environments. Acta Med Okayama. 1999 Oct;53(5):217-23. PubMed PMID: 10561730.
  21. Wieslander G, Norbäck D, Nordström K, Wålinder R, Venge P. Nasal and ocular symptoms, tear film stability and biomarkers in nasal lavage, in relation to building-dampness and building design in hospitals. Int Arch Occup Environ Health. 1999 Oct;72(7):451-61. PubMed PMID: 10541910.
  22. Tilsted D, Hansen AM, Rasmussen K. [Formaldehyde in the occupational environment. A possible cause of chemically induced reactive arthritis]. Ugeskr Laeger. 1996 Aug 5;158(32):4525-7. Danish. PubMed PMID: 8759390.
  23. Smedley J, Coggon D. Health surveillance for hospital employees exposed to respiratory sensitizers. Occup Med (Lond). 1996 Feb;46(1):33-6. PubMed PMID: 8672791.
  24. Malo JL, Cartier A, Pineault L, Dugas M, Desjardins A. Occupational asthma due to heated polypropylene. Eur Respir J. 1994 Feb;7(2):415-7. PubMed PMID: 8162997.
  25. Pertschuk LP, Kim YD, Axiotis CA, Braverman AS, Carter AC, Eisenberg KB, Braithwaite LV. Estrogen receptor immunocytochemistry: the promise and the perils. J Cell Biochem Suppl. 1994;19:134-7. Review. PubMed PMID: 7823585.
  26. West S, Hildesheim A, Dosemeci M. Non-viral risk factors for nasopharyngeal carcinoma in the Philippines: results from a case-control study. Int J Cancer. 1993 Nov 11;55(5):722-7. PubMed PMID: 7503957.
  27. Marcucci L, Canta S, Warsame MA, Paternesi A, Taglia C. [Primary amelanotic melanoma of the nasal fossa. Importance of ultrastructural study for diagnosis]. Acta Otorhinolaryngol Ital. 1989 May-Jun;9(3):311-8. Italian. PubMed PMID: 2816354.
  28. Norbäck D. Skin and respiratory symptoms from exposure to alkaline glutaraldehyde in medical services. Scand J Work Environ Health. 1988 Dec;14(6):366-71. PubMed PMID: 2975045.
  29. Degorce-Hecquet I, Gacouin JC, Sauvaget J. [Occupational asthma caused by formalin in a hospital milieu. Apropos of 3 cases]. Rev Pneumol Clin. 1987;43(2):91-4. French. PubMed PMID: 3616377.
  30. Kilburn KH, Warshaw R, Boylen CT, Johnson SJ, Seidman B, Sinclair R, Takaro T Jr. Pulmonary and neurobehavioral effects of formaldehyde exposure. Arch Environ Health. 1985 Sep-Oct;40(5):254-60. PubMed PMID: 4062359.
  31. Connor TH, Ward JB Jr, Legator MS. Absence of mutagenicity in the urine of autopsy service workers exposed to formaldehyde: factors influencing mutagenicity testing of urine. Int Arch Occup Environ Health. 1985;56(3):225-37. PubMed PMID: 4066051.
  32. Ward JB Jr, Hokanson JA, Smith ER, Chang LW, Pereira MA, Whorton EB Jr, Legator MS. Sperm count, morphology and fluorescent body frequency in autopsy service workers exposed to formaldehyde. Mutat Res. 1984 Dec;130(6):417-24. PubMed PMID: 6513969.
  33. Hansen KS. Occupational dermatoses in hospital cleaning women. Contact Dermatitis. 1983 Sep;9(5):343-51. PubMed PMID: 6226477.
  34. Agathos M, Bernecker HA. [Hand dermatitis in medical personnel]. Derm Beruf Umwelt. 1982;30(2):43-7. German. PubMed PMID: 6211342.
  35. Rudzki E. Occupational dermatitis among health service workers. Derm Beruf Umwelt. 1979;27(4):112-5. PubMed PMID: 161530.

Appendix SAF-4. Search for SAF1 and SAF11

15 March 2012 Iris Pasternack

Search strategy

  • 3 Add Search (safety[Title/Abstract]) AND #2 >18 references listed below
  • 2 Add Search (surgical pathology[Title/Abstract]) AND #1 246
  • 1 Add Search quality[Title/Abstract] 449032
  1. Grizzle WE, Bell WC, Sexton KC. Issues in collecting, processing and storing human tissues and associated information to support biomedical research. Cancer Biomark. 2011;9(1-6):531-49. PubMed PMID: 22112494.
  2. Smith ML, Raab SS. Assessment of latent factors contributing to error: addressing surgical pathology error wisely. Arch Pathol Lab Med. 2011 Nov;135(11):1436-40. PubMed PMID: 22032570.
  3. Nakhleh RE, Idowu MO, Souers RJ, Meier FA, Bekeris LG. Mislabeling of cases, specimens, blocks, and slides: a college of american pathologists study of 136 institutions. Arch Pathol Lab Med. 2011 Aug;135(8):969-74. PubMed PMID: 21809987.
  4. Raab SS, Grzybicki DM. Cytologic-histologic correlation. Cancer Cytopathol. 2011 Oct 25;119(5):293-309. doi: 10.1002/cncy.20165. Epub 2011 Jul 5. Review. PubMed PMID: 21732549.
  5. Minato H, Nojima T, Nakano M, Yamazaki M. [Safety management in pathology laboratory: from specimen handling to confirmation of reports]. Rinsho Byori. 2011 Mar;59(3):299-304. Review. Japanese. PubMed PMID: 21560413.
  6. Silverman JF. Recent trends in quality, patient safety, and error reduction in nongyn cytology. Adv Anat Pathol. 2010 Nov;17(6):437-44. Review. PubMed PMID: 20966649.
  7. Hunt JL. Identifying cross contaminants and specimen mix-ups in surgical pathology. Adv Anat Pathol. 2008 Jul;15(4):211-7. Review. PubMed PMID: 18580097.
  8. Kayser K, Görtler J, Goldmann T, Vollmer E, Hufnagl P, Kayser G. Image standards in tissue-based diagnosis (diagnostic surgical pathology). Diagn Pathol. 2008 Apr 18;3:17. PubMed PMID: 18423031; PubMed Central PMCID: PMC2362107.
  9. Nakhleh RE. Patient safety and error reduction in surgical pathology. Arch Pathol Lab Med. 2008 Feb;132(2):181-5. Review. PubMed PMID: 18251572.
  10. Association of Directors of Anatomic and Surgical Pathology. Recommendations for quality assurance and improvement in surgical and autopsy pathology. Am J Surg Pathol. 2006 Nov;30(11):1469-71. Erratum in: Am J Surg Pathol. 2007 Jan;31(1):160. PubMed PMID: 17063090.
  11. Association of Directors of Anatomic Surgical Pathology, Nakhleh R, Coffin C, Cooper K. Recommendations for quality assurance and improvement in surgical and autopsy pathology. Am J Clin Pathol. 2006 Sep;126(3):337-340. PubMed PMID: 16880147.
  12. Association Of Directors Of Anatomic And Surgical Pathology, Nakhleh R, Coffin C, Cooper K. Recommendations for quality assurance and improvement in surgical and autopsy pathology. Hum Pathol. 2006 Aug;37(8):985-8. Epub 2006 Jun 19. PubMed PMID: 16867860.
  13. Raab SS, Vrbin CM, Grzybicki DM, Sudilovsky D, Balassanian R, Zarbo RJ, Meier FA. Errors in thyroid gland fine-needle aspiration. Am J Clin Pathol. 2006 Jun;125(6):873-82. PubMed PMID: 16690487.
  14. Nakhleh RE. Error reduction in surgical pathology. Arch Pathol Lab Med. 2006 May;130(5):630-2. Review. PubMed PMID: 16683877.
  15. Raab SS, Nakhleh RE, Ruby SG. Patient safety in anatomic pathology: measuring discrepancy frequencies and causes. Arch Pathol Lab Med. 2005 Apr;129(4):459-66. PubMed PMID: 15794667.
  16. Morales AR, Nassiri M, Kanhoush R, Vincek V, Nadji M. Experience with an automated microwave-assisted rapid tissue processing method: validation of histologic quality and impact on the timeliness of diagnostic surgical pathology. Am J Clin Pathol. 2004 Apr;121(4):528-36. PubMed PMID: 15080304.
  17. Chillemi S, Sinardi D, Marino A, Mantarro G, Campisi R. The use of remifentanil for bloodless surgical field during vertebral disc resection. Minerva Anestesiol. 2002 Sep;68(9):645-9. PubMed PMID: 12370680.
  18. Tezuka F. [Challenges for pathologists in clinical laboratory medicine]. Rinsho Byori. 2001 Jun;49(6):593-5. Japanese. PubMed PMID: 11452548.
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