given the spread of Covid-19 infection with its serious consequences and given that the phenomenon has taken on partly unexpected epidemic dimensions which have required drastic Italian government restrictive measures to counteract its spread, in Our opinion it is legitimate to think of a reclassification of the risk category to which the pathogen Covid-19 belongs.
As it is known, Covid-19 is a viral pathogen of relatively recent acquisition in the human species which in its changed forms has presented over time health problems of growing social impact in different parts of the world and currently in Italy.
The SARS-1 (SARS-CoV, 2002, China) and MERS (2012, Saudi Arabia) forms have relatively little interest in Europe while the SARS-CoV-2 (China, Wuhan, 2019; Covid-19) has importantly spread in Italy.
So far beta-coronaviruses capable of causing disease in humans have been classified by WHO in the Risk Group (RG) 3: ”viral agent with high individual risk, but with a risk of collective spread assessed as low-moderate”.
So, the probability of propagation in the community of this virus was assessed as "moderate".
Also the NIH Guidelines defines the risk groups 3 as “high risk to an individual but a low risk to the community”
Furthermore, RG3 (NIH and WHO) is defined as to have efficient therapeutic approaches .
However, the present experience has led us to realize that Covid-19 has a very hig...
given the spread of Covid-19 infection with its serious consequences and given that the phenomenon has taken on partly unexpected epidemic dimensions which have required drastic Italian government restrictive measures to counteract its spread, in Our opinion it is legitimate to think of a reclassification of the risk category to which the pathogen Covid-19 belongs.
As it is known, Covid-19 is a viral pathogen of relatively recent acquisition in the human species which in its changed forms has presented over time health problems of growing social impact in different parts of the world and currently in Italy.
The SARS-1 (SARS-CoV, 2002, China) and MERS (2012, Saudi Arabia) forms have relatively little interest in Europe while the SARS-CoV-2 (China, Wuhan, 2019; Covid-19) has importantly spread in Italy.
So far beta-coronaviruses capable of causing disease in humans have been classified by WHO in the Risk Group (RG) 3: ”viral agent with high individual risk, but with a risk of collective spread assessed as low-moderate”.
So, the probability of propagation in the community of this virus was assessed as "moderate".
Also the NIH Guidelines defines the risk groups 3 as “high risk to an individual but a low risk to the community”
Furthermore, RG3 (NIH and WHO) is defined as to have efficient therapeutic approaches .
However, the present experience has led us to realize that Covid-19 has a very high propagation ability in the community as it spreads very easily from one individual to another, this is also reflected into the containment measures issued urgently by a number of National European governments.
In addition, for Covid-19 effective and validated therapies are not currently known and there is no vaccine available against it.
It should also be considered that validated serological diagnostics for Covid-19 infection are currently unavailable.
It therefore seems necessary to review the classification of the risk associated with Covid-19 infection and with it, it seems necessary to review the consequent safety levels (bio-containment), for laboratories that have to handle potentially infected material (WHO Laboratory biosafety manual, 2004, III edition).
The topic is of considerable importance as regards the autopsy activity on subjects with Covid-19 infection or with suspected Covid-19 infection.
This activity, prudently, should be carried out in safe environments and with procedures corresponding to those relating to the safety levels suitable for the biocontainment of RG4 agents, rather than those corresponding to the containment level for RG3.
Guidelines are urgently needed to help pathologists operate in the safest way, also contributing to harmonizing approach at European level.
It is proposed to ensure that:
1. in case of an ascertained death for SARS-CoV-2 (i.e. with a positive test for Covid-19) post-mortem autopsy should be avoided, unless the procedure is performed in environment and in ways appropriate for diagnostic activities at RG4 level;
2. in each hospitalized patient, molecular assessment (nasopharyngeal swab test) should be performed to determine Covid-19 presence;
3. when this first test is negative, a second diagnostic test should be carried out in the following 24 hours as recommended by the WHO;
4. when a person dies (irrespective if hospitalized or not), in the absence of documented molecular verification on Covid-19 presence, a nasopharyngeal swab should be performed just after having ascertained the death with the usual procedures;
5. in any case, when a documented valid verification on Covid-19 presence in the subject is absent, post-mortem invasive assessments and procedures should be carried out only with the precautions indicated for RG4;
6. in any case, based on the available medical documentation, in the present Covid-19 epidemic context the pathologist should be free to decide unquestionably whether to perform a complete autopsy or to perform a minimally invasive autopsy on selected areas of the body.
It is essential to remember that the goal of clinical pathology laboratory testing is not the acquisition of information itself, but to improve patient outcome through the promotion of proper laboratory test utilization, namely an appropriate test request and result utilization [1]. Given that pathology laboratory testing is reported to play a crucial role in 70% of clinical decisions and that the overall mean rate of inappropriate over-utilization is around 20% [2], innovations that rationalise and guide appropriate testing are welcome. Mahe et al are to be commended on defining an algorithm to determine which patients to test for the myeloproliferative neoplasm (MPN)-associated JAK2 V617F mutation [3]. Such an approach is particularly pertinent given that identification of this mutation has shifted from a confirmatory test for a relatively uncommon group of diseases to an advance screening test in the initial work up of patients in whom the numerous secondary causes that result in haematological indices similar to that of MPN have not been excluded. Also, the recent revision of World Health Organization classification of myeloid neoplasms lowered the threshold of haemoglobin level for considering a diagnosis of the MPN polycythaemia vera (PV) with a subsequent perceived and real impact on the level of JAK2 V617F testing [4, 5]. Using simple complete blood count (CBC) indices, Mahe et al found that application of their JAK2-tree algorithm to a historical dataset would hav...
It is essential to remember that the goal of clinical pathology laboratory testing is not the acquisition of information itself, but to improve patient outcome through the promotion of proper laboratory test utilization, namely an appropriate test request and result utilization [1]. Given that pathology laboratory testing is reported to play a crucial role in 70% of clinical decisions and that the overall mean rate of inappropriate over-utilization is around 20% [2], innovations that rationalise and guide appropriate testing are welcome. Mahe et al are to be commended on defining an algorithm to determine which patients to test for the myeloproliferative neoplasm (MPN)-associated JAK2 V617F mutation [3]. Such an approach is particularly pertinent given that identification of this mutation has shifted from a confirmatory test for a relatively uncommon group of diseases to an advance screening test in the initial work up of patients in whom the numerous secondary causes that result in haematological indices similar to that of MPN have not been excluded. Also, the recent revision of World Health Organization classification of myeloid neoplasms lowered the threshold of haemoglobin level for considering a diagnosis of the MPN polycythaemia vera (PV) with a subsequent perceived and real impact on the level of JAK2 V617F testing [4, 5]. Using simple complete blood count (CBC) indices, Mahe et al found that application of their JAK2-tree algorithm to a historical dataset would have reduced testing for this mutation by 15%, a considerable impact on workload [3]. Co-incidentally, another group have reported a similar attempt to refine JAK2 V617F testing for suspected PV by incorporating the immature platelet fraction into a CBC-based algorithm [6]. These two studies from Canada and New Zealand suggest that JAK2 V617F over-requesting is a widespread issue.
Given the specificity of the JAK2 V617F mutation for the MPN and the distinct haematological and clinical characteristics of these malignancies, it is disappointing to realise that similar to previous studies [7], Mahe et al note that the majority of JAK2 V617F requests had no clinical details provided. While obtaining CBC data for 95% of their historical cohort it should be mentioned that not all laboratories performing JAK2 V617F mutation studies might have access to corresponding CBC results, e.g. centralised genetic or molecular diagnostic facilities. Other (uncommon) instances that preclude application of this algorithm are when a bone marrow aspirate is provided for molecular analysis or in the acknowledged clinical scenario where splanchnic vein thrombosis unveils a haematologically latent MPN [8].
For other providers of a similar molecular diagnostic service it would be valuable for the authors to discuss how they actually intend to implement this algorithm prospectively and to educate users of their service. A review after a period of operation would reveal any issues regarding barriers to adherence and provide welcome evidence for reducing unnecessary JAK2 V617F testing in a real-world setting.
REFERENCES
1. Salinas M, López-Garrigós M, Flores E, et al. Managing inappropriate requests of laboratory tests: from detection to monitoring. Am J Manag Care 2016;22:e311-6.
2. Zhi M, Ding EL, Theisen-Toupal J, et al. The landscape of inappropriate laboratory testing: a 15-year meta-analysis. PLoS One 2013;8:e78962.
3. Mahe E, Mønsted Pedersen K, Çolak Y, et al. JAK2-tree: a simple CBC-based decision rule to guide appropriate JAK2 V617F mutation testing. J Clin Pathol 2019;72:172-6.
4. Sandes AF, Gonçalves MV, Chauffaille ML. Frequency of polycythemia in individuals with normal complete blood cell counts according to the new 2016 WHO classification of myeloid neoplasms. Int J Lab Hematol 2017;39:528-31.
5. Langabeer SE. An increase in diagnostic JAK2 V617F mutation testing: is masked polycythaemia vera the explanation? Eur J Intern Med 2018;52:e37-8.
6. Johnson S, Baker B. A CBC algorithm combined with immature platelet fraction is able to identify JAK2 V617F mutation-positive polycythaemia vera patients. Int J Lab Hematol 2019, Epub ahead of print, doi: 10.1111/ijlh.12967.
7. Langabeer SE. Referral centre variation in requesting JAK2 V617F mutation analysis for the investigation of a myeloproliferative neoplasm. J Clin Pathol 2012;65:1149-50.
8. Goulding C, Uttenhal B, Foroni L, et al. The JAK2 (V617F) tyrosine kinase mutation identifies clinically latent myeloproliferative disorders in patients presenting with hepatic or portal vein thrombosis. Int J Lab Hematol 2008;30:415-9.
Letter to the Editor – Journal of Clinical Pathology
We read with interest the invited editorial by Grealish et al. entitled “Standardisation of practice for Canadian pathologists' assistants.” First of all, we would like to congratulate the CAP-ACP Executive Committee on its accomplishments to date. Establishing a method for board certification of Canadian Pathologists’ Assistants (PAs) is an important achievement which promotes standardization and high quality anatomical pathology services.
However, our primary reason for writing is to address an error of omission. The editorial correctly notes that there are four two year long Master’s PA training programs in Canada; however, it should be also noted that these vary considerably in size with a ten-fold difference between the largest and the smallest based upon the number of students currently enrolled. The editorial then implies that Canadian training programmes are not accredited and are in need of some new mechanism to become accredited. The editorial states that “the pursuit of creating a ... Canadian accrediting body for PA training programme is ongoing.” We respectfully disagree. The two large Canadian training programmes, hosted by the University of Calgary and Western University, respectively have each been accredited by the National Accrediting Agency for Clinical Laboratory Sciences (NAACLS) (https://www.naacls.org/about.aspx ). NAACLS...
Letter to the Editor – Journal of Clinical Pathology
We read with interest the invited editorial by Grealish et al. entitled “Standardisation of practice for Canadian pathologists' assistants.” First of all, we would like to congratulate the CAP-ACP Executive Committee on its accomplishments to date. Establishing a method for board certification of Canadian Pathologists’ Assistants (PAs) is an important achievement which promotes standardization and high quality anatomical pathology services.
However, our primary reason for writing is to address an error of omission. The editorial correctly notes that there are four two year long Master’s PA training programs in Canada; however, it should be also noted that these vary considerably in size with a ten-fold difference between the largest and the smallest based upon the number of students currently enrolled. The editorial then implies that Canadian training programmes are not accredited and are in need of some new mechanism to become accredited. The editorial states that “the pursuit of creating a ... Canadian accrediting body for PA training programme is ongoing.” We respectfully disagree. The two large Canadian training programmes, hosted by the University of Calgary and Western University, respectively have each been accredited by the National Accrediting Agency for Clinical Laboratory Sciences (NAACLS) (https://www.naacls.org/about.aspx ). NAACLS is a highly coveted international standard that permits our graduates to write the American Society of Clinical Pathology (ASCP) board of certification (BOC) exam as well as the new Canadian Certification Council of Canada (CCCPA) exam and thus our graduates are able to practice on both sides of the border. Presently NAACLS accredits the eight PA training programs in the US (two more are in the final stages of approval) and the above named two in Canada (http://www.pathassist.org/?page=AboutUs_NAACLS); it also accredits training programs in a myriad of other technical arenas in the US and elsewhere. We would suggest that there is no need to create a redundant accreditation specific to Canada given that the two programs already represent the vast majority of Canadian trainees and given the undisputable standards of the NAACLS. Furthermore, nothing precludes other Canadian programmes from seeking and obtaining NAACLS accreditation. Grealish et al.’s suggestion that there should be a “Canadian accrediting body” to address four training programmes is not only unnecessary but would be costly and suffer from unavoidable conflicts of interest because of insufficient critical mass.
The appropriate ‘made in Canada’ solution was already found in the Canadian certification process. While there initially had been considerable enthusiasm in Canada for simply adopting the pre-existing American certification process, this approach did not address the needs of Canadian on-the-job trained (OJT) PAs, which as correctly noted in the editorial, began the profession in Canada and should be honoured. Therefore, separate certification examinations in Canada and the US were, unfortunately, unavoidable. However, having taken this approach to certification is not a good enough reason to start down the pathway of dual program accreditations. We would like to stress that North America-wide accreditation is the best solution for Canadian training programmes and their trainees. Quite simply, NAACLS accreditation is the gold standard and Canadians should not settle for anything less!
Reference:
Grealish M, Wolff A, Eastwood J, Lee D; PA Section of the CAP-ACP Executive Committee. Standardisation of practice for Canadian pathologists' assistants. J Clin Pathol. 2017 Dec;70(12):998-1000. Epub 2017 Sep 12.
We found the paper ‘Long QT syndrome and sudden unexpected infant death’ by Van Niekerk and colleagues to be comprehensive and interesting. We would like to point out that there appears to be a misunderstanding as the authors state that in Australia and New Zealand all sudden and unexpected deaths are mandated to undergo targeted post-mortem genetic testing. Guidelines published by TRAGADY (Trans-Tasman Response AGAinst sudden Death in the Young) advocate that material suitable for DNA extraction must be obtained as part of the best practice guidelines for investigation of sudden death of a young person (1). However, subsequent genetic analysis is not mandated. A policy on the genetic investigation of cause of death in coronial autopsy cases has been recently released by the Royal College of Pathologists of Australasia (RCPA) (2). It is likely this policy document was not available at the time Van Niekerk and colleagues were writing their paper. The RPCA policy states that genetic testing of the deceased is not endorsed in the absence of engagement of the family of the deceased with a genetic counselling service and confirmation of a family history compatible with a heritable disorder. Ideally, there should be identification in the living relatives of a putative genetic defect (or defects) or phenotype for which testing is available. For a number of reasons, some of which are outlined in the RCPA policy document, mandatory post-mortem genetic testing may not be benefic...
We found the paper ‘Long QT syndrome and sudden unexpected infant death’ by Van Niekerk and colleagues to be comprehensive and interesting. We would like to point out that there appears to be a misunderstanding as the authors state that in Australia and New Zealand all sudden and unexpected deaths are mandated to undergo targeted post-mortem genetic testing. Guidelines published by TRAGADY (Trans-Tasman Response AGAinst sudden Death in the Young) advocate that material suitable for DNA extraction must be obtained as part of the best practice guidelines for investigation of sudden death of a young person (1). However, subsequent genetic analysis is not mandated. A policy on the genetic investigation of cause of death in coronial autopsy cases has been recently released by the Royal College of Pathologists of Australasia (RCPA) (2). It is likely this policy document was not available at the time Van Niekerk and colleagues were writing their paper. The RPCA policy states that genetic testing of the deceased is not endorsed in the absence of engagement of the family of the deceased with a genetic counselling service and confirmation of a family history compatible with a heritable disorder. Ideally, there should be identification in the living relatives of a putative genetic defect (or defects) or phenotype for which testing is available. For a number of reasons, some of which are outlined in the RCPA policy document, mandatory post-mortem genetic testing may not be beneficial.
References:
1. Skinner J, Duflou JA, Semsarian C. Reducing sudden death in young people in Australia and New Zealand: the TRAGADY initiative. Med J Aust. 2008;189:539 - 40.
2. Royal College of Pathologists of Australasia. Genetic investigation of cause of death in coronial autopsy cases. Sydney, Australia; 2017 [updated 2017; cited 2018 1 January]; Available from: https://www.rcpa.edu.au/getattachment/0b40e990-3778-4aca-aaeb-1ea1d42441....
El Jabbour T et al. (Jun 2017) described the association between immunohistochemical PD-L1 positivity and loss of MMR proteins in colorectal cancer. However, the evaluation of Mismatch Repair Deficiency (dMMR) as a immunotherapy predictive marker is lacking for Malignant Melanoma (MM) and other malignancies, such as genitourinary, prostate, bladder, head and neck cancers, that are treated with immune checkpoint inhibitors (ICPI).
We recently assessed dMMR in MM patients treated with anti-PD-1/PD-L1 during 2014-2016 at University of Modena and Reggio Emilia: 7% of primary melanoma and 13% of metastasis showed the dMMR. We report a patient whose primary MM and metastasis showed dMMR with immunohistochemical lack of MSH6 expression. Her complex history was characterized by the regression of the multiple cerebral and visceral metastases after anti-PD-L1 therapy, and an extraordinary progression-free survival (1150 days) and overall-survival (2646 days). At present, she is still alive and well, and had the longest response to anti-PD-L1 treatment.
Our results emphasize that the immunohistochemical assessment of MMR protein expression in MM patients represents a useful predictive marker, which may have crucial importance for the determination of the response of anti-PD-1/PD-L1 therapy for MM and potentially for other solid malignancies treated with ICPI therapy.
Dear Editor,
given the spread of Covid-19 infection with its serious consequences and given that the phenomenon has taken on partly unexpected epidemic dimensions which have required drastic Italian government restrictive measures to counteract its spread, in Our opinion it is legitimate to think of a reclassification of the risk category to which the pathogen Covid-19 belongs.
As it is known, Covid-19 is a viral pathogen of relatively recent acquisition in the human species which in its changed forms has presented over time health problems of growing social impact in different parts of the world and currently in Italy.
The SARS-1 (SARS-CoV, 2002, China) and MERS (2012, Saudi Arabia) forms have relatively little interest in Europe while the SARS-CoV-2 (China, Wuhan, 2019; Covid-19) has importantly spread in Italy.
So far beta-coronaviruses capable of causing disease in humans have been classified by WHO in the Risk Group (RG) 3: ”viral agent with high individual risk, but with a risk of collective spread assessed as low-moderate”.
So, the probability of propagation in the community of this virus was assessed as "moderate".
Also the NIH Guidelines defines the risk groups 3 as “high risk to an individual but a low risk to the community”
Furthermore, RG3 (NIH and WHO) is defined as to have efficient therapeutic approaches .
However, the present experience has led us to realize that Covid-19 has a very hig...
Show MoreIt is essential to remember that the goal of clinical pathology laboratory testing is not the acquisition of information itself, but to improve patient outcome through the promotion of proper laboratory test utilization, namely an appropriate test request and result utilization [1]. Given that pathology laboratory testing is reported to play a crucial role in 70% of clinical decisions and that the overall mean rate of inappropriate over-utilization is around 20% [2], innovations that rationalise and guide appropriate testing are welcome. Mahe et al are to be commended on defining an algorithm to determine which patients to test for the myeloproliferative neoplasm (MPN)-associated JAK2 V617F mutation [3]. Such an approach is particularly pertinent given that identification of this mutation has shifted from a confirmatory test for a relatively uncommon group of diseases to an advance screening test in the initial work up of patients in whom the numerous secondary causes that result in haematological indices similar to that of MPN have not been excluded. Also, the recent revision of World Health Organization classification of myeloid neoplasms lowered the threshold of haemoglobin level for considering a diagnosis of the MPN polycythaemia vera (PV) with a subsequent perceived and real impact on the level of JAK2 V617F testing [4, 5]. Using simple complete blood count (CBC) indices, Mahe et al found that application of their JAK2-tree algorithm to a historical dataset would hav...
Show MoreLetter to the Editor – Journal of Clinical Pathology
We read with interest the invited editorial by Grealish et al. entitled “Standardisation of practice for Canadian pathologists' assistants.” First of all, we would like to congratulate the CAP-ACP Executive Committee on its accomplishments to date. Establishing a method for board certification of Canadian Pathologists’ Assistants (PAs) is an important achievement which promotes standardization and high quality anatomical pathology services.
However, our primary reason for writing is to address an error of omission. The editorial correctly notes that there are four two year long Master’s PA training programs in Canada; however, it should be also noted that these vary considerably in size with a ten-fold difference between the largest and the smallest based upon the number of students currently enrolled. The editorial then implies that Canadian training programmes are not accredited and are in need of some new mechanism to become accredited. The editorial states that “the pursuit of creating a ... Canadian accrediting body for PA training programme is ongoing.” We respectfully disagree. The two large Canadian training programmes, hosted by the University of Calgary and Western University, respectively have each been accredited by the National Accrediting Agency for Clinical Laboratory Sciences (NAACLS) (https://www.naacls.org/about.aspx ). NAACLS...
Show MoreWe found the paper ‘Long QT syndrome and sudden unexpected infant death’ by Van Niekerk and colleagues to be comprehensive and interesting. We would like to point out that there appears to be a misunderstanding as the authors state that in Australia and New Zealand all sudden and unexpected deaths are mandated to undergo targeted post-mortem genetic testing. Guidelines published by TRAGADY (Trans-Tasman Response AGAinst sudden Death in the Young) advocate that material suitable for DNA extraction must be obtained as part of the best practice guidelines for investigation of sudden death of a young person (1). However, subsequent genetic analysis is not mandated. A policy on the genetic investigation of cause of death in coronial autopsy cases has been recently released by the Royal College of Pathologists of Australasia (RCPA) (2). It is likely this policy document was not available at the time Van Niekerk and colleagues were writing their paper. The RPCA policy states that genetic testing of the deceased is not endorsed in the absence of engagement of the family of the deceased with a genetic counselling service and confirmation of a family history compatible with a heritable disorder. Ideally, there should be identification in the living relatives of a putative genetic defect (or defects) or phenotype for which testing is available. For a number of reasons, some of which are outlined in the RCPA policy document, mandatory post-mortem genetic testing may not be benefic...
Show MoreEl Jabbour T et al. (Jun 2017) described the association between immunohistochemical PD-L1 positivity and loss of MMR proteins in colorectal cancer. However, the evaluation of Mismatch Repair Deficiency (dMMR) as a immunotherapy predictive marker is lacking for Malignant Melanoma (MM) and other malignancies, such as genitourinary, prostate, bladder, head and neck cancers, that are treated with immune checkpoint inhibitors (ICPI).
We recently assessed dMMR in MM patients treated with anti-PD-1/PD-L1 during 2014-2016 at University of Modena and Reggio Emilia: 7% of primary melanoma and 13% of metastasis showed the dMMR. We report a patient whose primary MM and metastasis showed dMMR with immunohistochemical lack of MSH6 expression. Her complex history was characterized by the regression of the multiple cerebral and visceral metastases after anti-PD-L1 therapy, and an extraordinary progression-free survival (1150 days) and overall-survival (2646 days). At present, she is still alive and well, and had the longest response to anti-PD-L1 treatment.
Our results emphasize that the immunohistochemical assessment of MMR protein expression in MM patients represents a useful predictive marker, which may have crucial importance for the determination of the response of anti-PD-1/PD-L1 therapy for MM and potentially for other solid malignancies treated with ICPI therapy.
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