The authors of this paper observe that, "The severity of hypoxia
determines whether cells become apoptotic or adapt to hypoxia and survive.
A hypoxic environment devoid of nutrients prevents the cell undergoing
energy dependent apoptosis and cells become necrotic....During hypoxia, an
intricate balance exists between factors that induce or counteract
apoptosis, or even stimulate proliferation".[1]
The authors of this paper observe that, "The severity of hypoxia
determines whether cells become apoptotic or adapt to hypoxia and survive.
A hypoxic environment devoid of nutrients prevents the cell undergoing
energy dependent apoptosis and cells become necrotic....During hypoxia, an
intricate balance exists between factors that induce or counteract
apoptosis, or even stimulate proliferation".[1]
In myocytes the likelihood of devloping apoptosis appears to be
dependent upon interstitial pH increasing as the pH falls to abnormally
low levels[2] as it does when an energy deficit develops in cells.
In an earlier communication to Heart[3] it was asked, "Might it be
that apoptosis, an ATP-dependent process, is an altruistic sacrifice
intended to protect adjacent cells from the harmful effects of the
inflammatory response induced by free radical release and cellular
necrosis should it occur? [The absence of an inflammatory response in
apoptosis is a striking feature distinguishing it from necrosis]. Might
apoptosis even be a physiological stimulus for myocyte renewal?"
A corollary of this myocyte buddy hypothesis is that apoptotic cells
might protect contiguous cells under reductive/oxidative stress by
providing them with a supplementary supply of nutrients in times of stress
independently of an overextended blood supply. Necrosis might only occur,
and an inflammatory response be initiated, when this hypothetical
supplementary supply of nutrient fails to meet the metabolic needs of
stressed cells. [Anaerobic glycolysis is the dominant means of ATP
resynthesis in healing wounds and malignant tumours but hardly ever to the
total exclusion of oxygen. This implies that the dependence upon nutrient
relative to oxygen delivery is abnormally increased in these
circumstances].
What then determines the ultimate fate of cells? The studies cited
above suggest that apoptosis and/or necrosis might only occur when the
interstitial pH has fallen below 6.86 or even 6.80. In which case cells
exposed to an abnormally low pH higher than that, possibly one between
7.32 and 6.90, might be subjected to increasing cellular disorder the
effects of which could be an added risk of genetic damage and/or mutation.
This could be an evolutionary advantage in unicellular organisms and one
that might even be the product of quantum tunnelling.[4]
Cellular proliferation is induced under similar metabolic
circumstances in an healing wound but must be accompanied by an abnormal
elevation in pH because of the reductuive biosynthesis in progress.
Angiogenesis, which also appear to be induced by the hypoxia inducible
factor 1 [5], is presumably a prerequisite for the delivery of adequate
nutrient to sustain the anaerobic glycolysis needed in an healing wound
and indeed tumour growth. This requires an abnormally good supply of blood
for much more nutrient must be delivered to generate 1 mol ATP by
anaerobic glycolysis than by oxidative phosporylation. A return to a
nornal tissue pH (7.40) can be expected to occur in an healed wound but
might not occur in a growing tumour. Rapidly growing tumoursmight,
however, be especially susceptible to a precipitous decline in pH induced
by an nadequate supply of nutrient and hence to the cellular necrosis
commonly seen in the center of a rapidly growing tumour.
The "intricate balance [that] exists between factors that induce or
counteract apoptosis, or even stimulate proliferation"[1] and possibly
even invasion and metastatic spread might be defined and even determined
by the ambient pH. This appears not only to be an index of but might even
be a determinant of[6] the metabolic environment present. The activity of
HIF-1 may even be determined by the ambnient pH which falls precipitously
in stagnant hypoxia unless preceded by cardiac arrest.[7]
References
1. A E Greijer and E van der Wall
The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced
Apoptosis. J Clin Pathol 2004; 57: 1009-1014.
2. Thatte HS, Rhee JH, Zagarins SE, Treanor PR, Birjiniuk V,
Crittenden MD, Khuri SF. Acidosis-induced apoptosis in human and porcine
heart. Ann Thorac Surg. 2004 Apr;77(4):1376-83.
3. Richard G Fiddian-Green. A myocyte buddy system in stressed myocardium?
http://www.heartjnl.com/cgi/eletters/90/4/425#393, 2 Aug 2004
4. Jim Al Khalili. Quantum: A Guide for the Perplexed.
6. Cain SM. pH effects on lactate and excess lactate in relation to
O2 deficit in hypoxic dogs. J Appl Physiol. 1977 Jan;42(1):44-9.
7. Grum CM, Fiddian-Green RG, Pittenger GL, Grant BJ, Rothman ED,
Dantzker DR. Adequacy of tissue oxygenation in intact dog intestine.
J Appl Physiol. 1984 Apr;56(4):1065-9.
The article by WS Smellie and colleagues[1] recommends not requesting
total IgE levels when requesting allergen specific IgE. We agree that
total IgE on its own neither rules in nor rules out the diagnosis of
allergy. However, total IgE levels are useful in the interpretation of
specific IgE tests, because they permit the ascertainment of possible
false-negative or false-positive results. Although thi...
The article by WS Smellie and colleagues[1] recommends not requesting
total IgE levels when requesting allergen specific IgE. We agree that
total IgE on its own neither rules in nor rules out the diagnosis of
allergy. However, total IgE levels are useful in the interpretation of
specific IgE tests, because they permit the ascertainment of possible
false-negative or false-positive results. Although this may not be as
important in the interpretation of aeroallergen-specific IgE results, this
consideration is vital in determining possible causes of anaphylaxis.
High total IgE may cause false positive specific IgE tests. High IgE
level are more common in males, smokers and severe eczema [2]. Mehl A and
colleagues[3] found that the ratio of food-specific / total IgE had a
significant correlation with outcome from food challenge (cow’s milk,
hen’s egg, wheat and soy) but specific IgE estimations were just as
reliable. M Kerkhof and colleagues demonstrated that the elevated total
IgE ‘outpaces’ specific IgE in younger individuals (aged 20-44 years),
suggesting that in this cohort, negative specific IgE should guide the
clinician towards looking for IgE against other allergens [4].
Low IgE (<10 IU/ml) are rarely associated with findings of
positive specific IgE results, although positive IgE at these low total
IgE levels may be extremely significant [5]. Knowing that the total IgE is
low becomes essential when interpreting negative specific IgE tests in the
context of anaphylaxis for example.
Yours faithfully,
S Khan*
S Holding**
PC Doré**
WAC Sewell*
*Path Links Immunology, Scunthorpe General Hospital, Scunthorpe, DN15
7BH, UK.
**Department of Immunology, Hull Royal Infirmary, Hull, HU3 2JZ, UK.
Competing interests: None.
References
1.Smellie WS, Forth JO, McNulty CA, Hirschowitz L, Lilic D, Gosling R,
Bareford D, Logan E, Kerr KG, Spickett GP, Hoffman J, Galloway A, Bloxham
CA. Best practice in primary care pathology: review 2. J Clin Pathol. 2006
Feb; 59(2): 113-20.
2.Wuthrich B, Schindler C, Medici TC, Zellweger JP, Leuenberger P. IgE
levels, atopy markers and hay fever in relation to age, sex and smoking
status in a normal adult Swiss population. SAPALDIA (Swiss Study on Air
Pollution and Lung Diseases in Adults) Team. Int Arch Allergy Immunol.
1996 Dec; 111(4):396-402.
3.Mehl A, Verstege A, Staden U, Kulig M, Nocon M, Beyer K, Niggemann B.
Utility of the ratio of food-specific IgE/total IgE in predicting
symptomatic food allergy in children. Allergy. 2005 Aug; 60(8): 1034-9.
4.Kerkhof, M., Dubois, A. E. J., Postma, D. S., Schouten, J. P. &
Monchy, J. G. R. Role and interpretation of total serum IgE measurements
in the diagnosis of allergic airway disease in adults. Allergy 2003; 58
(9): 905-911.
5.Sinclair D, Peters SA The predictive value of total serum IgE for a
positive allergen specific IgE result.J Clin Pathol. 2004 ; 57(9): 956-9.
It was interesting to read the audit of thrombophilia screens [1]. It
was however stated that "Only 11 of the 47 laboratories surveyed routinely
carried out a total protein S assay" and "The BCSH guidelines suggest that
only the total protein S assay should be used as a screening test, and if
this is abnormal, then a free protein S assay should be performed”. In
fact the guideline [2] does not recommend...
It was interesting to read the audit of thrombophilia screens [1]. It
was however stated that "Only 11 of the 47 laboratories surveyed routinely
carried out a total protein S assay" and "The BCSH guidelines suggest that
only the total protein S assay should be used as a screening test, and if
this is abnormal, then a free protein S assay should be performed”. In
fact the guideline [2] does not recommend this and many laboratories
measure free protein S directly which is fully in accordance with the
guideline. However, for other reasons, we think the time has come to re-
write the guideline and the Haemostasis and Thrombosis Task Force of the
BCSH will be doing so this year.
References
1. Lyons, S., et al., An audit of thrombophilia screens: results from
the National Pathology Alliance benchmarking review. J Clin Pathol, 2006.
59(2): p. 156-9.
2. Walker, I.D., M. Greaves, and F.E. Preston, Investigation and
management of heritable thrombophilia. Br J Haematol, 2001. 114(3): p. 512-28.
Our best practice guidelines for the diagnosis of allergy advise that
routine requesting of total IgE measurements is not necessary; instead we
advise requesting allergen-specific IgE based on clinical findings. Khan
et al. argue that measurement of total IgE levels permits ascertainment of
possible false-negative or false-positive specific IgE results. However,
the examples given provide only a circum...
Our best practice guidelines for the diagnosis of allergy advise that
routine requesting of total IgE measurements is not necessary; instead we
advise requesting allergen-specific IgE based on clinical findings. Khan
et al. argue that measurement of total IgE levels permits ascertainment of
possible false-negative or false-positive specific IgE results. However,
the examples given provide only a circumstantial indication of the
possibility of false positive or negatives in rare cases. In the context
of primary care testing, the issue in question is whether total IgE should
be requested systematically alongside all specific IgE requests, or only a
posteriori in specific cases. Current evidence suggests that in the vast
majority of cases, assessment of total IgE increases costs unnecessarily
as it does not add to the diagnosis and management of allergy patients. In
the example given of anaphylaxis, we would recommend such cases to be
investigated in conjunction with a consultant immunologist.
The authors confirm that increased levels of total IgE may be found
in situations without an allergic background, are therefore not predictive
of allergic sensitisation and consequently have little positive predictive
value for the diagnosis of allergy. We agree with this statement. Further,
the authors acknowledge that low IgE does not rule out sensitisation,
which can only be assessed by testing for allergen-specific IgE; one of
the references quoted (Sinclaire d et al) – although advising that total
IgE should be performed as a screening test which would exclude specific
IgE if low – goes on to conclude that specific IgE testing should be
performed regardless of total IgE levels when there are convincing
clinical reasons to do so. We agree with this statement. The authors quote
findings in support of a correlation between total IgE and specific IgE
levels (Kerkhof m et al) in food allergy, although specific IgE alone was
found to be just as reliable. We again agree.
The authors however, correctly point out that very high levels of
total IgE can give false positive specific IgE results, which we did not
specifically address in our guidelines. We agree this can be relevant, but
feel that these situations are relatively rare and do not justify regular
requesting of total IgE; our advice would be to request total IgE a
posteriori if the results of specific IgE testing suggest that non-
specific binding is the reason for the false positive (i.e. multiple or
all allergens tested are positive).
Even though not mentioned in the letter, it is important to stress
that measuring total IgE may have previously been of significance in
calculating the amount (i.e. quantitation) of specific IgE present; this
is now bypassed by the inclusion of international reference standards for
total IgE in kits measuring specific IgE, enabling the expression of
specific IgE quantitatively in international units rather than semi-
quantitatively in scores.
Finally it is of note that the American Academy of Allergy, Asthma
and Immunology (AAAAI) and American College of Allergy, Asthma and
Immunology (ACAAI) recently published guidelines on food allergy (Annals
Asthma Allergy Immunol, 2006, 96(3) supp:1-68) in which they neither
mention nor recommend measurement of total IgE in patients with food
allergy.
We are grateful for the comments by Khan et al. These guidelines are
intended for regular review and wide professional input wherever possible.
The traditional criteria ever used to evaluate laboratory tests has
been the predictive 'accuracy' of the test.
None of the available laboratory tests used in the selection of
treatments for cancer patients have ever been tested for 'efficacy'. This
includes estrogen receptor, progesterone receptor, Her2/neu,
immunohistochemical staining for tumor classification, bacterial culture
and sensi...
The traditional criteria ever used to evaluate laboratory tests has
been the predictive 'accuracy' of the test.
None of the available laboratory tests used in the selection of
treatments for cancer patients have ever been tested for 'efficacy'. This
includes estrogen receptor, progesterone receptor, Her2/neu,
immunohistochemical staining for tumor classification, bacterial culture
and sensitivity testing, CT, MRI and FDG Pet Scans to measure tumor
response to treatment.
There is no literature establishing clinical 'efficacy' of these
laboratory tests, because the costs of such clinical trials are
prohibitive, granting agency support is non-existent, and no other
analogous tests have been or will likely ever be subjected to such an
unreasonably high bar criterion for clinical use.
The only data supporting any of them relate to test 'accuracy', and
there is a total lack of information regarding test 'efficacy'.
(randomized trials with outcome measurements for diagnostic tests)
Also, no one is seriously proposing that any of the molecular tests
now available (Oncotype DX, EGFR amplification/mutation) should have to be
proven 'efficacious', as opposed to merely 'accurate', before they are
used in clinical decisions regarding treatment selection.
The American Society of Clinical Oncology (ASCO) reviews of cell
culture assay tests for establishing clinical 'efficacy' specifically
excluded all studies reporting the predictive 'accuracy' of the tests. In
other words, they excluded reports that only reported correlations between
assay results and clinical outcomes.
Instead, ASCO reviews included old, previously-reviewed studies
comparing outcomes of patients who had treatment based on assay results
versus patients with empirically chosen therapy. The criteria of
laboratory assay 'efficacy', as opposed to laboratory assay 'accuracy'
sound reasonable, but it is unprecendented with regard to any other
laboratory test ever evaluated.
Cell culture assay tests have been well proven to have predictive
'accuracy' with that of estrogen receptor, progesterone receptor, Her2/neu
and the newer molecular tests. In light of the precious little in the way
of guidance from clinical trials with respect to best empiric therapy
(where the only thing that has been proven to correlate with treatment
decisions is reimbursement to the prescribing oncologist) and the
importance of basing cancer treatment at least in part on patient
preferences, it is entirely reasonable to support judicious application of
laboratory tests which have been well characterized with respect to test
'accuracy'. These are diagnostic tests and should be held to that
criteria, and not to that of therapy.
These laboratory tests are a tool for the oncologist. The oncologist
should take advantage of all the tools available to him/her to treat a
patient. And since studies show that only 25-30% of patients do respond to
chemotherapy that is available to them, there should be due consideration
to looking at the advantage of human tissue assay tests to the resistance
that has been found to chemotherapy drugs.
Cell culture drug resistance testing is for preventing use of known
anti-cancer drugs that are not likely effective in the specific tumor.
Cell culture drug sensitivity testing tries to determine specific drug and
dose effectiveness. The distinction between sensitivity and resistance is
more semantic than substantive.
In virtually all forms of cancer, clinical trials have failed to
identify best drug regimens for use in all individuals with a given form
of cancer.
Oncologists have been documented to use reimbursement (payment to the
oncologist) as the most important criterion for selecting between the
large array of otherwise equally acceptable regimens. (Jacobson,
M.,O'Malley, A.J., Earle, C.C., et al. Health Affairs 25(2):437-443, 2006)
& (Patterns of Care: 2005,Vol 2,Issue 1)
The established criterion on which to judge all laboratory tests used
to help in the selection of cancer treatment is test 'accuracy' and not
test 'efficacy'.
Cell culture assay tests with cell-death endpoints have been
exceedingly and reproducibly well established to be usefully 'accurate' in
correlation with and predicting for clinical outcomes, including tumor
response and patient survival.
There should an expansion of Medicare and private insurance
reimbursement to promote even greater utilization and development of
laboratory-based mechanisms, like cell culture assays, for improving the
match between tumors and an ever-increasing number of partially effective
and very expensive drug therapies.
We read with great interest the original article by Bernardi et al.
[1] in the December 2005 issue of the Journal.
According to literature previously published, the authors believe that
necroscopy is the standard method to determine the cause of death when
investigating clinicopathological discrepancies and the epidemiology of
disease. They reviewed the provisional and final reports of necropsies
per...
We read with great interest the original article by Bernardi et al.
[1] in the December 2005 issue of the Journal.
According to literature previously published, the authors believe that
necroscopy is the standard method to determine the cause of death when
investigating clinicopathological discrepancies and the epidemiology of
disease. They reviewed the provisional and final reports of necropsies
performed at their Institution in 2001 to check diagnostic changes between
initial gross diagnosis and subsequent histological analysis in several
organs. They found that microscopic examination has a major impact on
macroscopic diagnosis, altering and refining previous diagnoses,
especially in the lungs, liver and kidneys. Moreover Bernardi et al. [1]
raise the question that, in routine necropsies, histological sampling
increases costs and turnaround times, and consequently some pathologists
believe that histology may not always be necessary.
We found their discussion of literature and interpretation of the data
very pertinent and we wish to share with the authors and the readers our
experience.
We would like to stress out even further the necessity for the pathologist
to realize the usefulness of histological analysis. Due to a misbelief
that post mortem events alter morphology in such a way to prevent a
correct diagnosis, some pathologists decide not to take samples for
histology. Grellner and coll. [2] have systematically shown however that
histological analysis is feasible and useful even when the exam is made of
exhumed bodies months after burial.
At the autopsy, the pathologist should first describe the macroscopic
aspect of each organ and take samples of each visible lesion. A
provisional diagnosis may be given while histology is pending but the
diagnosis should be confirmed by histological analysis. It should be noted
that a correct sampling by the pathologist must be performed to avoid
forensic consequences from misdiagnosis.
Moreover pathologists should keep in mind that the classical pathological
patterns are changing due to the effects of novel and more prompt
interventions. In some cases alterations are identifiable only at a
microscopic level.
We would like to point out that the histological analysis of the heart
sometimes is fundamental to determine the cause of death and date the
event. This is especially important in such diseases as non-
atherosclerotic coronary pathology [3-5]. In our own small experience an
accurate histological examination allowed us to specify the chain of
events which brought on unexpected sudden death [6,7].
In conclusion we are grateful to the authors for addressing such a
relevant issue. Although it may appear time consuming and costly at first,
a more complete assessment would reveal that the risk of misdiagnosis
using macroscopic only analyses is relatively high, and an accurate
assessment of the scenario using histological analysis assures the
reliability of the findings, which is of particular relevance in forensic
medicine. Moreover, the detailed analysis under the microscope is the
access pathway to a different dimension where the pathologist sees not
only the end event but he has insight of the pathophysiologic cascade of
cellular and molecular events leading to the disease.
References
1. Bernardi FD, Saldiva PH, Mauad T. Histological examination has a major
impact on macroscopic necropsy diagnoses. J Clin Pathol 2005;58:1261-4.
2. Grellner W, Glenewinkel F. Exhumations: synopsis of morphological and
toxicological findings in relation to the postmortem interval. Survey on a
20-year period and review of the literature. Forensic Sci Int 1997;90:139-
59.
3. Corrado D, Basso C, Thiene G. Sudden cardiac death in young people with
apparently normal heart. Cardiovasc Res 2001;50:399-408.
4. De Giorgio F, Abbate A, Vetrugno G, et al. Non-atherosclerotic coronary
pathology causing sudden death. J Clin Pathol in press.
5. De Giorgio F, Abbate A, Capelli A, et al. Spontaneous rupture of
coronary artery in HIV+ patient treated with HAART. Am J Forensic Med
Pathol 2005;26:197.
6. De Giorgio F, Abbate A, Biondi-Zoccai GG, et al. Fatal choking due to
amyloid infiltration of the laryngeal plexus. Virchows Arch. 2005;447:115-
7. De Giorgio F, Abbate A, Biondi-Zoccai GG, et al. An unusual cause of
fatal pulmonary embolism. Int J Cardiol. in press.
I recently read the article, "Basal-like breast carcinomas; clinical
outcome and response to chemotherapy" by Banerjee et al. (corresponding
author, Prof. Smith), published online in Journal of Clinical Pathology on
23.03.06. I would like to point out that the authors incorrectly make
reference to a paper of mine (reference 3), published in Journal of
Clinical Oncology in 1995, in connection with
g...
I recently read the article, "Basal-like breast carcinomas; clinical
outcome and response to chemotherapy" by Banerjee et al. (corresponding
author, Prof. Smith), published online in Journal of Clinical Pathology on
23.03.06. I would like to point out that the authors incorrectly make
reference to a paper of mine (reference 3), published in Journal of
Clinical Oncology in 1995, in connection with
grade determination. I have never been involved in this particular field,
indeed I have serious doubts as to its reproducibility, and my article
cited does not deal with grading but with cell proliferation determined as
Thymidine Labelling Index.
Nakhleh R E (1) has excelled in giving us a brilliant account on
the
quality assuarance and improvement plan in surgical pathological
reporting
in a nutshell. An accurate, comprehensive, brief and timely surgical
pathology report would always facilitate the optimum management of the
patient and it would also satisfy the needs of the customer, in this
case
the clinician.Undoubtably all the clinicians...
Nakhleh R E (1) has excelled in giving us a brilliant account on
the
quality assuarance and improvement plan in surgical pathological
reporting
in a nutshell. An accurate, comprehensive, brief and timely surgical
pathology report would always facilitate the optimum management of the
patient and it would also satisfy the needs of the customer, in this
case
the clinician.Undoubtably all the clinicians would value and admire a
well
focused, informative and well directed surgical pathology report.
The final product of complete surgical pathology report is
multifactorial and it necessitates a multidisciplinary approach. Request
forms have to be well written with a short and a well directed clinical
history. It should elaborate the crux of the matter and be stressed to
all clinicians should be stressed the importance of it regardless of the
place
in the hierarchical structure. Specimen collection, analyzing, labeling,
transporting to the labouratory, reporting, report correction,
verification and report delivery should occur in a sequential well
directed flow.
The reporting has to be performed in a well formatted structured
manner and this kind of standardized proforma leads to better quality
surgical pathology reports(2). Most institutions have their own
proforma in
reporting histopathological specimens. But unfortunately people find it
difficult to adhere to a system (3) and some of the forms are found to
be
incomplete. This highlights the importance of training and motivating
the
work force.
There seems to be wide variation in interpretation of phrases used
in
histopathology reports between pathologists and clinicians
(4). Interdisciplinary meetings have to be conducted frequently and
they
would summarize the clinical findings, biochemical findings and finally
the histological findings and they would culminate to facilitate the
management plan of the patient concerned. They should be considered as
essential ingredients in the formula for a better patient care.
Moreover there should always be a better way of communication
between
the clinician and the pathologist when summating to an optimal
management
plan. So it would have been better if the review by Nakhleh R E had
included few words on the importance of communication between the
clinician and the pathologist, the importance of adhering to proforma
when
reporting, and interdisciplinary meetings.
References
(1) Nakhleh R E .What is quality in surgical pathology? Journal of
clinical
pathology 2006; 59:669-72.
(2) Beattie G C.Improvement in quality colorectal cancer pathology
reporting with a standardized proforma-a comparative study. Colorectal
Disease November 2003; Vol 5:558.
(3) Nagetaal I D.Pathology data in the central databases of
multicenter randomized trials needs to be based on pathology reports and
controlled by trained quality managers. Journal of Clinical Oncology,
Vol 18, Issue 8, (April), 2000:1771-1779.
(4) Hewavisenthi SJ De S, Fernando P.Use and interpretation of
phrases in histopathology reports. Ceylon Medical Journal 2005; 1:37-38.
Smellie et al, in their article Best Practice in Primary Care Pathology: Review 3(1) cite our article published in the BMJ in 1994.(2)
Unfortunately they state that this was a study of “people referred from primary care to a hospital lipid clinic” and it wasn’t. Our study was, on the contrary, a review of computerised medical records of a group
of patients with hyperlipidaemia in one general prac...
Smellie et al, in their article Best Practice in Primary Care Pathology: Review 3(1) cite our article published in the BMJ in 1994.(2)
Unfortunately they state that this was a study of “people referred from primary care to a hospital lipid clinic” and it wasn’t. Our study was, on the contrary, a review of computerised medical records of a group
of patients with hyperlipidaemia in one general practice which alone had the 1542 tests described.
The vast majority of people with raised lipids in the United Kingdom are not referred to hospital lipid clinics and the key clinical issue is how they should be best managed and treated in general practice.
Yours faithfully
Philip Evans, Denis Pereira Gray
References
(1) Smellie WSA, Forth J, Bareford D, Twomey P, Galloway MJ, Logan ECM et al. Best practice in primary care pathology: review 3. J Clin
Pathol 2006; 59(8):781-789.
(2) Evans P, Pereira Gray DJ. Value of screening for secondary causes of hyperlipidaemia in general practice. British Medical Journal 1994; 309:509-510.
I read with interest the article by Zhang et al published in the September 2006 issue of the Journal of Clinical Pathology (J Clin Pathol 2006;59:958–964.). The authors wrote on fascin, an actin-binding protein,
as a potential biomarker for early-stage oesophageal squamous cell carcinoma. There are a number of methodological issues with the research and paper that potentially weakens their findings and int...
I read with interest the article by Zhang et al published in the September 2006 issue of the Journal of Clinical Pathology (J Clin Pathol 2006;59:958–964.). The authors wrote on fascin, an actin-binding protein,
as a potential biomarker for early-stage oesophageal squamous cell carcinoma. There are a number of methodological issues with the research and paper that potentially weakens their findings and interpretation.
Firstly, the design of the study is suboptimal. The authors used two different patient groups for different aspects of the work. 102 archival materials from 2001 to 2003 were used for the immunohistochemical staining
and specimens from 49 patients with oesophageal cancer operated upon in 2003 and 2004 were used for the western blot and real-time RT-PCR analyses. However, the results from the two different groups were presented and compared as if from the same study population. Methodologically, it would have been better to use the 2003/2004 patient
cohorts for the whole research.
Immunohistochemical positivity was defined as cells showing >5% cytoplasmic staining in the methodology section. Later in the result section, the authors said they graded positivity as mild, moderate and severe but the readers are not told on what basis this grading was based.
For the RT-PCR analysis, they used beta-actin as the internal control (i.e. house-keeping gene). Given that fascin is an actin binding protein, surely the potential for interaction between the target gene and internal
control gene therefore exists.
Lastly, whilst the authors gave a good description of the statistical analysis carried out, I think they have employed wrong tests to analyse the data. Chi-squared test was used to analyse proportions but given that some of the data items were very small (<10) as presented in Table 2,
Fischer’s exact test would have been more appropriate in those situations. Also, for the continuous data presented in Tables 3 and 4 they used student’s t-test to analyse the data, thereby assuming normality. However, looking more closely at the data, there is a strong suggestion that the
data presented are not normally distributed with standard deviations as high (even higher) than the mean concentrations/levels of fascin (1). This is actually not a surprise, as it is generally known in statistics that
data obtained from ratios or concentrations are usually not normally distributed. Therefore, the authors should either have log transformed (2) their data before using student’s t-test or use a non-parametric test such as Mann-Whitney test for the statistical analysis.
The above methodological and statistical issues call into question the interpretation of the data generated and presented and therefore, weakens the conclusions reached. It would be interesting to hear the authors’ responses to the above points.
Yours truly
Dr Olorunda Rotimi MRCPath, PGDip Health Research
References
1. Altman DG, Bland JM. Detecting skewness from summary information. BMJ 1996;313:1200
2. Bland JM, Altman DG. Transforming data. BMJ 1996;312:770
Dear Editor,
The authors of this paper observe that, "The severity of hypoxia determines whether cells become apoptotic or adapt to hypoxia and survive. A hypoxic environment devoid of nutrients prevents the cell undergoing energy dependent apoptosis and cells become necrotic....During hypoxia, an intricate balance exists between factors that induce or counteract apoptosis, or even stimulate proliferation".[1]
...Dear Editor,
The article by WS Smellie and colleagues[1] recommends not requesting total IgE levels when requesting allergen specific IgE. We agree that total IgE on its own neither rules in nor rules out the diagnosis of allergy. However, total IgE levels are useful in the interpretation of specific IgE tests, because they permit the ascertainment of possible false-negative or false-positive results. Although thi...
Dear Editor,
It was interesting to read the audit of thrombophilia screens [1]. It was however stated that "Only 11 of the 47 laboratories surveyed routinely carried out a total protein S assay" and "The BCSH guidelines suggest that only the total protein S assay should be used as a screening test, and if this is abnormal, then a free protein S assay should be performed”. In fact the guideline [2] does not recommend...
Dear Editor,
Our best practice guidelines for the diagnosis of allergy advise that routine requesting of total IgE measurements is not necessary; instead we advise requesting allergen-specific IgE based on clinical findings. Khan et al. argue that measurement of total IgE levels permits ascertainment of possible false-negative or false-positive specific IgE results. However, the examples given provide only a circum...
Dear Editor,
The traditional criteria ever used to evaluate laboratory tests has been the predictive 'accuracy' of the test.
None of the available laboratory tests used in the selection of treatments for cancer patients have ever been tested for 'efficacy'. This includes estrogen receptor, progesterone receptor, Her2/neu, immunohistochemical staining for tumor classification, bacterial culture and sensi...
Dear Editor,
We read with great interest the original article by Bernardi et al. [1] in the December 2005 issue of the Journal. According to literature previously published, the authors believe that necroscopy is the standard method to determine the cause of death when investigating clinicopathological discrepancies and the epidemiology of disease. They reviewed the provisional and final reports of necropsies per...
Dear Editor,
I recently read the article, "Basal-like breast carcinomas; clinical outcome and response to chemotherapy" by Banerjee et al. (corresponding author, Prof. Smith), published online in Journal of Clinical Pathology on 23.03.06. I would like to point out that the authors incorrectly make reference to a paper of mine (reference 3), published in Journal of Clinical Oncology in 1995, in connection with g...
Dear Editor,
Nakhleh R E (1) has excelled in giving us a brilliant account on the quality assuarance and improvement plan in surgical pathological reporting in a nutshell. An accurate, comprehensive, brief and timely surgical pathology report would always facilitate the optimum management of the patient and it would also satisfy the needs of the customer, in this case the clinician.Undoubtably all the clinicians...
Dear Editor
Smellie et al, in their article Best Practice in Primary Care Pathology: Review 3(1) cite our article published in the BMJ in 1994.(2)
Unfortunately they state that this was a study of “people referred from primary care to a hospital lipid clinic” and it wasn’t. Our study was, on the contrary, a review of computerised medical records of a group of patients with hyperlipidaemia in one general prac...
Dear Editor
I read with interest the article by Zhang et al published in the September 2006 issue of the Journal of Clinical Pathology (J Clin Pathol 2006;59:958–964.). The authors wrote on fascin, an actin-binding protein, as a potential biomarker for early-stage oesophageal squamous cell carcinoma. There are a number of methodological issues with the research and paper that potentially weakens their findings and int...
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