The reliability of diagnostic and prognostic information in breast
core biopsies is an important factor to be considered by surgeons and
oncologists when planning treatment, especially if pre-operative
chemotherapy is under consideration. The recent report by O’Leary et al.[1] is
important because it considers whether the amount of tumour present in
core biopsies has any impact upon the reliabi...
The reliability of diagnostic and prognostic information in breast
core biopsies is an important factor to be considered by surgeons and
oncologists when planning treatment, especially if pre-operative
chemotherapy is under consideration. The recent report by O’Leary et al.[1] is
important because it considers whether the amount of tumour present in
core biopsies has any impact upon the reliability of the information.
We
completed a similar study of 134 women in whom core biopsies and a
subsequent excision was available for comparison between 2001 and 2002 in
Southampton. We showed similar results with a 69.1% overall agreement of
invasive tumour grade and 61.1% overall agreement in DCIS grade between
the core biopsy and excision with the grade tending to be underscored more
often than overscored in the core biopsy. Agreement of 75.8% was seen for
invasive tumour type. We also looked at the reliability of information
dependent upon the amount of invasive carcinoma present using a measure of
the linear length of tumour present in the cores. We analysed this by
comparing three groups (<_2mm _2-10mm="_2-10mm"/>10mm) and by a T-test (using
continuous lengths of tumour) and both analyses showed no significant
difference in the reliability of the prognostic information when the
extent of invasive tumour is limited.
Although as O’Leary indicates, this
is somewhat counterintuitive, it is a potentially important and reassuring
observation for clinical decision making.
Reference
(1) R O’Leary, K Hawkins, J C S Beazley, M R J Lansdown, and A M Hanby. Agreement between preoperative core needle biopsy and postoperative invasive breast cancer histopathology is not dependent on the amount of clinical material obtained. J Clin Pathol 2004; 57: 193-195
We read with interest the article by Scott and cols. in the February, 2004 issue of JCP, in which the expression of gastrin-releasing peptide and gastrin-releasing peptide receptors in gastrointestinal carcinoid tumors is discussed.[1]
Currently, we are completing a Phase I trial with the new synthetic bombesin/gastrin-releasing peptide antagonist RC-3095 in patients with advanced refractory solid m...
We read with interest the article by Scott and cols. in the February, 2004 issue of JCP, in which the expression of gastrin-releasing peptide and gastrin-releasing peptide receptors in gastrointestinal carcinoid tumors is discussed.[1]
Currently, we are completing a Phase I trial with the new synthetic bombesin/gastrin-releasing peptide antagonist RC-3095 in patients with advanced refractory solid malignancies. This agent was shown to produce marked tumor responses in a variety of human solid tumors, including those of gastrointestinal origin, in the nude mouse model, with negligible toxicity.[2] In our Phase I trial, five dose escalation steps were studied so far, from 8 to 96 ug/kg daily by subcutaneous injection, with no significant toxic effects. Notably, evidence of antitumor effects were documented in one patient with medullary carcinoma or the thyroid and in two patients with hormone-refractory prostatic cancer. In order to guide us in the identification of a
suitable dose to be applied in future Phase II trials of RC-3095, plasma gastrin levels were measured as a surrogate marker of its biological activity in patients included in the study. As a proof of concept, RC-3095 was also given as a single subcutaneous drug administration at the highest dose escalation level to a clearly hypergastrinemic patient with the Zollinger-Ellison syndrome. Interestingly, his basal plasma gastrin levels were almost 20 times above normal levels, and dropped dramatically to about 50% six hours following RC-3095 administration (from 1985,4 down to 1081,3 pg/ml). The observation of antitumor effects in patients included in our Phase I trial of RC-3095, as well as the rapid decrease in plasma gastrin levels in the patient with the Zollinger-Ellison syndrome gives support to the presence of an gastrin-releasing peptide-dependent autocrine/paracrine cell proliferation pathway in endocrine-related gastrointestinal tumors.
References
1. Scott N, Millward E, Cartwright EJ, Preston SR, Coletta PL. Gastrin releasing peptide and gastrin releasing peptide receptor expression in gastrointestinal carcinoid tumors. J. Clin. Pathol. 57(2):189-92, 2004.
2. Koppan M, Halmos G, Arencibia JM, Lamharzi N, Schally AV. Bombesin/gastrin releasing peptide antagonists RC-3095 and RC-3940II inhibit tumor growth and decrease the levels and mRNA expression of epidermal growth factor receptors in H-69 small cell lung carcinoma. Cancer, 83(7): 1335-1343, 1998.
We read with interest the case report from Karim and colleagues in
the Journal.[1] This case raises an important issue.
Our study [2] has been quoted as suggesting that we have described HAE
with normal C4. We do not entirely accept this interpretation. Although
there were HAE patients with normal C4 this was only achieved whilst on
adequate treatment. All 20 HAE patients in whom we were able...
We read with interest the case report from Karim and colleagues in
the Journal.[1] This case raises an important issue.
Our study [2] has been quoted as suggesting that we have described HAE
with normal C4. We do not entirely accept this interpretation. Although
there were HAE patients with normal C4 this was only achieved whilst on
adequate treatment. All 20 HAE patients in whom we were able to identify
samples either pre-treatment or when off treatment had a low C4
(sensitivity 100%).
This study prompted a review of 44 cases with a presumed diagnosis of
HAE and we have shown that misdiagnosis is not uncommon.[3] Of relevance
to the case of Karim and colleagues, two patient samples had apparently
low immunochemical C1 inhibitor levels but this was shown to be a method-
dependent phenomenon and levels were normal when rechecked at a second
laboratory. A further confounding factor was that one laboratory was using
an inappropriate reference range for C4, based on historical data. Recent
UK National Quality Assessment Scheme returns have highlighted the
importance of having current local reference ranges, as there are
substantial differences between some user groups.
Patients with normal C4 and putative HAE have been described
previously. Frank and colleagues [4] describe 4 angioedema cases with
normal C4 but it is unclear from the text whether this is at presentation
or on treatment. Importantly they note that C4 is never normal during an
attack. Sánchez Palacios and colleagues describe an unusual patient with
chronic angioedema, low C1 inhibitor and normal C4 but the diagnosis is
unclear[5]. On balance, HAE (Type I or Type II) seems unlikely. Our study [3] confirmed that ‘in unequivocal HAE, at presentation or when off
treatment, C4 is invariably below 40% of the normal mean level’.
The case of Karim and colleagues, describing angioedema with a normal
C4, is interesting. In these circumstances there may be alternative
causative mechanisms, other than HAE Type I or Type II, such as activation
of the of the kallikrein-bradykinin pathway. Reporting of such cases is
essential for further clarification. However, without further information
(i.e. genetic and functional studies on the family) we cannot conclude
that this represents a case of HAE Type I or Type II.
Serum C4, as with any pathological investigation, must be interpreted
in the clinical context of the patient. Serum C4, with a locally validated
reference range, is a very reproducible and reliable screening test for
HAE Type I and Type II.[2] However, in the face of a strong family history
or clinical history it should not be the sole test. This does not
invalidate the use of C4 as a screening test, especially in a condition
with a low prior probability and demanding immunochemical and functional
assays.
References
1. Karim, Y., Griffiths, H., Deacock, S. Normal complement C4 values
do not exclude hereditary angioedema. J Clin Pathol 2004;57:213-4.
2. Gompels, M. M., Lock, R. J., Morgan, J. E., Osborne, J., Brown,
A., Virgo, P. F. A multi-centre evaluation of the diagnostic efficiency of
serological investigations for C1 inhibitor deficiency. J Clin Pathol
2002;55:145-7.
3. Gompels, M. M., Lock, R. J., Unsworth, D. J., Johnston, S. L.,
Archer, C. B., Davies, S. V. Misdiagnosis of hereditary angioedema (Type 1
and Type 2). Br J Dermatol 2003;148:719-23.
4. Frank, M. M., Gelfand, J. A., Atkinson, J. P. Hereditary
angioedema: the clinical syndrome and its management. Ann Intern Med
1976;84:580-93.
5. Sánchez Palacios, A., Schamann Medina, F., García Marrero, J. A.
Chronic angioedema. Three relevant cases. Allergol et Immunopathol
1998;26:195-8.
Soilleux & Coleman report a study related to human immunodeficiency virus (HIV) infection through the human foreskin [1] They do not state whether the foreskin tissue was harvested from immature infants or from sexually mature adult males. Immature tissue may behave differently from mature tissue.
Caution must be observed when assuming in vitro viral behaviour is equivalent in vivo....
Soilleux & Coleman report a study related to human immunodeficiency virus (HIV) infection through the human foreskin [1] They do not state whether the foreskin tissue was harvested from immature infants or from sexually mature adult males. Immature tissue may behave differently from mature tissue.
Caution must be observed when assuming in vitro viral behaviour is equivalent in vivo.[2] The inner foreskin is bathed in sub-preputial moisture, which has been shown to contain lysozyme and other pathogen fighting substances.[2,3] Lee-Huang et al. report that lysozyme acts against HIV.[2,4] The authors must show that their findings hold true in vivo.
The recent Cochrane Review reports existing studies from Africa to be so methodologically flawed that insufficient evidence exists to support an intervention by circumcision to prevent female to male HIV infection.[2] Three randomized controlled trials (RCTs) are underway, and the results of those RCTs should be awaited.[2]
Even if the RCTs should show a protective effect by circumcision, recently published letters cite other adverse factors that must be considered along with that evidence.[5,6]
(1) Soilleux EJ, Coleman N. Expression of DC-SIGN in human foreskin may facilitate sexual transmission of HIV. J Clin Pathol 2004;57:77-8. [Abstract]
(2)Siegfried N, Muller M, Volmink J, Deeks J, Egger M, Low N, Weiss H, Walker S, Williamson P. Male circumcision for prevention of heterosexual acquisition of HIV in men (Cochrane Review). In: The Cochrane Library, Issue 3, 2003. Oxford: Update Software. [Abstract]
(3) Fleiss PM, Hodges FM, Van Howe RS. Immunological function of the human prepuce. Sex Trans Inf 1998;74:364-7.
(4) Lee-Huang S, Huang PL, Sun Y, et al. Lysozyme and RNases as anti-HIV components in beta-core preparations of human chorionic gonadotropin. Proc Natl Acad Sci U S A 1999;96(6):2678-81. [Full Text]
(5) Boyle GJ. Issues associated with the introduction of circumcision into a non-circumcising society. Sex Trans Inf 2003;79:427-8.
(6) Hill G, Denniston GC. HIV and circumcision: new factors to consider. Sex Trans Inf 2003; 79:495-6.
Dear Editor
The reliability of diagnostic and prognostic information in breast core biopsies is an important factor to be considered by surgeons and oncologists when planning treatment, especially if pre-operative chemotherapy is under consideration. The recent report by O’Leary et al.[1] is important because it considers whether the amount of tumour present in core biopsies has any impact upon the reliabi...
Dear Editor
We read with interest the article by Scott and cols. in the February, 2004 issue of JCP, in which the expression of gastrin-releasing peptide and gastrin-releasing peptide receptors in gastrointestinal carcinoid tumors is discussed.[1]
Currently, we are completing a Phase I trial with the new synthetic bombesin/gastrin-releasing peptide antagonist RC-3095 in patients with advanced refractory solid m...
Dear Editor
We read with interest the case report from Karim and colleagues in the Journal.[1] This case raises an important issue.
Our study [2] has been quoted as suggesting that we have described HAE with normal C4. We do not entirely accept this interpretation. Although there were HAE patients with normal C4 this was only achieved whilst on adequate treatment. All 20 HAE patients in whom we were able...
Dear Editor
Soilleux & Coleman report a study related to human immunodeficiency virus (HIV) infection through the human foreskin [1] They do not state whether the foreskin tissue was harvested from immature infants or from sexually mature adult males. Immature tissue may behave differently from mature tissue.
Caution must be observed when assuming in vitro viral behaviour is equivalent in vivo....
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