Journal of Experimental & Clinical Cancer Research - Latest Comments

Correction for 13C-NMR data of EPA

Colin Charles Duke — 2011-03-20T08:51:48Z

The 15 numbers for the 13C-NMR data of EPA are, in error, shown in the article as being the same as EPD.
The correction is as follows:-
Eremophila-1(10),11(13)-dien-12-oic acid (EPA)
¹³C-NMR (CDCl₃): 15.96, 20.71, 25.34, 27.00, 28.05, 30.41, 32.63, 36.24, 38.08, 40.50, 121.36, 124.72, 142.96, 145.12, 172.85.

Mino error

QIUYAN WANG — 2010-07-15T08:00:36Z

The legend of Figure 4 needs to be arranged.

INCIDENCE OF BREAST CANCER IN ITALY: WHY HOSPITALIZATION RECORDS ARE A VALUABLE OPPORTUNITY

Prisco Piscitelli — 2009-07-20T08:03:18Z

Although Cancer Registries remain the gold standard for epidemiologic evaluation of tumors, unfortunately they are not currently available in all Italian provinces. Therefore, in order to evaluate the incidence of neoplastic lesions at national level (as declared in its publications), the Italian Association of Cancer Registries must use other data sources (such as mortality rates provided by the National Instiute for Statistics, ISTAT) or refer to average values determined within the few existing registries (actually 70% of Italian population is not being covered by cancer registries). This means that national data concerning the incidence of cancers in Italy are the result of average estimations or statistical models and do not reflect a real "count" of overall cases. On the other hand, there is a huge National database which is available for researchers: the National hospitalization records database (SDO), which has already been validated in many internation publications, being also uses by Piemonte Region in its cancer surveillance programs (with good published results).

Therefore, authors of the article tried to use the National hospitalization database (SDO) as a potential datasource for determining the incidence of such an impactful tumour as breast cancer.

Concerning the SDO database, it must be pointed out that authors have excluded 1999 from the analysis because the Ministry of Health - at our knowledge - can provide complete archives since year 2000. However, if some hospital records would have not been sent to the central database, this could have produced only an underestimation and not an overestimation of the phenomenon.

While examining SDO database, authors DID NOT analyzed "diagnosis of breast cancer" because it would have produced too many bias due to the double count of the same patients hospitalized twice or more times with the same "major diagnosis". Authors have rather decided to analyze the number of surgical interventions, namely quadrantectomies and mastectomies in order to "count" the new breast cancer cases because:

- these procedures are used only in case of breast cancer;

- the risk of "double count" of the same patient is low because number of patients who undergo mastectomy or quadrantectomy twince in the same year is very very low, as assessed in a preliminary survey by the surgeons involved in the study;

- the risk of including prevalent cases in the "count" is also low because the time elapsing between new diagnosis of brest cancer and surgical intervention do not exceed 30 days according to the US and European guidelines; furthermore, relapses of the disease are mostly detected after 5 and even 10 years from the intervention (therefore outside of the range of the study period). If looking at the literature, the risk of relapses after mastectomy is 5-10% at 10 years, while the risk of relapses after quadrantectomy is 10-15% at 10 years; only breast relapsing leasions are eligible for new surgical procedures (actually metastases are treated in other ways), and only lesions relapsig after quadrantectomy are treated surgically with a new mastectomy.

On the other hand, even though authors have declared in methodological section the risk of a small overestimation of new breast cancer cases, the "count" provided in the article CANNOT consider all the breast cancers which are not treated by surgery (about 10% of new breast tumour diagnoses) and the small proportion of "in situ carcinomas" which are not treated with quadrantectomy but only with tumorectomy: so there is a wide underestimation preliminary effect to be taken into account, so that the surprising results of the study could be also regarded as conservative ! Furthermore, there's no risk of having included benign lesions because authors have counted MAJOR BREAST SURGICAL PROCEDURES (quadrantectomies and mastectomies) and have decided to exclude tumorectomies and excision biopsis from the analysis.

Concerning the comment of the colleague Paolo Contiero, who did a very good job in the right experimental perspective, it seems that he has analyzed SDO database of Varese province (where a cancer registry sortunately exists)looking for major diagnosis of breast cancer. On the contrary, authors of the article has examined only major breast surgical procedures, namely mastectomy (ICD9-CM code 85.4) and quadrantecomy (code 85.22), therefore resulting in an overestimation due to double count of the same patient. However, authors may also hypotize that data of Varese province could result in a small difference between the Cancer Registry and the SDO database (actually 2% as reported by Dr. Contiero), but the objective of the article was not to compare SDO database with Cancer Registries datasets, because there are no problem in assessing the phenomenon in those provinces where a Registry already exists.
Authors' aim was actually to overcome the existimations produced when computing incidence at national level by the methods currently used (average calculations and statistical models based on ISTAT mortality rates). In this perspective, and until cancer registries will not cover all the Country, SDO database could be a valuable opportunity to be successfully used as already has been done in Piemonte Region.

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Link to a lay summary of this research paper

Gustav Nilsonne — 2009-07-20T08:02:40Z

A short non-technical description of this research is available on my blog at this link.

Trend assesment by comparison with a Cancer Registry

Paolo Contiero — 2009-07-05T17:43:54Z

I have carefully read the paper, interesting because present a method to estimates breast cancer incidence, a so important topic for health service planning and primary prevention researches.
In my opinion, the weakness of this paper is the lack of a gold standard by which validate the method and its results. This could lead to the introduction of some bias in the estimates that are not possible to detect easily.
By this notes I show some data from the Cancer Registry of Varese and the hospital discharges of the same area.
The Cancer Registry of Varese began its activity in 1976 and its data was included in the last four editions of the Cancer Incidence in Five Continents.
The Cancer Registry data are linked with the hospital discharge (SDO), pathology report and death certificate files, all of these sources contain personal data.
The availability of the hospital discharge file gave me the possibility to evaluate the algorithm proposed versus a gold standard such as a Cancer Registry.
A Cancer Registry could be considered a gold standard because: i) it contains validated data, i.e. true cases and not false positives or not accurate diagnosis ii) it contains virtually all the cases of the target population, without selection related to diagnosis or treatment, as could be using surgical procedure to identify cases iii) it register personal data, avoiding the bias of counting twice or more patients with more that one SDO iv) it can correctly classify incident and prevalent cases.

The comparison considers four years of incidence, from 2000 to 2003.
I have applied the algorithm by Giordano to the SDO of the residents of Varese province, from 1/1/2000 to 31/12/2003.
I have linked those records with the Varese Cancer Registry.
The number of cases registered by the Registry, from year 2000 to 2003 are respectively:
721 , 729 , 731 , 739, with an increase in 2003 vs 2000 of 2.5 %. The algorithm identifies for the same years the following cases (% of lost cases): 653 (-9.4 %) , 674 (-7.5 %), 714 (-2.3 %), 704 (-4.7 %), with an increase in 2003 vs 2000 of + 7.8 %
The cases discarded by the registry and identified by the algorithm (390) were prevalent cases or cases with a diagnosis different from malignant neoplasm of breast. The cases not caught by the algorithm but identified by the Registry (565) were cases that have on the hospital discharges a diagnosis different from malignant neoplasm of breast or cases with none or different surgical procedures respect to those used by the algorithm.

Conclusion

The algorithm described in the paper produce an underestimate of the real number of cases that varies from 4.7 to 9.4 %. This is the result of two bias that act in two different directions. Prevalent cases inflates incidence meanwhile cases excluded by the algorithm for diagnostic or intervention codes produce a bias in the opposite direction.
The increase in the number of cases computed by the algorithm on the hospital discharges is 2.6 % per year on Varese data, similar to the data reported in table 4 of the paper by Giordano, meanwhile the Varese Cancer Registry reports an increase per year of 0.8 %.
By this comparison, it seems the increase computed by the algorithm doesn’t correspond to a real increase in the number of cases but that it depends only by the increasing use of surgical procedures.

Answer to comments of prof. Koninckx

Alfonso Baldi — 2009-06-07T08:07:40Z

Dear Editor,
We are very happy that our work is raising great interest in the scientific community (see for example Faculty of 1000 Medicine: evaluations for Signorile PG et al J Exp Clin Cancer Res 2009 28 :49 http://www.f1000medicine.com/article/id/1160737/evaluation).
We thank dr. Koninckx and colleagues for their comments on our paper supporting the embryological origin of endometriosis (1). Indeed, we have really appreciated some of the comments that will help us in our future investigations. Nevertheless, we strongly disagree with some of the claims of our colleagues. We will try to follow point-by-point their letter in order to clarify the issues raised.
The colleagues complain the absence of pictures or data of the endometrium. It is surprisingly that the colleagues did not notice that in three out of four of the histological figures we showed in the paper, the endometrium is clearly visible and expressing the same morphological and immunohistochemical pattern of the ectopic endometrium. We can agree with the colleagues that the choice of references to justify the use of oestrogen receptor and CA125 in the manuscript was not completely appropriate; nevertheless, ERalpha is known to be expressed in luminal epithelium of the endometrium and sub-epithelial stroma during the foetal life (2), while CA125 is well established marker of the gynecological tract also during the foetal life (3). Indeed, all the other information they ask about the morphology of the ectopic endometrium, are easily deducible from the histological pictures and from the description in the text, such as the fact that there is a case of adenomyosis, that all the lesions have tubular structure, that smooth muscle cells were not present in the lesions, etc.
The colleagues claim that mullerianosis has been clearly described as an entity separate and distinct from endometriosis (4). We know very well the interesting paper on mullerianosis by Batt and coll. Indeed, in this manuscript, the author speculate with brilliant arguments, based on the assumption that endometriosis is an acquired disease caused by retrograde menstruation, that mullerianosis is different from endometriosis. Unfortunately, they do not scientifically demonstrate this hypothesis, that is in contrast with several anatomo-clinical characteristics of the disease (see discussion of our manuscript). Indeed, in a recent and reliable review it is stated that, though there are several theories, research scientists remain unsure as to the definitive cause of endometriosis (5). In the same review it is clearly stated that proponents of Sampson’s theory have never been able to demonstrate in vivo the attachment of menstrual endometrium to peritoneal surfaces and the consequently proliferation and invasion. Consequently, the assumption “Endometriosis is an acquired disease whereas mullerianosis is congenital” is only an hypothesis and it has never been demonstrated. On the other hand, our observation that ectopic endometrium is present during the foetal life represents a proof that endometriosis can be caused by little defects during organogenesis, even if, it is not possible to exclude also other pathogenetic mechanisms.
Concerning the question about the relationship between endometriosis and cancer, we have indicated in the title the fact that there exists an epidemiologically proven association between endometriosis and the outbreak of some unrelated malignancy (see for example ref. 6). Indeed, in the text, as acknowledged by the colleagues, we clearly state that there are not definitive evidences that endometriosis itself is a precursor of cancer. We will stress this concept in our future works.
The colleagues question the fact that there is no evidence that the ectopic endometrial tissue would have persisted beyond birth or menarche. Indeed, the histological and immunohistochemical analysis of the eutopic and ectopic endometrium shows a very similar phenotype. This observation argues against the possibility that this ectopic endometrium could “disappear” during the final steps of organogenesis. Nevertheless, the presence of ectopic tissues of several organs (breast, appendix, spleen, thymus, thyroid, salivary glands, etc.) in adults is a quite common event and clearly demonstrate that dislocated tissues during organogenesis do not “disappear”.
Finally, we thank our colleagues for the invitation to persevere in the careful dissection of the reproductive organs in human foetuses. Indeed, our research group is intensely working on this topic since a long time and the results of this activity will be soon available to the scientific community.

References
1) Signorile PG, Baldi F, Bussani R, et al. 2009 ectopic endometrium in human fetuses is a common event and sustains the theory of mullerianosis in the pathogenesis of endometriosis, a disease that predisposes to cancer. Journal of Experimental & Clinical Cancer Research 28, 49.
2) Markey CM, Wadia PR, Rubin BS, et al. 2005 Long-term effects of fetal exposure to low doses of the xenoestrogen bisphenol-A in the female mouse genital tract. Biol Reprod 72, 1344-1351.
3) Nap M 1998 Immunohistochemistry of CA 125. Unusual expression in normal tissues, distribution in the human foetus and questions around its application in diagnostic pathology. International Journal of Biological Markers 13, 210-215.
4) Batt RE, Smith RA, Buck Louis GM 2007 Mullerianosis. Histology & Histopathology 22, 1161-1166.
5) Bulun SE 2009 Endometriosis. New England Journal of Medicine 360, 268-279.

Ectopic endometrium in the human foetus (Müllerianosis) must be interpreted cautiously

Philippe R. Koninckx — 2009-05-27T10:37:28Z

Dear Editor,
We read with great interest the nice observations by Signorile et al. of endometrium-like tissue in foetuses supporting the concept of müllerianosis. (1) The data, however, poorly support the speculative and overstretched conclusions. The title is misleading and the discussion partially incorrect.
In the absence of pictures or data of the endometrium and of the expression of estrogen receptors it is difficult to judge how specific this observation was. We therefore would be interested to have more information about the specificity of these markers and whether these markers were positive in all endometrium tissue. It is surprising not to find the word CA125, or the words ‘estrogen receptor’ in reference 1 quoted to support the choice of CA125 and of estrogen receptors as markers. Also reference 14 from 1989 deals with adult tissues.
The authors describe “organoid structures” of “misplaced endometrium in five different ectopic sites: in the rectovaginal septum, in the proximity of the Douglas pouch, in the mesenchymal tissue close to the posterior wall of the uterus, in the rectal tube at the level of the muscularis propria, and in the wall of the uterus.” To be able to judge whether this is not an over-interpretation, we have a series of questions: How many ectopic endometrium sites had definite “organoid structures”? What was the morphologic structure of each organoid lesion? Were they tubular structures? Did any appear to be rudimentary attempts to duplicate a müllerian duct? Were some solid adenomyotic nodules or adenomyosis? Were any in the form of peritoneal pockets? Were the ectopic endometrial lesions composed of glands and stroma, stroma only, or glands only? In which of the five ectopic sites, if any, did the endometrium lesions contain smooth muscle?
The title is misleading where it states that the data “sustain the theory of müllerianosis in the pathogenesis of endometriosis.” Assuming that the observation is indeed misplaced endometrial tissue, this would support the pathogenesis of developmentally misplaced müllerian tissue - müllerianosis. However, we question the relationship of the pathogenesis of müllerianosis to the pathogenesis of endometriosis since müllerianosis was clearly described as an entity separate and distinct from endometriosis. (2) Endometriosis is an acquired disease whereas müllerianosis is congenital. We do not see how the authors’ observations contribute to the different hypotheses concerning the pathogenesis of endometriosis. The conclusion of the abstract therefore is speculative and not supported by data.
We strongly disagree with the authors’ statement expressed in title and text that “endometriosis [is] a disease that predisposes to cancer,” since none of the data in this article support any relationship with cancer. To formulate this as a conclusion is scientifically incorrect and socially unacceptable. This title and conclusion might be picked up and quoted in the press creating fear for many women with endometriosis. Indeed, the same authors, citing Varma et al. (3) in a nearly contemporaneous review wrote more cautiously: “However, despite the histological and epidemiological evidence linking endometriosis and ovarian cancer, it is still not clear if endometriosis is a real precursor of ovarian cancer, or whether there is an indirect link involving common environmental, immunological, hormonal or genetic factors.” (4). Moreover using gene expression profiling of endometriotic cells, endometrial cells, and neoplastic cells, a recent study provides strong evidence that “endometriosis only very rarely degenerates into cancer.” (5).
In the discussion section of their paper, the authors called for specific research. Examination of Table 1 reveals that the four fetuses with evidence of ectopic endometrium were 25 weeks gestation or less. Only two fetuses of 16 and 18 weeks respectively– both voluntarily aborted – had the potential to survive as newborn females. Had they survived, there is no evidence that the ectopic endometrial tissue would have persisted beyond birth or menarche. Unfortunately, it is impossible to trace the chain-of-evidence of müllerianosis from fetal development to adolescence and maturity in the same female. However, the authors might continue their investigations at all stages of fetal growth and at autopsies of female adolescents and young adults. The authors are to be commended for their careful dissection of the reproductive organs in human fetuses.

Ronald E. Batt, University at Buffalo, State University of New York, USA
Lone Hummelshoj, Endometriosis.org, London, England
Charles Chapron, Université Paris Descartes, CHU Cochin, Paris, France
Dan C. Martin, University of Tennessee Health Science Center, Memphis, USA
Glenna C. Bett, University at Buffalo, State University of New York, USA
John Yeh, University at Buffalo, State University of New York, USA
Philippe R. Koninckx, KULeuven Belgium; University of Oxford, UK; and Università Cattolica, Roma, Italy.

References

1. Signorile PG, Baldi F, Bussani R, D’Armiento M, De Falco M, Baldi A. Ectopic endometrium in human fetuses is a common event and sustains the theory of müllerianosis in the pathogenesis of endometriosis, a disease that predisposes to cancer. J Exp Clin Cancer Res 2009;28:49-53.
2. Batt RE, Smith RA, Buck Louis GM, Martin DC, Chapron C, Koninckx PR, Yeh J. Müllerianosis. Histol Histopathol 2007;22:1161-1166.
3. Varma R, Rollason T, Gupta JK, Maher ER. Endometriosis and the neoplastic process. Reproduction 2004;127:293-304.
4. Baldi A, Campioni M, Signorile PG. Endometriosis: Pathogenesis, diagnosis, therapy and association with cancer (Review). Oncol Reports 2008;19:843-846.
5. Borghese B, Mondon F, Noel J-C Fayt I, Mignot T-M, Vaiman D, Chapron C. Gene expression profile for ectopic versus eutopic endometrium provides new insights into endometriosis oncogenic potential. Mol Endocrinol 2008;22:2557-2562.

Answer to the comment: Mulleriosis and not Mullerianosis by dr. Redwine

Alfonso Baldi — 2009-05-14T09:51:29Z

Dear Editor,
we have really appreciated the positive comments of dr. Redwine on our paper recently published in your journal (J Exp Clin Cancer Res 2009; 28:49). We are very happy that our discoveries on the pathogenesis of endometriosis raise the interest of the other scientists involved in this field of research. Concerning the question raised by dr. Redwine on the exact term to use for defining this phenotype, we used the term Mullerianosis, because it is the one mostly used by researcher to define this condition, while the term Mulleriosis has been used only by dr. Redwine (Letter to Am J Obstet Gynecol 1987; 156:769); anyway we have no any problem in using also this term in our next publications. Nevertheless, we think that the most important point of our manuscript is, as also recognized by dr. Redwine, the clear demonstration of the embryological origin of endometriosis. Finally, concerning the question about the abstract from dr. Redwine in which he claims the presentation of a single case of endometriosis in newborn (J Reprod Med 1988; 33: 915-920), we did not mention it in the reference list, because it was not found during our research in PubMed using our keywords. Indeed, we tried to find it in the PubMed with the exact reference given by dr. Redwine, but also in this case it did not come out. After a careful analysis of all the manuscripts of the journal cited in PubMed, we finally found that to the reference indicated by dr. Redwine corresponds the “Proceedings of the 16th annual meeting of the American Association of Gynecologic Laparoscopists” (J Reprod. Med 1998; 33:861-920). So it looks like that the manuscript indicated by dr. Redwine, is essentially a communication to a meeting, included in the Proceedings published by the journal, and not a full paper. Moreover, the communications included in that Proceedings are not singularly indicated by PubMed, neither is possible to even have access to an abstract. It is our policy to cite in the reference list only full articles published in peer-reviewed journals and consultable, at least at level of abstracts.
Sincerely,

Alfonso Baldi and Pietro Giulio Signorile
Fondazione Italiana Endometriosi
Rome, Italy

Mulleriosis not Mullerianosis

David Redwine — 2009-05-13T07:41:39Z

I read with great interest the recently published paper by Signorile
et al (1). They found evidence of endometriosis in 4 of 36 (11%) female
foetuses examined with step-sectioning of the posterior pelvis. They
correctly conclude that endometriosis begins in foetal life and is not
a product of reflux menstruation. Their work supports my work published
in 1988 (2), where I found apparent endometriosis in the cul de sac of
1 of 9 (11%) newborn females who died of sudden infant death syndrome,
although my work was not mentioned in the authors' reference list. I
would suggest that "Mulleriosis" would be a better term than
"Mullerianosis" for this ontogenic development. First, "Mulleriosis" as
an overarching term to describe the foetal development of endometriosis
and allied pathologies preceded by many years the use of the term
"Mullerianosis" as proposed more recently by other authors.
"Mulleriosis" is the name I have used for 21 years in lectures around
the world and in publications beginning in 1996 to describe the true
origin of endometriosis. (3) "Mulleriosis" also encompasses
embryologically patterned metaplasia and cell rests which explains the
observed natural history of the disease, including the response to
surgery. (4) Further, it can include any future discoveries of pathologies even in other organ systems which may be found to be associated with diseases of the female reproductive tract. Renaming a previously well-defined condition such as
Mulleriosis can be confusing and obscures the provenance of original
thought. Second, "Mullerianosis" was a term that was considered by
Sampson (5) to name the disease which eventually became known as
endometriosis, but which term he eventually discarded. Avoiding the
continued use of the ancient term "Mullerianosis" would help divorce
Sampson's thoughts on the origin of endometriosis from modern
consideration and would be a small but important symbolic step in
discarding the obsolete theory of reflux menstruation as the origin of
endometriosis. Anything that can help to eliminate obsolete thoughts
and associated terminology from contemporary consideration of
endometriosis will be a step forward in helping women with the disease
get rational surgical therapy.

David Redwine, M.D.
Bend, Oregon USA

References:

1.Signorile PG, Baldi F, Bussani R, D'Armiento M, De Falco M, Baldi
A. Ectopic endometrium in human foetuses is a common event and sustains
the theory of mullerianosis in the pathogenesis of endometriosis, a
disease that predisposes to cancer. Journal of Experimental & Clincal
Cancer Research 2009; 28:49 - 53.
2. Redwine DB. Mulleriosis: the single best fit model of origin of
endometriosis. J Reprod Med 1988;33:915-920.

3. Redwine DB. Endometriosis. In: Levine RL, Sanfilippo J, eds.,
Operative Gynecologic Endoscopy, 2nd edition. Springer-Verlag, New
York, 1996; 199 - 214.

4. Redwine DB. Was Sampson wrong? In: Surgical Treatment of
Endometriosis. Redwine DB, ed. London: Dunitz, 2003; 1 - 11.

5. Sampson JA. Heterotopic or misplaced endometrial tissue. Am J
Obstet Gynecol 1925, 10:649 - 664.

GenBank Accession No should be corrected

Haiyan Liu — 2009-02-26T14:28:29Z

Dear editor,
I’ m sorry for my mistake.
B 4.1 Knockdown of AEG-1 expression was achieved using transfection of AEG-1-siRNA. AEG-1-siRNA1 and AEG-1-siRNA2 targeting nucleotides 971-991 and 1355-1375 of human AEG-1 mRNA sequence (GenBank Accession No. NC_000008.9) NC_000008.9 should be changed to NM_178812.3
Thank you for your help.
Sincerely
Haiyan Liu