Johannes P. van Netten

Anti-angiogenic treatment for breast cancer?

http://dx.doi.org/10.1016/j.ctrv.2017.02.008 0305-7372/ 2017 Elsevier Ltd. All rights reserved. The article by Aalders et al. [1] in this journal addresses some very important aspects for the treatment of women with breast cancer such as successes, failure and future perspectives. How can it be improved? The opening sentence of the article states: ‘‘The importance of angiogenesis in the development of tumors and metastases is well established”. It cites the work of Folkman [1]. This work was done with breast cancer cells growing in animal systems. Such systems may not reflect the growth of spontaneous breast cancer growing in humans. For example, we have reported [2,3] on the relative absence of blood vasculature in IDC (Infiltrating Ductal Carcinoma) compared to lymphatic vasculature. This is in contrast to human breast cancer cells growing in mice producing red tumors that are very sensitive to anti-angiogenic treatment [4]. Also, when we analyzed a series of 268 fresh human IDC biopsies for color, we found 86% were reported as white, yellow or gray. In contrast, no red or reddish tumors were reported, while only 14% were described as pinkish during ‘rapid section’ analysis. Although this is subjective analysis, it does indicate to us that in general the blood vascular system is not well developed in spontaneous IDCs. It would appear that anti-lymphatic rather than anti-angiogenic treatment may be more useful for patients with IDC, although it is by no means certain.

Spontaneous remission of Crohn's disease following a febrile infection: case report and literature review

Crohns disease is a chronic illness that may often follow a relapsing-remitting course. Many of the factors that may be associated with the spontaneous remission of this disease (i.e. not related to specific treatment) remain to be determined. In the present report, we review the medical history of a patient with a long history of moderate to severe Crohns whose complete remission immediately followed the development of a febrile infection.Crohns disease is a chronic illness that may often follow a relapsing-remitting course. Many of the factors that may be associated with the spontaneous remission of this disease (i.e. not related to specific treatment) remain to be determined. In the present report, we review the medical history of a patient with a long history of moderate to severe Crohns whose complete remission immediately followed the development of a febrile infection.The patient first developed symptoms of Crohns in her late adolescent years. At the time of diagnosis at age 23, she was placed on mesalamine - without effective control her disease symptoms. Due to progressive deterioration, the patient underwent a bowel resection at age 25. Soon afterwards symptoms recurred, gradually increasing in severity. In February 2005, at age 36, the patient developed a painful abscess associated with a rectal fistula. Other symptoms at the time included chronic bone and stomach pain, swollen joints, and debilitating fatigue. Surgical correction was scheduled in mid-March. In late February, the patient developed a respiratory infection associated with fevers of 103-104°F. After the onset of fever, the abscess pain disappeared and this was soon followed by a disappearance of all other disease symptoms. By the time the corrective surgery occurred, she had no Crohns symptoms. Her remission lasted 10 weeks when the previous symptoms then reappeared. The patient has subsequently used a variety of conventional therapies, but still suffers from severe symptoms of her disease.In recent years, a growing body of literature has emphasized the important role that innate immunity plays in the etiology of Crohns disease; however, a key component of innate immunity, the febrile response, has been overlooked. Other cases of spontaneous remission following febrile infection in inflammatory bowel disease have been reported. Moreover, induction of a febrile response was in the past used as a treatment for inflammatory bowel disease, but was later replaced by surgery and corticosteroids. Further exploration of this arm of the innate immune response may provide new opportunities for patients where conventional therapies fail to secure relief.

The lymphatics in infiltrating ductal carcinoma (IDC) of the breast

https://doi.org/10.1016/j.ctrv.2017.10.015 0305-7372/ 2017 Elsevier Ltd. All rights reserved. ⇑ Corresponding author at: 4080 O’Toole Place, Victoria, B.C. V9C 3Z6, Canada. E-mail addresses: jpvannetten@shaw.ca (J.P. van Netten), hoptioncann@ubc.ca (S.H. Cann), carolian@shaw.ca (I.G. Thornton), finrory@hotmail.com (R.P. Finegan). Johannes P. van Netten a,⇑, Stephen Hoption Cann , Ian G. Thornton , Rory P. Finegan a

Growing concern following compression mammography

A patient without clinical symptoms had a mammogram in October 2008. The procedure caused intense persistent pain, swelling and development of a haematoma following mediolateral left breast compression. Three months later, a 9×11u2005cm mass developed within the same region. Core biopsies showed a necrotizing high-grade ductal carcinoma, with a high mitotic index. Owing to its extensive size, the patient began chemotherapy followed by trastuzumab and later radiotherapy to obtain clear margins for a subsequent mastectomy. The mastectomy in October 2009 revealed an inflammatory carcinoma, with 2 of 3 nodes infiltrated by the tumour. The stage IIIC tumour, oestrogen and progesterone receptor negative, was highly HER2 positive. A recurrence led to further chemotherapy in February 2011. In July 2011, another recurrence was removed from the mastectomy scar. She died of progressive disease in 2012. In this article, we discuss the potential influence of compression on the natural history of the tumour.

Stromal regulation of cancer growth: a balancing act in surgery.

There are examples in the literature of dormant cancer cells being stimulated after tissue injury. On the other hand, there are also reports of cancer regression following injury.6–8 What explanation can be offered for this discrepancy? The answer may involve the stroma or connective tissue bed of solid tumour. Traditionally this stroma has been regarded mainly as a physical support for the growing cancer cells. More recently, however, there is evidence that stromal cells, many of which are immune cells, may exude active growth control of cancer. For example, macrophages have been reported to produce many growth factors. These cells can also produce collagen,10 can differentiate into fibroblastlike cells, and it has also been suggested that macrophages can also transform into endothelial-like cells.13 The truly multifunctional capacity of macrophages gives them the potential to play a major role in tumour growth. In addition, other immune cells such as T-cells and B-cells have been reported to produce growth factors.14,15 Thus, stromal cell populations present in cancer tissue can be engaged in opposing functions such as paracrine growth regulation as well as the more traditional role of defense. A more comprehensive name may be needed to reflect the dual role of these stromal ‘immune’ cells. In fact, the reticulo-endothelial system (RES) described by Aschoff over 80 years ago comes close. Cancer develops with abnormal local growth of cells as well as stroma in the parent organ. The next step is metastatic spread. It is interesting to note that we found evidence that this metastatic spread may involve macrophage/cancer cell units17 migrating through the vascular system and establishing new growth at distant sites. Formation of such units suggests that paracrine growth regulation may occur at a very early stage of the metastatic process. At the metastatic site, cancer cells are still dependent on the presence of stroma for support and growth. End stage cancer, on the other hand, can be composed of cells that are completely independent of stromal regulation and can grow in the peritoneal or pleural cavity as isolated cells.18 Using such cells for the study of solid cancer growth regulation may not reflect the natural process. In the stromal dependent phase of tumour growth there is a window of opportunity to control cancer by interfering with this support. Examples are anti-angiogenic and anti-lymphagenic treatment, reducing of growth factor output, disrupting physical support, and increasing classical immunological activity, etc. Ultimately, the goal of such treatments is stromal collapse. An analogy may be drawn between this process and the shedding of the endometrium during the menstrual cycle where collagen producing cells (fibroblast-like) during the follicular phase can transform into phagocytic cells (macrophage-like) during the menstrual phase.19 This process is hormonally controlled. Likewise,

The lymphatic system in cancer

teleologically protective role for CD31/PECAM-1 in terms of invasiveness seems to be confirmed by followup experiments carried out in vivo in appropriate murine models injected with genetically modified human tumours (manuscript in preparation). Differences in the genetic backgrounds of the patients analysed may also account for the discrepancy observed. Moreover, the CD31/PECAM-1 gene is polymorphic itself, with different isoforms [2]. It may be resonable to suppose that the reactivity of the different antibodies may vary with discrete isoforms, recently attributed to specific functions and with the ability to interfere with other adhesion-related molecules such as cadherin [3]. Furthermore, this working hypothesis is strengthened by a recent report showing that CD31/PECAM-1 transgenic mice display alterations in normal mammary gland development [4]. This effect is probably due to CD31/PECAM-1 itself, since serving as scaffold, the molecule may modulate the phosphorylation level of selected proteins [5], important for mammary gland development. Finally, the lesson learned from the CD Workshop on Differentiation Antigens indicates that the majority of surface receptors feature multiple functions, not necessarily linked. The definition of several of such functions has often come from the analysis of disease models. Our wish is that analysis of CD31/PECAM-1 on the epithelial cell tumours may be informative to this aim. Anna Sapino, Massimo Bongiovanni, Paola Cassoni, Luisella Righi, Riccardo Arisio, Silvia Deaglio and Fabio Malavasi Department of Biomedical Sciences and Human Oncology, University of Torino Medical School, Torino, Italy Service of Surgical Pathology, ‘Sant’Anna’ Hospital, Torino, Italy Department of Genetics, Biology and Biochemistry, University of Torino Medical School, Torino, Italy