The impact of CpG island methylator phenotype and microsatellite instability on tumour budding in colorectal cancer

In colorectal cancer, tumour budding, a process likened to epithelial mesenchymal transition, is an adverse prognostic factor which is rarely found in tumours with high-level microsatellite instability (MSI-H). Cases with MSI-H or high-level CpG island methylator phenotype (CIMP-H) have similar histomorphological features, yet seemingly opposite prognosis. We hypothesized that tumour budding is related to CIMP, thus partially explaining this prognostic difference.

Intra-tumoral budding in preoperative biopsy specimens predicts lymph node and distant metastasis in patients with colorectal cancer

Tumor budding, a histological hallmark of epithelial-mesenchymal transition in colorectal cancer, is a parameter of tumor progression and according to the International Union Against Cancer/American Joint Committee on Cancer an 'additional' prognostic factor. The current definition of tumor budding is reserved for the invasive tumor front of colorectal cancer (so called peri-tumoral budding), but tumor buds can also be observed in small preoperative biopsy specimens. Whereas the prognostic value of peri-tumoral budding assessed in resection specimens has found wide acceptance, the value of budding in preoperative biopsies, which normally do not encompass the invasive tumor margin and hence can be called intra-tumoral budding, has not been systematically investigated yet. Therefore, the aim of this study is to assess the predictive value of intra-tumoral budding for lymph node and distant metastasis in preoperative biopsies. Preoperative biopsy samples and consecutive resection specimens from 72 patients with pathological information on TNM stage, vascular, lymphatic and perineural invasion, and tumor border configuration were used to evaluate intra-tumoral budding and peri-tumoral budding. Both parameters were scored semiquantitatively as 'high' (detectable at low power magnification × 2.5) and 'low' (occasional budding at intermediate magnification × 10, difficult to find or absent). In biopsy samples high intra-tumoral budding was observed in 12/72 patients (17%) and associated with high peri-tumoral budding in the corresponding resection specimens (P=0.008). Additionally, there was a correlation between high intra-tumoral budding and lymph node metastasis (P=0.034), distant metastasis (P=0.007) and higher tumor grade (P=0.025). Peri-tumoral budding was associated with higher N stage (P=0.004), vascular (P=0.046) and lymphatic invasion (P=0.019) as well as with an infiltrating tumor border (P<0.001), reflecting the predictive power of peri-tumoral budding for tumor progression. High intra-tumoral budding in preoperative biopsy samples of colorectal cancer patients predicts high peri-tumoral budding at the invasive margin and lymph node metastasis in the corresponding resection specimens as well as distant metastasis.

Role and extent of lymphadenectomy during radical cystectomy for invasive bladder cancer

There is substantial variability in the extent of the node dissection performed during radical cystectomy for bladder cancer. Here, we review the diagnostic assessment of lymph node metastasis and the prognostic and therapeutic benefit for pelvic node dissection for bladder cancer. A review of the applicable urologic literature regarding the topics of lymphadenectomy for bladder cancer was conducted. Nodal metastasis above a limited or standard template is not uncommon, with up to 16% of all nodal metastasis detected proximal to the aortic bifurcation. However, skip metastasis is extremely rare. Proteins associated purely with epithelial tissue such as cytokeratin (CK)-19, CK-20, and uroplakin II have been observed in reportedly negative nodal specimens, which indicates that routine microscopic analysis of nodal tissue may miss small foci of metastatic cancer. In addition to the surgical technique, the total number of lymph nodes removed is influenced by patient anatomy and pathologic processing and therefore may be unsuitable as a procedural quality statement. Consecutively, meticulous removal of tissue within a defined and uniformly applied template may be more relevant than absolute nodal count. Observational cohort series indicate an improved oncologic outcome for patients undergoing extensive nodal dissection. The results of two randomized controlled trials addressing the extent of nodal dissection for bladder cancer are forthcoming.

Palliative in-patient cancer treatment in an anthroposophic hospital: II. Quality of life during and after stationary treatment, and subjective treatment benefits

BACKGROUND: There is an increasing demand for comprehensive forms of palliative cancer care, meeting physical as well as emotional, cognitive, spiritual and social needs. Therapy programs of anthroposophic hospitals are aimed at improving health and quality of life (QoL) at these levels. However, data on the influence of these programs on QoL of patients with advanced cancer are scarce. PATIENTS AND METHODS: 144 in-patients with advanced epithelial cancers were treated at the anthroposophic Lukas Klinik, Arlesheim, Switzerland. QoL was assessed upon admission, discharge and after 4 months, using 20 functional scales from the questionnaires EORTC QLQ-C30, HADS and SELT-M. Statistical testing was performed with the Wilcoxon signed rank test. At month 4, subjectively perceived benefits from anthroposophic medicine (AM) and conventional cancer therapy (CCT) were assessed by telephone. OBJECTIVE: The aim was to provide an account of global, physical, emotional, cognitive-spiritual and social QoL developments in advanced cancer patients, during and after in-patient AM treatment, and to investigate subjective benefits from AM and CCT. RESULTS: QoL improvements were observed in all 20 dimensions (12 significant). Compared to related studies, improvements were fairly high. At month 4, QoL scores had decreased but were still above baseline in all 20 dimensions. Both AM and CCT were perceived as beneficial. CONCLUSION: Our data provide evidence that in-patient therapy at an anthroposophic hospital can lead to significant QoL improvements, especially in emotional, but also global, physical, cognitive-spiritual and social aspects. Benefits of AM were experienced on the physical, emotional, cognitive- spiritual and social level. Benefits of CCT were tumor-focused.

Palliative in-patient cancer treatment in an anthroposophic hospital: I. Treatment patterns and compliance with anthroposophic medicine

BACKGROUND: Complementary and alternative medicine (CAM) and most of all anthroposophic medicine (AM) are important features of cancer treatment in Switzerland. While the number of epidemiological investigations into the use of such therapies is increasing, there is a distinct lack of reports regarding the combination of conventional and CAM methods. PATIENTS AND METHODS: 144 in-patients with advanced epithelial cancers were enrolled in a prospective quality-of-life (QoL) study at the Lukas Klinik (LK), Arlesheim, Switzerland. Tumor-related treatment was assessed 4 months prior to admission, during hospitalization and 4 months after baseline. OBJECTIVE: We aimed at giving a detailed account of conventional, AM and CAM treatment patterns in palliative care, before, during and after hospitalization, with emphasis on compliance with AM after discharge. RESULTS: Certain conventional treatments featured less during hospitalization than before but were resumed after discharge (chemotherapy, radiotherapy, sleeping pills, psychoactive drugs). Hormone therapy, corticosteroids, analgesics WHO III and antidepressants remained constant. AM treatment consisted of Iscador? (mistletoe), other plant- or mineral-derived medication, baths, massage, eurythmy, art therapy, counseling and lactovegetarian diet. Compliance after discharge was highest with Iscador (90%) and lowest with art therapy (14%). Many patients remained in the care of AM physicians. Other CAM and psychological methods were initially used by 39.9% of patients. After 4 months, the use had decreased with few exceptions. CONCLUSION: During holistic palliative treatment in an anthroposophic hospital, certain conventional treatments featured less whereas others remained constant. After discharge, chemotherapy returned to previous levels, AM compliance remained high, the use of other CAM therapies low.

Chemosensitization of carcinoma cells using epithelial cell adhesion molecule-targeted liposomal antisense against bcl-2/bcl-xL

Nanoscale drug delivery systems, such as sterically stabilized immunoliposomes binding to internalizing tumor-associated antigens, can increase therapeutic efficacy and reduce toxicity to normal tissues compared with nontargeted liposomes. The epithelial cell adhesion molecule (EpCAM) is of interest as a ligand for targeted drug delivery because it is abundantly expressed in solid tumors but shows limited distribution in normal tissues. To generate EpCAM-specific immunoliposomes for targeted cancer therapy, the humanized single-chain Fv antibody fragment 4D5MOCB was covalently linked to the exterior of coated cationic liposomes. As anticancer agent, we encapsulated the previously described antisense oligonucleotide 4625 specific for both bcl-2 and bcl-xL. The EpCAM-targeted immunoliposomes (SIL25) showed specific binding to EpCAM-overexpressing tumor cells, with a 10- to 20-fold increase in binding compared with nontargeted control liposomes. No enhanced binding was observed on EpCAM-negative control cells. On cell binding, SIL25 was efficiently internalized by receptor-mediated endocytosis, ultimately leading to down-regulation of both bcl-2 and bcl-xL expression on both the mRNA and protein level, which resulted in enhanced tumor cell apoptosis. In combination experiments, the use of SIL25 led to a 2- to 5-fold sensitization of EpCAM-positive tumor cells of diverse origin to death induction by doxorubicin. Our data show the promise of EpCAM-specific drug delivery systems, such as antisense-loaded immunoliposomes, for targeted cancer therapy.

Higher frequency of chromosomal aberrations in ovarian endometriosis compared to extragonadal endometriosis: A possible link to endometrioid adenocarcinoma

Endometriosis may progress to invasive endometrioid adenocarcinoma, particularly in the ovary. Up to now, little is known of the molecular mechanisms possibly involved in the malignant transformation of endometriosis. Therefore, in this study, extragonadal endometriosis (n = 10), ovarian endometriosis without malignancy (n = 10), ovarian endometriosis with direct transition into endometrioid adenocarcinoma (n = 8), and normal endometrium (n = 12) were investigated for numerical chromosomal aberrations by fluorescence in situ hybridization using centromere enumeration probes. The proportions of cells with aneusomies were semiquantitatively assessed. Trisomies 1 and 7, and monosomies 9 and 17 were found in endometriosis, ovarian endometrioid adenocarcinoma, and normal endometrium. The proportions of aneusomic cells were significantly higher in ovarian endometrioid carcinoma compared with ovarian endometriosis (P < 0.001), and in ovarian endometriosis compared with extragonadal endometriosis and normal endometrium (P < 0.001). The data provide new evidence of a common lineage of endometriosis and ovarian endometrioid carcinoma. The higher frequency of chromosomal aberrations in endometrioid carcinoma than in endometriosis may reflect an expansion of aberrant cell clones already present in endometriosis during the progression to cancer. The higher frequency of chromosomal aberrations in ovarian endometriosis than in extragonadal endometriosis suggests a role of the ovarian stromal milieu in the induction of genetic changes, which may eventually lead to invasive cancer.

Controversies of adjuvant endocrine treatment for breast cancer and recommendations of the 2007 St Gallen conference

Endocrine treatment for breast cancer was introduced more than a century ago. The discovery of hormone receptors has allowed targeting of endocrine treatment to patients whose primary tumours express these receptors. In the adjuvant setting, different approaches are used in premenopausal or postmenopausal women. In premenopausal patients, suppression of ovarian function and the use of tamoxifen are the most important therapeutic options, even though questions on timing, duration, and combination of these compounds remain unanswered. The use of aromatase inhibitors in combination with ovarian-function suppression is currently under investigation in the premenopausal setting. In postmenopausal patients, aromatase inhibitors given after 2-3 years or 5 years of tamoxifen have shown a significant benefit over tamoxifen alone. However, questions on this treatment also remain unanswered. For example, whether all patients should receive an aromatase inhibitor or whether some subgroups of patients might be optimally treated by tamoxifen alone is yet to be established. In this paper we review the published work on adjuvant endocrine treatment in breast cancer and provide recommendations from the 2007 St Gallen International Conference on Primary Therapy of Early Breast Cancer.

Treatment of premenopausal women with early breast cancer: old challenges and new opportunities

Breast cancer occurring in women before the age of menopause continues to be a major medical and psychological challenge. Endocrine therapy has emerged as the mainstay of adjuvant treatment for women with estrogen receptor-positive tumours. Although the suppression of ovarian function (by oophorectomy, irradiation of the ovaries or gonadotropin releasing factor analogues) is effective as adjuvant therapy if used alone, its value has not been proven after chemotherapy. This is presumably because of the frequent occurrence of chemotherapy-induced amenorrhoea. Tamoxifen reduces the risk of recurrence by approximately 40%, irrespective of age and the ovarian production of estrogens. The worth of ovarian function suppression in combination with tamoxifen is unproven and is being investigated in an intergroup randomised clinical trial (SOFT [Suppression of Ovarian Function Trial]). Aromatase inhibitors are more effective than tamoxifen in postmenopausal women but are only being investigated in younger patients. The use of chemotherapies is identical in younger and older patients; however, at present the efficacy of chemotherapy in addition to ovarian function suppression plus tamoxifen is unknown in premenopausal patients with endocrine responsive disease. 'Targeted' therapies such as monoclonal antibodies to human epidermal growth factor receptor (HER)-2, HER1 and vascular endothelial growth factor, 'small molecule' inhibitors of tyrosine kinases and breast cancer vaccines are rapidly emerging. Their use depends on the function of the targeted pathways and is presently limited to clinical trials. Premenopausal patients are best treated in the framework of a clinical trial.

NPY receptors in human cancer: a review of current knowledge

Many peptide hormone receptors are over-expressed in human cancer, permitting an in vivo targeting of tumors for diagnostic and therapeutic purposes. NPY receptors are novel and promising candidates in this field. Using in vitro receptor autoradiography, Y1 and Y2 receptors have been found to be expressed in breast carcinomas, adrenal gland and related tumors, renal cell carcinomas, and ovarian cancers in both tumor cells and tumor-associated blood vessels. Pathophysiologically, tumoral NPY receptors may be activated by endogenous NPY released from intratumoral nerve fibers or tumor cells themselves, and mediate NPY effects on tumor cell proliferation and tumoral blood supply. Clinically, tumoral NPY receptors may be targeted with NPY analogs coupled with adequate radionuclides or cytotoxic agents for a scintigraphic tumor imaging and/or tumor therapy.

Antitumor activity of an epithelial cell adhesion molecule targeted nanovesicular drug delivery system

Site-specific delivery of anticancer agents to tumors represents a promising therapeutic strategy because it increases efficacy and reduces toxicity to normal tissues compared with untargeted drugs. Sterically stabilized immunoliposomes (SIL), guided by antibodies that specifically bind to well internalizing antigens on the tumor cell surface, are effective nanoscale delivery systems capable of accumulating large quantities of anticancer agents at the tumor site. The epithelial cell adhesion molecule (EpCAM) holds major promise as a target for antibody-based cancer therapy due to its abundant expression in many solid tumors and its limited distribution in normal tissues. We generated EpCAM-directed immunoliposomes by covalently coupling the humanized single-chain Fv antibody fragment 4D5MOCB to the surface of sterically stabilized liposomes loaded with the anticancer agent doxorubicin. In vitro, the doxorubicin-loaded immunoliposomes (SIL-Dox) showed efficient cell binding and internalization and were significantly more cytotoxic against EpCAM-positive tumor cells than nontargeted liposomes (SL-Dox). In athymic mice bearing established human tumor xenografts, pharmacokinetic and biodistribution analysis of SIL-Dox revealed long circulation times in the blood with a half-life of 11 h and effective time-dependent tumor localization, resulting in up to 15% injected dose per gram tissue. These favorable pharmacokinetic properties translated into potent antitumor activity, which resulted in significant growth inhibition (compared with control mice), and was more pronounced than that of doxorubicin alone and nontargeted SL-Dox at low, nontoxic doses. Our data show the promise of EpCAM-directed nanovesicular drug delivery for targeted therapy of solid tumors.

Cryopreservation and autotransplantation of human ovarian tissue prior to cytotoxic therapy--a technique in its infancy but already successful in fertility preservation

Increasing survival rates in young cancer patients, new reproductive techniques and the growing interest in quality of life after gonadotoxic cancer therapies have placed fertility preservation as an important issue to oncologists, fertility specialists and patients. Several techniques are now available for fertility preservation in these patients. A new promising method is cryopreservation and transplantation of ovarian cortex. Ovarian tissue can be extracted by laparoscopy without any significant delay of gonadotoxic therapy. The tissue can be cryopreserved by specialised centres of reproductive medicine and transplanted in case the women experience premature ovarian failure (POF). This review summarises the European expertise on cryopreservation and transplantation of ovarian tissue, following around 30 reported transplantations globally, resulting in six live births and several ongoing pregnancies. It emphasises that fertility preservation by the cryopreservation of ovarian tissue is a new but already a successful clinical option, which can be considered for selected cancer patients.

AKT/mTOR pathway activation and BCL-2 family proteins modulate the sensitivity of human small cell lung cancer cells to RAD001

PURPOSE: The Akt/mammalian target of rapamycin (mTOR) pathway is frequently activated in human cancers and plays an important role in small cell lung cancer (SCLC) biology. We investigated the potential of targeting mTOR signaling as a novel antitumor approach in SCLC. EXPERIMENTAL DESIGN: The expression of mTOR in patient specimens and in a panel of SCLC cell lines was analyzed. The effects on SCLC cell survival and downstream signaling were determined following mTOR inhibition by the rapamycin derivative RAD001 (Everolimus) or down-regulation by small interfering RNA. RESULTS: We found elevated expression of mTOR in patient specimens and SCLC cell lines, compared with normal lung tissue and normal lung epithelial cells. RAD001 treatment impaired basal and growth factor-stimulated cell growth in a panel of SCLC cell lines. Cells with increased Akt pathway activation were more sensitive to RAD001. Accordingly, a constitutive activation of the Akt/mTOR pathway was sufficient to sensitize resistant SCLC cells to the cytotoxic effect of RAD001. In the sensitive cells, RAD001 showed a strong additive effect to the proapoptotic action of the chemotherapeutic agent etoposide. Intriguingly, we observed low Bcl-2 family proteins levels in the SCLC cells with a constitutive Akt pathway activation, whereas an increased expression was detected in the RAD001-resistant SCLC cells. An antisense construct targeting Bcl-2 or a Bcl-2-specific inhibitor was able to sensitize resistant SCLC cells to RAD001. Moreover, SCLC tumor growth in vivo was significantly inhibited by RAD001. CONCLUSION: Together, our data show that inhibiting mTOR signaling with RAD001 potently disrupts growth and survival signaling in human SCLC cells.

[New strategies for fertility preservation in young women with cancer]

Especially young women with cancer face rising survival rates due to remarkable progress in oncologic therapies. Preserving fertility is a major concern for both patients and their next of kin. Well established reproductive technologies such as cryopreservation of fertilized oocytes after in vitro fertilization already make fertility preservation possible for some patients. This review is dedicated to the emerging techniques that are becoming widely accepted for fertility preservation in young women and girls with cancer, such as auto transplantation of ovarian tissue cryopreservation and in vitro maturation (IVM) of either oocytes or follicles. First results are encouraging. But some challenges still have to be tackled in order for these novel technologies to be routinely employed with the aim of successful fertility preservation.