Resveratrol--from the bottle to the bedside?

Resveratrol, a naturally occurring plant antibiotic has been the focus of a number of studies investigating its biological attributes, which include anti-oxidant activity, anti-platelet aggregation effect, anti-atherogenic property, estrogen-like growth promoting effect, growth inhibiting activity, immunomodulation, and chemoprevention. More recently, since the first report on the apoptosis inducing activity of resveratrol in human cancer cells, the interest in this molecule as a potential chemotherapy agent has significantly intensified. Not only has its role as an anti-cancer agent been corroborated, but the precise mechanism(s) of the anti-cancer activity of resveratrol is/are being elucidated. Our group has been active in studying the cross talk between the caspase family of proteases and mitochondria, in drug-induced apoptosis. In this regard, we have shown that the cancer preventive activity of resveratrol could be attributed to its ability to trigger apoptosis in human leukemia and breast carcinoma cells. The cytotoxicity of resveratrol is restricted against these transformed cell types due to its ability to selectively upregulate CD95-CD95L interaction on the tumor cell surface, unlike normal peripheral blood cells. Despite the involvement of the CD95 signaling pathway, apoptosis induced by resveratrol is not accompanied by robust caspase 8 activation, but involves mitochondrial release of cytochrome C and downstream activation of caspases 9 and 3. We also extrapolate these in vitro findings in a murine model of carcinogensis, and demonstrate in vivo induction of apoptosis in mouse skin papillomas. These findings highlight the chemotherapeutic potential of this polyphenolic compound.     

Gastric cancer: Where is the place for the surgeon,the oncologist and the endoscopist today?

Gastric cancer remains a major health issue and a leading cause of death worldwide.While the incidence is decreasing in western countries,there has been a shift to more proximal cancers of the diffuse type,which are usually more aggressive and associated with a worse prognosis.Radical surgery still offers the only chance of long term survival,but surgery has reached a plateau of effectiveness and more aggressive approaches like"ultraradical" lymphadenectomy have not improved prognosis.There are three options to improve the situation:Earlier detection,neoadjuvant chemotherapy and adjuvant therapy.Whilst systematic gastroscopic screening makes sense in countries with a high incidence of gastric cancer,in other regions targeted investigation of risk groups including first-degree relatives of cancer patients,patients with a chronic corpusdominant gastritis or with defined genetic abnormalities may help to detect cancer at an earlier stage.Neoadjuvant chemotherapy has meanwhile proved to significantly improve the prognosis not only in patients with a locally advanced cancer who cannot be resected for cure but but also in those who are potentially amenable to curative resection.In the largest randomised study so far reported,perioperative chemotherapy raised overall survival after 5 years from 23%to 36%.The role of adjuvant chemotherapy has been discussed for over 30 years.Meta-analyses demonstrate a small but significant effect which,however,seems to be restricted to Asian patients.In a large USstudy,adjuvant radiochemotherapy appeared to significantly improve outcomes.However,less than 50%of the study patients underwent a systematic lymphadenectomy and so the results of the therapy group were not better to those of"only resected"patients in two large European studies.Thus,the indication of adjuvant(radio-)chemotherapy in gastric cancer currently remains uncertain.Endoscopists have found a therapeutic role through endoscopic resection of early cancers,introduced mainly by Japanese authors.With the development of high resolution endoscopy,endosonography and adequate equipment,the endoscopic curative resection of T1a-tumors(restricted to the mucosal layer) has been established.     

Can the stroma provide the clue to the cellular basis for mammographic density?

Mammographic density is recognised as a useful phenotypic biomarker of breast cancer risk. Deeper understanding is needed of the cellular basis, but evidence is limited because of difficulty in designing studies to validate hypotheses. The ductal epithelial components do not adequately explain the physical and dynamic features observed. The stroma is thought to interact with ductal structures in cancer initiation. Stromal tissues might account for the mammographic features, and this interplay can be hypothesised to relate risk to density. In a paper in this issue of Breast Cancer Research, Alowami has shown a relationship between density and stromal proteins, which might provide useful insight into mammographic density.     

How generalizable are the SEER registries to the cancer populations of the USA?

Background

We determined whether the current SEER registries are representative of the nation’s cancer cases or the socio-demographic characteristics.

Methods

We used breast cancer (BC) and colorectal cancer (CRC) cases diagnosed 2004–2009 from the US Cancer Statistics (USCS) database. Cases were classified into groups residing in SEER coverage areas and the other areas. We compared difference between SEER and non-SEER areas in: age–race-specific proportions of late-stage BC or CRC, area demographics and socioeconomic factors, and data quality.

Results

For late-stage CRC diagnosis, SEER areas contained lower proportions of people with other race and higher proportions of Asian and Hispanic females aged <40, than non-SEER areas. For late-stage BC diagnosis, SEER and non-SEER estimates were comparable. SEER areas had lower percentages of whites and higher percentages of young people, were more urban, and had higher percentage of poor, lower educational attainment, and higher unemployment. SEER areas also tended to have a higher percentage of case completeness than non-SEER areas.

Conclusion

Overall, SEER registries were not significantly different from non-SEER areas in terms of average age–race-specific proportions of late-stage BC or CRC, except for estimates of late-stage CRC for other race and young Asian and Hispanic women. Although case completeness was better in SEER areas than non-SEER areas, SEER areas had greater economic disadvantage and greater minority diversity among the population. This study demonstrated a need for caution in using SEER data and discussed advantages of using the more complete USCS database.

     

Gene therapy: the end of the rainbow?

Background

Papillary carcinoma is the most common differentiated malignant thyroid neoplasm. The biological course of this cancer is typically indolent with a protracted clinical course. Metastases commonly occur in regional lymph nodes, and distant metastasis is a late and rare occurrence. We report a patient who presented with cerebellar metastasis prior to the diagnosis of papillary thyroid carcinoma and review the literature of brain metastasis from papillary thyroid carcinoma.

Results

A 75-year old female presented at the emergency room with progressive dizziness, headache and vomiting, where a brain CT and MRI showed a posterior cerebellar tumor. Surgical resection revealed papillary carcinoma consistent with thyroid origin. Subsequent ultrasound and CT-scan revealed a thyroid nodule, after which the patient underwent total thyroidectomy. Pathologic evaluation was consistent with papillary thyroid carcinoma.

Conclusion

Brain metastasis may rarely be the initial presentation of papillary thyroid carcinoma. Solitary brain metastasis can completely be resected with better prognosis.     

Paget’s disease of the breast: the experience of the European institute of oncology and review of the literature

Background Paget’s disease of the breast is an uncommon presentation of breast malignancy, accounting for 1–3% of all the breast tumors and presents in different histopathologic patterns: in association with an underlying invasive or non invasive carcinoma, or without any underlying neoplasia. In the literature, different methods are used for the treatment. Mastectomy with or without axillary dissection has been considered as the standard treatment procedure for many years. Several studies have already shown that breast conservation with radiation therapy is an oncologically safe option. Regarding the axillary approach, several studies have documented the presence of positive sentinel lymph node even in Paget’s disease alone. The objective of this study was to retrospectively analyze outcome of patients affected by Paget’s breast disease and to define our institutional experience. Patients and methods Between May 1996 and February 2003, 114 patients with confirmed Paget’s disease of the breast were retrieved and underwent surgery at the European Institute of Oncology of Milan, Italy. The median age of the patients was 54 years at the time of the diagnosis. In our study, the histopathological examination of the operated specimen revealed one hundred seven patients with Paget’s disease associated with an underlying invasive or non invasive carcinoma, and seven patients without underlying carcinoma. Patients underwent either conservative breast surgery or mastectomy, with or without sentinel lymph node biopsy and/or axillary surgery. Each patient was evaluated after surgery at a multidisciplinary meeting to selecting systemic therapy. Results Seven patients had “pure” Paget’s disease of the breast and one hundred seven had the disease associated with an underlying carcinoma. As surgical techniques 71 mastectomies and 43 breast conserving surgeries have been performed. Complete axillary dissection was done in patients with clinically positive lymph node and/or sentinel lymph node biopsy positive. Sentinel lymph node biopsy was performed in nineteen patients with invasive component and five were positive and underwent axillary dissection. Eleven sentinel lymph node biopsies were done in patients with non invasive component and none of them was positive. Adjuvant systemic therapies were based on the final tumor, node and metastasis stage: thirty patients received adjuvant chemotherapy alone, fourteen received endocrine treatment alone, twenty-six patients were evaluated to receive both chemo and endocrine therapy. The median duration of follow up was 73 months and was updated in the last 6 months. Five patients developed local recurrence, one had regional recurrence, another two had loco-regional recurrences and fourteen had distant metastasis as a first event. Malignancy-related deaths were censored in the statistical analyses cancer for and due to another tumor in eleven patients. Additionally, deaths were not related to malignancy totally in thirteen patients. Conclusions Screening examination and imaging techniques are fundamental. Breast conserving surgery combined with breast irradiation for patients with invasive and non invasive breast carcinoma has become the treatment of first choice. All surgical conservative approaches should include the complete nipple–areolar complex and margins of resected specimen free of tumor. Thanks to the evolution of the conservative approach, good cosmetic result can be obtained. To be informed about the axillary lymph node status and to avoid the patient to have a second surgical approach, sentinel lymph node biopsy should be performed.     

Why do results conflict regarding the prognostic value of the methylation status in colon cancers? the role of the preservation method

Background  

In colorectal carcinoma, extensive gene promoter hypermethylation is called the CpG island methylator phenotype (CIMP). Explaining why studies on CIMP and survival yield conflicting results is essential. Most experiments to measure DNA methylation rely on the sodium bisulfite conversion of unmethylated cytosines into uracils. No study has evaluated the performance of bisulfite conversion and methylation levels from matched cryo-preserved and Formalin-Fixed Paraffin Embedded (FFPE) samples using pyrosequencing.     

Does the reservoir for self-renewal stem from the ends?

Stem cell research is a burgeoning field with an alluring potential for therapeutic intervention, and thus begs a critical understanding of the long-term consequences of stem cell replacement. Operationally, a stem cell may be defined as a rarely dividing cell with the capacity for self-renewal throughout the lifetime of the organism, and an ability to reconstitute its appropriate lineages via proliferation and differentiation. In many differentiated normal and cancer cell types, the maintenance of telomeres plays a pivotal role in their continued division potential. Taken together with the presence of the enzymatic activity responsible for telomere addition, telomerase, in several progenitor cell lineages, it is presumed that telomere maintenance will be critical for the replenishment of stem cells or their successors. The purpose of this review is to discuss the role of telomere length maintenance in self-renewal, and the consequent challenges and potential pitfalls to the manipulation of normal and cancer-derived stem cells.     

Remission induction therapy: the more intensive the better?

Intensive induction therapy in acute myeloid leukemia (AML) as in some other systemic malignancies is a strategy fundamentally different from post-remission strategies. Approaches such as consolidation treatment, prolonged maintenance, and autologous or allogeneic transplantation in first remission are directed against the minimal residual disease in which a malignant cell population has survived induction treatment and shows resistance due to special genetic or kinetic features. In contrast, induction therapy deals with naive tumor cells possibly different from their counterparts in remission in terms of their kinetic status and sensitivity. Therefore, in AML the introduction of intensification strategies into the induction phase of treatment has been suggested as a new step in addition to intensification in the postremission phase. As expected from the dose effects observed in post-remission treatment with high-dose cytarabine (AraC) or longer treatment, similar dose effects have been found in induction treatment both from the incorporation of high-dose AraC and from the double-induction strategy used in patients up to 60 years of age. As a particular effect, patients with poor-risk AML according to an unfavorable karyotype, high LDH in serum, or a delayed response show longer survival following double induction containing high-dose AraC as compared to standard-dose AraC. A corresponding dose effect in the induction treatment of patients aged 60 years and older has been found with daunorubicin 60 vs 30 mg/m2 as part of the thioguanine/ AraC/daunorubicin (TAD) regimen with the higher dosage significantly increasing the response rate and survival in these older patients who represent a poor-risk group as a whole. Thus we have been able to demonstrate both in younger and older patients that a poor prognosis can be improved by a more intensive induction therapy. High-dose AraC in induction, however, exhibits cumulative toxicity in that repeated courses containing high-dose AraC in the post-remission period lead to long-lasting aplasias of about 6 weeks. Thus after intensive induction treatment, high-dose chemotherapy in remission may be practicable using stem-cell rescue and may contribute to a further improvement in the outcome in poor-risk as well as average-risk patients with AML. These approaches are currently under investigation by the German AML Cooperative Group (AMLCG). "The more intensive the better" is certainly not the way to go in the management of AML and other systemic malignancies but some increase in intensity may be possible and better.     

Do the risks of Lynch syndrome-related cancers depend on the parent of origin of the mutation?

Familial Cancer - Individuals who carry pathogenic mutations in DNA mismatch repair (MMR) genes have high risks of cancer, and small studies have suggested that these risks depend on the sex of the...