Ioannis A. Voutsadakis

Thrombocytosis as a prognostic marker in gastrointestinal cancers

Thrombocytosis is an adverse prognostic factor in many types of cancer. These include breast cancer, ovarian and other gynecologic cancers, renal cell carcinoma and lung cancers. In gastrointestinal cancers of various locations and histologic types, thrombocytosis has been reported in general to be associated with adverse clinical outcomes. Platelet count measurement is well standardized and available in every clinical laboratory, making its use as a prognostic marker practical. This paper will discuss the data on the prognostic value of thrombocytosis in gastrointestinal cancers as well as pathogenic aspects of the association that strengthen the case for its use in clinical prognostication.

Thrombocytosis as a prognostic marker in stage III and IV serous ovarian cancer.

Objective Thrombocytosis is an adverse prognostic factor in many types of cancer. We investigated if pre-treatment increased platelet counts provide prognostic information specifically in patients with stage III and IV serous ovarian cancer which is the most common clinical presentation of ovarian cancer. Methods Platelet number on diagnosis of stage III and IV serous ovarian adenocarcinoma was evaluated in 91 patients for whom there were complete follow-up data on progression and survival. Survival and progression free survival of patients with normal platelet counts (150-350 ×109/L) was compared with that of patients with thrombocytosis (>350×109/L) by χ2 and logrank tests. Results The median age of the patients was 66 years-old. From the 91 patients, 52 (57.1%) had normal platelet counts (median, 273×109/L; range, 153-350) at diagnosis of their disease and 39 patients (42.9%) had thrombocytosis (median, 463×109/L; range, 354-631). In the group of patients with normal platelet counts, 24 of the 52 patients had died with a median survival of 43 months (range, 3-100). In the group of patients with thrombocytosis, 24 of the 39 patients had died with a median survival of 23 months (range, 4-79). In the entire group of 91 patients there was a statistically significant difference of the overall survival and progression-free survival between the two groups (logrank test P=0.02 and P=0.007, respectively). Conclusion In this retrospective analysis of stage III and IV ovarian cancer patients, thrombocytosis at the time of diagnosis had prognostic value regarding overall survival and progression-free survival.

Epithelial to mesenchymal transition in the pathogenesis of uterine malignant mixed Müllerian tumours: the role of ubiquitin proteasome system and therapeutic opportunities

Malignant mixed Müllerian tumours (malignant mixed mesodermal tumours, MMMT) of the uterus are metaplastic carcinomas with a sarcomatous component and thus they are also called carcinosarcomas. It has now been accepted that the sarcomatous component is derived from epithelial elements that have undergone metaplasia. The process that produces this metaplasia is epithelial to mesenchymal transition (EMT), which has recently been described as a neoplasia-associated programme shared with embryonic development and enabling neoplastic cells to move and metastasise. The ubiquitin proteasome system (UPS) regulates the turnover and functions of hundreds of cellular proteins. It plays important roles in EMT by being involved in the regulation of several pathways participating in the execution of this metastasis-associated programme. In this review the specific role of UPS in EMT of MMMT is discussed and therapeutic opportunities from UPS manipulations are proposed.

Ubiquitin- and ubiquitin-like proteins-conjugating enzymes (E2s) in breast cancer

Breast cancer is the most common malignancy in women and a significant cause of morbidity and mortality. Sub-types of breast cancer defined by the expression of steroid hormones and Her2/Neu oncogene have distinct prognosis and undergo different therapies. Besides differing in their phenotype, sub-types of breast cancer display various molecular lesions that participate in their pathogenesis. BRCA1 is one of the common hereditary cancer predisposition genes and encodes for an ubiquitin ligase. Ubiquitin ligases or E3 enzymes participate together with ubiquitin activating enzyme and ubiquitin conjugating enzymes in the attachment of ubiquitin (ubiquitination) in target proteins. Ubiquitination is a post-translational modification regulating multiple cell functions. It also plays important roles in carcinogenesis in general and in breast carcinogenesis in particular. Ubiquitin conjugating enzymes are a central component of the ubiquitination machinery and are often perturbed in breast cancer. This paper will discuss ubiquitin and ubiquitin-like proteins conjugating enzymes participating in breast cancer pathogenesis, their relationships with other proteins of the ubiquitination machinery and their role in phenotype of breast cancer sub-types.

Bortezomib reverses the proliferative and antiapoptotic effect of neuropeptides on prostate cancer cells.

Objectives:  Neuropeptides are important signal initiators in advanced prostate cancer, partially acting through activation of nuclear factor kappa B. Central to nuclear factor kappa B regulation is the ubiquitin‐proteasome system, pharmacological inhibition of which has been proposed as an anticancer strategy. We investigated the putative role of the proteasome inhibitor bortezomib in neuropeptides signaling effects on prostate cancer cells.

Pre-treatment platelet counts as a prognostic and predictive factor in stage II and III rectal adenocarcinoma

AIM To investigate if pre-treatment platelet counts could provide prognostic information in patients with rectal adenocarcinoma that received neo-adjuvant treatment. METHODS Platelet number on diagnosis of stage II and III rectal cancer was evaluated in 51 patients receiving neo-adjuvant treatment and for whom there were complete follow-up data on progression and survival, as well as pathologic outcome at the time of surgery. Pathologic responses on the surgical specimen of patients with lower platelet counts (150-300 × 109/L) were compared with these of patients with higher platelet counts (> 300 × 109/L) by the χ2 test. Overall and progression free survival Kaplan-Meier curves of the two groups were constructed and compared with the Log-Rank test. RESULTS A significant difference was present between the two groups in regards to pathologic response with patients with lower platelet counts being more likely to exhibit a good or complete response to neo-adjuvant treatment than patients with higher platelet counts (P = 0.015). Among other factors evaluated, there was also a significant difference between the carcinoembryonic antigen (CEA) at presentation of patients that exhibited a good or complete response and those that had no response or a minimal to moderate response. Patients with a good or complete response were more likely to present with a CEA of less than 5 μg/L (P = 0.00066). There was no significant difference in overall and progression free survival between the two platelet count groups (Log-Rank tests P = 0.42 and P = 0.35, respectively). CONCLUSION In this retrospective analysis of stage II and III rectal cancer patients, platelet counts at the time of diagnosis had prognostic value for neo-adjuvant treatment pathologic response. Pre-treatment CEA also held prognostic value in regards to treatment effect.

Cutaneous leukocytoclastic vasculitis associated with letrozole

Aromatase inhibitors are increasingly used in the treatment of early and metastatic breast cancer. They can produce various skin adverse effects but are only rarely associated with cutaneous vasculitis. We report the first case of cutaneous vasculitis clearly associated with the use of aromatase inhibitor letrozole.

Targeted treatments for metastatic esophageal squamous cell cancer.

Squamous cell carcinoma, one of the two major sub-types of esophageal carcinomas, constitutes the great majority of tumors in the upper and middle third of the organ. Declining in incidence in western countries, it continues to be a significant public health problem in the far east. Targeted treatments are novel therapies introduced in the clinical therapeutic armamentarium of oncology in the last 10-15 years. They represent a rational way of treating various cancers based on their molecular lesions. Although no such agent has been approved so far for the treatment of esophageal squamous cell carcinomas (ESCC), several are in clinical trials and several others have displayed pre-clinical activity that would justify the efforts and risks of pursuing their clinical development in this disease. This paper discusses some of these targeted agents in more advanced development in metastatic ESCC, as well as some promising drugs with pre-clinical or initial clinical data in the disease.

Acute Cerebrovascular Accident after Cisplatin Treatment in a Patient Taking Letrozole

Vascular thrombotic events are common in patients with cancer and chemotherapy is considered a contributing factor. Venous thrombotic events are more common than arterial ones which are less documented. In this report, we describe a patient with right homonymous hemianopsia following treatment with cisplatin for small cell lung carcinoma while also taking letrozole. A brief review of the literature on arterial thrombotic events after chemotherapy follows.

The platelets-neutrophils to lymphocytes ratio: a new prognostic marker in metastatic colorectal cancer

Background The cancer micro-environment is recognized as having an increasing importance in cancer progression. Immune cells originating from the peripheral blood are important elements of this environment. Thrombocytosis, neutrophilia and lymphocytopenia have been found to be negative prognostic indicators in many cancers. This study aims to evaluate the potential of the use of a novel hematological marker, the platelet-neutrophil to lymphocyte ratio (PNLR) as a practical, reliable, and inexpensive prognostic tool in metastatic colorectal adenocarcinomas. Methods Charts from 305 patients with colorectal cancer were retrospectively reviewed. Of these, 152 had metastatic disease with complete follow-up data on progression and survival. Data were extracted and stratified by a PNLR cut-off point of 2,000. Baseline parameters of the two groups were evaluated and compared with the χ2 test. Univariate and multivariate Cox proportional-hazards regression analyses were performed on variables of interest. Results A total of 102 (67.1%) patients had a PNLR of less than 2,000 while the index for 50 (32.9%) patients was 2,000 or higher. Patients with a PNLR above 2,000 had a shorter median progression-free survival (PFS) [6.5 vs. 13.3 months; hazard ratio (HR), 2.05; 95% CI, 1.32-3.19, P=0.001] than in patients with a PNLR below the threshold. Similar results were observed for median overall survival (OS) (9.6 vs. 21.8 months; HR, 2.33; 95% CI, 1.44-3.79, P=0.001). PNLR had a higher predictive HR than Eastern Cooperative Oncology Group (ECOG) performance status (PS). Conclusions In this retrospective analysis of metastatic colorectal cancer patients, PNLR had prognostic value for both OS and PFS. While other variables held significance for poorer prognosis, PNLR had the highest HR and the highest significance in multivariate analysis for both PFS and OS. Thus, it represents a powerful and objective prognostic tool in the evaluation of metastatic colorectal cancer patients that is readily available and does not require any additional expenses.