Clinico-pathological correlation of serial measurement of circulating tumor cells in 24 metastatic colorectal cancer patients receiving chemotherapy reveals interpatient heterogeneity correlated with CEA levels but independent of KRAS and BRAF mutation.

BACKGROUND: The Veridex CellSearch is an FDA-approved technology for enumerating circulating tumor cells in blood samples of metastatic colorectal cancer mCRC) patients and has prognostic value. It is important to understand how counts of circulating tumor cells (CTCs), which are advocated to be tools for "liquid biopsy" of tumors, correlate with clinical and pathologic variables of significance in these patients. In this study, we have attempted to make such correlations along with evaluating how CTC counts change during the course of chemotherapy. PATIENTS AND METHODS: Following an IRB-approved protocol, blood samples were collected from 24 patients with mCRC along with relevant clinico-pathological data. Blood was collected at defined time-points both prior to as well as during the course of treatment with combination chemotherapy, and CTC counts were enumerated from 7.5 ml of blood. RESULTS: Seventeen out of 24 patients with mCRC showed a CTC count of 2 or less cells in 7.5 ml of blood at base-line assessment before chemotherapy while 7 patients showed 3 or more cells in 7.5 ml of blood at that point. A correlation was found between high carcino-embryonic antigen (CEA) levels and high CTC counts (P = 0.018) although it was also found that some patients had elevated CTCs without an elevated CEA. No correlation with the time interval between detection of primary tumor and appearance of secondary (metastatic) tumor(s) was found. CTC counts did not correlate with the presence of lung or liver metastases, i.e. a number of mCRC patients with lung or liver metastases had a count of zero CTCs at baseline. We also noted no correlation between CTC number and the status of KRAS or BRAF mutation. CTC counts dropped immediately after the start of chemotherapy in 11 out of 21 patients, and also reduced from the baseline at the end of chemotherapy in 5 out of 10 patients. Six of 7 patients who started with 3 or more CTCs in 7.5 ml at baseline also showed a final CTC reduction at the end of the therapy assessment. CONCLUSIONS: Analysis of circulating tumor cells may be of use in monitoring response to therapy in mCRC, either in combination with CEA monitoring or alone when CTCs are elevated but CEA level is not.

Apoptotic circulating tumor cells (CTCs) in the peripheral blood of metastatic colorectal cancer patients are associated with liver metastasis but not CTCs.

Enumeration of circulating tumor cells (CTCs) by the CellSearch system provides prognostic information in metastatic colorectal cancer, regardless of metastatic site. We found that CTCs generally represent <1% of observed events with CellSearch analysis and adapted scoring criteria to classify other peripheral blood events. Examination of twenty two metastatic colorectal cancer patients' blood revealed that patients with high CEA or liver metastases, but not lung or distant lymph node metastases, possessed significant numbers of apoptotic CTCs prior to treatment initiation by Fischer's exact test. Six out of eleven patients with liver metastasis possessed apoptotic CTCs whereas one of nine patients with other metastases had measurable apoptotic CTCs. An elevated CTC number was not necessarily associated with apoptotic CTCs or CTC debris by Spearman's correlation, suggesting the metastatic site rather than CTCs per se as contributing to the origin of these events.

Novel antineoplastics targeting genetic changes in colorectal cancer.

Cytotoxic chemotherapy remains the mainstay of the medical -management of colorectal cancer (CRC). Research over the last two decades has led to a molecular understanding of the oncogenic mechanisms involved in CRC and has contributed to the rational development of antineoplastics that target these mechanisms. During carcinogenesis, genetic changes often occur in molecules that play key functional roles in cancer such as cell proliferation, angiogenesis, apoptosis, cell death and immune-mediated destruction of cancer cells. Here, we review novel antineoplastics that are approved or in development for CRC that target molecules associated with genetic aberrations in CRC. Some of these targeted antineoplastics have proven effective against other solid tumors and hold promise in treating CRC whereas others are now routinely used in combination with cytotoxic agents. This article reviews antineoplastics that target genetic changes in CRC, their antitumor mechanisms, and their stage of development.

Emerging molecular therapies for the treatment of acute lymphoblastic leukemia.

The improved molecular understanding of cancer initiation, progression, and therapeutic resistance has yielded several novel molecular events that are being targeted by emerging therapies. While the treatment of ALL is a success story in the pediatric population, achieving a sustained remission in the adult population remains an area of investigation. Nevertheless, certain therapies have significantly improved the overall survival for adult ALL patients that should continue to improve with the discovery of better molecular targets and targeted agents. Here, we discuss novel therapeutic options under clinical investigation for the treatment of Philadephia chromosome negative ALL including immunotherapy, monoclonal antibodies, and small molecules that may be used as single agent or adjuvant therapy in the management of adult ALL.

Perceived levels of pain associated with bone marrow aspirates and biopsies.

BACKGROUND: Little is known about the degree of pain experienced by patients undergoing a bone marrow aspiration and biopsy (BMAB). OBJECTIVE: To evaluate the effectiveness of several strategies aimed at reducing the pain score. METHODS: We conducted a retrospective analysis of 258 consecutive adult patients who underwent BMAB via 6 different approaches, the first 5 of which were performed by one physician. Group A received local anesthesia with 1% lidocaine hydrochloride (5 mL) and a 5-minute wait time before the procedure; group B received local anesthesia with a double dose (10 mL) of lidocaine; group C received 5 mL of local anesthesia with a 10-minute wait; group D received 5 mL of local anesthesia plus a topical spray with ethyl chloride; group E received oral analgesia and anxiolysis 30 minutes before the procedure in addition to the group A dosage of lidocaine; and group F received the same anesthesia as did group A, but the BMAD was performed by a less experienced practitioner. RESULTS: On a 0 to 10 scale, the mean pain level among the 258 patients was 3.2 (standard deviation = 2.6). Rate of complications was low (<1%). Several strategies failed to improve the pain level, including the administration of a double dose of local anesthesia, waiting longer for the anesthesia effect, and the additional use of a topical anesthetic spray or oral analgesia and anxiolysis. Pain levels were not increased when the procedure was done by a less experienced practitioner. Younger age and female gender were associated with higher pain levels. CONCLUSIONS: Given that the average level of perceived pain during BMAB is low to moderate (approximately 3 on a 0-10 scale), the routine use of conscious sedation for this procedure may not be indicated. Several strategies aimed at reducing the pain level, including doubling the dose of anesthesia and using an oral prophylactic regimen of analgesia and anxiolysis, failed to improve pain scores.

Obatoclax mesylate : pharmacology and potential for therapy of hematological neoplasms.

INTRODUCTION: Augmentation and acceleration of apoptosis for cancer therapy are logical therapeutic strategies given the increasing body of data suggesting the dysregulation of control of cell death in many neoplasms. Apoptosis is particularly well studied in hematological neoplasms, thus these varied diseases present opportunities for pro-apoptotic drug development both as single agents and in combination with established therapies. Accordingly, several agents targeting function of anti-apoptotic Bcl-2 family members have entered clinical trials in the last decade and are discussed. AREAS COVERED: The pan Bcl-2 family member BH3 domain mimetic obatoclax (GX15-070) is currently under clinical evaluation in solid tumors and hematological neoplasms. This agent offers the attractive property of uniformly inhibiting all of the anti-apoptotic members of the Bcl-2 protein family. Its chemistry and preclinical development and activity are reviewed. Pharmacology, pharmacodynamics, drug resistance and clinical use of this agent in leukemias and lymphomas are discussed. The prospects for obatoclax in changing clinical practice are addressed. EXPERT OPINION: Obatoclax may not prove to have dramatic single agent activity for hematological neoplasms. It seems more likely that its activity will be manifest in combination therapy with other agents, particularly cytotoxic chemotherapies. Results of ongoing studies are awaited.