The Utility of Differential Scanning Calorimetry Curves of Blood Plasma for Diagnosis, Subtype Differentiation and Predicted Survival in Lung Cancer.

Early detection of lung cancer (LC) significantly increases the likelihood of successful treatment and improves LC survival rates. Currently, screening (mainly low-dose CT scans) is recommended for individuals at high risk. However, the recent increase in the number of LC cases unrelated to the well-known risk factors, and the high false-positive rate of low-dose CT, indicate a need to develop new, non-invasive methods for LC detection. Therefore, we evaluated the use of differential scanning calorimetry (DSC) for LC patients' diagnosis and predicted survival. Additionally, by applying mass spectrometry, we investigated whether changes in O- and N-glycosylation of plasma proteins could be an underlying mechanism responsible for observed differences in DSC curves of LC and control subjects. Our results indicate selected DSC curve features could be useful for differentiation of LC patients from controls with some capable of distinction between subtypes and stages of LC. DSC curve features also correlate with LC patients' overall/progression free survival. Moreover, the development of classification models combining patients' DSC curves with selected plasma protein glycosylation levels that changed in the presence of LC could improve the sensitivity and specificity of the detection of LC. With further optimization and development of the classification method, DSC could provide an accurate, non-invasive, radiation-free strategy for LC screening and diagnosis.

A phase 2 trial of consolidation pembrolizumab following concurrent chemoradiation for patients with unresectable stage III non-small cell lung cancer: Hoosier Cancer Research Network LUN 14-179.

BACKGROUND: Five-year overall survival (OS) for patients with unresectable stage III non-small cell lung cancer (NSCLC) is poor. Until recently, a standard of care was concurrent chemoradiation alone. Patients with metastatic NSCLC treated with anti-programmed death 1 antibodies have demonstrated improved OS. This trial evaluated pembrolizumab as consolidation therapy after concurrent chemoradiation in patients with unresectable stage III disease. METHODS: Patients with unresectable stage III NSCLC received concurrent chemoradiation with cisplatin and etoposide, cisplatin and pemetrexed, or carboplatin and paclitaxel and 59.4 to 66.6 Gy of radiation. Patients with nonprogression of disease were enrolled and received pembrolizumab (200 mg intravenously every 3 weeks for up to 12 months). The primary endpoint was the time to metastatic disease or death (TMDD). Secondary endpoints included progression-free survival (PFS) and OS. RESULTS: The median follow-up for 93 patients (92 for efficacy) was 32.2 months (range, 1.2-46.6 months). The median TMDD was 30.7 months (95% confidence interval [CI], 18.7 months to not reached), which was significantly longer than the historical control of 12 months (P < .0001). The median PFS was 18.7 months (95% CI, 12.4-33.8 months), and the median OS was 35.8 months (95% CI, 24.2 months to not reached). The 1-, 2-, and 3-year OS estimates were 81.2%, 62.0%, and 48.5%, respectively. Forty patients (43.5%) completed 12 months of treatment (median number of cycles, 13.5). Symptomatic pneumonitis (grade 2 or higher) was noted in 16 patients (17.2%); these cases included 4 grade 3 events (4.3%), 1 grade 4 event (1.1%), and 1 grade 5 event (1.1%). CONCLUSIONS: Consolidation pembrolizumab after concurrent chemoradiation improves TMDD, PFS, and OS in comparison with historical controls of chemoradiation alone. Rates of grade 3 to 5 pneumonitis were similar to those reported with chemoradiation alone.

Treatment and outcomes of non-small-cell lung cancer patients with high comorbidity.

BACKGROUND: The life expectancy of untreated non-small-cell lung cancer (NSCLC) is dismal, while treatment for NSCLC improves survival. The presence of comorbidities is thought to play a significant role in the decision to treat or not treat a given patient. We aim to evaluate the association of comorbidities with the survival of patients treated for NSCLC. METHODS: We performed a retrospective study of patients aged ≥66 years with invasive NSCLC between the years 2007 and 2011 in the Surveillance, Epidemiology, and End Results Kentucky Cancer Registry. Comorbidity was measured using the Klabunde Comorbidity Index (KCI), and univariate and multivariate logistic regression models were used to measure association between receiving treatment and comorbidity. Kaplan-Meier plots were constructed to estimate time-to-event outcomes. RESULTS: A total of 4014 patients were identified; of this, 94.9% were white and 55.7% were male. The proportion of patients who did not receive any treatment was 8.7%, 3.9%, 19.1%, and 23.5% for stages I, II, III, and IV, respectively (p<0.0001). In multivariate analysis, older age, higher stage, and higher comorbidity (KCI ≥3) were associated with a lower likelihood of receiving any treatment. The median overall survival (OS) for untreated and KCI=0 was 17.7 months for stages I and II, 2.3 months for stage III, and 1.3 months for stage IV. The median OS for treated and KCI=0 was 58.9 months for stages I and II, 16.8 months for stage III, and 5.8 months for stage IV (p<0.01). Treatment was an independent predictor of OS in multivariate analysis that included KCI scores. CONCLUSION: Our data suggest that lung cancer patients may derive a survival benefit from therapies, regardless of the presence of comorbidities, although the degree of benefit seems to decrease with higher KCI scores.

Phase II Trial on Extending the Maintenance Flushing Interval of Implanted Ports.

PURPOSE: Retrospective studies suggest that it may be safe to extend the maintenance flushing interval of implanted ports from once every month, as recommended by the manufacturer, to once every 3 months, but no prospective cohort studies have been done specifically assessing the safety and feasibility of this intervention. METHODS: This was a phase II study in oncologic patients who retained a functional port after completion of systemic chemotherapy. Patients enrolled in the study had their port flushed once every 3 months and were observed until completion of five scheduled flushes (one on enrollment and four additional flushes, one every 3 months) or development of any port-related complication, including infections, thrombosis, and occlusions. The primary end points were frequency of port-related complications and port failure requiring removal. RESULTS: A total of 87 patients were enrolled in the study. The median follow-up time was 308 days, accounting for a total of 24,202 catheter-days. There were 10 port-related complications (11.49%; 95% CI, 4.85% to 18.14%). No infection or symptomatic thrombosis occurred. The mean time to port-related complication was 184 days. No patients developed port failure while on protocol, but on subsequent medical record review, four patients developed a complication that required port removal or port revision within 30 days of being removed from the trial (4.6%; 95% CI, 0.4% to 8.8%; 0.17/1,000 catheter-days). CONCLUSION: Extending the maintenance flushes of implanted ports in adult oncologic patients to once every 3 months is safe, effective, and likely to increase patient adherence and satisfaction while decreasing the associated cost.

Novel targeted therapies for resistant ALK-rearranged non-small-cell lung cancer: ceritinib and beyond.

Lung cancer is the leading cause of cancer-related mortality in both sexes, accounting for over one quarter of cancer deaths. Non-small-cell lung cancer (NSCLC) comprises 85%-90% of lung cancer diagnoses and despite advances in multimodality therapies, 5-year survival rates remain dismal with a median survival for patients with metastatic disease of 1 year. The positive outcomes of targeted therapies against the kinase domain of epidermal growth factor receptor in NSCLC triggered consistent efforts to identify the so-called driver mutations as other potential targets. Anaplastic large-cell kinase (ALK) gene rearrangements were identified and targeted resulting in promising response rates in early studies. Unfortunately, most of the patients treated with crizotinib, the first-generation ALK inhibitor, progressed within 9 months. Ceritinib is a second-generation ALK inhibitor that has demonstrated activity in crizotinib-resistant patients, becoming a promising treatment option in this population. Furthermore, additional novel ALK inhibitors and agents targeting alternative pathways have been recruited to rechallenge this evasive disease post-crizotinib resistance.

CXCR6 expression in non-small cell lung carcinoma supports metastatic process via modulating metalloproteinases.

Lung cancer (LuCa) is the leading cause of cancer-related deaths worldwide regardless of the gender. High mortality associated with LuCa is due to metastasis, molecular mechanisms of which are yet to be defined. Here, we present evidence that chemokine receptor CXCR6 and its only natural ligand, CXCL16, are significantly expressed by non-small cell lung cancer (NSCLC) and are involved in the pathobiology of LuCa. CXCR6 expression was significantly higher in two subtypes of NSCLC (adenocarcinomas-ACs and squamous cell carcinoma-SCCs) as compared to non-neoplastic tissue. Additionally, serum CXCL16 was significantly elevated in LuCa cases as compared to healthy controls. Similar to CXCR6 tissue expression, serum level of CXCL16 in AC patients was significantly higher than SCC patients. Biological significance of this axis was validated using SCC and AC cell lines. Expression of CXCR6 was higher in AC cells, which also showed higher migratory and invasive potential than SCC. Differences in migratory and invasive potential between AC and SCC were due to differential expression of metalloproteinases following CXCL16 stimulation. Hence, our findings suggest clinical and biological significance of CXCR6/CXCL16 axis in LuCa, which could be used as potential prognostic marker and therapeutic target.

Expression and clinical significance of CXCR5/CXCL13 in human non­small cell lung carcinoma.

CXCR5 and/or CXCL13 expression is elevated in certain carcinomas and lymphomas. To determine if these factors are involved in progression of non-small cell lung cancer (LuCa), we evaluated their expression in patients with various forms of this disease. Lung biopsies from patients with non-neoplastic cells (n=8), squamous cell carcinoma (SCC; n=24), or adenocarcinoma (AC; n=54) were stained for CXCR5. Histopathological analysis of these samples showed significantly higher expression of CXCR5 (p<0.001) in carcinomas (i.e., SCCs and ACs) relative to non­neoplastic lung tissue. Nuclear and membrane CXCR5 intensities were highest in ACs, with median values of 185 and 130, respectively, followed by SCCs with median values of 170 and 110, respectively. The lowest nuclear and membrane expressions of CXCR5 were found in non-neoplastic tissues, having median values of 142 and 90, respectively. Sera from SCC patients (n=17), AC patients (n=14), and healthy controls (n=9) were tested for the presence of CXCL13. Serum CXCL13 levels in LuCa patients were higher than in healthy controls. CXCR5 expression in cell lines of human non-small cell lung carcinoma (NCI-H1915) and small cell lung carcinoma (SW-1271) were evaluated by flow cytometry. CXCR5 expression was higher in NCI-H1915 cells relative to SW-1271 cells. The functional significance of CXCR5 expression was tested in a migration assay. In response to CXCL13, more NCI-H1915 cells migrated than SW-1271 cells. These findings suggest that the CXCR5­CXCL13 axis influences LuCa progression. After validation in larger patient groups, CXCR5 and CXCL13 may prove useful as biomarkers for LuCa. Correspondingly, blockade of this axis could serve as an effective therapy for LuCa.

CCR9/CCL25 expression in non-small cell lung cancer correlates with aggressive disease and mediates key steps of metastasis.

Poor clinical outcome of lung cancer (LuCa) is primarily due to lack of knowledge about specific molecules involved in its progression and metastasis. In this study, we for the first time show the clinical and biological significance of CC chemokine receptor-9 (CCR9) in non-small cell lung cancer (NSCLC). Expression of CCR9 and CCL25, the only natural ligand of CCR9, was significantly higher (p<0.0001) in NSCLC tissues and serum respectively, compared to their respective controls. Interestingly, expression of both CCR9 and CCL25 was significantly higher in adenocarcinomas (ACs) compared to squamous cell carcinomas (SCCs) (p = 0.04, and p< 0.0001). Similar to tissues, AC and SCC cell lines were positive for CCR9 expression. Despite of marginal difference in CCR9 expression, AC cells showed higher migratory and invasive potential in response to CCL25, compared to SCC cells. This differential biological response of AC cells was primarily due to differential expression of matrix metalloproteinases and tissue inhibitor of metalloproteinases under the influence of CCL25. Our results suggest CCR9 as a potential target for developing new treatment modality for NSCLC. Additionally, differential serum CCL25 level in ACs and SCCs, two NSCLC subtypes, suggest its potential as a non-invasive diagnostic/prognostic biomarker.

Hepatoid adenocarcinoma of the lung: report of five cases and review of the literature.

The current diagnostic criteria for hepatoid adenocarcinoma of lung include typical acinar or papillary adenocarcinoma and a component resembling hepatocellular carcinoma and expressing α-fetoprotein (AFP). Distinguishing hepatoid adenocarcinoma of lung from hepatocellular carcinoma metastatic to lung is difficult in patients with both lung and liver masses and in patients at risk for lung and liver cancer because of smoking and viral hepatitis, respectively. We studied morphologic features of hepatoid adenocarcinoma of lung and established an immunohistochemical panel to facilitate distinction of hepatoid adenocarcinoma of lung from hepatocellular carcinoma metastatic to lung. Five cases of hepatoid adenocarcinoma of lung were stained with hematoxylin and eosin and mucicarmine for histomorphologic evaluation. The 14-marker immunohistochemical profile was established for hepatoid adenocarcinoma of lung and compared with that of hepatocellular carcinoma. Two cases of hepatoid adenocarcinoma of lung had signet-ring cell components. Three cases were pure hepatoid adenocarcinoma without components of acinar or papillary adenocarcinoma, signet-ring cells or neuroendocrine carcinoma. Like hepatocellular carcinoma, hepatoid adenocarcinoma of lung expresses CK8 (5/5), CK18 (5/5), AFP (3/5) and HepPar1 (5/5), shows cytoplasmic staining with TTF-1 (5/5) and does not express CK14 (0/5). Unlike hepatocellular carcinoma, it expresses CK5/6 (1/5), CK7 (3/5), CK19 (4/5), CK20 (1/5), HEA125 (5/5), MOC31 (5/5), monoclonal CEA (3/5) and napsin A (1/5). An immunohistochemical panel that includes a variety of cytokeratins, monoclonal CEA and EpCAM markers (HEA125 and MOC31) facilitates distinction of hepatoid adenocarcinoma of lung from hepatocellular carcinoma metastatic to lung, especially when correlated with clinical and radiologic findings. We propose modification of the current diagnostic criteria for hepatoid adenocarcinoma of lung. Tumor composition can be either pure hepatoid adenocarcinoma or hepatoid adenocarcinoma with components of typical acinar or papillary adenocarcinoma, signet-ring cells or neuroendocrine carcinoma. AFP expression is not requisite for diagnosis as long as other markers of hepatic differentiation are expressed.

Detection of Immunoglobulin G against E7 of Human Papillomavirus in Non-Small-Cell Lung Cancer.

Background. A significant number of non-small-cell lung cancers (NSCLC) have human papillomavirus (HPV) DNA integrated in their genome. This study sought to further establish HPV's possible etiologic link to NSCLC by evaluating an immune response to HPV's oncogene, E7, in patients with NSCLC. Patients and Methods. Antibodies (IgG) in serum against E7 for HPV 16 and 18 in 100 patients with NSCLC were examined by enzyme-linked immunosorbent assay (ELISA). Results. Sixteen NSCLC patients were found to have a high titration of IgG for HPV oncogenic E7 protein. 23.5% of adenocarcinomas (AC,) and 15.4% of squamous cell carcinomas (SCC) were positive for IgG against HPV E7. HPV-18 (11%) had a slightly higher frequency than HPV-16 (6%). Of the six positive cases for HPV-16, 3 were AC, 2 SCC, and 1 NOS (not otherwise specified). For the 11 HPV-18 positives, 7 were AC, and 4 SCC. The one case with IgG against HPV 16 and 18 was AC. One case had high cross-reactive levels against E7 of HPV 16 and 18. Two (28%) of 7 patients who reported never smoking were positive for HPV, and 12 (13.6%) of 88 smokers were HPV positive. Conclusions. The study detected high levels of IgG against E7 in 16% of NSCLC patients. This adds evidence to a potential role of HPV in the pathogenesis of NSCLC.

Radon and lung cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide. Radon exposure is the second leading cause of lung cancer, following tobacco smoke. Radon is not only an independent risk factor; it also increases the risk of lung cancer in smokers. Numerous cohort, case-control, and experimental studies have established the carcinogenic potential of radon. The possibility of radon having a causative effect on other cancers has been explored but not yet proven. One of the postulated mechanisms of carcinogenesis is DNA damage by alpha particles mediated by the production of reactive oxygen species. The latter are also thought to constitute one of the common mechanisms underlying the synergistic effect of radon and tobacco smoke. With an estimated 21,000 lung cancer deaths attributable to radon in the United States annually, the need for radon mitigation is well acknowledged. The Environmental Protection Agency (EPA) has established an indoor limit of 4 picocuries (pCi)/L, and various methods are available for indoor radon reduction when testing shows higher levels. Radon mitigation should accompany smoking cessation measures in lung cancer prevention efforts.

Pemetrexed with or without matuzumab as second-line treatment for patients with stage IIIB/IV non-small cell lung cancer.

INTRODUCTION: This randomized phase II study investigated pemetrexed in combination with the epidermal growth factor receptor (EGFR)-targeting monoclonal antibody matuzumab compared with pemetrexed alone as second-line therapy for patients with advanced non-small cell lung cancer. METHODS: Patients received pemetrexed 500 mg/m every 3 weeks either alone (n = 50) or in combination with matuzumab at either 800 mg weekly (n = 51) or 1600 mg every 3 weeks (n = 47). The primary end point was objective response, as assessed by an independent review committee. RESULTS: Tumor EGFR expression was detected in 87% of randomized patients. The objective response rate for the pooled matuzumab-treated arms was 11% compared with 5% for pemetrexed alone (p = 0.332). Apart from one patient in the pemetrexed alone group, all responses occurred in patients whose tumors expressed EGFR. The objective response rate for patients receiving weekly matuzumab was 16% compared with 2% for those receiving matuzumab every 3 weeks. There was also a trend for improved overall survival in patients receiving matuzumab weekly versus every 3 weeks (12.4 months versus 5.9 months, respectively, versus 7.9 months for pemetrexed alone). The combination of pemetrexed and matuzumab demonstrated an acceptable safety profile, with the most common grade 3/4 adverse event being neutropenia. CONCLUSION: Although the analysis on the pooled matuzumab-treated arms did not demonstrate a statistically significant improvement in objective response for the addition of matuzumab to pemetrexed compared with pemetrexed alone, the trends for improvement in objective response and overall survival for pemetrexed plus weekly matuzumab compared with pemetrexed alone warrant confirmation in additional clinical trials.

Human papillomavirus (HPV) and Merkel cell polyomavirus (MCPyV) in non small cell lung cancer.

Certain types of human papillomavirus (HPV) induce cancers, especially cervical cancers in women. A meta-analysis of the literature suggests that HPV is also associated with 20%-25% of non small cell lung carcinoma (NSCLC). Merkel cell Polyomavirus (MCPyV) causes most Merkel cell carcinomas in immunocompromised hosts, and is associated with some squamous carcinomas of skin in immunocompetent individuals. Since both oncogenic viruses appear to involve the tonsils and, therefore, have clear access to the lungs, we examined that the possible association of HPV and MCPyV infections with lung cancers, especially, NSCLC. DNAs were extracted from 51 frozen tissues from 30 lung cancer patients, and examined for the presence of HPV and MCPyV by PCR and DNA sequencing analysis. Clinical data was correlated with the viral status. HPVs were only detected in 5 adenocarcinomas (16.7% of all lung cancers examined). Three were positive for HPV-16, 1 for HPV-11 and 1 had an unknown HPV type DNA. None was identified in benign tissue. MCPyV DNA was detected in 5 NSCLCs (16.7%). Three of the 5 were identified in squamous carcinomas, 1 in adenocarcinoma, and 1 in an unspecified NSCLC. Two additional samples were positive for MCPyV DNA within benign adjacent lung tissue only. In one adenocarcinoma, HPV-11 was identified in an adenocarcinoma, and MCPyV DNA was detected in the adjacent "benign" tissue. HPV and MCPyV were directly associated with 33.3% of NSCLC. Further studies are necessary to determine if polyomavirus and papillomavirus are necessary risk factors for some cases of NSCLC.

Fixed-dose every-other-week capecitabine and oxaliplatin for refractory squamous cell carcinoma of the head and neck.

AIMS: To maximize the palliative benefits of capecitabine and oxaliplatin for patients with refractory squamous cell carcinoma of the head and neck (SCCHN). METHODS: Patients received fixed-dose capecitabine (1500 mg orally twice a day) on days 1 to 7 and oxaliplatin (85 mg/m) days 1 and 14. RESULTS: Fifteen patients with refractory SCCHN were enrolled. All patients had relapsed after surgery and had failed radiation therapy. Eighty-seven percent (13) had progressed after chemotherapy. The most common toxicities were grades 1 or 2 fatigue and anemia. There was a 13% partial response rate and 33% stable disease rate for a clinical benefit of 46% by Response Evaluation Criteria in Solid Tumors criteria. CONCLUSIONS: Fixed-dose capecitabine and oxaliplatin combination on an every-other-week schedule showed activity in refractory SCCHN. The simplicity and toxicity profile of this regimen compares favorably with other commonly used chemotherapies and should be tested in larger studies.

Obtaining routine blood cultures during interleukin-2-containing therapy is unnecessary.

PURPOSE: To evaluate the usefulness of routine blood cultures in patients who develop temperatures of 38.5 degrees C or higher while treated with interleukin-2 (IL-2). METHODS: Retrospective chart review study. Charts of patients treated with high-dose IL-2 or biochemotherapy for metastatic melanoma were reviewed at the University of Louisville from 2005 to 2007. The study objective was to estimate the frequency of true and false positive blood cultures. RESULTS: A total of 205 blood cultures in 46 patients (27 male, 19 female) were reviewed. The average age was 53 years (25-71 years). The patients had an average of 3 cycles of therapy. The mean temperature of the febrile episodes was 38.7 degrees C. The mean absolute neutrophil count was 5.1 K/microL. Of these 205 febrile episodes, only 1 blood culture was true positive. The patient had methicillin sensitive staphylococcus aureus bacteremia. There were 5 false positive blood cultures. Four hundred thirty-four further febrile episodes were documented without blood cultures drawn. None of these patients were found to be infected. The yield of true positive blood cultures in this setting was 0.5% (0%-3%, CI). There was, however, a higher number of false positive blood cultures, 2.4% (0.5%-4.5%, CI). CONCLUSIONS: Blood cultures during IL-2 containing therapy are very inefficient to differentiate between infections versus IL-2-related fever.

Exosomal microRNA: a diagnostic marker for lung cancer.

PURPOSE: To date, there is no screening test for lung cancer shown to affect overall mortality. MicroRNAs (miRNAs) are a class of small noncoding RNA genes found to be abnormally expressed in several types of cancer, suggesting a role in the pathogenesis of human cancer. PATIENTS AND METHODS: We evaluated the circulating levels of tumor exosomes, exosomal small RNA, and specific exosomal miRNAs in patients with and without lung adenocarcinoma, correlating the levels with the American Joint Committee on Cancer (AJCC) disease stage to validate it as an acceptable marker for diagnosis and prognosis in patients with adenocarcinoma of the lung. RESULTS: To date, 27 patients with lung adenocarcinoma AJCC stages I-IV and 9 controls, all aged 21-80 years, were enrolled in the study. Small RNA was detected in the circulating exosomes. The mean exosome concentration was 2.85 mg/mL (95% CI, 1.94-3.76) for the lung adenocarcinoma group versus 0.77 mg/mL (95% CI, 0.68-0.86) for the control group (P < .001). The mean miRNA concentration was 158.6 ng/mL (95% CI, 145.7-171.5) for the lung adenocarcinoma group versus 68.1 ng/mL (95% CI, 57.2-78.9) for the control group (P < .001). Comparisons between peripheral circulation miRNA-derived exosomes and miRNA-derived tumors indicated that the miRNA signatures were not significantly different. CONCLUSION: The significant difference in total exosome and miRNA levels between lung cancer patients and controls, and the similarity between the circulating exosomal miRNA and the tumor-derived miRNA patterns, suggest that circulating exosomal miRNA might be useful as a screening test for lung adenocarcinoma. No correlation between the exosomal miRNA levels and the stage of disease can be made at this point.

A phase I study of thalidomide, capecitabine and temozolomide in advanced cancer.

AIM: To develop a novel oral antiangiogenic and immunomodulatory chemotherapy regimen against advanced cancers. METHODS: Patients were enrolled in cohorts of three or six in a standard phase I design. Thalidomide 100 mg was kept stable for all cohorts. If well tolerated after one week, capecitabine and temozolomide (TCT) fixed-dose were given daily without rest and escalated one at a time until dose limiting toxicity (DLT) occurred. If no DLT occurred within 28 days (1 cycle), the subsequent group was enrolled into the next dose level. RESULTS: Twenty-three adult patients with objective documentation of progressive metastatic cancer after a median of two therapies (range 0-4) received TCT in this study. Based on DLT within the first 28 days, the MTD of daily TCT therapy was thalidomide 100 mg, capecitabine 2000 mg and temozolomide 100 mg. With long-term treatment, majority of the patients required dose interruptions due to fatigue, hand-foot syndrome, and neutropenia. A dose level consisting of daily thalidomide and three-weeks-on one-week-off capecitabine and temozolomide was implemented and administered to six patients without DLT. Out of 23 subjects, four (17%) achieved a partial response (renal, gastric, prostate 2), and four patients (17%) had stable disease (renal, colon, pancreas 2), adding to a clinical benefit of 34%. CONCLUSIONS: TCT is an effective palliative oral chemo-immunotherapy for patients with advanced cancer. The recommended dose for phase II trial is thalidomide 100 mg daily without a break, capecitabine 2000 mg and temozolomide 100 mg daily three-weeks on and one-week off.

Argatroban for anticoagulation during cardiac surgery.

BACKGROUND: The aim of this study was to report our experience and review the published data on argatroban administration during adult cardiac surgery. METHODS: The information on all reported cases of argatroban use in adults, during cardiac surgery was reviewed, including that of the patient described here. This analysis focused on patient characteristics, type of surgery, argatroban dosing schedule, monitoring of anticoagulation and outcomes. RESULTS: Twenty-one cases have been reported. Fifteen patients underwent off-pump surgical procedures with the argatroban dose adjusted to maintain an activated clotting time (ACT) range between 200 and 300 s. Three intraoperative thrombi occurred in two patients when the ACT was <280 s. None had coagulopathy. Six cases reported the use of argatroban during on-pump cardiac surgery dosed to keep the ACT >400 s. Intraoperative thrombotic complications were not reported in this group; however, one clot in the pump was noted after the procedure when the ACT was between 300 and 350 s. All six cases required larger volumes of perioperative blood products and three had severe coagulopathy. Of the 21 cases, seven had an indication for continued anticoagulation following surgery. Four cases did not report further use of argatroban after surgery. Three patients received argatroban after surgery without complications. Recommendations for how to use argatroban during cardiac surgery are proposed. CONCLUSIONS: Argatroban, with ACT monitoring, might be safely used for anticoagulation during cardiac surgery.