Radiation-associated sarcoma after recurrent colorectal primary tumor: A complex surgical case.

Radiation associated sarcoma is a significant consequence of cancer therapy. Incidence of radiation associated sarcoma correlates with overall radiotherapy exposure. Prognosis is generally poor with 5 year survival rates lower than that for spontaneously occurring sarcomas. Surgical management presents many challenges including having to work in irradiated tissue planes while trying to achieve negative margins. We present a patient with a rare radiation associated pelvic sarcoma whose course illustrates the complexity of this problem.

Trojan-horse nanotube on-command intracellular drug delivery.

A major challenge to nanomaterial-based medicine is the ability to release drugs on-command. Here, we describe an innovative drug delivery system based on carbon nanotubes (CNTs), in which compounds can be released inside cells from within the nanotube "on-command" by inductive heating with an external alternating current or pulsed magnetic field. Without inductive heating the drug remains safely inside the CNTs, showing no toxicity in cell viability tests. Similar to the "Trojan-Horse" in function, we demonstrate the delivery of a combination of chemotherapeutic agents with low aqueous solubility, paclitaxel (Taxol), and C6-ceramide, to multidrug resistant pancreatic cancer cells. Nanotube encapsulation permitted the drugs to be used at a 100-fold lower concentration compared to exogenous treatment yet achieve a comparable ~70% cancer kill rate.

Selective organ preservation in operable locally advanced head and neck squamous cell carcinomas guided by primary site restaging biopsy: long-term results of two sequential brown university oncology group chemoradiotherapy studies.

OBJECTIVES: The long-term outcomes of selective organ preservation in operable, locally advanced head and neck cancers in two sequential chemoradiotherapy (CRT) protocols (HN-53, HN-67) are reported. METHODS: A total of 65 patients were treated with CRT consisting of carboplatin (AUC=1/week) and paclitaxel (60 or 40 mg/m2/week) with radiation (1.8 Gy/day). After 5 weeks of CRT, if primary site biopsies were pathologically negative, then completion CRT to 67-72 Gy was done with neck dissection in node-positive cases. Alternatively, a positive rebiopsy required primary site resection and neck dissection followed by radiotherapy boost as deemed necessary. RESULTS: Pathologic complete responses occurred in 71% patients who then completed CRT; the remaining 29% patients underwent primary site surgery. The 5-year and median overall survival were 47% and 57 months with no statistically significant differences between the two groups. Overall long-term failure rates were: 6% local, 6% regional, and 32% distant. CONCLUSIONS: This strategy of selective organ preservation was effective in 71% patients with CRT, whereas salvage surgery was required in the remainder. Long-term survival was equivalent in both treatment groups.

Factors predictive of the status of sentinel lymph nodes in melanoma patients from a large multicenter database.

BACKGROUND: Numerous predictive factors for cutaneous melanoma metastases to sentinel lymph nodes have been identified; however, few have been found to be reproducibly significant. This study investigated the significance of factors for predicting regional nodal disease in cutaneous melanoma using a large multicenter database. METHODS: Seventeen institutions submitted retrospective and prospective data on 3463 patients undergoing sentinel lymph node (SLN) biopsy for primary melanoma. Multiple demographic and tumor factors were analyzed for correlation with a positive SLN. Univariate and multivariate statistical analyses were performed. RESULTS: Of 3445 analyzable patients, 561 (16.3%) had a positive SLN biopsy. In multivariate analysis of 1526 patients with complete records for 10 variables, increasing Breslow thickness, lymphovascular invasion, ulceration, younger age, the absence of regression, and tumor location on the trunk were statistically significant predictors of a positive SLN. CONCLUSIONS: These results confirm the predictive significance of the well-established variables of Breslow thickness, ulceration, age, and location, as well as consistently reported but less well-established variables such as lymphovascular invasion. In addition, the presence of regression was associated with a lower likelihood of a positive SLN. Consideration of multiple tumor parameters should influence the decision for SLN biopsy and the estimation of nodal metastatic disease risk.

Targeting the growth factors and angiogenesis pathways: small molecules in solid tumors.

Research over the last decades has provided us with a better understanding of the biology of solid tumors. In some solid tumor malignancies single molecular events leading to malignant transformation have been identified, whilst in others multiple pathways seem to play a role simultaneously. The delineation of such pathways has led to the identification of therapeutic targets. Multiple compounds are available now to treat those molecular aberrations. With the wider use of newer biologic therapies, the understanding of biologic characteristics predicting a clinical response has broadened. This review focuses on the clinical management of gastrointestinal stromal tumors as well as hepatocellular, non small cell lung, renal cell and breast cancer with small molecule tyrosine kinase inhibitors, integrating some of the clinical advances with monoclonal antibody therapies in solid tumor malignancies. It highlights recent advances in relevant biomarkers to predict efficacy of biologic therapies and elaborates on their relevance in the clinical management of patients with solid tumor malignancies.

The neoadjuvant therapy of colorectal hepatic metastases and the role of biologic sensitizing and resistance factors.

Liver metastasis represents a common systemic complication of colorectal cancers (CRCs). Partial liver resection has been demonstrated to result in long-term survival in certain well-selected patients with otherwise well-controlled systemic disease. Neoadjuvant therapy has been demonstrated to result in improved resectability and potentially longer survival in patients with liver metastases from CRC. The addition of biologic agents to chemotherapy has been shown to improve response rates and overall survival in patients with metastatic CRC. Here, we are discussing the role of biologic agents in the treatment of patients with liver metastases from CRC. We also discuss the role of biomarkers for response and resistance to such novel therapies.

Salvage of pelvic recurrence of colorectal cancer.

Although the incidence of locally recurrent colorectal cancer has been reduced by improved surgical techniques and the frequent use of multimodality therapy, pelvic recurrence remains a significant problem. Radiation or chemotherapy may provide palliation but it is often short-lived. For fit candidates without evidence of extrapelvic disease, surgical resection (anterior resection, abdominoperineal resection, pelvic exenteration, or abdominosacral resection) may be the most appropriate treatment. For patients with unresectable disease, isolated pelvic perfusion may provide effective palliation.

Cetuximab with concurrent chemoradiation for esophagogastric cancer: assessment of toxicity.

PURPOSE: To determine the feasibility and toxicity of the addition of cetuximab with paclitaxel, carboplatin, and radiation for patients with esophagogastric cancer on a Phase II study. METHODS AND MATERIALS: Patients with locoregional esophageal and proximal gastric cancer without distant organ metastases were eligible. All patients received cetuximab, paclitaxel, and carboplatin weekly for 6 weeks with 50.4 Gy radiation. RESULTS: Sixty patients were enrolled, 57 with esophageal cancer and 3 with gastric cancer. Forty-eight had adenocarcinoma and 12 had squamous cell cancer. Fourteen of 60 patients (23%) had Grade 3 dermatologic toxicity consisting of a painful, pruritic acneiform rash on the face outside of the radiation field. The rates of Grades 3 and 4 esophagitis were 12% and 3%, respectively. Three patients had Grade 3/4 cetuximab hypersensitivity reactions and were not assessable for response. Forty of 57 patients (70%) had a complete clinical response after chemoradiation. CONCLUSION: Cetuximab can be safely administered with chemoradiation for esophageal cancer. Dermatologic toxicity and hypersensitivity reactions were associated with the addition of cetuximab. There was no increase in esophagitis or other radiation-enhanced toxicity.

Isolated chemotherapeutic perfusion of pelvis as neoadjuvant or palliative therapy for advanced cancer of the rectum.

INTRODUCTION: Previously irradiated recurrent rectal cancer is a formidable patient threat with limited treatment options. Isolated pelvic perfusion (IPP) by the balloon-occlusion technique provides high-dose regional chemotherapy that may facilitate resection if appropriate or palliate pain and fungating tumor mass in the symptomatic patient. We currently report our results in 49 recurrent rectal cancer patients (26 had neoadjuvant IPP with intent to resect and 23 had IPP for palliation). METHODS: IPP was done for 1 hour with paclitaxel 30 mg/m(2), 5 fluorouracil 1500 mg/m(2), cisplatin/oxaliplatin 60-130 mg/m(2), and mitomycin C 10 to 15 mg/m(2) (the latter three achieving pelvic-to-systemic drug ratios of 6-9:1). RESULTS: Neoadjuvant perfusion in 26 patients achieved a response in 14 patients (made resectable). Seven had R0 resections (clear margins), six by abdominal sacral resection (ABSR), and one by an extended APR. Of seven other patients, one had a complete pathologic response negating planned resection, one had >50% tumor regression in pelvis (but developed distant metastases), and three refused ABSR. Planned ABSR in two patients was aborted because of complicating cardiovascular issues. A variety of medical and cancer issues precluded resection in the remaining 12 of these 26 neoadjuvant patients. Within the neoadjuvant group, median survival was 24 months in the responding (made resectable) group (14 patients) and it was 8 months in the non-resectable group (12 patients), p = 0.0001. In the responding (made resectable) group, seven patients had R0 resections (median survival 26 months) and seven patients were not resected (median survival 18 months), p = 0.0198. In the IPP group for palliation, 17 of 23 patients (74%) had significant relief of pain, and other tumor-related symptoms (mean survival 11 months). CONCLUSION: Isolated pelvic perfusion using a simplified balloon-occlusion technique has promise in palliation of or augmenting resectability of advanced rectal malignancy in patients not amenable to treatment with conventional modalities.

Regional chemotherapy: overview.

Regional chemotherapy was developed in the 1950s and continues to play an integral part in the development of newer therapies for advanced solid malignancies. Regional therapies have evolved in complexity but are still based on the pharmacokinetics of drug delivery to solid malignancies. Newer techniques demonstrate that the combination of regional therapies, hyperthermia, and surgery is essential in promoting improved patient outcomes.

Clinical pharmacokinetics of isolated pelvic perfusion.

The pharmacokinetic results of this study indicate that there is significant enhancement of pelvic drug levels with isolated pelvic perfusion, with the potential of increasing the therapeutic index and clinical efficacy. This system would seem to be ideal for evaluating fast-acting and highly toxic experimental drugs on human pelvic cancers having treatment protocols of limited clinical success. Pharmacokinetic modeling using empiric approximations for the kinetic rate constants is a convenient and novel way of fitting data using relatively simple mathematics and commercially available spreadsheets.

Pelvic perfusion for advanced colorectal cancers.

Isolated pelvic perfusion (IPP) is a form of intra-arterial local-regional treatment of tumor-bearing organs. IPP using a simplified balloon occlusion technique has shown promise in palliation of resectability of advanced rectal cancer in patients not amenable to treatment with conventional chemoradiation. This article reviews technique criteria and the response to IPP from seven literature studies of isolated pelvic perfusion with colorectal cancer. Current efforts should be directed to improving anti-tumor responses by optimizing chemotherapeutic protocols and modifying perfusion parameters, so that hopefully, this will lead to a more standardized and improved procedure for the isolated pelvic perfusion technique.

Inhibition of EGFR/PI3K/AKT cell survival pathway promotes TSA's effect on cell death and migration in human ovarian cancer cells.

Trichostatin A (TSA), a hydroxamate-type inhibitor of mammalian histone deacetylases, is emerging as one of a potentially new class of anticancer agents. TSA is known to act by promoting the acetylation of histones, leading to uncoiling of chromatin and activation of a variety of genes implicated in the regulation of cell survival, proliferation, differentiation, and apoptosis. In addition, there is an increasing appreciation of the fact that TSA may act through mechanisms other than induction of histone acetylation. Accumulated experimental data indicate that TSA activates phosphatidyl inositol-3-kinase (PI3K)/AKT signaling. Using human ovarian cancer cell line Caov3 cells, we observed that TSA induced cell death in a time- and dose-dependent manner and also inhibited cell migration. TSA transiently activated EGFR tyrosine phosphorylation and AKT activation in a time- and dose-dependent manner, which had been inhibited by EGFR inhibitor PD153035 and PI3 kinase inhibitor LY294002. We also observed that TSA transiently induced survivin expression that had been inhibited by PD153035 and LY294002, suggesting that TSA-induced survivin expression is mediated by EGFR/PI3 kinase pathway. Combination of EGFR inhibitor 153035 or PI3 kinase inhibitor LY294002 with TSA enhanced TSA-induced cell death and TSA reduction of cell migration. Collectively, our data demonstrate that TSA transiently activated EGFR/PI3K/AKT cell survival pathway, leading to expression of survivin. Inhibition of this pathway enhanced TSA-induced cell death and inhibited cell migration. Our data suggest that combination of EGFR/PI3K/AKT cell survival pathway inhibitors with TSA be a better approach to ovarian cancer treatment.

Paclitaxel and ceramide synergistically induce cell death with transient activation of EGFR and ERK pathway in pancreatic cancer cells.

The molecular and cellular mechanism of the development of pancreatic cancer is under constant and intensive study, and yet the cure is still out of reach. While surgical treatment is optional, conventional chemotherapy or chemo-radiotherapy remains the best choice. Among others, paclitaxel is proven to be a popular and, to a certain extent, effective chemotherapy agent. We proposed that the combination of paclitaxel and membrane permeable ceramide would enhance the fatality of cancer cells, and reported that the combination increased cell death of both head and neck and leukemic cancer cells. In this study, we treated pancreatic cancer cells (L3.6 cells) with paclitaxel and ceramide at the concentrations of clinical relevance, and treatment was then followed up with an investigation of the molecular mechanism of the synergism of paclitaxel and ceramide. The results of Western blot analysis indicated that the combo synergistically induced ERK and JNK phosphorylation, but not p38 and Akt phosphorylation. We also found that the combination (combo) induced EGFR phosphorylation in a synergistic manner. Furthermore, we observed that paclitaxel, ceramide, or combo-induced EGFR phosphorylation was inhibited by EGFR inhibitor, PD153035, while paclitaxel, ceramide, or combo-induced JNK and ERK phosphorylation was blocked by EGFR inhibitor, PD153035 and ERK inhibitor, U126. Taken together, our results demonstrated that the combination of paclitaxel and ceramide synergistically induced pancreatic cancer cell death through differential activation of EGFR-mediated MAP kinases. EGFR and ERK inhibitors may further enhance the paclitaxel and ceramide effect.

Impact of sentinel node status and other risk factors on the clinical outcome of head and neck melanoma patients.

OBJECTIVE: To determine the impact of sentinel lymph node (SLN) status and other risk factors on recurrence and overall survival in head and neck melanoma patients. DESIGN: The SLN Working Group, based in San Francisco, Calif, with its 11 member centers, the John Wayne Cancer Institute, and The University of Texas M. D. Anderson Cancer Center pooled data on 629 primary head and neck melanoma patients who had selective sentinel lymphadenectomy. A total of 614 subjects were analyzable. All centers obtained internal review board approval and adhered to the Health Insurance Portability and Accountability Act of 1996 regulations. A Cox proportional hazards model was used to identify factors associated with overall and disease-free survival. SETTING: Tertiary care medical centers. MAIN OUTCOME MEASURE: Clinical outcome of head and neck melanoma patients undergoing selective sentinel lymphadenectomy. RESULTS: Overall, 10.1% (n = 62) of the subjects had at least 1 positive node. Subjects with positive SLN status had significantly thicker tumors (mean thickness, 2.8 vs 2.1 mm; P < .001), and were more likely to have ulcerated tumors (P = .004). During the median follow-up of 3.3 years, the overall mortality from head and neck melanoma was 10%, with more than 20% experiencing at least 1 recurrence. Multivariate analysis showed that tumor site was an independent predictor of mortality; location on the scalp had a more than 3-fold (P < .001) greater mortality than tumors on the face. Tumor thickness was also an independent predictor of overall survival, and SLN status was the most important predictor of disease-free survival in the multivariate model (P < .001). Tumors on the scalp had the highest rate of recurrence, while those on the neck had the lowest. Tumor ulceration was the significant predictor of time to recurrence or disease-free survival (P < .001). CONCLUSION: In this multicenter study, SLN status and other risk factors have an effect on recurrence and/or overall survival.

Targeted inhibition of transient activation of the EGFR-mediated cell survival pathway enhances paclitaxel-induced ovarian cancer cell death.

Emerging studies have suggested that transient activation of the cell survival pathway may be the strategy for cancer cells to fight against chemotherapy and eventually mysteriously evade paclitaxel-induced cell death. Modulation of the EGFR-mediated survival pathway in addition to the utilization of paclitaxel renders a promise of better clinical management. The objective of this study was to understand the molecular mechanism of transient induction of EGFR-mediated cell survival by paclitaxel. We utilized ovarian cancer cell line, Caov3, cells to investigate the effect of paclitaxel on EGFR-mediated MAP kinase and AKT activation, and the expression of survivin. We found that paclitaxel transiently induced EGFR phosphorylation and ERK and AKT activation but not JNK and p38. Paclitaxel-induced ERK and AKT activity was inhibited by the EGFR inhibitor, PD153035; ERK inhibitor, U0126; and PI3 kinase inhibitor, LY294002, respectively. We observed that paclitaxel transiently induced expression of survivin in the early hours of treatment. Paclitaxel-induced survivin expression was inhibited by the EGFR inhibitor, PD153035. Inhibitors of EGFR, ERK and PI3 kinase all enhanced paclitaxel-induced cell death. We conclude that paclitaxel transiently transactivates EGFR, leading to activation of cell survival factors, such as ERK and AKT, and expression of survivin, which are all inclusively accountable for ovarian cancer cell resistance to paclitaxel treatment. A combination of these inhibitors with paclitaxel may be a better option for ovarian cancer treatment.

Transient activation of EGFR/AKT cell survival pathway and expression of survivin contribute to reduced sensitivity of human melanoma cells to betulinic acid.

Betulinic acid (BA), a pentacyclic triterpene first identified less than a decade ago, has served as a melanoma-specific cytotoxic agent, and yet its specificity is being challenged. Recently, we found that human melanoma cells exhibited less sensitivity to betulinic acid than human skin keratinocytes. This study was designed to investigate the cell signaling pathway leading human melanoma cells to increased resistance to betulinic acid treatment. In vitro experiments using cultured human melanoma cells indicated that betulinic acid transiently induced survivin expression. The expression of survivin started 30 min post-betulinic acid treatment, peaked at 2 h, remained elevated for 8 h and returned to basal level within 24 h. Similarly, epithelial growth factor (EGF) treatment induced expression of survivin in a time-dependent manner. Since epithelial growth factor receptor (EGFR) activation leads to the activation of cell signaling components that are important to cell survival, we next examined whether BA-induced survivin expression is mediated by the EGFR pathway. The results showed that BA induced EGFR tyrosine phosphorylation in a time-dependent manner. Further, BA strongly induced AKT phosphorylation in a similar pattern. AKT activation started 15 min post-treatment, peaked at approximately 1 h, remained elevated for 4 h and returned to basal level within 8 h. BA also induced ERK activation and, in contrast, weakly induced JNK and p38 activation. Pretreatment of EGFR inhibitor PD153035 blocked BA-induced EGFR phosphorylation, ERK and AKT activation, and survivin expression. Results of the MTT dye assay showed that a combination of PD153035 and BA enhanced melanoma cell death. Collectively, we conclude that betulinic acid transiently activated the EGFR/AKT cell survival pathway and induced survivin expression, contributing to less sensitivity in human melanoma cells. The data suggest that a combination of the EGFR inhibitor and betulinic acid may be a better clinical option to treat human melanoma.

Isolated pelvic perfusion: plasma pharmacokinetics depend primarily on drug dosage and not the type of drug.

PURPOSE: Comparison of the pharmacokinetics of four drugs with the isolated pelvic perfusion protocol showed linear relationships between drug dosage and two isolated pelvic plasma parameters, mean AUC (pelvic exposure, microM min) and the mean maximum pelvic drug level (microM). It appears that the pharmacokinetics are sufficiently defined as to predict plasma distribution curves for an additional drug with this protocol. Recent FDA approval of oxaliplatin allowed an evaluation of this premise. METHODS: Linearity of drug dosage with maximum drug levels and exposure (AUC) in the isolated pelvic plasma yields initial estimates of these parameters for additional drugs. Use of an empirical, four-compartment pharmacokinetic model (Wanebo and Belliveau in Cancer Chemother. Pharmacol. 43:427, 1999) allowed the generation of predictive plasma distribution curves. These curves were established by optimizing the initial estimates of maximum drug levels and exposure along with estimates of two additional parameters (half-life of pelvic clearance and pelvic to systemic exposure ratio) from experimental data of the four drugs pharmacokinetically characterized. RESULTS: Calculated plasma distribution curves for oxaliplatin matched the experimental curves from the first three patients receiving oxaliplatin therapy, given the experimental ranges of pharmacokinetic parameters seen with the initial four drugs. CONCLUSION: These results give an overall picture for the plasma pharmacokinetics during the isolation period for the isolated pelvic perfusion protocol. Enough experimental data have been accumulated for five drugs to establish a simple pharmacokinetic model (Wanebo and Belliveau in Cancer Chemother Pharmacol 43:427, 1999) and interdrug relationships (i.e., this report) which can be used to predict reasonable plasma distribution curves for additional drugs with this protocol.

Synergistic effect of interleukin-2 and a vaccine of irradiated melanoma cells transfected to secrete staphylococcal enterotoxin A.

We have previously reported that immunization of mice with melanoma cells transfected to secrete the superantigen, Staphylococcal enterotoxin A (SEA), increased the production of antibodies to the B700 melanoma antigen, stimulated the production of endogenous interleukin 2 (IL-2), activated the expression of CD4, CD8 and CD25 T cell markers and enhanced NK cell activity. Now we show that immunization of mice with a vaccine of irradiated sea-transfected melanoma cells coupled with IL-2 therapy was even more effective in inhibiting the growth of primary melanoma tumors and the development of lung metastases than was the irradiated melanoma cell vaccine alone or IL-2 alone. The morphological and immunological effectiveness of the therapy was dose-dependent on IL-2.