Clinical implications of acellular mucin pools in resected rectal cancer with pathological complete response to neoadjuvant chemoradiation.

AIM: Approximately 20% of rectal cancers treated with neoadjuvant chemoradiation achieve a pathological complete response (pCR), which is associated with an improved oncological outcome. However, in a proportion of patients with a pCR, acellular pools of mucin are present in the surgical specimen. The aim of this study was to evaluate the clinical implications of acellular mucin pools in patients with rectal adenocarcinoma achieving a pCR after neoadjuvant chemoradiation followed by proctectomy. METHOD: A single-centre colorectal cancer database was searched for patients with clinical Stage II and Stage III rectal adenocarcinoma who achieved a pCR (i.e. ypT0N0M0) after neoadjuvant chemoradiation followed by proctectomy between 1997 and 2007. Patients were categorized according to the presence or absence of acellular mucin pools in the resected specimen, and groups were compared. Patient demographics, tumour and treatment characteristics, and oncological outcomes were recorded. Primary outcomes were 3-year local and distant recurrences, and disease-free and overall survivals. RESULTS: Two hundred and fifty-eight patients with clinical Stage II or Stage III rectal adenocarcinoma were treated by neoadjuvant chemoradiation. Fifty-eight of these patients had a 58 pCR. Eleven of the 58 patients with a pCR had acellular mucin pools in the surgical specimen. The median follow up was 40 months. The groups were statistically similar with respect to demographics, chemoradiation regimens, distance of tumour from the anal verge, clinical stage and surgical procedure. No patient had local recurrence. Patients with acellular mucin pools had increased distant recurrence (21%vs 5%), decreased disease-free survival (79%vs 95%) and decreased overall survival (83%vs 95%) rates, although none of these differences was statistically significant. CONCLUSION: The presence of acellular mucin pools in a proctectomy specimen with a pCR does not affect local recurrence, but may suggest a more aggressive tumour biology.

Predictors of clinical outcomes of resected ampullary adenocarcinoma: a single-institution experience.

BACKGROUND: In the absence of prospective data, the use of adjuvant therapy in ampullary adenocarcinoma is contingent upon the clinicopathological features which can correlate to 5-year post-operative survival and disease relapse. METHODS: We investigated the factors associated with clinical outcomes among 72 patients who underwent pancreatoduodenectomy at the Cleveland Clinic from 1995 to 2007 for histologically confirmed adenocarcinoma of the ampulla of Vater. RESULTS: R0 resection was achieved in 96% of patients (median age, 72 years; 58% males, 89% Caucasians). Nineteen patients experienced disease relapse after surgery and 61% were alive within 5 years of follow up. Thirty five percent of patients received some form of adjuvant therapy. Perineural tumor invasion (p < 0.01) and presence of ulcerated tumor on histopathology (p < 0.01) were associated with higher rates of tumor relapse and poor 5-year overall survival in multivariable analysis. Lymph node involvement (p = 0.02) also portended poor overall survival after adjustment for other covariates. Although adjuvant therapy was associated with poor clinical outcomes in univariate analysis, it demonstrated a favorable albeit non-significant trend in multivariable analysis. CONCLUSIONS: Factors associated with poor clinical outcomes in this contemporary single-institution study, included perineural invasion, tumor ulceration, and lymph node involvement. No definite conclusion could be made in regards to adjuvant treatment.

Phase I trial of three-weekly docetaxel, carboplatin and oral lenalidomide (Revlimid) in patients with advanced solid tumors.

INTRODUCTION: Lenalidomide is an immunomodulatory derivative of thalidomide with significantly greater in vitro activity and a different toxicity profile. In preclinical trials it has shown synergy with chemotherapy. PATIENTS AND METHODS: Primary objective of this study was to determine the maximum tolerated doses of docetaxel and carboplatin when combined with oral lenalidomide in a standard phase I study design. Between September 2004 and May 2005, 14 patients with pathologically proven solid tumors, < or =2 prior chemotherapy regimens, performance status ECOG 0/1, and adequate organ function were enrolled. Dose limiting toxicities (DLT) were defined as > or = grade 3 non-hematological, or grade 4 hematological toxicity. No growth factors were used during cycle 1. RESULTS: Three of four patients treated at dose level 1, docetaxel 60 mg/m(2) and carboplatin AUC 6 on Day 1, and lenalidomide 10 mg orally daily on Days 1-14 of a 21 day cycle experienced DLT (grade 3 electrolyte changes in two patients, and grade 4 neutropenia in one patient). Ten patients were treated at dose level -1, docetaxel 60 mg/m(2) and carboplatin AUC 6 on Day 1, and lenalidomide 5 mg orally daily on Days 1-14 of a 21 day cycle with one DLT (Grade 4 neutropenia). There were no treatment-related deaths or irreversible toxicities. Of the 14 response-evaluable patients, five achieved a partial response (5 out of 9 patients with non-small cell lung cancer. CONCLUSIONS: Docetaxel 60 mg/m(2) and carboplatin AUC 6 on Day 1, with lenalidomide 5 mg orally daily on Days 1-14 days of a 21 day cycle is the maximum tolerated dose without the use of prophylactic growth factors. This combination is active and further evaluation in a phase II trial is warranted.

Oxaliplatin: a new agent for colorectal cancer.

For nearly 40 years, the medical treatment of colorectal cancer had been limited to the fluoropyrimidines until the recent development of irinotecan (CPT-11). In the past decade, a new agent has appeared, oxaliplatin. This third-generation platinum compound has synergistic activity with 5-fluorouracil and is non-cross-resistant with 5-fluorouracil, CPT-11, and other platinum agents. Numerous clinical trials in Europe have demonstrated the activity of oxaliplatin in patients with untreated and refractory metastatic colorectal cancer. Nevertheless, the US Food and Drug Administration recently denied approval for oxaliplatin as first-line treatment of colorectal cancer because of a lack of clear-cut survival advantage in clinical trials. Additional clinical trials in patients with colorectal cancer are ongoing in the United States and will test the activity of oxaliplatin in the metastatic and adjuvant setting. These studies will define the role for what appears to be a very useful and important agent.

A phase II pharmacodynamic study of pyrazoloacridine in patients with metastatic colorectal cancer.

PURPOSE: To perform a phase II trial of pyrazoloacridine (PZA), a novel DNA intercalator, in patients with metastatic colorectal carcinoma and no previous therapy. METHODS: PZA was administered at a dose of 750 mg/m2 intravenously over 3 h every 21 days. Pharmacokinetic studies to determine PZA plasma concentrations were performed. RESULTS: No responses were seen in 14 response-evaluable patients. Patients received a median of two cycles of PZA (range 1-6). Toxicity included neutropenia and neurologic side-effects, which were > or = grade III in 73% and 14%, respectively. High plasma concentrations of PZA (Cmax) correlated with low neutrophil counts (P = 0.04). CONCLUSIONS: PZA is inactive at this dose and schedule in colorectal cancer, and produces moderately severe toxicity.

Induction of primary cutaneous melanomas in C3H mice by combined treatment with ultraviolet radiation, ethanol and aloe emodin.

The role of ultraviolet (UV) radiation in the induction of nonmelanoma skin cancer is widely accepted, although its precise contribution to the development of primary cutaneous melanoma skin cancer requires further definition. We found that painting aloe emodin, a trihydroxyanthraquinone from Aloe barbadensis, in ethyl alcohol vehicle on the skin of mice in conjunction with exposure to UVB (280-320 nm) radiation results in the development of melanin-containing skin tumors. C3H/HeN mice were treated thrice weekly with aloe emodin in a 25% ethanol in water vehicle and exposed to 15 kJ/m2 UV radiation. Neither ethanol vehicle nor aloe emodin alone induced skin tumors in the absence of UV radiation. In two separate experiments, 20-30% of the mice treated with a combination of UV radiation and ethanol vehicle and 50-67% of the UV-irradiated animals given aloe emodin in ethanol vehicle developed primary cutaneous melanin-containing tumors. The diagnosis of melanoma was established using Fontana silver stain for melanin; these tumors were negative for vimentin and keratin. Melanin-containing melanosomes were observed by transmission electron microscopy in tumors diagnosed as melanomas. Although the mechanism of carcinogenesis in these mice is currently unknown, our findings have led to the development of the first facile murine model for the induction of primary melanoma. This model has the potential to clarify the role of UV radiation in the etiology of malignant melanoma.

Phase II trial of liposomal doxorubicin (Doxil) in advanced soft tissue sarcomas.

PURPOSE: To assess the objective response rate, toxicity experienced, progression-free survival, and overall survival of patients with previously untreated advanced soft tissue sarcomas treated with a liposomal doxorubicin formulation (Doxil). METHODS: Patients with metastatic or recurrent soft tissue sarcoma who had received no prior chemotherapy for advanced disease were treated with liposomal doxorubicin (Doxil) according to a two stage accrual design. Doxil was administered at 50 mg/m2 every 4 weeks. A total of 15 patients were treated and are evaluable for response and toxicity. RESULTS: The male/female ratio was 7/8, the median age was 60 years (34-75) and the ECOG performance status was 0-1 in >90% of patients. Leiomyosarcoma (7/15) and malignant fibrous histiocytoma (2/15) were the most common histologic diagnoses. No objective responses were observed in the 15 evaluable patients. No lethal toxicity occurred. Grade 3-4 leukopenia or neutropenia were reported in 3/15 (20%) patients. Grade 3 mucositis or hand-foot syndrome occurred in 2/15 (13%) and 1/15 (7%) patients respectively and seemed more severe in older patients. The median time to progression was 1.9 months (range 0.9-6.2). Twelve patients have now died. The Kaplan-Meier estimate of median overall survival is 12.3 months. As called for in the study design, accrual was terminated because no responses were obtained in the first 15 patients. CONCLUSION: Though well-tolerated, Doxil given according to this dose and schedule to patients with advanced soft tissue sarcoma had no significant therapeutic activity. A correlation between older age and skin/mucosal toxicity of Doxil is suggested in this study but needs confirmation. Future investigations of Doxil in soft tissue sarcomas should use a different schedule and dose.

Treatment of colon and rectal cancer.

This article discusses multimodal treatment of noncomplicated colon and rectal cancer, considerations for specific types of colon cancer, considerations that may modify the extent and technique of surgery, the role of adjuvant chemotherapy for colon adenocarcinoma and rectal cancer, and surgical treatment of complicated colorectal cancer.

Plants, polysaccharides, and the treatment and prevention of neoplasia.

Plants and Fungi have traditionally been the single largest source of lead compounds for the development of therapeutics by the pharmaceutical industry. Currently mushroom and plant polysaccharides brought to attention by Complementary and Alternative medicine, are undergoing scientific analysis and development to prevent and treat cancer, Two classes of saccharides are under investigation-beta glucan polysaccharides as biological response modifiers for the adjuvant treatment of cancer and "Oligosaccharin"-related oligosaccharides for the prevention of sun-induced skin cancer. Beta glucans already in human trials in the Far East will require mechanistic pharmacologic studies and definition of stucture function relationships before they are ready for clinical trials in the West. Other beta glucans that prime natural killer cells for antibody dependent cell-mediated cytotoxicity are approaching clinical trials. Oligosaccharides that downregulate production of immunosuppressive cytokines by ultraviolet radiation injured keratinocytes are promising agents for the prevention of environmental skin cancer.

Inhibition of UV-induced immune suppression and interleukin-10 production by plant oligosaccharides and polysaccharides.

Application of Aloe barbadensis poly/oligosaccharides to UV-irradiated skin prevents photosuppression of delayed-type hypersensitivity (DTH) responses in mice. We tested the hypothesis that these carbohydrates belong to a family of biologically active, plant-derived polysaccharides that can regulate responses to injury in animal tissues. C3H mice were exposed to 5 kJ/m2 UVB from unfiltered FS40 sunlamps and treated with between 1 pg and 10 micrograms tamarind xyloglucans or control polysaccharides methylcellulose or dextran in saline. The mice were sensitized 3 days later with Candida albicans. Tamarind xyloglucans and purified Aloe poly/oligosaccharides prevented suppression of DTH responses in vivo and reduced the amount of interleukin (IL)-10 observed in UV-irradiated murine epidermis. Tamarind xyloglucans were immunoprotective at low picogram doses. In contrast, the control polysaccharides methylcellulose and dextran had no effect on immune suppression or cutaneous IL-10 at any dose. Tamarind xyloglucans and Aloe poly/oligosaccharides also prevented suppression of immune responses to alloantigen in mice exposed to 30 kJ/m2 UVB radiation. To assess the effect of the carbohydrates on keratinocytes, murine Pam212 cells were exposed to 300 J/m2 UVB radiation and treated for 1 h with tamarind xyloglucans or Aloe poly/oligosaccharides. Treatment of keratinocytes with immunoprotective carbohydrates reduced IL-10 production by approximately 50% compared with the cells treated with UV radiation alone and completely blocked suppressive activity of the culture supernatants in vivo. The tamarind xyloglucans also blocked UV-activated phosphorylation of SAPK/JNK protein but had no effect on p38 phosphorylation. These results indicate that animals, like plants, may use carbohydrates to regulate responses to environmental stimuli.

Recent advances in systemic therapy for gastrointestinal neuroendocrine tumors.

Neuroendocrine tumors of the gastrointestinal tract are rare tumors which can be classified as amine precursor uptake and decarboxylation tumors (APU-Domas). Although the majority of clinically apparent tumors are malignant, they are frequently slow growing. Despite this characteristic, they may generate disabling hormonal syndromes requiring aggressive treatment to achieve palliation. Recent advances in understanding the pathophysiology of these tumors has led to better medical therapy with chemotherapeutic agents, somatostatin analogues, and biologic therapies. This review will update the recent efforts in systemic therapies of the gastrointestinal neuroendocrine tumors.

Aloe barbadensis extracts reduce the production of interleukin-10 after exposure to ultraviolet radiation.

Cutaneous exposure to ultraviolet radiation suppresses the induction of T cell mediated responses such as contact and delayed type hypersensitivity (DTH) by altering the function of immune cells in the skin and causing the release of immunoregulatory cytokines. Extracts of crude Aloe barbadensis gel prevent this photosuppression. Because the regulation of contact hypersensitivity and DTH responses differ, we investigated whether protection was afforded by a single or multiple agents in Aloe and the mechanism by which this material prevents suppression of DTH immunity. The ability of Aloe gel to prevent suppression of contact hypersensitivity responses to hapten decayed rapidly after manufacture. In contrast, agents that protected against systemic suppression of DTH responses to Candida albicans were stable over time. Oligosaccharides prepared from purified Aloe polysaccharide prevented suppression of DTH responses in vivo and reduced the amount of IL-10 observed in ultraviolet irradiated murine epidermis. To assess the effect of Aloe extracts on keratinocytes, Pam 212 cells were exposed in vitro to ultraviolet radiation and treated for 1 h with Aloe oligosaccharides. Culture supernatants were collected 24 h later and injected into mice. Supernatants from ultraviolet irradiated keratinocytes suppressed the induction of DTH responses, whereas Aloe oligosaccharide treatment reduced IL-10 and blocked the suppressive activity of the supernatants. These results indicate that Aloe contains multiple immunoprotective factors and that Aloe oligosaccharides may prevent ultraviolet induced suppression of DTH by reducing keratinocyte derived immunosuppressive cytokines.

Randomized trial of carboplatin plus amifostine versus carboplatin alone in patients with advanced solid tumors.

BACKGROUND: To test the hypothesis that the cytoprotectant amifostine attenuates the thrombocytopenia produced by carboplatin, the authors performed a randomized trial comparing treatment with carboplatin alone versus the combination of amifostine and carboplatin. METHODS: Patients with refractory or carboplatin-sensitive malignancies were randomized to receive either carboplatin, 500 mg/m2 alone or carboplatin, 500 mg/m2 in conjunction with 2 doses of amifostine of 910 mg/m2 each. RESULTS: Fifty-five patients with a variety of malignancies were entered on this study. One patient withdrew from each arm prior to the administration of any therapy, leaving 30 evaluable patients treated with carboplatin alone and 23 treated with the combination of amifostine and carboplatin. For 82 cycles of therapy with amifostine plus carboplatin, the median platelet nadir was 127 x 10(9)/L while the median platelet nadir was 88 x 10(9)/L over the 80 courses of therapy with carboplatin alone (P = 0.023). The median platelet nadir after the first cycle of therapy was 144 x 10(9)/L for patients treated with amifostine plus carboplatin and 85 x 10(9)/L for patients treated with carboplatin alone (P = 0.24). The median survival for 9 patients with advanced nonsmall cell lung carcinoma treated with carboplatin alone was 39 weeks whereas the median survival for 12 such patients treated with amifostine plus carboplatin was 52 weeks (P = 0.116). CONCLUSIONS: These data support the hypothesis that amifostine attenuates the myelosuppression of carboplatin. Additional studies of amifostine in combination with carboplatin-containing chemotherapy regimens are warranted.

Adjuvant therapy for colorectal cancer: present and future perspectives.

In recent years, adjuvant therapy for colorectal cancer has advanced considerably. This article reviews these advances and provides an update of the most recent and ongoing trials. In 1990, adjuvant therapy became the "standard of care" for patients with Stage III colon cancer (Dukes C) in the United States. Recent clinical trial data indicate that adjuvant treatment may also be effective in patients with Stage II (Dukes B2) colon cancer. The combination of 5-fluorouracil plus leucovorin may slightly improve survival (5-10 percent) compared with the standard 5-fluorouracil plus levamisole combination. The three-drug regimen (5-fluorouracil plus levamisole plus leucovorin) is more toxic, with no superior effect on survival. Intraportal chemotherapy, although it may significantly improve patient survival, does not decrease the frequency of liver metastases. However, it is still a promising form of adjuvant therapy owing to its short treatment period and relatively equivalent effects in survival compared with that of systemic therapy. For patients with Stage II or Stage III rectal cancer, postoperative systemic 5-fluorouracil plus radiation therapy plus protracted venous 5-fluorouracil infusion is the most effective postoperative adjuvant regimen. However, results from several studies show that preoperative radiation alone or chemoradiation for advanced local rectal cancers might also be effective while also improving resectability, decreasing morbidity, and increasing the chance that a sphincter-sparing procedure may be performed. The role of leucovorin in rectal cancer remains to be determined. Immune therapies with agents such as interferon-alpha-2a, monoclonal antibody 17-1A, and autologous tumor vaccines are being assessed and could further improve survival.

Recent advances in diagnosis and therapy of neuroendocrine tumors of the gastrointestinal tract.

Neuroendocrine tumors of the gastrointestinal tract are rare tumors that can be classified as APU-Domas (amine precursor uptake and decarboxylation). They can be subdivided into the carcinoid tumors of the gastrointestinal submucosa and the islet cell endocrine tumors of the pancreas. Although the majority of tumors that become clinically apparent are malignant, they are frequently slow growing. Despite this, neuroendocrine tumors may generate disabling hormonal syndromes requiring aggressive treatment to achieve palliation. Recent advances in understanding the pathophysiology of these tumors has led to better radiographic imaging and more accurate localization techniques. Medical therapies with somatostatin analogues, omeprazole, and locoregional tumor ablation have made a positive impact on curative and palliative therapy. This review updates the recent efforts made in the radiographic imaging and therapeutics of the gastrointestinal neuroendocrine tumors.

Role of chemotherapy in the palliation of gastrointestinal malignancies.

In 1994, more than 200,000 patients in the United States were diagnosed with colon, gastric, or pancreatic cancer. Over half of these patients eventually will have recurrent, incurable disease and require palliative therapy. Although chemotherapy has no role in the primary treatment of most gastrointestinal cancers, and only a limited role as a form of adjuvant treatment in colon cancer, it is sometimes the only systemic treatment available for palliation. Effective chemotherapeutic agents for gastrointestinal cancers are few, and after more than three decades of research, 5-fluorouracil remains one of the few useful agents. This article reviews the role of chemotherapy in palliative therapy for the common gastrointestinal cancers. Discussion also includes recent advances in modulating 5-fluorouracil activity and the many attempts to study newer agents.

A minor tyrosine phosphorylation site located within the CAIN domain plays a critical role in regulating tissue-specific transformation by erbB kinase.

Avian c-erbB encodes a protein that is homologous to the human epidermal growth factor receptor. Truncation of the amino-terminal, ligand-binding domain of this receptor results in an oncogene product which is a potent inducing agent for erythroleukemias but not fibrosarcomas in chickens. Here we show that mutation of a single tyrosine residue, p5, in the carboxyl terminus of the erbB oncogene product allows it to become sarcomagenic in vivo and to transform fibroblasts in vitro. Mutations of other autophosphorylation sites do not generate comparable effects. The increased transforming activity of the p5 mutant is accompanied by an elevated level of mitogen-activated protein kinase phosphorylation. By analogy to the human epidermal growth factor receptor, p5 is a minor autophosphorylation site and is located in a domain known to be involved in regulating calcium influx and receptor internalization (CAIN domain). This area of the erbB product has been found to be repeatedly deleted in various sarcomagenic avian erythroblastosis virus isolates. We precisely deleted the CAIN domain and also made point mutations of the acidic residues within the CAIN domain. In both cases, fibroblast-transforming potential is activated. We interpret these data to mean that p5 and its surrounding region negatively regulate fibroblast-transforming and sarcomagenic potential. To our knowledge, this represents the first point mutation of an autophosphorylation site that activates erbB oncogenicity.

Amifostine: potential for clinically useful cytoprotection.

The ability to target malignant cells for cytotoxicity while sparing normal host tissues has proven to be limited. These limitations have resulted in unacceptable toxicity or insufficiently effective therapy. Continuing investigation of new, potentially useful cytotoxic agents must continue. An alternative approach, also worthy of study, is the selective protection of normal tissues. This approach, used in conjunction with available therapeutic agents, may open the therapeutic window and incrementally enhance the effectiveness of cytotoxic therapy. A variety of methods have been used to protect normal tissues selectively. Regional protection can be used for certain organ systems, such as the oral mucosa. Selective protection on a systemic level is more difficult but agents that seem to protect normal but not malignant tissues selectively are being developed. Among these is amifostine, which was originally selected by the U.S. defense department for study as a radioprotectant. Pre-clinical studies have suggested that amifostine is differentially concentrated in normal tissues but not in malignant tissues. Tissue-specific differences in the activity of alkaline phosphatase, which dephosphorylates amifostine to its active metabolite WR-1065, and in pH are thought to be involved in this relative specificity. Clinical studies indicate that amifostine can reduce the myelosuppression produced by cyclosphosphamide, the combination of cyclophosphamide and cisplatin, and, perhaps, carboplatin. The protective effects of amifostine on nonhematopoietic toxicities are being investigated. Future trials will investigate the integration of amifostine with cytokine-based supportive care in order to define the role of this potentially clinically useful cytoprotectant agent.

Modulation of erbB kinase activity and oncogenic potential by single point mutations in the glycine loop of the catalytic domain.

Avian c-erbB is activated to a leukemia oncogene following truncation of its amino-terminal ligand-binding domain by retroviral insertion. The insertionally activated transcripts encode protein products which have constitutive tyrosine kinase activity and can induce erythroleukemia but not sarcomas. We have previously found that a valine-to-isoleucine point mutation at position 157 (V157I mutant) within the tyrosine kinase domain of this truncated erbB can dramatically activate the sarcomagenic potential of the oncogene and increase the kinase activity of this oncoprotein. This mutation lies at position 157 of the insertionally activated c-erbB product, affecting a highly conserved valine residue of the glycine loop involved in ATP binding and phosphate transfer. To investigate the functional importance of this residue in the catalytic activity of kinases, we have introduced at this position, by site-directed mutagenesis, codons representing the remaining 18 amino acid residues. Most of the mutants have diminished activity, with six of them completely devoid of kinase activity, indicating the sensitivity of this region to conformational changes. Some of these mutants displayed increased kinase activity and greater transforming potential in comparison with IA c-erbB, but none had levels as high as those of the V157I mutant. In general, the sarcomagenic potential of the various erbB mutants correlated with their autophosphorylation state and their ability to cause phosphorylation of MAP kinase. However, there are important exceptions such as the V157G mutant, which lacks enhanced autophosphorylation but is highly sarcomagenic. Studies of this and other autophosphorylation site mutants point to the existence of an autophosphorylation-independent pathway in sarcomagenesis. The requirement for leukemogenic potential is much less stringent and correlates with positivity of kinase activity. When the valine-to-isoleucine substitution was put in context of the full-length erbB protein, the mutation relaxed the ligand dependence and had a positive effect on the transforming potential of the full-length c-erbB.