Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

6 patients with cutaneous malignant melanoma and multiple secondary cutaneous lesions were treated with intralesional methanol extraction residue of bacillus Calmette Guerin (MER-BCG). Separate lesions were injected with purified protein derivatives (PPD) in 5 of the study patients. 5 of the 6 MER-BCG injection lesions developed marked inflammation clinically. Excisional biopsy 7-14 days later demonstrated complete dissolution of tumor in 2 patients and was accompanied by infiltration with acute and chronic inflammatory cells; 3 lesions revealed necrosis with residual tumor, and in 1 patient there was no apparent host response. Clinical tumor regression was not observed with PPD applied intralesionally, although histopathologic analysis revealed a granulomatous inflammatory response in 3 of 5 patients. No patient demonstrated regression of uninjected cutaneous lesions (4 evaluable patients) or visceral lesions (2 patients). The critical determinants of tumor regression are the size, site and depth of the lesion in relationship to the cutaneous surface. The mechanism of tumor eradication may be related to 'innocent bystander' necrosis secondary to nonspecific inflammation rather than immunologically mediated via host sensitization.
 ...
PMID:Intralesional immune therapy: methanol extraction residue of BCG or purified protein derivative. 48 45

Experimental and clinical observations of the proliferation of cancer cells and their responses to cytotoxic drugs already have had an impact on the design of anticancer therapies and it is possible that further understanding of the natural history of tumors will enable better treatments to be developed. This review addresses several approaches to improving the prognosis for patients with breast cancer in which our understanding of tumor dynamics plays an important role. Increasing dose intensity can be achieved by dose escalation (increasing the amount of drug) or increasing dose density (reducing the time between treatments). The Gompertzian model of tumor growth, which is concordant with many experimental and clinical observations, can offer an explanation why, although dose escalation improves the number of clinical responses, cure is still uncommon. In the Gompertzian model, smaller tumors grow faster, so tumor regrowth between treatment cycles is more rapid when cell kill is greatest. Reducing the time available for tumor regrowth (increasing dose density), which is now possible through the use of colony-stimulating factors to hasten hematopoietic recovery, may have a greater impact on clinical outcome than dose escalation. Sequential schedules allow optimal doses to be used in dose-dense cycles. Several cycles of the optimal dose of agent A, followed by several cycles of the optimal dose of agent B, may be more effective than the simultaneous combination of suboptimal doses of A and B. In this context, agents A and B may be single agents or established combinations. This tactic allows new agents, such as the taxoids, to be used in conjunction with established therapies, such as doxorubicin plus cyclophosphamide, at optimal doses in dose-intensive regimens. Although such regimens may maximize cytoreduction, this may not be sufficient to improve significantly the long-term outcome for patients with breast cancer. A recent trial using high-dose consolidation chemotherapy with autologous bone marrow support has thrown doubt on the assertion, implicit in Gompertzian cytodynamics, that optimal cytotoxic therapy can kill all tumor cells. The results of this trial suggest that a consistent number of tumor cells remain whether high-dose chemotherapy with autologous bone marrow support is used in patients in complete pathologic remission or in patients with overt relapse. If there is a lower limit to cytoreduction, other approaches must be developed to control or prevent the regrowth of residual tumor cells. This will require a better understanding of the molecular biology of breast cancer and the ability to predict and assess the sensitivity of individual patient's tumors to particular therapies. Factors such as HER2 overexpression are already being linked to sensitivity to particular agents and the products of oncogenes such as HER2 may be targeted by biologic therapies such as monoclonal antibodies. Furthering our understanding of the biology and behavior of tumor cells may lead to significant improvements in the long-term prognosis for patients with early and advanced breast cancer.
 ...
PMID:Evolving concepts in the systemic drug therapy of breast cancer. 927

A large number of oncogenes have been identified as aberrant in gliomas, but only the erbB oncogene (gene encoding the epidermal growth factor receptor [EGFR]) is amplified in an appreciable number. The loss or mutation of tumor-suppressor genes located on different autosomes may be associated with progression of malignant gliomas. The p53 tumor-suppressor gene (located on chromosome 17) is frequently associated with the loss of one allele in malignant gliomas, although a large number of malignant gliomas have no p53 mutations. Some of the latter tumors have an amplified murine double minute 2 (MDM2) gene, which suppresses p53 gene activity. Genetic material from chromosome 10 may also be lost, especially in glioblastoma multiforme. In addition to the aberrant expression of EGFR, another growth factor, platelet-derived growth factor, or PDGF (ligand and/or receptors) can be overexpressed, giving cells a selective growth advantage. The blood-brain barrier is substantially altered in malignant gliomas, resulting in cerebral edema. Therapy for malignant gliomas includes surgery, radiation therapy, and chemotherapy. Surgical resection that leaves little residual tumor produces longer survival than less vigorous surgery. Radiation therapy to a dose of at least 60 Gy is required to treat malignant gliomas. Increased survival beyond that produced by standard external radiotherapy requires much larger doses; interstitial radiotherapy permits such dosing. Radiosurgery is being tested. Chemotherapy with nitrosoureas is modestly useful but appears to benefit patients with anaplastic astrocytoma more so than those with glioblastoma.
 ...
PMID:Biology and treatment of malignant glioma. 950 24

Neoplastic meningitis (NM) results from leptomeningeal dissemination of cancers arising within the central nervous system or metastasizing to the leptomeninges from systemic neoplasms. The inability to produce therapeutic drug levels intrathecally (i.t.) with systemic administration and the minimal efficacy of chemotherapeutic agents currently available for direct i.t. use limit therapy. Temozolomide [8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4([3H])-one] is a novel methylating agent with proven activity against intraparenchymal malignant gliomas (MGs). Insolubility of the standard formulation prevents its efficacious use as an i.t. agent, however. To overcome this obstacle, we have developed a unique microcrystalline formulation of temozolomide with greatly enhanced solubility. Treatment of athymic rats bearing subarachnoid MER- human MG xenografts with four doses of i.t. microcrystalline temozolomide over a 2-week period produced a 142% increase in median survival at individual doses of 2.2 micromol (P = 0.0073) and a >367% increase in median survival at individual doses of 6.8 micromol (P = 0.0015). At the higher dose tested, three of eight rats treated developed no neurological symptoms and had no evidence of residual tumor on histological examination after treatment. Use of this microcrystalline formulation in athymic rats bearing subarachnoid MER+ human MG xenografts increased median survival >132% (P < 0.0058) at both dose levels tested. Toxicity directly attributable to the i.t. administration of microcrystalline temozolomide was exhibited in the highest dose groups only and was limited to small patchy areas of focal demyelination involving <5% of spinal cord long tracks.
 ...
PMID:Treatment of neoplastic meningitis with intrathecal temozolomide. 1035 55

Some investigators have found an increased incidence of papillary carcinoma (PC) of the thyroid in patients with Hashimoto's (autoimmune) thyroiditis (HT), which raises the possibility that there may be more than an incidental association between these 2 diseases. In this study, we analyzed the pathology of Hashimoto's-associated thyroid carcinomas to see if these tumors showed any distinctive features. The possible significance of solid cellular nodules as preneoplastic lesions in patients with HT was investigated. A review of all the cases of HT during a 16-year period yielded 30 PC and 3 follicular carcinomas (FC). Within the PC there were 7 (23%) follicular variants. Twenty (67%) of the PC showed various degree of intratumoral fibrosis, ranging from thick fibrous septa separating tumor nodules to almost complete obliteration of the tumor by the fibrosis, with only microscopic residual tumor nests. In most of the cases, the desmoplastic response within the tumors was of the fibromatosis-like type with dense hyalinized collagen and bland-appearing spindle cells. All the tumors, independently of the degree of fibrosis, showed the nuclear features of PC. No correlation was found between the degree of fibrosis in the tumors and the thyroid gland outside the tumors. There were tumors with marked fibrosis without fibrosis outside the tumors. Four cases of PC (13%) showed a growth pattern characterized by cystic spaces with thick hyalinized walls and focal papillary hyperplasia lined by flat and cuboidal epithelium, reminiscent of a vascular neoplasm. There were 4 atypical solid microscopic nodules with confluent cellularity; 2 of them associated with a PC and the other 2 with diffuse HT without PC. These nodules were composed of cells with clear nuclei and occasional grooves without nuclear pseudoinclusions. By immunohistochemistry, 2 of 3 nodules showed cytoplasmic reactivity for cytokeratin 19, and 2 of 3 nodules were positive for the RET/PTC (rearranged during transfection, papillary thyroid carcinoma) antibody. In summary, HT-associated PC may frequently display prominent stromal desmoplasia and a pseudovascular pattern, both of which can present diagnostic difficulties if the cytologic features of PC are not recognized because of the marked obliteration of the tumor by the fibrosis. Atypical nodules may represent a precursor lesion of PC in patients with HT.
 ...
PMID:Pathologic features of Hashimoto's-associated papillary thyroid carcinomas. 1117 91

HER2 is an attractive immunotherapeutic target for neoplastic disease because this cell surface molecule is overexpressed on a large fraction of malignant tumor cells. To directly assess therapeutic responses to targeted therapy by noninvasive in vivo imaging in small animals, human HER2-expressing ovarian carcinoma cells were genetically modified with a firefly luciferase gene, and light emission was used for visualization of tumor growth and response to therapy. This imaging approach was able to demonstrate in real-time tumor regression in a HER2 xenograft mouse model by adoptive transfer of in vitro induced and expanded cytotoxic CD8+ natural killer T (NKT) cells retargeted with a humanized bispecific antibody F(ab')(2)HER2xCD3. Immunotherapy with effector cells alone or a humanized monoclonal antibody anti-p185(HER2) (4D5-8) resulted in significant but slower reduction in tumor burden. Long-term survival of tumor xenografts correlated inversely with visible residual tumor burden. In vitro, F(ab')(2)HER2xCD3 substantially augmented cytotoxic activity of CD8+ NKT cells. By flow-sorting, CD8+ NKT cells coexpressing CD56 were found to have the highest redirected killing ability. Treatment with concanamycin A or EGTA abrogated CD8+ NKT cytotoxicity indicating that perforin is a major pathway of tumor cell lysis. In contrast, when CD8+ NKT cell were cross-linked with F(ab')(2)HER2xCD3 neither the immunosuppressants cyclosporine A and FK506, nor the increase of intracellular cyclic AMP by dibutyryl cyclic AMP were able to inhibit cytotoxicity demonstrating that signaling via the CD3 antigen changes the biological activity of non-MHC-restricted effector cells. These studies have demonstrated that CD8+ NKT cells can be successfully redirected to tumor cells using bispecific antibodies and offer a promising strategy for adoptive immunotherapy of neoplastic diseases.
 ...
PMID:Visualization of effective tumor targeting by CD8+ natural killer T cells redirected with bispecific antibody F(ab')(2)HER2xCD3. 1238 39

Although the majority of mesenchymal lesions of the gastrointestinal tract are neoplastic in nature, nonneoplastic reactive processes may involve the gastrointestinal tract and mesentery, causing diagnostic confusion with more aggressive neoplasms, such as fibromatosis or gastrointestinal stromal tumors. In this study, we report a series of fibroinflammatory lesions of the gastrointestinal tract that we think represent a relatively cohesive group of tumors and describe the clinical and pathologic features of this entity, which we have termed "reactive nodular fibrous pseudotumor." The tumors affected five patients (four male and one female patient) who ranged in age from 48 to 71 years (mean 56 years). Two patients presented with acute abdominal pain without a significant past medical history, two had incidental lesions discovered during evaluation for other medical conditions, and one was found to have an abdominal mass. Three patients had a history of abdominal surgery. The tumors were multiple in three patients and solitary in two patients. In four cases, at least one of the tumors involved the small intestine or colon, and the lesion was confined to the peripancreatic soft tissue in one case. The tumors were firm, tan-white, ranged in size from 4.3 to 6.5 cm in greatest dimension, and were grossly well circumscribed. All of the lesions were of low to moderate cellularity and composed of stellate or spindled fibroblasts arranged haphazardly or in intersecting fascicles. Three cases had microscopically infiltrative borders. The stroma was rich in collagen, which was wire-like, keloidal, or hyalinized. Intralesional mononuclear cells were sparse but were more numerous peripherally and frequently arranged in lymphoid aggregates. Immunohistochemical stains demonstrated that all of the tumors stained for vimentin, 80% stained for CD117 or muscle specific actin, 60% stained for smooth muscle actin or desmin, and none of the tumors stained for CD34, S-100 protein, or anaplastic lymphoma kinase-1. Follow-up information was available in all cases: four patients had no residual disease following surgical resection (mean follow-up 16.3 months) and one patient who had an incomplete surgical resection had stable disease at 26 months. In summary, we report a series of distinct intraabdominal fibroinflammatory pseudotumors that we have collectively termed "reactive nodular fibrous pseudotumors." These lesions are uncommon and may infiltrate the bowel wall, thereby mimicking primary bowel neoplasms or intraabdominal fibromatosis. Recognition of these nonneoplastic lesions is important, as they pursue a benign clinical course, but may be confused with other mesenchymal neoplasms that require more aggressive treatment.
 ...
PMID:Reactive nodular fibrous pseudotumor of the gastrointestinal tract and mesentery: a clinicopathologic study of five cases. 1510 9

TP-38 is a recombinant chimeric targeted toxin composed of the EGFR binding ligand TGF-alpha and a genetically engineered form of the Pseudomonas exotoxin, PE-38. After in vitro and in vivo animal studies that showed specific activity and defined the maximum tolerated dose (MTD), we investigated this agent in a Phase I trial. The primary objective of this study was to define the MTD and dose limiting toxicity of TP-38 delivered by convection-enhanced delivery in patients with recurrent malignant brain tumors. Twenty patients were enrolled in the study and doses were escalated from 25 ng/mL to 100 with a 40 mL infusion volume delivered by two catheters. One patient developed Grade IV fatigue at the 100 ng/mL dose, but the MTD has not been established. The overall median survival after TP-38 for all patients was 23 weeks whereas for those without radiographic evidence of residual disease at the time of therapy, the median survival was 31.9 weeks. Overall, 3 of 15 patients, with residual disease at the time of therapy, have demonstrated radiographic responses and one patient with a complete response and has survived greater than 83 weeks.
 ...
PMID:Progress report of a Phase I study of the intracerebral microinfusion of a recombinant chimeric protein composed of transforming growth factor (TGF)-alpha and a mutated form of the Pseudomonas exotoxin termed PE-38 (TP-38) for the treatment of malignant brain tumors. 1464 83

Successful treatment of MTC depends heavily on early diagnosis and treatment. Often, this is not possible for sporadic MTC; however, genetic testing for hereditary MTC makes this possible if genetic carriers have surgery before C cells undergo malignant transformation. All patients who have MTC should be tested for RET mutations, including putative sporadic cases. The leukocytes of suspected carriers and sporadic MTC cases should be tested for MEN2-associated germ-line mutations by polymerase chain reaction amplification of the appropriate RET gene exons, including 10, 11,13, 14, 15, and 16 (see Table I). When a RET mutation is found, all first-degree relatives must be screened to determine which individuals carry the gene. If these exons are negative, the other 15 should be sequenced because a small risk of hereditary MTC remains if no germ-line mutation is found. The probability that a first-degree relative will inherit an autosomal dominant gene for MTC from an individual who has sporadic MTC in whom no germ-line mutation is found is 0.18% . Patients who have MEN2B or RET codon 883 or 918 mutation should have a total thyroidectomy within the first 6 months of life, preferably within the first month of life. Patients who have 634 mutations, which account for approximately 70% of all MTC mutations, should undergo thyroidectomy by age 5 years. The recommendations for the timing of prophylactic thyroidectomy are not consistent for the less common mutations (see Table 2). There is a balance between performing prophylactic thyroidectomy earlier than at the youngest age at with MTC has been reported to occur for a specific RET mutation (see Fig. 3 and Table 2) and the complications of thyroidectomy, including permanent hypoparathyroidism and laryngeal nerve damage. Preoperative measurement of plasma free metanephrine and neck ultrasonography always should be done if the diagnosis of MTC is known preoperatively. Initial treatment of MTC is total thyroidectomy, regardless of its genetic type or putative sporadic nature, because surgery offers the only chance for a cure. Treatment with 1311 has no place in the management of MTC. Plasma CT measurements provide an accurate estimate of tumor burden and are especially useful in identifying patients who have residual tumor. Pentagastrin- or calcium-stimulated plasma CT testing is useful in identifying CCH or early MTC in carriers of RET mutations that are associated with late onset MTC. Pheochromocytoma may occur before or after MTC and is an important cause of mortality, even in young patients. HPT is an important aspect of MEN2A and requires surgery according to current guidelines for the management of primary HPT. Early thyroidectomy and appropriate management of pheochromocytoma clearly have modified the course of this disease, but more research is necessary in kindreds who have rare MTC mutations. Moreover, new treatments for widespread MTC are necessary because current chemotherapy agents offer little benefit. New drugs that lock the action of tyrosine kinase offer some hope.
 ...
PMID:Diagnosis and management of medullary thyroid carcinoma. 1515 57

Length mutations within the FLT3 gene (FLT3-LM) can be found in 23% of acute myeloid leukaemia (AML) and thus are the most frequent mutations in AML. FLT3-LM are highly correlated with AML with normal karyotype and other cytogenetic aberrations of the prognostically intermediate group. This group is supposed to be a mixed group of AML with differences in the underlying pathogenesis. For more individualized treatment options it would be helpful to better characterize this large AML group not only by molecular mutations but also use these markers for the definition of minimal residual disease (MRD). However, so far the cytogenetically intermediate AML has been lacking suitable markers for PCR-based MRD detection like the fusion genes in the prognostically favourable subgroups. The suitability of the FLT3-LM as a target for PCR-based MRD was discussed controversially as it seemed to be a rather unstable marker. Thus, we aimed at the evaluation of FLT3-LM as a marker for residual disease in a large cohort of AML. Paired samples of 97 patients with AML at diagnosis and at relapse were analyzed. It could be shown that in only four cases a loss of the length mutation was detected. This is in the range of other well-characterized AML relapsing with a different geno- and/or phenotype. In contrast, a change in the ratio of the mutated allele in comparison to the wild-type allele was frequently observed. In detail, the FLT3-LM showed a tendency to accumulate during disease progression and was found more frequently at relapse than at diagnosis. In addition, 45 patients were analyzed at different time points during and after therapy. Using conventional PCR it clearly could be shown that for most of the patients positive at presentation FLT3-LM is a reliable PCR marker for monitoring treatment response. Even an early detection of relapse was possible in some cases.
 ...
PMID:FLT3 length mutations as marker for follow-up studies in acute myeloid leukaemia. 1517 6


1 2 3 4 5 6 7 8 9 10 Next >>