Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Judging from recent data, heritable forms account for 30-40% of pheochromocytomas. The molecular basis for the familial pheochromocytoma has been largely elucidated and the role of germline mutation of the VHL, RET, SDHB, and SDHD genes has been established. However, on genotyping a group of 172 sporadic or familial pheochromocytomas, we characterized four unrelated probands with familial pheochromocytomas without any sequence variants of RET (exons 8, 10, 11, 13, 14, 15, and 16) or the entire coding sequence of VHL, SDHB, SDHC, SDHD, and EGLN3 (exon-intron boundaries included). The proband of family 1 is a man who had a bilateral pheochromocytoma at the age of 32 and a local recurrence at the age of 48 years. His brother died of malignant pheochromocytoma and his nephew died suddenly of an undiagnosed pheochromocytoma. The proband of family 2 is a female who had a 5-cm benign adrenal pheochromocytoma at the age of 34 years, while her cousin (maternal branch) had a monolateral pheochromocytoma at the age of 42 years. No other tumors had been reported in either family. The proband of family 3 is a female who had a bilateral pheochromocytoma at the age of 66 years. Her sister had a bilateral pheochromocytoma and breast cancer at the age of 54 years. Several other tumors were recorded in this family, including laryngeal cancer, leukemia, and a case of medullary thyroid carcinoma (MTC) in one brother. MTC was naturally ruled out in the proband and her sister. In family 4, the proband was a female who had a bilateral pheochromocytoma at the age of 46 years and a local recurrence a few years later, with liver metastases from the pheochromocytoma. Her brother had a monolateral benign pheochromocytoma. The proband also had a melanoma and bilateral renal cysts. This case revealed a VHL sequence variant IVS2+43 A>G, which was also found in one other unrelated sporadic pheochromocytoma. VHL mRNA integrity is currently being evaluated. The proband had no cerebellar or spinal NMR findings or retinal alterations. In family 5, the proband was a female who had a right adrenal pheochromocytoma at the age of 50 years and a breast cancer at 49 years of age. Her mother had had a right adrenal pheochromocytoma at 61 years of age. Although other molecular mechanisms, such as particular variants in untranslated regions or partial gene deletions, cannot be ruled out, we think finding families with nonsyndromic pheochromocytoma without any RET, VHL, SDHB, SDHC, SDHD, or EGLN3 mutation may argue in favor of the presence of other pheochromocytoma susceptibility genes.
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PMID:Familial nonsyndromic pheochromocytoma. 1710 81

Patients with metastatic breast cancer to the liver are generally considered to have a poor prognosis. The purpose of this study was to identify factors contributing to long term survival in 11 patients who were 35 76 years old at the time of diagnosis with liver metastasis, and survived for 5 years. No patients were treated with a standard systemic chemotherapy alone. All of the 11 patients received OK 432 combined adoptive immunotherapy (OK-AIT), 5 underwent hepatectomy as an additional local therapy, and 2 were additionally treated by hepatic arterial infusion chemotherapy. The liver was the primary and secondary sites of metastasis in 8 and 3 of the 11 patients, respectively. In all of the 128 patients given OK-AIT at 5 years after diagnosis, the 5-year survival rates with primary and secondary liver metastases were 11.8. and 5%, respectively. Hormone receptors (HR) were undetermined in 4 patients, positive in 6, and negative in 1 patient, who was also positive for HER2. To determine the relationships among the prognosis of the liver metastasis, AIT indications, HR, and HER2, we analyzed our 139 liver metastasis patients encountered in 2001 and onwards. Fifty-one patients with primary liver metastasis had a median survival time (MST) of 31 months, and a 5-year survival rate of 25%, indicating an improved prognosis. In particular, a MST of 50 months (n=18) in HR (+), HER2 (-) patients was in sharp contrast to the poor prognosis (a MST of 6 months, n=2) in HR (-) HER2 (-) patients. HER2 (+) patients had a MST of 27 months (n=31). Eighty-eight patients with secondary liver metastasis had a MST of only 11 months and a 5-year survival of only 6%; however, the MST in these patients showed the same tendency as in the primary liver metastasis patients: ER (+) HER2 (-) >HER2 (+) >HR (-) HER2 (-) (17, 13, and 4 months, respectively). The response rates of OK-AIT in the primary and secondary liver metastasis patients were 52 and 34%, respectively, showing no significant difference. However, there was a significant difference in the response rate between the HR (+) and HR (-) patients, at 52 and 12%, respectively (p=0.0041). Of the patients in the past, 18 with primary liver metastasis underwent hepatectomy in combination with OK-AIT. Of these 18 patients, 5 had concurrent metastases to other sites, but achieved a 5-year survival rate of 56%, suggesting that it is incorrect to conclude that patients with liver metastasis have generally a poor prognosis. Key
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PMID:[Analysis of long-term (5-year) survival in patients with metastatic breast cancer to the liver]. 1721 6

We report on a patient with rectal malignant melanoma. The patient was a 40-year-old man who complained of anal bleeding. His grandmother had died of pancreatic cancer and his mother had been operated for rectal cancer. Physical examination revealed a hard mass at the 12 o'clock position, 2 cm from the anal verge. A colonoscopic examination revealed an irregular surface mass, approximately 4.0 cm in size, located on the anterior wall of the lower rectum. A biopsy of the rectal tumor showed the proliferation of epithelioid cells with pleomorphic features. Immunohistochemical analysis was performed. S-100 protein, CD-56, and KIT expression were positive, but HMB-45 expression was negative. Abdominopelvic computed tomography (CT) revealed multiple liver and lymph node metastases. With the diagnosis of neuroendocrine carcinoma of the rectum, abdominoperineal resection was performed. After the operation, the serum lactate dehydrogenase level had rapidly increased. An abdominal CT showed progressive liver metastases. Thirteen days after the surgery, abdominal angiography was performed, which showed multiple hypervascular tumor stains in the liver. The reservoir was implanted transcutaneously with the aid of angiography and the catheter was fixed to the proper hepatic artery. Neoadjuvant chemotherapy using cisplatin and irinotecan via the subcutaneous reservoir port was performed and a partial response was obtained. However, the final pathological diagnosis of the surgically resected specimen was malignant amelanotic melanoma of the rectum. Immunohistochemical expression differed between rectal biopsy specimens and surgically resected specimens. HMB-45 expression was positive and KIT expression was negative in the resected specimen. As preoperative pathological diagnosis showed rare rectal tumor, we measured the chemosensitivity of the rectal tumor using the collagen gel droplet-embedded culture drug sensitivity test (CD-DST) to determine the most appropriate chemotherapy regimen for the patient. However, there were no anticancer drugs tested by CD-DST for malignant melanoma. With informed consent, the patient received two cycles of immunochemotherapy consisting of dacabazine, nimustine hydrochloride, vincristine sulfate, and interferon -beta. Although the patient was treated with immunochemotherapy for metastatic liver tumor, he died because of progression of metastases.
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PMID:Case of rectal malignant melanoma showing immunohistochemical variability in a tumor. 1796 34

We report the case of a woman with HER2-positive metastatic breast cancer who achieved prolonged complete remission of multiple liver metastases after treatment with weekly trastuzumab plus paclitaxel but relapsed in the brain soon after stopping trastuzumab maintenance therapy which had been prosecuted for almost three years. In the absence of randomized trials, the optimal duration of trastuzumab administration after achieving complete remission of metastatic breast cancer remains questionable.
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PMID:When should trastuzumab be stopped after achieving complete response in HER2-positive metastatic breast cancer patients? 1803 83

Signalling pathways that emerge from EGFR activation are critical in colon cancer (CC) biology. Its targeting with specific drugs has opened a new window in the treatment of this disease. In this regard, monoclonal antibodies (mAb) have evidenced a high degree of efficiency opposed to the uselessness of tyrosine-kinase inhibitors. Cetuximab is the mAb that has evidenced most activity in CC. After its initial approval as an irinotecan-resistance reversal agent, cetuximab has demonstrated its efficiency from the first line to heavily pretreated patients. In the first line, its addition may increase response rate to chemotherapy, improving liver metastases resection rate. Another promising approach has been suggested from combination schedules with bevacizumab. Panitumumab has been recently approved for CC. Although there is limited clinical experience, the latest data have confirmed its activity in heavily pretreated patients resulting in a clinical benefit vs. best support care. In spite of the clinical benefits, adverse events and the high sanitary cost derived from these drugs force the selection of patients with the highest probability of benefit. At the moment, when EGFR expression evidenced by immunohistochemistry has no value, skin toxicity and, fundamentally, K-Ras mutations may hint at critical information for confirmatory prospective studies.
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PMID:EGFR and colon cancer: a clinical view. 1820 87

Constitutive activation of KIT receptor tyrosine kinase is a critical factor in the pathogenesis of gastrointestinal stromal tumors. Imatinib mesylate (IM, Glivec), a selective tyrosine kinase inhibitor, has been shown in clinical studies to work against such tumors. But there is little information on whether combination of IM and surgical treatment can prolong survival in cases with unresectable multiple liver metastases. We report a case of successful treatment of huge peritoneal metastasis from duodenal gastrointestinal stromal tumor resistant for IM. Therefore, we discuss some important implications. This 41-year-old Japanese man underwent a pancreaticoduodenectomy for GIST of the duodenum in January 2003. The postoperative course was good at first, but 3 months after the initial operation, MRI showed multiple liver metastases. The patient was treated with 400 mg of IM once daily with only weak liver dysfunction as a side effect. The initial response to treatment of CR continued for 20 months. Then huge mass of rt. abdomen appeared and gradually increased in size. Examination revealed that this mass is recurrent of peritoneal metastasis of the GIST. Extirpation was performed and this huge mass was recurrent GIST from omentum. Currently, IM is the first-line therapy for non-resectable GISTs, but a single agent therapy often leads to tumor resistance. IM-resistant GIST are treated with combination of novel molecular targeted-drug, RF, TAE, however, the effect is not enough. Surgical treatment is one of the successful treatments of huge peritoneal metastasis from duodenal gastrointestinal stromal tumor resistant for IM. Further examination in more cases of recurrent GIST is also necessary to estimate the effectiveness of treatment with IM.
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PMID:[Successful treatment of huge peritoneal metastasis from duodenal gastrointestinal stromal tumor resistant for imatinib mesylate]. 1821 26

Systemic chemotherapy has limited success in treating liver metastasis of colorectal cancer. Alternative approaches such as hepatic arterial infusion or trans arterial chemoembolisation aim to deliver the chemotherapy locally to address the predominant liver disease. Chemoembolisation with drug eluting beads (DEB) designed to deliver drug at the target over a protracted period of time is a new strategy to reduce the tumor burden of liver metastases. To test this hypothesis, DEB possessing anionic groups capable of ionically complexing with cationic drugs were synthesised by a suspension polymerisation method and were fractionated to produce an average size of 75 microm. The DEB were loaded with the desired concentration of either doxorubicin hydrochloride or irinotecan hydrochloride prior to administration by immersion in the drug solution, yielding essentially 100% loading efficiency. To determine their effect in vivo, a transplantable orthotopic and isogenic rat liver metastasis model was used which is based on intraportal injection of 4 x 10(6) beta-galactosidase transfected CC531 rat colorectal cancer cells into male WAG/Rij rats. By MTT assay, the cells were shown to be sensitive to both drugs in vitro with the IC(50) being by two orders of magnitude lower for doxorubicin (110 nM after 72 h) compared to irinotecan (25 microM after 72 h). For the in vivo phase, a differential expression of the ERK MAP kinase between tumor cells cultured in vitro and those inoculated in vivo was noted using Western blotting techniques. This was considered to be indicative of passage-induced cell senescence that reduced the sensitivity of the tumor cells to DEB chemoembolisation. This notwithstanding, administration of DEB loaded with irinotecan or doxorubicin by single injection into the hepatic artery showed significant anticancer activity, as measured by a reduction in the tumor burden of the liver and a corresponding reduction in liver weight. Comparing the two agents, irinotecan appears more advantageous because of its significant activity and excellent tolerability following administration at two dosages of either 20 or 30 mg/kg. Doxorubicin showed a narrower window of activity, being effective at 4 mg/kg but ineffective at the lower dose of 2 mg/kg. We conclude that chemoembolisation with DEB with either agent may have potential for treating patients with colorectal liver metastasis, although irinotecan DEB appeared to have a more favourable safety profile.
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PMID:Chemoembolisation of rat colorectal liver metastases with drug eluting beads loaded with irinotecan or doxorubicin. 1825 82

The presence of invasive micropapillary component has been reported to be associated with salivary duct carcinoma and poor outcomes. Herein is described a rare case of invasive micropapillary salivary duct carcinoma of the parotid gland in a 60-year-old man. The micropapillary component was approximately 70% of the area of the tumor. Squamous differentiation was focally seen adjacent to the micropapillary component. On immunohistochemistry the ordinary salivary duct carcinoma component was positive for gross cystic disease fluid protein-15 (GCDFP-15), androgen receptor (AR), and HER2/neu, whereas both micropapillary and squamous components were negative for GCDFP-15 and AR. Immunohistochemical staining for D2-40 highlighted the lymph vessel invasion of tumor cells. This patient developed metastases in the lymph nodes of the neck, and also in the liver, lung, and brain. The lymph nodes and liver metastases had both ordinary salivary duct carcinoma and micropapillary components. The patient died of tumor 11 months after the initial surgical operation. The results support that the presence of micropapillary component is associated with more aggressive behavior of salivary duct carcinoma. It is also important for pathologists to recognize that GCDFP-15 and AR expression can be reduced in micropapillary carcinoma in the differential diagnosis of metastatic tumor.
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PMID:Aggressive invasive micropapillary salivary duct carcinoma of the parotid gland. 1842 33

Tolerability and response rate to weekly combination chemotherapy with trastuzumab and vinorelbine in Japanese women with HER2-overexpressing breast cancer not previously receiving either therapy were assessed. Tumor response was evaluated every 4 weeks and adverse events were graded. A total of 23 patients from six participating centers in Japan were enrolled. Median dose intensity of vinorelbine was 16.9 mg/m2/week and response rate was 73% (complete response+partial response); complete response=9%, partial response=64%, and progressive disease=5%. Time to progression was 361 days, with 75.0% of liver metastases and 60% of lung metastases responding to this treatment. The most common adverse events were leukocytopenia and neutropenia (96%); however, hematologic toxicity associated with vinorelbine was manageable by adjusting the dose. No pharmacokinetic differences for vinorelbine were found between single administration and combination with trastuzumab. This combination therapy produced high response rates and good tolerability, indicating a promising role in first-line chemotherapy for HER2-overexpressing metastatic breast cancer in Japan.
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PMID:Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II and pharmacokinetic study in Japan. 1859 20

The introduction of modern chemotherapeutic drugs and targeted therapies has substantially changed the treatment of advanced colorectal cancer (aCRC). Thus, median survival of stage IV patients was increased from 6 months under best supportive care to over 2 years if all drugs are administered. Also, new combination therapies may cause irresectable liver metastases to shrink to such an extent that they may be resected (downsizing). Patients who were formerly treated with palliative intent may now be cured. However, not all patients benefit from the new compounds. Very recently, new genetic characteristics were identified as potential molecular biomarkers that may predict response to anti-EGFR therapy, a specific targeted therapy; the marker detected is the mutational status of the oncogene k-ras. Only patients with wild-type k-ras-expressing tumors respond to anti-EGFR antibodies. The integration of biomarker analysis into the clinical routine represents an important step toward customized treatment of cancer patients.
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PMID:[Systemic treatment of advanced colorectal cancer]. 1879 19


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