Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report a case of gastrointestinal stromal tumor (GIST) with multiple hepatic metastases that responded to tyrosine kinase inhibitor STI571. A 30-year-old woman underwent total gastrectomy on July 10, 1998, with a diagnosis of submucosal tumor of the stomach. Pathological analysis of the primary lesion revealed strong expression of c-kit, and it was diagnosed as GIST. The patient underwent tumor excision due to peritoneal recurrence on May 1, 2000 and November 13, 2000. On August 8, 2001, multiple liver metastases were detected by abdominal CAT scan. Treatment with STI571 at a dose of 400 mg/day for 28 days was initiated on September 14, 2000. CAT scan showed rapid tumor shrinkage after 3 weeks of treatment (reduction rate of 56%) and the response continued after 7 weeks of treatment (reduction rate of 71%). Thus, we evaluated the response as PR. Leukocytopenia, edema, diarrhea and nausea were observed; however, all toxicities were mild and tolerable. This case suggests the efficacy of STI571 for metastatic GIST.
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PMID:[A patient with metastatic gastrointestinal stromal tumor who responded to STI571]. 1197 48

Autoimmune impairment and destruction of the enteric nervous plexus are thought to play a central role in the pathogenesis of paraneoplastic motility disorders. We present a case of a small-cell lung carcinoma-related paraneoplastic motility disorder associated with abnormal interstitial cells of Cajal networks. Antibodies against c-Kit and protein gene product 9.5 were used to selectively stain interstitial cells of Cajal and the enteric nervous plexus, respectively. A 68-yr-old man presented with anorexia, early satiety, nausea, and weight loss. Investigations revealed gastroparesis, delayed small intestinal transit, and mediastinal lymphadenopathy. The patient was seropositive for type 1 antineuronal nuclear autoantibody and P/Q-type calcium channel antibody. Biopsy of mediastinal lymph nodes revealed metastatic small-cell carcinoma cells that were immunoreactive for c-Kit. Immunohistochemical staining of a full-thickness small intestinal biopsy revealed a relatively intact myenteric plexus but a sparse and disorganized interstitial cells of Cajal network. The histopathology of this case suggests that interstitial cells of Cajal may be a target in the pathogenesis of paraneoplastic motility disorders.
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PMID:Paraneoplastic dysmotility: loss of interstitial cells of Cajal. 1213 44

Neoangiogenesis has been shown to play an important role in the pathogenesis of acute myeloid leukemia (AML). Autocrine and paracrine secretion of angiogenic and hematopoietic growth factors such as vascular endothelial growth factor (VEGF) and stem cell factor (SCF) in the bone marrow microenvironment may promote proliferation and survival of leukemic blasts. This concept represented the rationale for the initiation of a multicenter phase 2 trial of SU5416, a small molecule inhibitor of phosphorylation of VEGF receptors 1 and 2, c-kit, the SCF receptor, and fms-like tyrosine kinase-3 (FLT3) in patients with advanced AML. Entered into the study were 43 patients with refractory AML or elderly patients not judged medically fit for intensive induction chemotherapy; 42 patients received at least one dose of study drug. Treatment was generally well tolerated, with nausea, headache, and bone pain the most frequent treatment-related side effects. One patient had a morphologic remission (French-American-British [FAB] criteria of complete response without normalization of blood neutrophil and platelet counts) lasting for 2 months. There were 7 patients who achieved a partial response (reduction of blasts by at least 50% in bone marrow and peripheral blood) lasting 1 to 5 months. Patients with AML blasts expressing high levels of VEGF mRNA by quantitative polymerase chain reaction (PCR) had a significantly higher response rate and reduction of bone marrow microvessel density than patients with low VEGF expression consistent with the antiangiogenic effects of SU5416.
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PMID:A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia. 1284 1

GIST is a rare neoplasm, the majority of GISTs are located in the stomach and small intestine. Most GISTs are diagnosed histopathologically after resection because of submucosal location. A 37-year-old female patient presented with a 2-weeks history of generalized weakness, nausea accompanied by intermittent passage of black, tarry stools. Esophagogastroduodenoscopy and ERCP showed a large round mass measuring 5 cm in diameter in the ampulla of Vater with ulcer crack. Endoscopic multiple biopsies from the mass including ulcer base were taken. Light microscopic findings showed spindle-shaped and epitheloid tumor cells having high cellularity and frequent mitotic figures. On immunohistochemical stainings, the tumor cells were positive for CD34 and smooth muscle actin. Based on these preoperative findings, a diagnosis of malignant GIST of the ampulla of Vater was made probably. After operation, immunohistochemical studies revealed positive reaction for c-kit and vimentin, as well as focally reactive for CD34 and smooth muscle actin. We report a case of GIST in the ampulla of Vater presenting with melena that was diagnosed preoperatively and postoperatively.
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PMID:Malignant gastrointestinal stromal tumor of the ampulla of Vater: a case report. 1474 56

PTK787/ZK 222584 (PTK/ZK) is an oral angiogenesis inhibitor targeting vascular endothelial growth factor (VEGF) receptor tyrosine kinases, including VEGFR-1/Flt-1, VEGFR-2/KDR, VEGFR-3/Flt-4, the platelet-derived growth factor receptor tyrosine kinase and the c-kit protein tyrosine kinase. The objective of this Phase I study was to evaluate the safety, tolerability, biologic activity and pharmacologic profile of PTK/ZK administered orally, twice daily, on a continuous dosing schedule in patients with primary refractory or relapsed acute myeloid leukemia (AML), secondary AML, poor-prognosis de novo AML or advanced myelodysplastic syndrome (MDS). Acute myeloid leukemia patients for whom PTK/ZK monotherapy was ineffective could receive PTK/ZK combined with standard induction chemotherapy. Sixty-three patients received PTK/ZK at doses of 500-1000 mg orally b.i.d. Safety and pharmacokinetic data were collected. Responses were evaluated according to standard bone marrow and peripheral blood criteria. At 1000 mg b.i.d., dose-limiting toxicities of lethargy, hypertension, nausea, emesis and anorexia were observed. Other adverse events related to PTK/ZK were dizziness, weakness, fatigue, diarrhea and pruritus; these were generally mild and reversible. Pharmacokinetic data showed that steady state was reached by day 14, there was no accumulation with repeat dosing and there was no significant increase in exposure at steady state beyond the maximum tolerated dose (MTD). Complete remission was observed in five of 17 AML patients treated with PTK/ZK combined with chemotherapy. In conclusion, the MTD of PTK/ZK is 750 mg orally b.i.d. The drug is generally well tolerated and can be given in combination with chemotherapy for patients with MDS and AML.
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PMID:Phase 1 study of PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor, for the treatment of acute myeloid leukemia and myelodysplastic syndrome. 1661 23

Malignant gastrointestinal stromal tumor (GIST) consists a rare neoplasm, developing in small intestine and stomach. The presenting manifastations include weakness, weight loss, nausea, melena and anaemia. The present case refers to a 65 years old female patient with a GIST of the ampulla of Vater presenting with obstructive jaundice. Diagnosis was achieved pre-operatively by biopsies collected through diagnostic ERCP. The tumour was locally excised, with preservation of the ampulla. The histological analysis suggested low grade GIST positive for both CD 117 (c-kit) and CD34. Two years after the surgery the patient remains free of disease. Malignant GIST of the ampulla of the Vater is extremely rare as only few similar cases have been described in the literature. This is the first time a GIST being presented as obstructive jaundice ever reported. Despite the unavailability of EUS-FNA, the diagnosis was set preoperatively and the tumor was resected.
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PMID:Malignant gastrointestinal stromal tumor of the ampulla of Vater presenting with obstructive jaundice. 1685 23

A 57-year-old man with gastrointestinal stromal tumor (GIST) of the stomach with peritoneal dissemination underwent gastrectomy. After surgery, he was treated with 400 mg/day of imatinib, without recurrence, for 26 months. At 26 months, the imatinib dose was reduced because of nausea, and 4 months after the dose reduction, recurrence of GIST was detected, for which surgical resection was performed again. The first surgical specimen had a mutation of exon 11 in the c-kit receptor gene. Intriguingly, the second surgical specimen had a novel mutation of exon 17, in addition to the above-mentioned mutation, in the c-kit receptor gene. Based on the result of molecular analysis, the novel mutation of exon 17, induced by longterm chemotherapy, was judged to have been responsible for the recurrence, which perhaps was triggered by the dose reduction of imatinib.
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PMID:Recurrent gastrointestinal stromal tumor (GIST) of the stomach associated with a novel c-kit mutation after imatinib treatment. 1695 44

Receptor activated tyrosine kinases such as c-kit, c-fms and PDGFR are known targets of inhibition by imatinib mesylate (Gleevec) and are expressed on AML blasts. Marrow stromal cells and monocytes express KIT ligand, M-CSF and PDGF and are therefore capable of activating survival pathways in these leukemic cells. Given the synergy in vitro between Ara-C and imatinib mesylate on AML cell growth inhibition, we initiated a Phase I study combining CLAG+imatinib mesylate in AML patients. Patients with relapsed, refractory AML or CML myeloid blast crisis were eligible to receive Cladribine 5mg/m(2) days 3-7, Cytarabine 2gm/m(2) days 3-7, G-CSF 300mcg days 2-7, and escalating doses of imatinib mesylate given on days 1-15. The level 1 Gleevec dose was 400mg, while level 2 was 600mg and the level 3 dose 800mg. A total of 16 patients were enrolled, 15 AML and 1 CML myeloid blast crisis. The dose escalation occurred as planned and there was no clear evidence of added toxicity due to imatinib mesylate. One patient with an extensive cardiac history died of cardiac causes on day 1 of therapy however no other deaths occurred within 30 days of starting therapy. One patient had a Grade 3 skin rash at dose level 2. The most common toxicities encountered during induction therapy were nausea, vomiting, rash and diarrhea that were transient and/or reversible. At the 800mg dose 1 patient developed a decline in cardiac ejection fraction on day 20 who later died of sepsis, so this was considered a dose limiting toxicity. Of 16 evaluable patients 11 achieved a hypocellular marrow after initial induction with 1 additional patient achieving a hypocellular marrow following a second course of the same regimen. Four patients (25%) achieved a complete morphologic response with normal cytogenetics, 2 patients (12.5%) achieved a complete morphologic response only and 1 patient had a complete response in the bone marrow but incomplete blood count recovery. The overall response rate was 43.8%. The median overall survival was 175 days (95% CI 16.24-333.76) and the median relapse free survival was 76 days. The addition of imatinib mesylate to CLAG was well tolerated with acceptable toxicities and response rates comparable to other salvage regimens. To assess the efficacy of imatinib mesylate in combination with CLAG, a larger phase II trial is now planned.
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PMID:Phase I study of cladribine, cytarabine (Ara-C), granulocyte colony stimulating factor (G-CSF) (CLAG Regimen) and simultaneous escalating doses of imatinib mesylate (Gleevec) in relapsed/refractory AML. 1857 21

A 71-year-old man visited the hospital complaining of nausea in December 2002. Following a diagnosis of a gastrointestinal stromal tumor (GIST), partial resection of the stomach was performed in January 2003. The tumor was immunohistochemically positive for c-kit and CD34. The tumor size was 6.5 x 5.0 x 4.5 cm with a mitotic index of 25 out of 50 in the high-power field. The pathological diagnosis indicated a high-risk GIST. Treatment with imatinib at a dose of 400 mg/day was started because of liver metastasis of the GIST in January 2004. The liver metastasis was gradually reduced and exhibited cystic change. We considered that there was a complete response without accumulation by FDG-PET in June 2007. An hepatic segmentectomy was performed and imatinib was discontinued in July 2007. Most intratumorale in the specimen underwent hyaline degeneration after pathological examination, but there were viable cells in a portion of the tumor border. Imatinib treatment was resumed because of recurrence in the remnant stomach four months postoperatively owing to imatinib withdrawal. In making a diagnosis at the cell level by FDG-PET, it was difficult to determine the effectiveness of imatinib, and therefore, it is suggested that imatinib treatment must be continued after surgical resection.
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PMID:[A resected case of postoperative liver metastasis of a gastrointestinal stromal tumor showing complete response after imatinib treatment]. 1901 49

PURPOSE Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit. This randomized, double-blind, placebo-controlled phase III study evaluated efficacy and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). PATIENTS AND METHODS Adult patients with measurable, locally advanced, and/or metastatic RCC were randomly assigned 2:1 to receive oral pazopanib or placebo. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, tumor response rate (Response Evaluation Criteria in Solid Tumors), and safety. Radiographic assessments of tumors were independently reviewed. Results Of 435 patients enrolled, 233 were treatment naive (54%) and 202 were cytokine pretreated (46%). PFS was significantly prolonged with pazopanib compared with placebo in the overall study population (median, PFS 9.2 v 4.2 months; hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P < .0001), the treatment-naive subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P < .0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; P < .001). The objective response rate was 30% with pazopanib compared with 3% with placebo (P < .001). The median duration of response was longer than 1 year. The most common adverse events were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. There was no evidence of clinically important differences in quality of life for pazopanib versus placebo. CONCLUSION Pazopanib demonstrated significant improvement in PFS and tumor response compared with placebo in treatment-naive and cytokine-pretreated patients with advanced and/or metastatic RCC.
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PMID:Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. 2081 65


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