CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer.

BACKGROUND & AIMS: The CpG island methylator phenotype (CIMP), defined by a high frequency of aberrantly methylated genes, is a characteristic of a subclass of colon tumors with distinct clinical and molecular features. Cohort studies have produced conflicting results on responses of CIMP-positive tumors to chemotherapy. We assessed the association between tumor CIMP status and survival of patients receiving adjuvant fluorouracil and leucovorin alone or with irinotecan (IFL). METHODS: We analyzed data from patients with stage III colon adenocarcinoma randomly assigned to groups given fluorouracil and leucovorin or IFL after surgery, from April 1999 through April 2001. The primary end point of the trial was overall survival and the secondary end point was disease-free survival. DNA isolated from available tumor samples (n = 615) was used to determine CIMP status based on methylation patterns at the CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1 loci. The effects of CIMP on survival were modeled using Kaplan-Meier and Cox proportional hazards; interactions with treatment and BRAF, KRAS, and mismatch repair (MMR) status were also investigated. RESULTS: Of the tumor samples characterized for CIMP status, 145 were CIMP positive (23%). Patients with CIMP-positive tumors had shorter overall survival times than patients with CIMP-negative tumors (hazard ratio = 1.36; 95% confidence interval: 1.01-1.84). Treatment with IFL showed a trend toward increased overall survival for patients with CIMP-positive tumors, compared with treatment with fluorouracil and leucovorin (hazard ratio = 0.62; 95% CI: 0.37-1.05; P = .07), but not for patients with CIMP-negative tumors (hazard ratio = 1.38; 95% CI: 1.00-1.89; P = .049). In a 3-way interaction analysis, patients with CIMP-positive, MMR-intact tumors benefited most from the addition of irinotecan to fluorouracil and leucovorin therapy (for the interaction, P = .01). CIMP was more strongly associated with response to IFL than MMR status. Results for disease-free survival times were comparable among all analyses. CONCLUSIONS: Patients with stage III, CIMP-positive, MMR-intact colon tumors have longer survival times when irinotecan is added to combination therapy with fluorouracil and leucovorin.

Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone.

PURPOSE: When designing this trial, there was no evidence that salvage chemotherapy (SLC) in advanced gastric cancer (AGC) resulted in substantial prolongation of survival when compared with best supportive care (BSC). However, SLC is often offered to pretreated patients with AGC for anecdotal reasons. PATIENTS AND METHODS: Patients with AGC with one or two prior chemotherapy regimens involving both fluoropyrimidines and platinum and with an Eastern Cooperative Oncology Group performance status (PS) 0 or 1 were randomly assigned in a ratio of 2:1 to SLC plus BSC or BSC alone. Choice of SLC-either docetaxel 60 mg/m(2) every 3 weeks or irinotecan 150 mg/m(2) every 2 weeks-was left to the discretion of investigators. Primary end point was overall survival (OS). RESULTS: Median OS was 5.3 months among 133 patients in the SLC arm and 3.8 months among 69 patients in the BSC arm (hazard ratio, 0.657; 95% CI, 0.485 to 0.891; one-sided P = .007). OS benefit for SLC was consistent in most of the prospectively defined subgroups, including age, PS, number of prior treatments, metastatic sites, hemoglobin levels, and response to prior chemotherapy. SLC was generally well tolerated, and adverse events were similar in the SLC and BSC arms. We found no median OS difference between docetaxel and irinotecan (5.2 v 6.5 months; P = .116). CONCLUSION: To our knowledge, this is the largest phase III trial comparing SLC plus BSC with BSC alone in AGC. In pretreated patients, SLC is tolerated and significantly improves OS when added to BSC.

Vascular events in Korean patients with myeloproliferative neoplasms and their relationship to JAK2 mutation.

Evaluation of the Janus kinase 2 (JAK2) V617F mutation has been widely used for the diagnosis of myeloproliferative neoplasms (MPN). However, its prognostic relevance to clinical outcome is not completely understood. We investigated the association of JAK2 V617F with vascular events in Korean patients with myeloproliferative neoplasms (MPN). We studied 283 patients from 15 centers, who were diagnosed with MPN. The JAK2 V617F status was evaluated by allele-specific polymerase chain reaction (PCR) and sequencing. The patients' diagnoses were essential thrombocythemia (ET n = 146), polycythemia vera (PV n = 120), primary myelofibrosis (n = 12), and unclassifiable MPN (MPNu n = 5). JAK2 V617F was detected in 89 (61%) patients with ET, 103 (86%) with PV, four (33%) with myelofibrosis, and four (80%) with MPNu. A higher number of leukocytes, haemoglobin levels and BM cellularity as well as an older age, lower platelet counts, and diagnosis of PV were significantly correlated with JAK2 V617F. Eighty-three and 43 episodes of thrombosis and bleeding occurred in 100 patients each before and after the diagnosis. Vascular events more frequently occurred in 37% of patients with JAK2 V617F than in 29% of those without the mutation (p = 0.045). Among 175 patients whose samples were available for sequencing, 28 patients with homozygous JAK2 V617F had vascular events more frequently (57%) than those who were heterozygotes (39%) or had the wild type (27%) (p = 0.03). The multivariate analysis showed that a JAK2 homozygous mutation, hypercholesterolemia and older age were independent risk factors for a vascular event. The results of this study showed that Korean patients with MPN had a similar JAK2 mutation rate and frequency of vascular events when compared to Western patients. The presence of V617F was significantly related to vascular events. Therefore, initial evaluation for the JAK2 mutation and careful monitoring for vascular events should be performed in MPN patients.

Mitomycin C plus S-1 as second-line therapy in patients with advanced gastric cancer: a noncomparative phase II study.

S-1 is an oral fluoropyrimidine consisting of the 5-fluorouracil prodrug tegafur combined with two modulating substances, gimeracil and potassium oxonate. On the basis of the potential additive effect between mitomycin C (MMC) and 5-fluorouracil as a continuous infusion, we conducted a phase II study to assess the efficacy and tolerability of the combination of S-1 and MMC as second-line chemotherapy for advanced gastric cancer (AGC). Patients with measurable AGC, progressive after one prior chemotherapy for metastatic disease, received MMC (7 mg/m2) on day 1 and S-1 (40 mg/m2) twice daily as an intermittent regimen of 4 weeks of treatment followed by a 2-week rest. Treatment was repeated every 6 weeks. The primary objective was the response rate. For 43 patients registered, 42 patients were treated with MMC plus S-1. A total of 121 chemotherapy cycles were delivered (median: 2; range: 1-6). The patients' median age was 53 years (range: 31-75) and nine (21%) had an Eastern Cooperative Oncology Group performance status of 2. In an intent-to-treat analysis, nine patients (21%) achieved an objective response, which was maintained for 4.1 months. The median progression-free and overall survivals were 3.4 months (95% confidence interval: 2.3-4.5) and 8.0 months (95% confidence interval: 6.1-9.9), respectively. Although fatigue was the most frequently encountered toxicity safety profiles were generally predictable and manageable. One patient developed hemolytic anemia, which was resolved spontaneously. Grade > or = 2 hand-foot syndrome was observed in only three patients. Second-line chemotherapy with MMC and S-1 is an active and tolerable regimen for AGC patients with good performance status.

A randomized double-blind placebo-controlled study of low-dose intravenous Lorazepam to reduce procedural pain during bone marrow aspiration and biopsy.

OBJECTIVE: To evaluate the efficacy of intravenous lorazepam as premedication for bone marrow aspiration and biopsy (BMAB). DESIGN: Randomized, double-blind, placebo-controlled. PATIENTS: One hundred and thirty-eight consenting patients planned to receive BMAB. INTERVENTION: Patients were randomly assigned to receive either intravenous lorazepam 1 mg or placebo just prior to BMAB. SETTING: Tertiary referral center, inpatient setting. OUTCOME MEASURES: A questionnaire was used to determine the patient perception about the procedure and pain at baseline, which was completed just after the procedure, and the next day after the BMAB. Pain was rated using a 10-cm linear visual analog scale (VAS). RESULTS: The mean VAS scores measured during the BMAB examination were 6.0 for lorazepam vs 6.2 for placebo. Few adverse events were noted during intravenous lorazepam administration. The patients in the lorazepam group were more likely to accept the next BMAB (P = 0.044). CONCLUSION: Intravenous lorazepam was safe in patients undergoing BMAB and was more effective than placebo in enhancing cooperation during BMAB and willingness to undergo another procedure. However, use of lorazepam 1 mg provided no reduction in the pain associated with BMAB. Further studies should focus on providing appropriate analgesia for this potentially painful procedure.

Self-reported health-related quality of life predicts survival for patients with advanced gastric cancer treated with first-line chemotherapy.

PURPOSE: To determine whether patients' self-reported quality-of-life (QOL) parameters could predict survival for patients with advanced gastric cancer (AGC) treated with first-line chemotherapy, we performed this analysis based on the data obtained from 254 patients enrolled in three consecutive prospective randomized trials at a single institution. METHODS: Consenting patients with AGC received first-line chemotherapy as specified in the protocols. QOL was assessed at baseline using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaires. Baseline univariate and multivariate analyses were performed on the QOL data and the recognized clinical predictors for survival. RESULTS: Of 254 patients, 164 completed the QOL questionnaire at baseline. All patients received fluorouracil-containing first-line chemotherapy for AGC. With 88% observed deaths and a reported median survival of 9.5 months [95% confidence interval (CI) 8.8-10.2 months], there were no significant differences in survival between patients with or without QOL data. The final Cox multivariate model revealed four prognostic factors: age [hazard ratio (HR) 2.08, 95% CI 1.32-3.33, P = 0.002], bone metastasis (HR 2.70, 95% CI 1.30-5.56, P = 0.008), hemoglobin (HR 0.58, 95% CI 0.37-0.92, P = 0.020), and social functioning (HR 0.40, 95% CI 0.23-0.64, P = 0.001). When adjusting for clinical parameters, social functioning was an independently significant prognostic factor for longer survival. CONCLUSION: Baseline social functioning, along with age, presence of bone metastasis, and baseline hemoglobin level, independently predicts survival of AGC patients treated with first-line chemotherapy. QOL assessment should be routinely included to provide useful prognostic information concerning AGC patients.

A randomized trial of anemia correction with two different hemoglobin targets in the first-line chemotherapy of advanced gastric cancer.

PURPOSE: To evaluate if raising baseline and maintaining hemoglobin (Hb) levels with red blood cell (RBC) transfusion could improve the outcomes of chemotherapy for advanced gastric cancer (AGC). METHODS: Patients were randomized to receive RBC transfusion to maintain their Hb levels >or=10 g/dl (arm 1) or >or=12 (arm 2) before the start of their 5-fluorouracil-based first-line chemotherapy. Objective response, KPS and quality of life (QOL) data were measured. RESULTS: For 87 patients enrolled, mean baseline Hb was 10.1 g/dl, and 54 patients received RBC prior to chemotherapy initiation. Despite transfusion, we failed to maintain the Hb level above the predefined target range. Eighteen patients experienced brief and reversible adverse events during transfusion, including two patients with acute pulmonary edema. KPS was improved from baseline to post-chemotherapy in both arms. QOL data showed improvement in some symptom scores, but there was no difference in the QOL scores between the two arms at baseline and all four cycles of treatment. Similar response rates were observed in both arms (arm 1, 30%; arm 2, 35%). Both arms showed similar chemotherapy duration (3.8 and 4.1 months, respectively), progression-free survival (4.0 and 4.1 months) and overall survival (9.9 and 9.3 months). CONCLUSIONS: Red blood cell transfusion achieving Hb level above 10 g/dl might contribute to the improvement of the KPS and QOL seen in patients with AGC. The observation of equivalent outcomes at the two target Hb levels supports the feasibility of anemia correction to Hb 10 g/dl, which merits further evaluation.

Early imatinib-mesylate-induced hepatotoxicity in chronic myelogenous leukaemia.

Imatinib mesylate is the first molecule of targeted therapy in chronic myelogenous leukaemia inhibiting constitutively activated BCR-ABL kinase. There are no long-term follow-up studies of large sample sizes to assess the toxicity of the use of imatinib mesylate over 10 years. Several cases of hepatotoxicity, including fatal liver failure, have been associated with the long-term use of imatinib mesylate. We report here on a patient who experienced immediate dominant cholestatic damage of the liver and mild hepatocyte damage during imatinib mesylate therapy. This differs from most reports showing dominantly acute hepatitis with necrosis associated with the use of imatinib mesylate.

Intestinal marginal zone B-cell lymphoma of MALT type: clinical manifestation and outcome of a rare disease.

Intestinal marginal zone B-cell lymphoma of the MALT type (I-MZL) is a relatively uncommon form of lymphoma. Twenty-seven patients with histologically-confirmed I-MZL were analyzed. The patients initially presented with abdominal pain (62.9%), and diarrhea (22.2%). The most common involved site was the ileo-caecal area (40.7%). Musshoff's stage I(E), II(E)1, II(E)2, III(E) and IV were present in 44%, 15%, 11%, 7.4% and 22% respectively. Sixty-three percent were in the low-risk group according to the Follicular Lymphoma International Prognostic Index. Complete response and partial response were achieved in 82% and 4% patients. The estimated 5-year overall survival (OS) and progression-free survival (PFS) rates were 86% and 54%. Stage > or = II(E)2 was determined to be a poor prognostic factor for PFS and OS. I-MZL commonly manifests in an early-stage, low-risk state and tends to respond well to local and systemic treatment with favorable prognosis. I-MZL tends to be an indolent disease - characterized by prolonged survival with frequent relapses, similarly to other site MZLs.

Nail toxicity after treatment with docetaxel: a prospective analysis in patients with advanced non-small cell lung cancer.

OBJECTIVE: Nail toxicity is one of the most frequent non-hematologic toxicities of docetaxel and often deteriorates patients' quality of life, leading to treatment discontinuation. To define the incidence of nail change as well as its association with specific risk factors, we prospectively investigated data of 84 consecutive patients with advanced non-small cell lung cancer who received first-line docetaxel/cisplatin combination chemotherapy. METHODS: Chemotherapy-naïve patients were treated with docetaxel, either 3-weekly or weekly, in combination with cisplatin. All patients received adequate premedications including corticosteroids, antiemetics and intravenous hydration. Toxicity was evaluated using National Cancer Institute (NCI) CTCAE version 3. RESULTS: Twenty-two patients (26%) developed nail changes, including nine (11%) with grade 3. Nine patients who developed grade 3 nail changes (seven of whom received weekly docetaxel) were not able to complete planned chemotherapy despite topical and/or oral antibiotic treatment. Most occurrences of nail changes were diagnosed in patients who were treated with weekly schedule (P = 0.02). The number of chemotherapy cycles and cumulative docetaxel doses were strongly associated with the development of nail changes. The cumulative hazard of developing nail changes increased above 10% after 2.8 months up to 40% at 6 months. A multivariate analysis of factors associated with the development of nail changes identified the following to have independent adverse significance: weekly docetaxel administration (odds ratio, 0.084; 95% CI, 0.014-0.510; P = 0.01) and the number of chemotherapy cycles given (odds ratio, 0.232; 95% CI, 0.067-0.805; P = 0.02). CONCLUSION: Nail changes occur with more frequent and prolonged use of docetaxel.

Window narrowing: a new method for standardized assessment of the tissue at risk-maximum of infarction in CT based brain perfusion maps.

BACKGROUND: Mapping of brain perfusion using bolus tracking methods is increasingly used to assess the amount and severity of cerebral ischemia in acute stroke. Using relative perfusion maps, however, it is difficult to identify the tissue at risk-maximum (TARM) of infarction with sufficient reliability and reproducibility. METHODS: We analysed 76 perfusion computed tomography (PCT) derived maps of cerebral blood flow (CBF), cerebral blood volume (CBV) and time-to-peak (TTP) in 40 acute stroke patients using multidetector row technology and standard software (Somatom VolumeZoom, Siemens, Germany). 'Window narrowing' of the color maps was performed until color homogenisation of the contralateral unaffected hemisphere was reached. Tissue still depictable on the affected hemisphere after sufficient window narrowing was defined as the TARM. We analysed presence and size of the TARM on PCT maps, its relative perfusion values by comparison with contralateral, mirrored tissue, and its correlation with occurrence and final size of cerebral infarction on follow-up imaging. RESULTS: An ischemic area was visible in 64, 58.9 and 72.6% on the conventional CBF, CBV and TTP maps, respectively. After window narrowing, a TARM was present in 56.8, 54.1 and 63.0% of slices comprising 11.9, 11.6 and 21.1% of the ipsilateral hemisphere (CBF, CBV and TTP), respectively. The relative perfusion values were 38.7 (CBF) and 43.0% (CBV) for the entire ischemic area and 11.3 (CBF) and 13.3% (CBV) for the TARM. Definite cerebral infarction was visible on 68.1% of the target slices comprising 23.7 +/- 22.9% of the ipsilateral hemisphere. The size of the TARM correlated slightly better with the final infarction size (r=0.74-0.82) than the entire ischemic area (r=0.61-0.79). With respect to the occurrence of cerebral infarction, the presence of a TARM on CBF maps showed the best positive (97.9%) and negative (72.7%) predictability. DISCUSSION: On PCT maps, window narrowing provides a standardized display of the TARM in peracute stroke. The severely reduced values of relative CBF and CBV suggest the TARM to indicate tissue most prone to infarction.

Malignant gastrointestinal stromal tumor in a patient with neurofibromatosis type 1.

Neurofibromatosis type 1 (von Recklinghausen's disease, NF-1) is an autosomal-dominant neurocutaneous disorder characterized by abnormal skin pigmentation (café au lait spots and axillary freckling), cutaneous and plexiform neurofibromas, skeletal dysplasias, and Lisch nodules (pigmented iris hamartomas). Gastrointestinal stromal tumors (GISTs) are the most common tumors of mesenchymal origin in the gastrointestinal tract, mesentery, omentum, and retroperitoneum. Here, we report a case of GIST in the ileum of a 76-year-old woman previously diagnosed as NF-1. She was admitted due to sudden onset of abdominal pain. Contrast enhanced CT scan revealed a moderately defined, peripherally enhanced soft tissue mass of about 8.8 x 7.3cm, originating from the small bowel in the left of the abdomen. Surgical excision was performed and the tumor was found to be composed of tumor cells that were positive for c-kit protein. The patient started imatinib treatment a month later, but stopped medication due to dyspepsia after a few months and eventually progressed after 18 months.

Nodal marginal zone B-cell lymphoma: Analysis of 36 cases. Clinical presentation and treatment outcomes of nodal marginal zone B-cell lymphoma.

Nodal marginal zone B-cell lymphoma (NMZL) is a relatively uncommon type of lymphoma. Because of the rarity, the natural history and the optimal treatment modality have not been well defined. Therefore, we performed a retrospective analysis of the clinical features and treatment outcomes of NMZL. Thirty-six patients who were histologically diagnosed as NMZL were included in the analysis. Fifty-three percent of the patients had localized disease (stages I and II), and 21.2% (7/33) had bone marrow involvement at presentation. B symptom was present in only three patients (8.3%). Most patients were categorized as low or low-intermediate risk group by international prognostic index (IPI) (77.1%). Majority (94.4%) of the patients with localized disease achieved complete remission (CR) after the initial treatment. Of the seven patients with disseminated disease, who were treated with anthracycline-based chemotherapy, four patients achieved CR. Of the seven patients who received nonanthracycline-based chemotherapy, no patient achieved CR. After the median follow-up duration of 36 months, the median progression-free survival (PFS) was 3.9 (95% CI; 2.9-5.6) years, and the estimated 5-year PFS and overall survival rates were 47.2 and 82.7%, respectively. The significant predictive factors for PFS were performance status, advanced stage, and follicular lymphoma IPI (FLIPI) in this study. This clinical feature is similar to FL rather than to MZL-MALT type.

Thalidomide for treating metastatic hepatocellular carcinoma: a pilot study.

BACKGROUND: Thalidomide has been reported to have antitumor activity for treating metastatic hepatocellular carcinoma (HCC). We evaluated the safety and efficacy of using thalidomide for treating selected patients with unresectable or metastatic HCC, and their disease was refractory to systemic chemotherapy. METHODS: Eight patients with measurable and metastatic HCC that had progressed with prior systemic chemotherapy and who desired further active therapy were enrolled in this study. Thalidomide was given orally at bedtime and it was started at 200 mg/day with no further dose escalation. The response was measured at 2-month intervals. RESULTS: The median age was 44 years (range: 34-52 years) and all the patients had received doxorubicin-based systemic chemotherapy prior to their enrollment. Each patient received thalidomide for a median of 152 days (range: 5-422 days). One partial response was observed (12.5%, 95% CI; 0-42%) along with 4 cases of stable diseases. The most commonly encountered toxicity was somnolence; grade 3 somnolence was noted for one patient, which led to treatment discontinuation. Skin rash was observed in one responding patient. CONCLUSIONS: The results indicate that thalidomide may feasibly offer disease stabilization to metastatic HCC patients. Further dose escalation of thalidomide, or its combination with other chemotherapeutic agents, may be of interest and this should be investigated for treating patients with metastatic HCC.

A pilot study of cisplatin, irinotecan, leucovorin and 5-fluorouracil (PILF) combination chemotherapy for advanced gastric cancer.

PURPOSE: Irinotecan, in combination with leucovorin/5-fluorouracil (FU) or with cisplatin, is known to be active for treating advanced gastric cancer (AGC). This pilot study evaluated a novel three-drug combination of irinotecan, leucovorin/FU and cisplatin as a first-line treatment of AGC. The primary endpoint was to assess the feasibility in anticipation of conducting a larger phase II study. MATERIALS AND METHODS: Chemotherapy-naive AGC patients received irinotecan 150 mg/m(2) on day 1, and leucovorin 200 mg/m(2) and a 22-h infusion of FU 1000 mg/m(2) on days 1 and 2. Cisplatin 30 mg/m(2) was administered on day 2. Treatment was repeated every 2 weeks until disease progression or unacceptable toxicity. RESULTS: Of the 17 eligible patients, two patients had an ECOG performance status of 2 and their median age was 48 years (range: 31 to 69). A total of 117 chemotherapy cycles were delivered (median: 6, range: 1 to 12). The causes of treatment discontinuation were disease progression in 9 patients (53%), refusal (35%) and toxicity (12%). Although grade 3 or 4 neutropenia (41% of patients) was the major toxicity that required dose adjustments, only one episode of febrile neutropenia occurred. Grade 3 or 4 nausea and vomiting, diarrhea and fatigue were observed in 35%, 35% and 29% of patients, respectively. None of the patients died of toxicity during treatment. Of the 16 patients who were evaluable for response, 7 (44%) experienced a partial response. CONCLUSION: This novel multi-drug combination was tolerated well in patients with AGC. Based on the encouraging efficacy and tolerability, a randomized phase II study is ongoing in this disease setting.

Expression of cyclooxygenase-2 in human breast cancer: relationship with HER-2/neu and other clinicopathological prognostic factors.

PURPOSE: Previous epidemiologic studies have demonstrated that nonsteroidal anti-inflammatory drugs can reduce the risk of breast cancer, and this possibly happens via cyclooxygenase (COX) inhibition. Moreover, growth factor-inducible COX-2, which is overexpressed in neoplastic tissue, is an attractive therapeutic target. Thus, we evaluated the expression of COX-2 in breast cancer tissues, and we assessed the association between COX-2 expression and HER-2/neu expression and also with several clinicopathological features. MATERIALS AND METHODS: We analyzed the surgical specimens from 112 women with breast cancer who had undergone lumpectomy or mastectomy. The expressions of COX-2, HER-2/neu, MMP-2 and TIMP-2 were determined immunohistochemically. The correlations between COX-2 expression and several variables, including clinicopathological factors, HER-2/neu expression, MMP-2 expression and TIMP-2 expression were analyzed. Survival analysis was also performed with respect to COX-2 overexpression. RESULTS: The overexpression of COX-2 protein was observed in 28.6% of the breast cancer tissues. Tumors with lymph node metastasis more frequently showed COX-2 overexpression than did those tumors without metastasis (p=0.039), and the increased COX-2 expression correlated positively with HER-2/neu overexpression (p=0.000). No significant differences were found for the MMP-2 or TIMP-2 expression rates in the COX-2 positive and negative groups. The survival analysis revealed no significant differences according to the COX-2 expression. CONCLUSION: This study results suggest that increased COX-2 expression is related with the progression of breast cancer, e.g., with lymph node invasion. COX-2 overexpression found to be related with HER-2/neu overexpression, but not with MMP-2 or TIMP-2 expression. These results support the potential use of selective agents that inhibit COX-2 or HER-2/neu for the management of breast cancer.

Potential prognostic significance of p185(HER2) overexpression with loss of PTEN expression in gastric carcinomas.

AIMS AND BACKGROUND: The HER2 gene encodes a 185-kd transmembrane glycoprotein receptor (p185(HER2)) that has partial homology with the epidermal growth factor receptor and shares intrinsic tyrosine kinase activity. The phosphatase and tensin homolog mutated on chromosome ten (PTEN) gene product is a protein tyrosine phosphatase that participates in modulating the phosphoinositide 3-kinase pathway which has antagonizing activity to protein tyrosine kinase. The authors investigated the correlation between clinicopathologic variables including survival and the overexpression of the p185(HER2) with loss of PTEN expression in gastric adenocarcinoma patients. METHODS: The protein expression of p185(HER2) and PTEN was examined by immunohistochemical stain in paraffin-embedded tissues of 94 (M:F, 52:42) gastric adenocarcinoma patients by using monoclonal antibody, and the results were related to clinicopathological variables and survival. RESULTS: p185(HER2) overexpression correlated positively with lymph node metastasis, distant metastasis, AJCC classification, higher relapse rate. Patients with overexpression of p185(HER2) were found to have significantly lower disease-free survival (P = 0.003) and overall survival (P = 0.0004). Loss of PTEN expression correlated positively with depth of invasion (T stage) and was more frequent in the advanced stage. The patient group with p185(HER2) overexpression and loss of PTEN expression showed significantly shorter disease-free and overall survival (P = 0.03, P = 0.01) than the other groups. CONCLUSIONS: Our observations suggest potential prognostic significance of p185(HER2) overexpression with PTEN loss in gastric adenocarcinoma patients. This opens up the possibility of considering p185(HER2)and PTEN as a therapeutic target in gastric cancer.

Acute stroke assessment with CT: do we need multimodal evaluation?

PURPOSE: To assess detection of stroke and prediction of extent of infarction with multimodal computed tomographic (CT) evaluation (unenhanced CT, perfusion CT, and CT angiography) in patients suspected of having acute stroke. MATERIALS AND METHODS: Forty-four consecutive patients with a mean National Institutes of Health Stroke Scale score of 10.45 and suspected of having ischemic stroke of the anterior circulation were examined with multi-detector row CT within 8 hours (mean, 3.05 hours) of onset of symptoms. All evaluations were performed with the knowledge that acute stroke was suspected but without detailed clinical information. The extent of ischemia or final infarction on the baseline unenhanced CT scan and follow-up images was assessed with the Alberta Stroke Program Early CT score. Different perfusion maps and follow-up images were assessed to determine the percentage of the ischemia-affected hemisphere. Each component, as well as the multimodal CT evaluation, was compared with follow-up unenhanced CT scans or magnetic resonance images after a mean time of 2.32 days. RESULTS: Multimodal CT revealed true-positive findings in 30 of 41 patients and true-negative findings in three, resulting in a sensitivity of 78.9%. Unenhanced CT, CT angiography, and perfusion CT showed sensitivities of 55.3%, 57.9%, and 76.3%, respectively. In eight patients, small infarctions (mean size, 1.47 cm) that were proved at follow-up were missed with all modalities at initial multimodal CT. With perfusion CT, four of these small infarctions were missed within the white matter of the section levels. Maps of cerebral blood flow showed the best correlation with the final size of infarction with an r(2) value of 0.71. CONCLUSION: The presented multimodal CT evaluation improves detection rate and prediction of the final size of infarction in comparison with unenhanced CT, CT angiography, and perfusion CT alone.

On the origin of microembolic signals--a clinical and postmortem study.

BACKGROUND AND PURPOSE: Clinically silent circulating microembolic signals (MES) can be identified by transcranial Doppler ultrasound (TCD). It is not yet clear whether their occurrence is always linked to the presence of embolic sources. METHODS: 24 terminally ill patients (7 women, 17 men; mean age 68 years) were investigated by TCD of the middle cerebral arteries. These findings were correlated with a complete post-mortem examination of potential embolic pathways. RESULTS: Four patients out of the 24 under investigation showed MES, 2 of them bilaterally. All these 4 MES-positive patients had a definite embolic source, i. e. bilateral carotid artery occlusive disease, endocarditis with thrombotic valvular adhesions and severe plaques in the aortic arch, dilated left atrium and a patent foramen ovale, or severe plaques in the aortic arch and a dilated left atrium, respectively. CONCLUSION: In the investigated patient group, we could demonstrate that MES can only be found when an embolic source is present. The finding of MES justifies an extensive clinical and laboratory search for potential embolic sources including extracranial and intracranial colour-coded duplex ultrasound, ECG, Holter-ECG, and TEE.

The Prognostic Significance of the Overexpression of HER-2/ neu in Korean Gastric Carcinomas and the In Vitro Effects of Anti-HER-2/neu Antibody on Cell Growth in the Gastric Carcinoma Cell Lines.

PURPOSE: The HER2 gene encodes a 185-kd transmembrane glycoprotein receptor (p185(HER2)) that has partial homology with the epidermal growth factor receptor (EGFR) and shares intrinsic tyrosine kinase activity. The HER2 gene has been found to be amplified in various human cancers and to be associated with poor prognosis. The authors investigated the correlation between clinicopathologic factors and the overexpression of the p185(HER2) in Korean gastric adenocarcinoma patients, and determined whether the antiproliferative effects of anti- p185(HER2) antibody can also be observed on gastric cancer cell lines that overexpress this growth factor receptor. MATERIALS AND METHODS: We evaluated the relationship between p185(HER2) overexpression and clinicopathological features in 94 (M: F=52: 42) gastric adenocarcinoma patients (median age 59 years). Protein expression was analysed by immunohistochemical staining in paraffin embedded tissues with monoclonal antibody for p185(HER2). To explore the role of humanized anti-p185(HER2) monoclonal antibody trastuzumab (Herceptin ) in vitro, the growth curve of Korean gastric cancer cells that overexpress the p185(HER2) protein was studied and a cell cycle analysis was performed. RESULTS: p185(HER2) overexpression correlates positively with lymph node metastasis (p=0.002), distant metastasis (p=0.01), AJCC classification (p=0.01), higher relapse rate p=0.001), and a tendential association with the pT stage (p=0.054). p185(HER2) overexpression was found to be more frequent in advanced gastric cancer than early gastric cancer (54.1% vs 24.2%, p=0.008). Patients with overexpression of p185(HER2) were found to have significantly lower relapse-free (p=0.003) and overall survival (p= 0.0004) than patients without overexpression. Among several Korean gastric cancer cell lines, SNU-1, SNU-5, and SNU-620 overexpress p185(HER2). Trastuzumab inhibited the proliferation of p185(HER2) overexpressed Korean gastric cancer cell line by 21% with down-regulation of p185(HER2) protein expression. DNA fluorescence flow cytometry of propidium iodide-stained nuclei showed a reduction in the fraction of the S phase following treatment with trastuzumab. CONCLUSION: S: Taken together, our observations suggest the potential prognostic significance of p185(HER2) overexpression in Korean gastric adenocarcinoma patients and point to the need for further research on this mechanism. This suggests the possible use of p185(HER2) as a therapeutic target in gastric cancer.