Gene expression profiling of epidermal growth factor receptor/KRAS pathway activation in lung adenocarcinoma

We examined the genome-wide expression profiles of 86 primary lung adenocarcinomas and compared them with the mutation status of the four key molecules (EGFR, ERBB2, KRAS and BRAF) in the EGFR/KRAS/BRAF pathway. Unsupervised classification revealed two subtypes (the bronchial type and the alveolar type) of lung adenocarcinoma. Mutually exclusive somatic mutations of the epidermal growth factor receptor (EGFR) gene (36/86, 41.8%), K-ras gene (11/86, 12.8%) and BRAF gene (1/86, 1.1%) were detected. KRAS mutations were observed significantly frequently in bronchial-type tumors, whereas the frequencies of EGFR mutations were similar in both the alveolar and bronchial types. Twenty-seven genes showed increased expression in EGFR-mutated tumors and these included molecules that function in the EGFR/KRAS/BRAF pathway (EGFR, AKT1 and BCR). In particular, expression of BCR, which is required for EGFR protein degradation, was induced by EGF stimulation, suggesting a negative feedback loop in lung cancer. A subgroup of the alveolar type tumors showed significantly better prognosis than other tumors. Integrated analysis of genetic and gene expression profiling aimed to delineate inherent oncogenic pathways in cancer will be valuable not only for the understanding of molecular pathogenesis, but also for discovering novel biomarkers and predicting clinical outcome.     

Retrospective analysis of 27 consecutive patients treated with docetaxel/nedaplatin combination therapy as a second-line regimen for advanced esophageal cancer

Background The aim of this study was to evaluate the efficacy and safety of combination therapy with docetaxel and nedaplatin in advanced esophageal cancer as a second-line regimen in an outpatient setting. Methods Twenty-seven consecutive patients with advanced esophageal cancer who received docetaxel/nedaplatin combination therapy as a second-line regimen were retrospectively evaluated. The combination therapy consisted of intravenous administration of docetaxel 30 mg/m² and nedaplatin 40 mg/m² every 2 weeks. Results The patients received a median of 7.4 cycles of treatment (range, 2–25 cycles ). No complete response was observed, and 3 of the 27 patients (11%) achieved partial responses. The disease control rate (partial response + stable disease) was 52%. The median survival time (MST) was 11.4 months. Severe hematological adverse events (grade 3–4) were: neutropenia (n = 10; 37%) and anemia (n = 5; 19%); there was neither febrile neutropenia nor grade 3-4 thrombocytopenia. Furthermore, no severe nonhematological adverse events or treatment-related deaths were observed. Conclusion Combination therapy of docetaxel with nedaplatin was safe and well tolerated; however, the development of more effective therapy is warranted to improve the prognosis of esophageal cancer.     

Epidermal growth factor receptor mutation status and clinicopathological features of combined small cell carcinoma with adenocarcinoma of the lung

In lung cancer, somatic mutations of epidermal growth factor receptor ( EGFR ) are concentrated in exons 18–21, especially in adenocarcinoma (Ad), but these mutations have rarely been reported in small cell lung carcinoma (SCLC). Combined SCLC is rare, and the EGFR mutation status and its relationship to the clinicopathological features of this tumor type have not yet been elucidated. We retrospectively studied six patients with combined SCLC with Ad components among 64 consecutive patients who underwent resection of SCLC. The clinicopathological features of each patient were reviewed, especially for the distribution pattern of the Ad component and lymph node metastases. EGFR mutations were screened by high-resolution melting analysis in each case, and were confirmed by sequencing of each mutation in the microdissected SCLC or Ad components. Regarding EGFR , no specific mutation was detected in five of the six patients, whereas one female patient who had never smoked had a missense mutation. In this case, both the SCLC and Ad components shared the same mutation in exon 21 (L858R). We identified a patient with combined SCLC with Ad sharing an identical EGFR mutation in both the SCLC and Ad components. In addition to the clinicopathological characteristics of this rare histological type of lung cancer, these findings provide useful information for better understanding the biology, natural history and clinical management of SCLC. ( Cancer Sci 2007; 98: 1714–1719)     

Activation of downstream epidermal growth factor receptor (EGFR) signaling provides gefitinib-resistance in cells carrying EGFR mutation

Patients with pulmonary adenocarcinoma carrying the epidermal growth factor receptor (EGFR) mutation tend to display dramatic clinical response to treatment with the EGFR tyrosine kinase inhibitor gefitinib. Unfortunately, in many cases the cancer cells eventually acquire resistance, and this limits the duration of efficacy. To gain insight into these acquired resistance mechanisms, we first prepared HEK293T cell line stably transfected with either wild-type (WT) or mutant (L858R) EGFR, and then expressed oncogenic K-Ras12V mutant in the latter transfectant. Although 293T cells expressing wild-type EGFR did not show any growth inhibition by gefitinib treatment similarly to the non-transfected cells, the cells expressing the EGFR-L858R were exquisitely sensitive. Consistently, phospho-Akt levels were decreased in response to gefitinib in cells expressing EGFR-L858R but not in cells with EGFR-WT. In contrast, 293T cells expressing both EGFR-L858R and oncogenic K-Ras were able to proliferate even in the presence of high concentration of gefitinib probably by inducing Erk1/2 activation. We also expressed K-Ras12V in the gefitinib-sensitive pulmonary adenocarcinoma cell line PC-9, which harbors an in-frame deletion in the EGFR gene. The activated K-Ras inhibited the effects of gefitinib treatment on cell growth, cell death induction and levels of phospho-Akt, as well as phospho-Erk. These data indicate that activated Ras could substitute most of the upstream EGFR signal, and are consistent with the hypothesis that mutational activation of targets immediately downstream from the EGFR could induce the secondary resistance to gefitinib in patients with lung cancer carrying EGFR mutation.     

Surgical interventions for focal progression of advanced gastrointestinal stromal tumors during imatinib therapy

Background Although imatinib has shown high activity in the majority of patients with advanced gastrointestinal stromal tumors (GIST), it has become clear that secondary resistance appears during chronic therapy. The aim of this study was to retrospectively analyze the safety and prognostic effects of surgical interventions for focal progression during imatinib treatment. Methods Between January 2002 and May 2005, 16 patients who had focal lesions of secondary-resistant GIST to imatinib treatment (male/female, 12 : 4; median age, 62 years) underwent surgical interventions such as resection, radiofrequency ablation, and their combination. Results Postoperative complications, including liver abscess, bile leak, wound infection, and ileus were mostly mild, and the patients recovered with conservative therapy. There was no hospital death. The median time to progression (TTP) of all patients was 5.5 months, and only one patient died of the disease; the others are alive after a median follow up of 12.4 months. Patients with complete resections of resistant lesions (n = 7) showed significantly better median TTP than those with incomplete resections (n = 9; P = 0.014). The impact of curability on focal lesions with secondary resistance was mainly significant in patients with tumors of stomach origin (P = 0.013), and a smaller number (P = 0.014) and smaller size (P = 0.018) of resistant lesions. Overall survival was 100% at 1 year and 75% at 2 years. Conclusion Our study indicates that surgical interventions in patients with GIST resistant to imatinib therapy are efficacious when complete resections are performed, when the lesions are of gastric origin, when the number of lesions is lower, and when the lesions are a smaller size.     

An immunohistochemical evaluation of BMP-2, -4, osteopontin, osteocalcin and PCNA between ossifying fibromas of the jaws and peripheral cemento-ossifying fibromas on the gingiva

The present study examined histological difference between ossifying fibromas (OF, n=5) and peripheral cemento-ossifying fibromas (PCOF, n=7). Bone morphogenetic proteins (BMP)-2 and -4, osteopontin (OPN), osteocalcin (OCN) and proliferating cell nuclear antigen (PCNA) were used for the immunohistochemical examinations. Oxytalan fibers present at the periodontal tissue were stained to determine the tumor cell origin. Many OFs showed high immunohistochemical reactions for BMP-2, -4 and OPN compared to those of PCOFs. PCNA index (IP) of OFs was significantly higher than that of PCOFs. All the PCOFs showed a high expression of oxytalan fibers. Only two OFs exhibited a small number of oxytalan fibers. These results suggest that PCOF has only little ability to form hard tissue and seems to be a reactive lesion. The expression of oxytalan fibers reveals that OF does not only originate from periodontal tissue.     

Validity of recommended minimum dose of prior morphine to initiate transdermal fentanyl patch in prescribing information - multicenter survey of on prescriptions by palliative care specialists in Japan

For initiating the minimum-size (0.25 microg/hour) transdermal fentanyl patch (TDF), 45 mg a day of oral morphine is the recommended minimum dose (RMD) in Japan according to the prescribing information. However, little is known about the validity of the RMD, and we can presume there are many cases where clinicians are inclined to initiate the minimum-size TDF at the early stage contrary to the RMD due to the high morbidity rate of digestive system cancer in Japan. In order to verify the validity of the RMD, we collected 71 retrospective cases where the minimum-size TDF was initiated against the restriction of RMD. The prior morphine (or equivalent doses of other opioids) was prescribed by palliative care specialists at 5 facilities which belong to Symptom Control Research Group (SCORE-G). Then, the side effects and pain control from the 1st to the 4th day were analyzed. The mean age of subjects was 68, and the main reason for initiating TDF therapy was gastrointestinal symptoms (63.4%). The frequency of side effects such as somnolence, nausea, vomiting and constipation did not show a significant correlation with the prior opioid dose.However,severe dyspnea and respiration depression were documented in two patients, and the above rate was three times higher than the nationwide result of the same side effects (0.9 8%). According to the Numeric Rating Scale (from 0: no pain to 10: the worst pain), the pain intensity decreased from 6.6 on the 1st day to 2.8 on the 2nd day, 3.3 on the 3rd day, and 2.9 (p < 0.001) on the 4th day. We conclude that, although introducing the minimum-size TDF against the RMD served to decrease the pain intensity,it raised the side effects on the respiratory system even when prescribed by palliative care specialists. Therefore,the RMD regulation is valid for general practitioners from a medical safety standpoint.     

Hospital procedure volume and survival of cancer patients in Osaka, Japan: a population-based study with latest cases

BACKGROUND: Recent studies reported that hospital procedure volume (i.e. volume of patients per hospital receiving a particular treatment)was directly proportional to cancer survival; however the degree of association might be different according to the primary tumor site, extent of disease and year of diagnosis. We performed a systematical examination of survivals by hospital procedure volume according to the primary site with inclusion of latest cases in Osaka, Japan. METHODS: Individual data on reported cancer cases with active follow-up information and diagnosis between 1994 and 1998 were retrieved from Osaka Cancer Registry's database. The analysed primary sites included oesophagus, stomach, large bowel, liver, gall bladder, pancreas, lung, breast, uterus, ovary, prostate, bladder and lymphoma. Hospitals were ranked as high-, medium-, low- and very low-volume hospitals for every primary site by dividing the number of cancer patients who received treatment in hospitals into four quartiles. RESULTS: The primary sites could be classified into three categories based on the association between hospital procedure volume and cancer survival: In type 1, a better survival was associated with a higher procedure volume as for oesophagus, liver, lung, ovary, prostate, or lymphoma; in type 2, a better survival was associated with a higher procedure volume but there was no significant difference in survival between high- and medium-volume hospitals as for uterus; and in type 3, there was no significant difference in survival among high-, medium- and low-volume hospitals as for stomach, large bowel, gall bladder, pancreas, breast, or bladder sites. CONCLUSIONS: A higher procedure volume was generally associated with a better survival; however, this association could be classified into three types according to the primary site.     

Cancer screening of healthy volunteers using whole-body 18F-FDG-PET scans: The Nishidai clinic study

In order to evaluate the diagnostic performance of cancer screening using whole-body (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) scanning for asymptomatic subjects, we conducted a historical cohort study. The study group comprised 5807 individuals who underwent PET scanning from 2002 to 2003. Each subject had carried out a procedure with whole-body (18)F-FDG-PET scan with some other diagnostic tests. Out of 5807 participants, data from 4881 subjects were analysed. Among them, PET screening revealed abnormal FDG uptake in 562 subjects, and possible or probable malignancy in 324 subjects, and histological diagnosis of cancer in 36 subjects (16 thyroid, seven colon, four lung, five breast, two prostate, and two others) out of them. The overall cancer detection rate was 0.7%, and PET scanning had a sensitivity of 70.6% and a specificity of 94.0%. This result warrants further prospective cohort studies to evaluate the usefulness of PET cancer screening for cancer prevention.