The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers.

PURPOSE: Recent studies reported that clinical responsiveness to gefitinib was associated with somatic mutation of epidermal growth factor receptor (EGFR) gene in non-small cell lung cancers (NSCLC). Here, we investigated the relationship between EGFR mutation and clinicopathologic features. EXPERIMENTAL DESIGN: EGFR mutational status of 120 NSCLCs was determined mainly in EGFR exons 18 to 21 by direct sequence and correlated with clinicopathologic parameters. RESULTS: EGFR mutations were present in 38 cases (32%) and the majority of mutations were in-frame deletions of exon 19 (19 cases) and a missense mutation in exon 21 (18 cases). EGFR mutations were frequently associated with adenocarcinoma (P < 0.0001), never smoker (P < 0.0001), and female gender (P = 0.0001). Of interest, increasing smoke exposure was inversely related to the rate of EGFR mutation (P < 0.0001). Multivariate analysis showed that smoking and histology were independent variables. Furthermore, gender difference was observed for the mutational location (P = 0.01) dominance of exon 19 for males and exon 21 for females. Twenty-one cases were treated with gefitinib and found that EGFR mutation was significantly related to gefitinib responsiveness (P = 0.002). In addition, median survival times of patients with and without EGFR mutations treated with gefitinib were 25.1 and 14.0 months, respectively. Patients with EGFR mutations had approximately 2-fold survival advantage; however, the difference was not significant. CONCLUSIONS: We show that EGFR mutations were significantly related to histology and smoke exposure and were a strong predictive factor for gefitinib responsiveness in NSCLC.     

Hand-assisted laparoscopic surgery for a large gastrointestinal stromal tumor of the stomach

We report two cases of large gastrointestinal stromal tumor (GIST) of the stomach that were successfully treated by hand-assisted laparoscopic surgery (HALS). Two patients, a 56-year-old woman and a 60-year-old man, were admitted to our department for the treatment of a large submucosal tumor of the stomach. After gastrointestinal endoscopy, ultrasonography, computed tomography, and magnetic resonance imaging, we suspected that the masses, measuring 7.0 cm and 8.0 cm in diameter, respectively, were GISTs in the stomach. However, preoperatively, we could not rule out the possibility of malignant neoplasms, because they had been bleeding or gradually growing. Hand-assisted laparoscopic wedge resection was safely performed for the diagnosis and treatment of the submucosal tumor of the stomach. The immunohistochemical diagnosis in both patients was GIST of the stomach with intermediate-grade malignancy. HALS may be a good indication for large GISTs of the stomach that are difficult to diagnose preoperatively, whether they are malignant or benign, because it is safe and minimally invasive, promoting rapid recovery.     

Inhibition of angiogenesis as a mechanism for inhibition by 1alpha-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 of colon carcinogenesis induced by azoxymethane in Wistar rats.

The effects of 1alpha-hydroxyvitamin D3[1alpha(OH)D3] and 1,25-dihydroxyvitamin D3[1,25(OH)2D3] on the incidence of colon tumors induced by azoxymethane and on the labeling index and angiogenesis of colon tumors were investigated in Wistar rats. Rats received 10 weekly injections of 7.4 mg/kg body weight of azoxymethane and i.p. injections of 1alpha(OH)D3 and 1,25(OH)2D3 at lower and higher doses every other day for 45 weeks. Prolonged administration of both 1alpha(OH)D3 and 1,25(OH)2D3 at a higher dose significantly reduced the incidence of colon tumors in week 45. However, administration of 1alpha(OH)D3 or 1,25(OH)2D3 had little or no effect on the histologic type of colon tumors and cancers. Administration of 1alpha(OH)D3 and 1,25(OH)2D3 at higher doses significantly decreased the labeling index, the immuno-histochemical staining for vascular endothelial growth factor and microvessel counts in colon tumors. Our findings suggest that both 1alpha(OH)D3 and 1,25(OH)2D3 inhibit development of colon tumors. A possible mechanism of inhibition of colon carcinogenesis by 1alpha(OH)D3 and 1,25(OH)2D3 is the inhibition of angiogenesis as well as an anti-proliferative effect.     

Attenuation by ambroxol of monochloramine-enhanced gastric carcinogenesis: a possible prevention against Helicobacter pylori-associated gastric carcinogenesis

Effects of acetaminophen (AAP) pretreatment on hepatic aflatoxin B₁ (AFB₁)-DNA binding, cellular proliferation, and AFB₁-induced glutathione S-transferase placental form (GST-P) positive hepatocytes and foci have been examined in young male rats and hamsters. Intraperitoneal (i.p.) dosing of 600 mg AAP 3 h before AFB₁ i.p. injection showed three-fold more AFB₁-DNA binding in hamsters and 40% less binding in rats. Cell proliferation analyzed by bromodeoxyuridine incorporation was not significant (0.4–0.6%) 24–96 h after AAP (600 mg) treatment of rats; however, proliferation was stimulated and was maximum (11%) in hamsters at 72 h after AAP treatment. Dosing of rats with AFB₁ alone at 0.5 or 2.5 mg level gave an appreciable number of GST-P positive minifoci (two to nine cells) with a few foci larger than 100 μm; pretreatment with AAP (300 or 600 mg) 48 h before 0.5 or 2.5 mg AFB₁ had no effect on the number and focal area of foci. In hamsters, 1 or 2 mg AFB₁ alone yielded GST-P positive hepatocytes without any minifoci. Pretreatment with AAP (600 mg) 48 or 72 h before 1 or 2 mg AFB₁ produced increases in both GST-P positive hepatocytes and minifoci. Thus, marked changes are observed after AAP pretreatment in hamsters compared to rats.     

Receptor ligand-triggered resistance to alectinib and its circumvention by Hsp90 inhibition in EML4-ALK lung cancer cells

Alectinib is a new generation ALK inhibitor with activity against the gatekeeper L1196M mutation that showed remarkable activity in a phase I/II study with echinoderm microtubule associated protein-like 4 (EML4) - anaplastic lymphoma kinase (ALK) non-small cell lung cancer (NSCLC) patients. However, alectinib resistance may eventually develop. Here, we found that EGFR ligands and HGF, a ligand of the MET receptor, activate EGFR and MET, respectively, as alternative pathways, and thereby induce resistance to alectinib. Additionally, the heat shock protein 90 (Hsp90) inhibitor suppressed protein expression of ALK, MET, EGFR, and AKT, and thereby induced apoptosis in EML4-ALK NSCLC cells, even in the presence of EGFR ligands or HGF. These results suggest that Hsp90 inhibitors may overcome ligand-triggered resistance to new generation ALK inhibitors and may result in more successful treatment of NSCLC patients with EML4-ALK.     

Change in Nutritional Status during Hospitalization and Prognosis in Patients with Heart Failure with Preserved Ejection Fraction

The impact of changes in nutritional status during hospitalization on prognosis in patients with heart failure with preserved ejection fraction (HFpEF) remains unknown. We examined the association between changes in the Geriatric Nutritional Risk Index (GNRI) and prognosis during hospitalization in patients with HFpEF stratified by nutritional status on admission. Nutritional status did and did not worsen in 348 and 349 of 697 patients with high GNRI on admission, and in 142 and 143 of 285 patients with low GNRI on admission, respectively. Kaplan–Meier analysis revealed no difference in risk of the composite endpoint, all-cause death, or heart failure admission between patients with high GNRI on admission whose nutritional status did and did not worsen. In contrast, patients with low GNRI on admission whose nutritional status did not worsen had a significantly lower risk of the composite endpoint and all-cause death than those who did. Multivariable analysis revealed that worsening nutritional status was independently associated with a higher risk of the composite endpoint and all-cause mortality in patients with low GNRI on admission. Changes in nutritional status during hospitalization were thus associated with prognosis in patients with malnutrition on admission, but not in patients without malnutrition among those with HFpEF.     

Pilot study of the optimal protocol of low dose step‐up follicle stimulating hormone therapy for infertile women

Purpose

To evaluate the optimized protocol of low dose follicle‐stimulating hormone (FSH) therapy that has a starting dose of 50 IU/62.5 IU with a small increment dose (12.5 IU) for women with World Health Organization (WHO) II ovulatory disorder and unexplained infertility.

Methods

Anovulatory women with WHO group II ovulatory disorder (ovulation induction [OI] patients, n = 29), and with an unexplained infertility (ovarian stimulation [OS] patients, n = 21) were enrolled. The protocol of low dose step‐up FSH therapy was optimized for the starting dose as 50 IU (body mass index [BMI] < 20 group) and 62.5 IU (BMI ≥ 20 group) with the increment dose of 12.5 IU. Study outcomes were ovulation, monofollicular development and other variables.

Results

In the OIpatients, the ovulation rate was 100% (BMI < 20 group) and 90.9% (BMI ≥ 20 group). Monofollicular development was 80.0% (BMI < 20) and 77.3% (BMI ≥ 20). The pregnancy rate was 60% (3/5 BMI < 20) and 18.2% (4/22 BMI ≥ 20). There was no multiple pregnancy. In the OSpatients, the ovulation rate was 100%. Monofollicular development was 85.7% (BMI < 20) and 76.6% (BMI ≥ 20). No pregnancy was achieved in the OSpatients.

Conclusion

Optimized protocol of low dose FSH therapy setting a starting dose 50 IU/62.5 IU by BMI with an increment dose of 12.5 IU was safe and highly effective in WHO group II anovulatory patients. However, this protocol seemed uneffective for patients with unexplained infertility.