Gender differences in prognosis after esophagectomy for esophageal cancer

Purpose

The purpose of this study was to clarify the gender differences in the prognosis, as well as mortality and morbidity, of patients who have undergone esophagectomy for esophageal cancer.

Methods

The clinical results of esophagectomy were compared between 975 male and 156 female patients with esophageal cancer.

Results

The male to female ratios of cervical and thoracic esophageal cancer were 1.87 and 7.38, respectively (P < 0.01). The incidence of preoperative comorbidities was 32.4 and 17.4 %, respectively, and the rates of both tobacco and alcohol abuse were significantly lower in the females than in the males. The mortality rate was lower in the females (3.8 %) than in the males (5.7 %), although the differences were not significant. The overall survival was significantly better in the female than in the male patients (P = 0.039). The 5- and 10-year overall survival rates were 32.6 and 20.5 % in the males and 39.5 and 32.5 % in the females, respectively. A multivariate analysis revealed gender to be an independent prognostic factor. However, no significant differences were recognized in disease-specific survival.

Conclusions

These results suggest that the prognosis of females with esophageal cancer is better than that of males after esophagectomy, most likely due to multiple clinical factors, such as a more favorable lifestyle and general status.     

Surgical strategies for esophageal cancer associated with head and neck cancer

Esophageal cancer is frequently associated with squamous cell carcinoma in the head and neck. Both cigarette smoking and alcohol consumption are risk factors for multiple cancers of the head and neck, as well as the esophagus. Routine screening and close follow-up for second cancers are important in patients with esophageal cancer or head and neck cancer. For this purpose, endoscopy with Lugol’s staining, as well as narrow-band imaging combined with magnifying endoscopy, is a powerful tool for the early detection of esophageal cancer. Multimodal therapy is essential for patients with double cancers. When considering surgical treatment, the curability of both cancers must be carefully evaluated. If both tumors are potentially curable, each lesion should be treated individually. In patients with metachronous double cancers, the prior treatment of the first primary carcinoma often affects the treatment of the second cancer. Close cooperation among medical staff members is essential for complicated surgeries for double cancers. Techniques that are appropriate for each case must be adopted, such as careful dissection, staged operations, muscular flaps and microvascular anastomosis.     

Preoperative evaluation and indications for pulmonary metastasectomy

Pulmonary metastasectomy (PM) is an established treatment that can provide improved long-term survival for patients with metastatic tumor(s) in the lung. In the current era, where treatment options other than PM such as stereotactic body radiation therapy (SBRT), immunotherapy, and molecular-targeted therapy are available, thoracic surgeons should review the approach to the preoperative evaluation and the indications. Preoperative evaluation consists of history and physical examinations, physiological tests, and radiological examinations. Radiological examinations serve to identify the differential diagnosis of the pulmonary nodules, evaluate their precise number, location, and features, and search for extra thoracic metastases. The indication of PM should be considered from both physiological and oncological points of view. The general criteria for PM are as follows; (I) the patient has a good general condition, (II) the primary malignancy is controlled, (III) there is no other extrapulmonary metastases, and (IV) the pulmonary lesion(s) are thought to be completely resectable. In addition to the general eligibility criteria of PM, prognostic factors of each tumor type should be considered when deciding the indication for PM. When patients have multiple poor prognostic factors and/or a short disease-free interval (DFI), thoracic surgeons should not hesitate to observe the patient for a certain period before deciding on the indication for PM. A multidisciplinary discussion is needed in order to decide the indication for PM.     

Comparative study of the loop-mediated isothermal amplification method and the QIAGEN therascreen PCR kit for the detection of EGFR mutations in non-small cell lung cancer

BackgroundEpidermal growth factor receptor (EGFR) mutations are important biomarkers in the treatment of patients with advanced or metastatic diseases. The therascreen EGFR Rotor-Gene Q (RGQ) PCR Kit^® (Qiagen, Inc.) is an approved diagnostic test for EGFR mutations in non-small cell lung cancer (NSCLC). This study aims to investigate the diagnostic capability of a loop-mediated isothermal amplification (LAMP) assay as an accurate, efficient, and cost-effective alternative to the therascreen assay.MethodsEGFR mutations were investigated by LAMP and therascreen assays using tissue samples that were surgically resected or biopsied from 117 consecutive patients with NSCLC tumors. The EGFR status from the LAMP assay was compared with that of the therascreen assay. Next-generation sequencing (NGS) was performed to confirm EGFR status of tumors that did not match in both assays. To establish an optimal LAMP AUC value, receiver operating characteristics (ROC) curve analysis was performed within tumors with exon 19 deletion or L858R point mutation.ResultsOf the 117 tumors assayed, 45 tumors with EGFR mutations and 68 tumors with EGFR wild type were matched in both assays, four tumors having mismatched EGFR statuses. NGS further confirmed that two of the four discordant tumors had the same EGFR status that was determined by the LAMP assay. The AUC values were 0.973 (95% CI: 0.929–1.00) in exon 19 deletion, and 0.952 (95% CI: 0.885–1.00) in L858R point mutation. In exon 19 deletion, sensitivity, specificity, and accuracy were 89.3%, 98.9%, and 96.6%, respectively, and 94.7%, 95.9%, and 95.7%, respectively, in L858R using AUC value of 0.222.ConclusionsThe LAMP assay compared favorably with the therascreen assay and has potential as an effective, simple, rapid, and low-cost diagnostic alternative. Based on these results, a liquid biopsy LAMP system should be developed for point-of-care testing of oncogenes in the near future.     

Characterization of a novel missense mutation E637K in the pore-S6 loop of HERG in a patient with long QT syndrome

OBJECTIVE: In a 32-year-old woman with marked QT prolongation (QTc=0.61 s) and repeated episodes of syncope, we identified a single pertinent base substitution (G to A at 1909) in HERG by genetic analysis. This novel missense mutation is predicted to cause an amino acid substitution of lysine for glutamic acid at position 637 (E637K) in the pore-S6 loop. Therefore, we investigated the role of a glutamic acid at the vicinity of the pore in HERG channels by mutating it to a lysine. METHODS: We characterized the electrophysiological properties of the E637K mutation using a Xenopus oocyte heterologous expression system. RESULTS: Injection of the E637K mutant cRNA alone into Xenopus oocytes did not result in any expression of detectable currents. Coexpression of wild-type (WT) and E637K (E637K/WT) elicited only about 30% of the control peak tail current that was expected from expression of WT alone. Kinetic analyses revealed that E637K/WT decelerated the rate of channel activation and enhanced steady-state inactivation. Furthermore, the reversal potentials at low concentrations of K+ showed a positive shift in oocytes injected with E637K/WT compared with WT alone. CONCLUSIONS: These results indicated that the E637K mutation causes apparent dominant negative suppression of WT HERG channel function and suggest that E637 at the Pore-S6 is a crucial component of the activation and inactivation gate of HERG channels.     

Modulation of potassium channel function by methionine oxidation and reduction

Oxidation of amino acid residues in proteins can be caused by a variety of oxidizing agents normally produced by cells. The oxidation of methionine in proteins to methionine sulfoxide is implicated in aging as well as in pathological conditions, and it is a reversible reaction mediated by a ubiquitous enzyme, peptide methionine sulfoxide reductase. The reversibility of methionine oxidation suggests that it could act as a cellular regulatory mechanism although no such in vivo activity has been demonstrated. We show here that oxidation of a methionine residue in a voltage-dependent potassium channel modulates its inactivation. When this methionine residue is oxidized to methionine sulfoxide, the inactivation is disrupted, and it is reversed by coexpression with peptide methionine sulfoxide reductase. The results suggest that oxidation and reduction of methionine could play a dynamic role in the cellular signal transduction process in a variety of systems.     

Spherical aggregates of beta-amyloid (amylospheroid) show high neurotoxicity and activate tau protein kinase I/glycogen synthase kinase-3beta

beta-Amyloid (Abeta) acquires toxicity by self-aggregation. To identify and characterize the toxic form(s) of Abeta aggregates, we examined in vitro aggregation conditions by using large quantities of homogenous, chemically synthesized Abeta1-40 peptide. We found that slow rotation of Abeta1-40 solution reproducibly gave self-aggregated Abeta1-40 containing a stable and highly toxic moiety. Examination of the aggregates purified by glycerol-gradient centrifugation by atomic force microscopy and transmission electron microscopy revealed that the toxic moiety is a perfect sphere, which we call amylospheroid (ASPD). Other Abeta1-40 aggregates, including fibrils, were nontoxic. Correlation studies between toxicity and sphere size indicate that 10- to 15-nm ASPD was highly toxic, whereas ASPD <10 nm was nontoxic. A positive correlation between the toxicity and ASPD >10 nm also appeared to exist when Abeta1-42 formed ASPD by slow rotation. However, Abeta1-42-ASPD formed more rapidly, killed neurons at lower concentrations, and showed approximately 100-fold-higher toxicity than Abeta1-40-ASPD. The toxic ASPD was associated with SDS-resistant oligomeric bands in immunoblotting, which were absent in nontoxic ASPD. Because the formation of ASPD was not disturbed by pentapeptides that break beta-sheet interactions, Abeta may form ASPD through a pathway that is at least partly distinct from that of fibril formation. Inhibition experiments with lithium suggest the involvement of tau protein kinase I/glycogen synthase kinase-3beta in the early stages of ASPD-induced neurodegeneration. Here we describe the identification and characterization of ASPD and discuss its possible role in the neurodegeneration in Alzheimer's disease.     

Risk stratification of patients with non-ST-elevation acute coronary syndromes by assessing global longitudinal strain

Noninvasive detection of left main/three-vessel diseases (LM/3VD) among patients with non-ST-elevation acute coronary syndromes (NSTEACS) has been difficult using echocardiography. However, two-dimensional (2D) strain/strain-rate analysis is more sensitive in quantitatively assessing contractile abnormality. Accordingly, we aimed to clarify the usefulness of 2D strain/strain-rate analysis for risk stratification of NSTEACS. A total of 50 patients with NSTEACS underwent echocardiography and coronary angiography. We evaluated global longitudinal peak strain (global PS), peak systolic strain rate (global SSR), early diastolic global peak strain rate (global ESR), time from aortic valve closure to peak strain (TAVC-global PS), and global ESR (TAVC-global ESR) in apical four-, two-, and three-chamber views. Patients were divided into two groups according to coronary angiographic findings, the high-risk group (n = 15) with either of left main or three-vessel disease, and the low-risk group (n = 35). There were no significant differences in global SSR and global ESR between the two groups. The amplitude of global PS was significantly reduced in high-risk patients with LM/3VD in comparison with low-risk patients (?17.5 ± 2.4 % vs ?19.8 ± 2.7 %, P = 0.007, respectively). TAVC-global PS and TAVC-global ESR were significantly prolonged in high-risk patients with LM/3VD in comparison with low-risk patients (15.3 ± 25.7 ms vs ?36.8 ± 32.7 ms, P < 0.0001 and 162.8 ± 32.7 ms vs 135.7 ± 41.5 ms, P < 0.03, respectively). Receiver-operating characteristic analysis demonstrated that TAVC-global PS most strongly detected high-risk patients with sensitivity of 100 % and specificity of 74.3 % (area under the curve = 0.938, 95 % confidence interval 0.832–0.986, P = 0.0001). Temporal analysis of 2D strain appeared to be useful in detecting high-risk patients with LM/3VD among patients with NSTEACS.