Prognostic impact of circumferential resection margin in esophageal cancer with or without neoadjuvant chemoradiotherapy.

The prognostic impact of circumferential resection margin (CRM) in surgically resected esophageal squamous cell carcinoma (ESCC) has been controversial. This investigation assessed the prognostic impact of CRM in surgically resected pathologic T3 ESCC patients with or without neoadjuvant chemoradiotherapy (nCRT). We reviewed consecutive p/yp T3 ESCC patients undergoing esophagectomy from two medical centers between January 2009 and December 2016. The cohort was divided into two groups: upfront esophagectomy (upfront surgery) and nCRT followed by esophagectomy (nCRT + surgery). CRM status was assessed and divided into CRM > 1 mm, 0 < CRM < 1 mm, and tumor at CRM. A total of 217 p/yp T3 ESCC patients undergoing esophagectomy (138 patients in the upfront surgery group and 79 in the nCRT + surgery group) were enrolled. In the upfront surgery group, patients with 0 < CRM < 1 mm showed equivalent overall survival to those with CRM > 1 mm (log-rank P = 0.817) and significantly outlived those with tumor at CRM (log-rank P < 0.001). However, in the nCRT + surgery group, CRM > 1 mm failed to show survival superiority to CRM between 0 and 1 mm or involved by cancer (log-rank P = 0.390). In conclusion, a negative CRM, even though being <1 mm, is adequate for pT3 ESCC patients undergoing upfront esophagectomy. In contrast, the CRM status is less prognostic in ypT3 ESCC patients undergoing nCRT followed by esophagectomy.

Thrombotic Ringed Polytetrafluoroethylene Graft With Infection After Living-Donor Liver Transplantation.

BACKGROUND: The safety of the living donor in living-donor liver transplantation (LDLT) is always the first priority, meanwhile, the graft-to-recipient weight ratio (GRWR) and the anatomy of the liver allograft must also not be compromised in order to warrant tranplatation success. When it comes to the allograft of the right lobe of the liver without the middle hepatic vein (R-M), the outflow and adequate drainage for the territory of middle hepatic vein (MHV) is one critical concern. Despite publications in some high-volume transplant centers on the positive results of using expanded polytetrafluoroethylene (ePTFE) grafts to substitute those of autologous veins, complications related to the ePTFE graft have not been well discussed. METHODS: From July 2012 to June 2016, 129 adult patients who underwent living donor liver transplantation in Taipei Veterans General Hospital were analyzed. There were 3 cases of adjacent organ erosion with gas bubbles in the lumen of an ePTFE graft, including gastrointestinal (GI) tract penetration in 2 out of the first 15 cases that used the venous graft of ringed expanded polytetrafluoroethylene (rPTFE). The patient survival rate during this period was compared and radiological findings of rPTFE function and clinical signs of erosion with infection were also examined to raise the concerns of safety as well as early detection of complications of rPTFE. RESULTS: The overall 1-year patient survival rate was 90%, of which the right lobe wih MHV (R+M) group was 93.5% and the R-M group was 91.9%. For the mean of GRWR, the R+M group was 1.05 ± 0.19 and R-M group was 1.19 ± 0.27, while those who needed reconstruction with vein grafts was 0.96 ± 0.11. Among the R-M group, 24 out of 88 cases (27.3%) needed reconstruction of MHV tributaries. Of the 24 cases, 15 cases were done with rPTFE and the 1-year patient survival rate of the rPTFE group was 73%, which is significantly worse (P = .008) than the non-rPTFE (89%) and non-reconstructed (97%) groups. The mean GRWR is significantly higher (P = .001) in the non-reconstructed group (1.19 ± 0.27) than in the rPTFE (0.99 ± 0.11) and non-rPTFE (0.94 ± 0.11) groups. The venous grafts patency rate between the different graft types is no different, and there is also significance in warm ischemic time (P = .009) between the non-reconstructed (49 ± 15), rPTFE (81 ± 51), and non-rPTFE (56 ± 18) groups in the mean minutes. CONCLUSION: In cases of fever of unknown cause in patients receiving LDLT with rPTFE graft, a regular computed tomography (CT) scan with contrast and gas bubbles within the graft lumen is the best way for early detection of graft related infection and suspicious GI tract penetration. To decrease the risks of tissue reaction induced by ePTFE graft in LDLT, omentum patches or other inert agents can be introduced as a buffer between the graft and adjacent organs, especially the GI tracts. However, research in material science shall be explored to solve the problem in the future.

Long-term results of coronary artery bypass grafting in patients with dialysis-dependent renal failure.

AIM: Coronary artery disease is the main cause of mortality and morbidity in dialysis-dependent renal failure patients. Both the prevalence and incidence of renal failure are high in Taiwan. However, there were few reports exploring the outcome of coronary aortic bypass grafting (CABG) in these patients. The aim of this study was to determine the survival outcome and risk factors for mortality from CABG in this population. METHODS: The operative, early postoperative and late results of 170 dialysis patients undergoing isolated coronary artery bypass grafting from January, 2000 to January, 2012 were retrospectively reviewed. Operative mortality, long-term survival, and risk factors were analyzed. RESULTS: One hundred and seventeen patients (68.8%) were male, and the mean age was 61.5±10.3 years (range, 34-86 years). Follow-up was 40.3±32.1 months. Operative mortality was 8.2%. Actuarial survival, including operative mortality, was 81±3% at 1 year, 68±4% at 3 years, 58±5% at 5 years and 49±6% at 10 years, better than the natural course of dialysis-dependent renal failure patients. Age, emergent operation, postoperative ventricular tachycardia or fibrillation, postoperative intra-aortic balloon pump insertion, gastrointestinal bleeding, and left internal mammary artery graft were significant predictors of operative or long term mortality. Most causes of late death were due to infection or cardiac events. CONCLUSION: CABG in dialysis patients is associated with a higher incidence of complications, but has acceptable mortality. CABG is beneficial in this population. Internal mammary artery grafting may provide more favorable long term outcomes.

Exploratory modeling and simulation to support development of motesanib in Asian patients with non-small cell lung cancer based on MONET1 study results.

The motesanib phase III MONET1 study failed to show improvement in overall survival (OS) in non-small cell lung cancer, but a subpopulation of Asian patients had a favorable outcome. We performed exploratory modeling and simulations based on MONET1 data to support further development of motesanib in Asian patients. A model-based estimate of time to tumor growth was the best of tested tumor size response metrics in a multivariate OS model (P < 0.00001) to capture treatment effect (hazard ratio, HR) in Asian patients. Significant independent prognostic factors for OS were baseline tumor size (P < 0.0001), smoking history (P < 0.0001), and ethnicity (P < 0.00001). The model successfully predicted OS distributions and HR in the full population and in Asian patients. Simulations indicated that a phase III study in 500 Asian patients would exceed 80% power to confirm superior efficacy of motesanib combination therapy (expected HR: 0.74), suggesting that motesanib combination therapy may benefit Asian patients.

Risk factors for liver abscess formation in patients with blunt hepatic injury after non-operative management.

PURPOSE: To identify risk factors for liver abscess formation in patients with blunt hepatic injury who underwent non-operative management (NOM). METHODS: From January 2004 to October 2008, retrospective data were collected from a single level I trauma center. Clinical data, hospital course, and outcome were all extracted from patient medical records for further analysis. RESULTS: A total of 358 patients were enrolled for analysis. There were 13 patients with liver abscess after blunt hepatic injury. Patients with abscess had a significant increase in glutamic oxaloacetic transaminase (GOT, p = 0.006) and glutamic pyruvic transaminase (GPT, p < 0.0001), and a decrease in arterial blood pH (p = 0.023) compared to patients without abscess in the univariate analyses. In addition, high-grade hepatic injury and transarterial embolization (TAE, p < 0.001) were also risk factors for liver abscess formation. Five factors (GOT, GPT, pH level in the arterial blood sample, TAE, and high-grade hepatic injury) were included in the multivariate analysis. TAE, high-grade hepatic injury, and GPT level were statistically significant. The odds ratios of TAE and high-grade hepatic injury were 15.41 and 16.08, respectively. A receiver operating characteristic (ROC) analysis was used for GPT, and it suggested cutoff values of 372.5 U/L. A prediction model based on the ROC analysis had 100 % sensitivity and 86.7 % specificity to predict liver abscess formation in patients with two of the three independent risk factors. CONCLUSIONS: TAE, high-grade hepatic injury, and a high GPT level are independent risk factors for liver abscess formation.

Activation of transient receptor potential vanilloid 1 decreases endothelial nitric oxide synthase phosphorylation at Thr497 by protein phosphatase 2B-dependent dephosphorylation of protein kinase C.

AIMS: We investigated the effects and underlying molecular mechanism of transient receptor potential vanilloid 1 (TRPV1), a calcium (Ca(2+) )-permeable non-selective cation channel, on phosphorylation of endothelial nitric oxide synthase (eNOS) at threonine 497 (Thr497) in bovine aortic endothelial cells (BAECs) and in mice. METHODS: Western blotting and immunoprecipitation were used for the evaluation of protein phosphorylation; protein phosphatase 2B (PP2B) activity was assessed by convention kit; Griess assay was for NO production; tube formation and Matrigel plug assay were used for angiogenesis. RESULTS: In BAECs, treatment with the TRPV1 ligand evodiamine decreased the phosphorylation of eNOS at Thr497, protein kinase Cα (PKCα) at Serine 657 (Ser657) and PKCß2 at Ser660. Evodiamine increased protein phosphatase 2B (PP2B) activity and promoted the formation of a PP2B-PKC complex. Inhibition of TRPV1 activation by the pharmacological antagonists, removal of extracellular Ca(2+) or pharmacological inhibition of PI3K/Akt/calmodulin-dependent protein kinase II/AMP-activated protein kinase signalling pathway abolished the evodiamine-induced alterations in phosphorylation of eNOS at Thr497, PKCα at Ser657, PKCß2 at Ser660 and PP2B activity, as well as the formation of a PP2B-PKC complex. Inhibition of PP2B activation partially reduced the evodiamine-induced NO bioavailability and tube formation in endothelial cells (ECs) and angiogenesis in mice. Moreover, evodiamine decreased the phosphorylation of eNOS at Thr497, PKCα at Ser657 and PKCß2 at Ser660 in apolipoprotein E (ApoE)-deficient mouse aortas but not TRPV1-deficient or ApoE/TRPV1 double-knockout mice. CONCLUSION: TRPV1 activation in ECs may elicit a Ca(2+) -dependent effect on PP2B-PKC signalling, which leads to dephosphorylation of eNOS at Thr497 in ECs and in mice.

Thioflavin T and its photoirradiative derivatives: exploring their spectroscopic properties in the absence and presence of amyloid fibrils.

In this work, we found that, during storage or after UV irradiation, ThT is demethylated or oxidized, forming three derivatives. These three derivatives were purified by high performance liquid chromatography and characterized by mass and nuclear magnetic resonance spectroscopy and the spectroscopic properties of pure ThT and the derivatives carefully compared. Our results show that the emission peak at 450 nm results from oxidized ThT and not from the monomeric form of ThT, as previously proposed. The partial conversion of ThT into oxidized and demethylated derivatives has an effect on amyloid detection using ThT assay. Irradiated ThT has the same lag time as pure ThT in the amyloidogenesis of insulin, but the intensity of the emitted fluorescence is significantly decreased.

Simulations using a drug-disease modeling framework and phase II data predict phase III survival outcome in first-line non-small-cell lung cancer.

Simulations were performed for carboplatin/paclitaxel (C/P) plus motesanib or bevacizumab vs. C/P as first-line treatment for advanced non-small-cell lung cancer (NSCLC) using a published drug-disease model. With 700 patients in each arm, simulated hazard ratios for motesanib (0.87; 95% confidence interval [CI], 0.71-1.1) and bevacizumab (0.89; 95% CI, 0.73-1.1) agreed with results from the respective phase III studies but did not discriminate between failed and successful studies. The current model may require further enhancement to improve its utility for predicting phase III outcomes.

Oral coadministration of ß-glucuronidase to increase exposure of extensively glucuronidated drugs that undergo enterohepatic recirculation.

Extensive first-pass metabolism can significantly limit a drug's oral exposure levels. In this work, we introduce an innovative approach for increasing the oral bioavailability of a drug that undergoes extensive reversible glucuronidation and enterohepatic recirculation through intraduodenal coadministration of the deconjugating enzyme ß-glucuronidase. Intraduodenal administration of JNJ-10198409 (10 mg/kg) with ß-glucuronidase (34,000-140,000 units/kg) to catheterized rats resulted in a significant increase (p < 0.005) in the mean area under the plasma concentration versus time curve (AUC; approx. threefold) and maximum plasma concentration (C(max); approx. twofold) of JNJ-10198409. The AUC and C(max) were 60 ± 18 ng h/mL and 76 ± 29 ng/mL, respectively, with no enzyme and 177 ± 55 ng h/mL and 129 ± 41 ng/mL, respectively, with ß-glucuronidase coadministered. Moreover, the AUC of the primary glucuronide metabolite increased approximately sevenfold from 1173 ± 361 (ng h)/mL with no enzyme coadministered to 8723 ± 2133 ng h/mL with coadministered enzyme. These pharmacokinetic data support the hypothesis that when the primary glucuronide is secreted into the duodenum via the bile duct, the glucuronide is converted by ß-glucuronidase back to the parent compound. The parent compound is then reabsorbed and reconjugated, resulting in elevated systemic exposures to both parent and glucuronide. Potential clinical and preclinical applications and considerations for this approach are discussed.

Clinical significance of tumor suppressor PTEN in colorectal carcinoma.

BACKGROUND: It has been demonstrated that the deletion, mutation, hypermethylation and subcellular location of the tumor suppressor phosphatase and tensin homologue (PTEN) are closely correlated with carcinogenesis, progression and prognosis of malignancy. Both mutation and the microsatellite instability of the PTEN gene influence regulation of the PI3K/Akt signaling pathway. This study investigated whether loss of nuclear PTEN is correlated with chemosensitivity, clinicopathological parameters and survival. METHODS: Intracellular levels of PTEN of multiple cell lines of colorectal carcinoma (CRC) were evaluated by Western blotting and immunocytochemistry. The chemosensitivity of cell lines with various expression levels of PTEN was evaluated using 5-flurouracil (5-FU), oxaliplatin and irinotecan (CPT), and clinical significance was evaluated by immunohistochemical analysis of 133 CRC specimens. RESULTS: Colon cancer cell lines HT-29, LoVo and SW480 differed in expression of PTEN, with high, moderate and low levels, respectively. HT-29 and LoVo PTEN expression was suppressed by a low concentration of 5-FU and oxaliplatin; however, SW480 was insensitive to these chemotherapeutic agents. Nuclear PTEN was overexpressed in most (>80%) normal colon mucosa samples, but the incidence significantly decreased (89.2% → 53.4%) in the CRC group. PTEN in the nucleus was negatively correlated with tumor size and vascular invasion in CRC, and CRC patients with negative PTEN expression in the nucleus exhibited poor survival. CONCLUSION: Cell lines with a high expression of PTEN are sensitive to chemotherapy with 5-FU and oxaliplatin. Nuclear PTEN expression gradually decreases after malignant transformation, and loss of PTEN expression in the nucleus is associated with tumor progression and poor clinical outcome in CRC.

Phase 1 study of conatumumab, a pro-apoptotic death receptor 5 agonist antibody, in Japanese patients with advanced solid tumors.

PURPOSE: Conatumumab is a fully human monoclonal agonist antibody against human death receptor 5 (DR5). The primary objectives of this phase 1 study were to assess the safety, tolerability, and pharmacokinetics (PK) of conatumumab in Japanese patients with advanced solid tumors. METHODS: This is an open-label ascending dose study with a starting dose level of 3 mg/kg. Subsequent doses of 10 and 20 mg/kg were planned. Six patients were enrolled into 1 of 3 dose cohorts (3, 10, or 20 mg/kg) of conatumumab administered intravenously once every 2 weeks as a single agent. No conatumumab was administered on day 43 to allow the assessment of terminal PK parameters. The primary endpoints were the incidence of dose-limiting toxicities (DLTs) and assessment of PK parameters of conatumumab. RESULTS: Eighteen patients received at least 1 dose of conatumumab. There were no DLTs observed as defined in the protocol. No patients had an adverse event leading to conatumumab discontinuation. Conatumumab demonstrated dose-linear kinetics. A best response of stable disease was reported in nine patients. Monocytes were found to express DR5 and showed a high degree of conatumumab receptor occupancy after treatment at all dose levels. CONCLUSIONS: Conatumumab administered up to 20 mg/kg once every 2 weeks was well tolerated in Japanese patients with advanced solid tumors. Adverse events and PK in these patients were similar to those in the first in human (FIH) study.

Pre-tracheal lymph node metastasis in squamous cell carcinoma of the thoracic esophagus.

AIMS: To clarify the incidence of pre-tracheal lymph node metastasis in squamous cell carcinoma of the esophagus, and their impact on survival. METHODS: A cohort of 101 patients with squamous cell carcinoma of the thoracic esophagus who underwent esophagectomy together with 2-field lymphadenectomy including the pre-tracheal region was analysed, retrospectively. The p-TNM staging included stage I in 9, stage IIa in 33, stage IIb in 4, stage III in 43, and stage IV in 12 cases. RESULTS: Nodal metastases were identified in 56 patients (55.4%). Subcarinal lymph node and pre-tracheal lymph-node metastases were found in 24 patients (23.8%) and 15 patients (14.9%), respectively. The 5-year cumulative survival rates were 26.5 and 2.5% in nodal negative and nodal positive patients, respectively. Patients with pre-tracheal nodal metastasis all died within 2 years. Cox proportional hazards model in patients with nodal involvement revealed T-factor (p=0.0017), pre-tracheal nodal involvement (p=0.0055) and distant metastasis (p=0.0024) as independent prognostic factors. CONCLUSIONS: Our findings suggest that pre-tracheal lymph node metastasis indicates a dismal prognosis. Its occurrence is not unusual, especially in tumour of upper or middle thoracic esophagus. The subcarinal node cannot be regarded as a sentinel node of the pre-tracheal nodal station. Complete lymphadenectomy excluding the pre-tracheal lymph nodes in treating esophageal cancers is only a myth.

Development and characterization of an immobilized human organic cation transporter based liquid chromatographic stationary phase.

Membranes from a stably transfected cell line that expresses the human organic cation 1 transporter (hOCT1) have been immobilized on the immobilized artificial membrane (IAM) liquid chromatographic stationary phase to form the hOCT1(+)-IAM stationary phase. Membranes from the parent cell line that does not express the hOCT1 were also immobilized to create the hOCT1(-)-IAM stationary phase. Columns were created using both stationary phases, and frontal displacement chromatography experiments were conducted using [(3)H]-methyl phenyl pyridinium ([(3)H]-MPP(+)) as the marker ligand and MPP(+), verapamil, quinidine, quinine, nicotine, dopamine and vinblastin as the displacers. The K(d) values calculated from the chromatographic studies correlated with previously reported K(i) values (r(2)=0.9987; p<0.001). The data indicate that the hOCT1(+)-IAM column can be used for the on-line determination of binding affinities to the hOCT1 and that these affinities are comparable to those obtained using cellular uptake studies. In addition, the chromatographic method was able to identify a previously undetected high affinity binding site for MPP(+) and to determine that hOCT1 bound (R)-verapamil to a greater extent than (S)-verapamil.

Comparison between the right side and subxiphoid bilateral approaches in performing video-assisted thoracoscopic extended thymectomy for myasthenia gravis.

BACKGROUND: This study aimed to compare the efficacy of the right thoracoscopic (RtT) approach and the subxiphoid bilateral thoracoscopic (SxBiT) approach in performing thymectomy for myasthenia gravis. METHODS: Between March 2001 and April 2003, 27 myasthenic patients were enrolled in this prospective study. The operations were conducted by two surgical teams in a single institute. The surgical procedures included RtT for 12 patients and SxBiT for 15 patients. The operation time, resected thymus weights, and thoracic drainage periods were compared. RESULTS: Subxiphoid video-assisted thoracoscopic extended thymectomy (SxVATET) and right-side thoracoscopic extended thymectomy (RtVATET) were performed for 27 consecutive myasthenic patients. The mean operation time, weights of resected specimens, and duration of hospital stay for the SxVATET and RtVATET groups were, respectively, 151.3 min (range, 120-200 min) versus 191.5 min (range, 120-225 min) (p = 0.0012), 73.3 g (range, 40-90 g) versus 50.8 g (range, 5-90 g) (p = 0.0029), and 3.1 days (range, 2-4 days) versus 3.8 days (range, 2-4 days) (p = 0.914). Ten patients (37%) had complete remission, observed during a mean follow-up period of 18.5 months (range, 6-30 months). CONCLUSIONS: During this consecutive experience, both the RtT and SxBiT approaches showed satisfactory results for nonthymomatous myasthenic patients. However, a better view of the bilateral pleural cavities and more radical thymectomy could be achieved only by the SxBiT approach.

Concordant expression of the telomerase-associated genes in non-small cell lung cancer.

AIMS: h-TERT is the keystone gene in controlling telomerase expression under the modulation of many associated genes. Our study was designed to observe the concordant expression of the telomerase associated genes in NSCLC (non-small cell lung cancer). METHODS: Between January 1999 and December 1999, 78 NSCLC patients were studied. The telomerase activity was measured by TRAP (telomeric repeat amplification protocol) assay, and the associated genes (h-TERT, h-TERC, TP1, c-Myc, TRF1, and TRF2) were detected using RT-PCR method. RESULTS: Positive telomerase activity was identified in 47 (60.3%) patients. Expression of the h-TERT, h-TERC, TP1, c-Myc, TRF1 and TRF2 genes were observed in 66.6, 92.3, 100.0, 91.0, 74.4 and 83.3% of the tumor tissues, respectively. Higher expression of the telomerase activity was found in advanced T-status (p=0.0265), and late TNM stages (p=0.0497) patients. In addition to the tumor tissue itself (p<0.0001), higher telomerase expression rates were observed in positive h-TERT (p<0.0001), and positive TRF1 (p=0.003) tumor tissues compared to their normal counterparts. Furthermore, h-TERT expression was closely related to the TRF1 (p=0.003), TRF2 (p=0.024), and c-Myc (p=0.042) expression. CONCLUSIONS: Our data demonstrate that expression of the telomerase activity can be observed in the majority of NSCLC tumor tissues, and is also closely related to the T-status and TNM stage of the tumor. h-TERT expression and subsequent telomerase activation leads to telomere repair under modulation by the TRF1, TRF2 and c-Myc genes.

Subxiphoid approach for thoracoscopic thymectomy.

Avoiding sternotomy, cumulative experience has demonstrated the efficacy and safety of minimally invasive thoracoscopic thymectomy. Previous reports describing the transcervical, left or right thoracic approach, although demonstrating promising results, involve some compromise of the surgical exposure. We designed a new approach through the subxiphoid route to perform extended thymectomy using the standard thoracoscopic technique. We used this approach on two consecutive patients. Additional port sites were created on both sides of the anterior chest wall for introducing instruments. This approach provides an excellent view of the bilateral pleural cavities, which is essential for adequate mediastinal fatty tissue dissection, especially because the surgical plan calls for removal of all the bilateral pericardiophrenic fat pads and the mediastinal fat tissue between the bilateral phrenic nerves. This approach omits the sternotomy while making extended thymectomy possible through the bilateral access. All the possible thymic-bearing mediastinal fat tissues can be removed under direct thoracoscopic view, which may subsequently translate into better results.

Suppression of proline-directed protein kinase F(A) potentiates apoptotic induction and greatly enhances chemosensitivity in human acute lymphoblastic leukemia cells.

BACKGROUND: Previously, the authors reported that specific antisense suppression of overexpressed proline-directed protein kinase (PDPK) F(A) enhances the chemosensitivity of various clinical anticancer drugs up to > 100-fold in human prostate carcinoma cells, suggesting an association of PDPK F(A) with drug resistance in human malignancies. METHODS: In this report, by using a similar approach, the authors demonstrate further that the suppression of PDPK F(A) enhances even more dramatically the chemosensitivity of clinically used anticancer drugs in various types of human acute lymphoblastic leukemia (ALL) cells. RESULTS: Compared with parental and control transfected cells, transduced ALL cells (both Jurkat and CCRF-CEM cells) with low levels of PDPK F(A) displayed an enhanced sensitivity to vincristine, vinblastine, paclitaxel, methotrexate, doxorubicin, and daunorubicin. Estimation of the 50% inhibitory concentration (IC(50)) index further revealed that the transduced cells displayed up to > 3000-fold drug sensitivity, and there was a correlation between suppressed levels of PDPK F(A) and drug sensitivity. A mechanistic study further revealed that the enhanced chemosensitivity in transduced ALL cells was due mainly to the potentiation of apoptotic induction. CONCLUSIONS: Taken together, the results demonstrate that the suppression of overexpressed PDPK F(A) greatly enhances the chemosensitivity of various clinical anticancer drugs in both types of human ALL cells, providing initial evidence for an important role of this PDPK in controlling multidrug resistance of ALL.

Experiences in thoracoscopic sympathectomy for axillary hyperhidrosis and osmidrosis: focusing on the extent of sympathectomy.

HYPOTHESIS: A more selective sympathectomy can improve the outcome of axillary hyperhidrosis and osmidrosis and minimize the potential sequelae. DESIGN: Retrospective cohort. SETTING: Tertiary care center. PATIENTS: Between July 1, 1996, and May 30, 2000, 171 patients with axillary hyperhidrosis and osmidrosis were studied. INTERVENTIONS: T3-4 sympathectomies were performed in 40 patients (group 1), T4 sympathectomies were performed in 56 patients (group 2), and T4-5 sympathectomies were performed in 75 patients (group 3). MAIN OUTCOME MEASURES: The surgical outcomes were evaluated by direct patient interview in the outpatient clinic or by telephone or mail questionnaires. The results were categorized as excellent (significant or complete disappearance of symptoms), good (>/=50% improvement), or poor (<50% improvement). RESULTS: There were no surgical mortalities in this study. Twenty-eight group 1 patients (70%), 16 group 2 patients (29%), and 22 group 3 patients (29%) developed compensatory perspiration (P<.001). Six group 1 patients (15%), 1 group 2 patient (2%), and 1 group 3 patient (1%) developed dry hands (P =.02). In the group 1 patients, the surgical outcomes were excellent in 21 (52%), good in 6 (15%), and poor in 13 (32%). In the group 2 patients, the surgical outcomes were excellent in 29 (52%), good in 10 (18%), and poor in 17 (30%). In the group 3 patients, the surgical outcomes were excellent in 53 (71%), good in 11 (15%), and poor in 11(15%) (P =.04). (Percentages may not sum to 100 because of rounding.) CONCLUSION: T4-5 sympathectomies provide higher patient satisfaction rates in treating axillary hyperhidrosis and osmidrosis, with fewer sequelae.

Correlation between epithelial cell permeability of cephalexin and expression of intestinal oligopeptide transporter.

The proton-coupled oligopeptide transporter (PEPT1) has been shown to mediate mucosal cell transport of di- and tripeptide, and some peptidomimetic drugs. In this study, we determined the correlation between PEPT1 protein expression and the permeability of cephalexin, a substrate of PEPT1, in human PEPT1 (hPEPT1)-overexpressed Caco-2 cells (Caco-2/hPEPT1 cells) and rat jejunum. Caco-2/hPEPT1 cells with various levels of hPEPT1 expression were established by an adenoviral transfection system. The effective intestinal permeability (P(eff)) in rat jejunum was evaluated using a single pass in situ perfusion method. The level of PEPT1 in Caco-2/hPEPT1 cells and rat intestinal mucosal samples was quantitated by densitometry after immunoblotting and enhanced chemiluminescence detection. In Caco-2/hPEPT1 cells, an excellent correlation was observed between cephalexin uptake and hPEPT1 expression (R2 = 0.96, P < 0.005). This demonstrates that cephalexin uptake is directly proportional to hPEPT1 expression. In the rat perfusion study, the mean P(eff) +/- S.D. (n = 15) of cephalexin was 3.89 +/- 1.63 x 10(-5) cm/s. A very significant correlation between PEPT1 expression and cephalexin permeability with an R2 = 0.63 (P < 0.001) was observed. This indicates that the variation in PEPT1 expression is one of the major factors accounting for variable intestinal cephalexin absorption. To our knowledge, this is the most direct evidence that variation of PEPT1 expression is correlated with absorption permeability variation of peptide-like compounds in vitro and in vivo.

Study of anticipation in Chinese families with schizophrenia.

The anticipation phenomenon is an important aspect in several genetic disorders in which the age at onset (AAO) decreases and the severity of illness increases in successive generations. This phenomenon has been reported in several schizophrenic family studies, and expanded repeat mutations are implicated. In the present study, we investigate the anticipation phenomenon in Chinese schizophrenic families. We compare the AAO between two generations of 38 unilinear schizophrenic families. Intergenerational comparisons show that the AAO was significantly earlier in the offspring generation (mean AAO, 22.2 years) than that in the parental generation (mean AAO, 31.0 years) (P < 0.001). When only including the offspring generation who married, the AAO difference between the two generations was not significant (28.4 years vs 31.0 years, P = 0.151). Our findings suggest that a selection bias in the parental group might greatly impact the study of anticipation in schizophrenia. Other unavoidable biases associated with these analyses are discussed in the text.