Conserved Role for Biofilm Matrix Polysaccharides in Candida auris Drug Resistance.

Candida auris has emerged as an outbreak pathogen associated with high mortality. Biofilm formation and linked drug resistance are common among Candida species. Drug sequestration by the biofilm matrix accounts for much of the antifungal tolerance. In this study, we examine the biofilm matrix composition and function for a diverse set of C. auris isolates. We show that matrix sequesters nearly 70% of the available triazole antifungal. Like the biofilms formed by other Candida spp., we find that the matrix of C. auris is rich in mannan-glucan polysaccharides and demonstrate that their hydrolysis reduces drug tolerance. This biofilm matrix resistance mechanism appears conserved among Candida species, including C. aurisIMPORTANCECandida auris is an emerging fungal threat linked to poor patient outcomes. The factors responsible for this apparent increase in pathogenicity remain largely unknown. Biofilm formation has been suggested as an important factor for persistence of this organism in patients and the environment. Our findings reveal one mechanism utilized by C. auris to evade the effect of triazole antifungal therapy during biofilm growth. The conservation of the protective biofilm matrix among Candida spp. suggests that is a promising pan-fungal Candida biofilm drug target.

Occupational stress and burnout among Hong Kong dentists.

INTRODUCTION: Professional burnout has been described as a gradual erosion of a person and may be one of the possible consequences of chronic occupational stress. Although occupational stress has been surveyed among dentists in Hong Kong, no study has been published about burnout in the profession. This study aimed to evaluate burnout among Hong Kong dentists and its association with occupational stress. METHODS: We surveyed a random sample of 1086 registered dentists in Hong Kong, which formed 50% of the local profession. They were mailed an anonymous questionnaire about burnout and occupational stress in 2015. The questionnaire assessed occupational stress, coping strategies, effects of stress, level of burnout, and socio-demographic characteristics of the respondents. Occupational stress assessment concerned 33 stressors in five groups: patient-related, time-related, income-related, job-related, and staff-/technically related. Level of burnout was assessed by the Maslach Burnout Inventory-Human Services Survey (22 items) with three scores: emotional exhaustion, depersonalisation, and personal accomplishment. RESULTS: Completed questionnaires were received from 301 dentists (response rate, 28.3%), of whom 25.4% had a high level of emotional exhaustion, 17.2% had a high level of depersonalisation, and 39.0% had a low level of personal accomplishment. Only 7.0% of respondents, however, had a high level of overall burnout (high emotional exhaustion, high depersonalisation, and low personal accomplishment). A high level of overall burnout was significantly associated with a higher mean score for job-related stressors and lack of postgraduate qualifications (P<0.05). CONCLUSIONS: Patient-related stressors are the top occupational stressors experienced by dentists in Hong Kong. In spite of this, a low proportion of dentists have a high level of overall burnout. There was a positive association between occupational stress and level of burnout.

Chaperones and intimate physical examinations: what do male and female patients want?

INTRODUCTION: Many studies of patients' perception of a medical chaperone have focused on female patients; that of male patients are less well studied. Moreover, previous studies were largely based on patient populations in English-speaking countries. Therefore, this study was conducted to investigate the perception and attitude of male and female Chinese patients to the presence of a chaperone during an intimate physical examination. METHODS: A cross-sectional guided questionnaire survey was conducted on a convenient sample of 150 patients at a public teaching hospital in Hong Kong. RESULTS: Over 90% of the participants considered the presence of a chaperone appropriate during intimate physical examination, and 84% felt that doctors, irrespective of gender, should always request the presence of a chaperone. The most commonly cited reasons included the availability of an objective account should any legal issue arise, protection against sexual harassment, and to provide psychological support. This contrasted with the experience of those who had previously undergone an intimate physical examination of whom only 72.6% of women and 35.7% of men had reportedly been chaperoned. Among female participants, 75.0% preferred to be chaperoned during an intimate physical examination by a male doctor, and 28.6% would still prefer to be chaperoned when being examined by a female doctor. Among male participants, over 50% indicated no specific preference but a substantial minority reported a preference for chaperoned examination (21.2% for male doctor and 25.8% for female doctor). CONCLUSIONS: Patients in Hong Kong have a high degree of acceptance and expectations about the role of a medical chaperone. Both female and male patients prefer such practice regardless of physician gender. Doctors are strongly encouraged to discuss the issue openly with their patients before they conduct any intimate physical examination.

Impact of thoracic radiotherapy timing in limited-stage small-cell lung cancer: usefulness of the individual patient data meta-analysis.

BACKGROUND: Chemotherapy (CT) combined with radiotherapy is the standard treatment of 'limited-stage' small-cell lung cancer. However, controversy persists over the optimal timing of thoracic radiotherapy and CT. MATERIALS AND METHODS: We carried out a meta-analysis of individual patient data in randomized trials comparing earlier versus later radiotherapy, or shorter versus longer radiotherapy duration, as defined in each trial. We combined the results from trials using the stratified log-rank test to calculate pooled hazard ratios (HRs). The primary outcome was overall survival. RESULTS: Twelve trials with 2668 patients were eligible. Data from nine trials comprising 2305 patients were available for analysis. The median follow-up was 10 years. When all trials were analysed together, 'earlier or shorter' versus 'later or longer' thoracic radiotherapy did not affect overall survival. However, the HR for overall survival was significantly in favour of 'earlier or shorter' radiotherapy among trials with a similar proportion of patients who were compliant with CT (defined as having received 100% or more of the planned CT cycles) in both arms (HR 0.79, 95% CI 0.69-0.91), and in favour of 'later or longer' radiotherapy among trials with different rates of CT compliance (HR 1.19, 1.05-1.34, interaction test, P < 0.0001). The absolute gain between 'earlier or shorter' versus 'later or longer' thoracic radiotherapy in 5-year overall survival for similar and for different CT compliance trials was 7.7% (95% CI 2.6-12.8%) and -2.2% (-5.8% to 1.4%), respectively. However, 'earlier or shorter' thoracic radiotherapy was associated with a higher incidence of severe acute oesophagitis than 'later or longer' radiotherapy. CONCLUSION: 'Earlier or shorter' delivery of thoracic radiotherapy with planned CT significantly improves 5-year overall survival at the expense of more acute toxicity, especially oesophagitis.

Routine exercise ameliorates the metabolic side-effects of treatment with the atypical antipsychotic drug olanzapine in rats.

Second generation antipsychotic (SGA) drugs are effective treatments for psychosis. Common side-effects of SGAs include metabolic dysregulation and risk of cardiometabolic disorders. Metabolic side-effects, including glucose intolerance, can be accurately modelled in rodents. The benefits of interventions used for treating metabolic side-effects of SGAs are mostly unknown. In a 9 wk longitudinal study, female rats were given daily olanzapine (10 mg/kg s.c.) or vehicle. Animals were either sedentary or allowed 1 or 3 h daily access to a running wheel, with total wheel revolutions electronically quantified to reflect exercise intensity. Glucose tolerance tests were performed once weekly to measure glycemic control. Drug levels were measured at week 4. At week 9, abdominal fat and skeletal muscle levels of Glucose Transporter 4 (GLUT4) were measured. Exercise intensity progressively increased over time in all groups given access to running wheels; however, rats treated with olanzapine consistently exercised less than those given the vehicle. Olanzapine caused acute and persistent glucose intolerance throughout the study, which was markedly, though incompletely, ameliorated by exercise. Exercise did not affect glycemic regulation in vehicle-treated rats. Olanzapine-treated rats showed greater central adiposity. Levels of GLUT4 in skeletal muscle were higher in both groups of exercising than in sedentary rats, and GLUT4 values were negatively correlated with glucose intolerance. Routine exercise reduced olanzapine-induced glucose intolerance and increased skeletal muscle levels of GLUT 4, the insulin-responsive transporter that mediates glucose uptake into cells. The current animal model is suitable for evaluating physiological pathways involved with glucose intolerance.

Heat dissipation performance of a high-brightness LED package assembly using high-thermal conductivity filler.

This paper presents a thermal analysis and experimental validation of natural convective heat transfer of a high-brightness light-emitting diode (LED) package assembly. The substrate materials used in the LED package assembly were filled and doped using boron nitride (BN) filler. The thermal conductivity of the BN-filled substrate was measured. The temperature distribution and heat flow of the LED package were assessed by thermal profile measurement using an infrared (IR) camera and thermocouples. In addition, the heat transfer process of the LED package assembly in natural convection was also simulated using the computational fluid dynamics method. The optical performance of the LED package was monitored and investigated with various filler contents. The heat conduction mechanism in the substrate was analyzed. IR thermogram showed that the BN-doped substrate could effectively lower the surface temperature of the LED package by 21.5°C compared with the traditional FR4 substrate. According to the IESNA LM 80 lifetime testing method, reduction in LED temperature can prolong the LED's lifetime by 19,000 h. The optical performance of the LED package assembly was also found to be improved significantly in lighting power by 10%. As a result, the overall heat dissipation capability of the LED package to the surrounding is enhanced, which improves the LED's efficacy.

Dual enteric and respiratory tropisms of winter dysentery bovine coronavirus in calves.

Although winter dysentery (WD), which is caused by the bovine coronavirus (BCoV) is characterized by the sudden onset of diarrhea in many adult cattle in a herd, the pathogenesis of the WD-BCoV is not completely understood. In this study, colostrum-deprived calves were experimentally infected with a Korean WD-BCoV strain and examined for viremia, enteric and nasal virus shedding as well as for viral antigen expression and virus-associated lesions in the small and large intestines and the upper and lower respiratory tract from 1 to 8 days after an oral infection. The WD-BCoV-inoculated calves showed gradual villous atrophy in the small intestine and a gradual increase in the crypt depth of the large intestine. The WD-BCoV-infected animals showed epithelial damage in nasal turbinates, trachea and lungs, and interstitial pneumonia. The WD-BCoV antigen was detected in the epithelium of the small and large intestines, nasal turbinates, trachea and lungs. WD-BCoV RNA was detected in the serum from post-inoculation day 3. These results show that the WD-BCoV has dual tropism and induces pathological changes in both the digestive and respiratory tracts of calves. To our knowledge, this is the first detailed report of dual enteric and respiratory tropisms of WD-BCoV in calves. Comprehensive studies of the dual tissue pathogenesis of the BCoV might contribute to an increased understanding of similar pneumoenteric CoV infections in humans.

Improving outcomes in the treatment of locally-advanced NSCLC with gemcitabine.

Multiple approaches of combined modality therapy have emerged as potential treatments for improving unresectable, locoregionally advanced non-small-cell lung cancer (NSCLC). Several agents have been used either sequentially or concurrently in clinical trials of combined chemoradiotherapy. However, no specific regimen has been clearly defined, particularly with regard to the timing of chemotherapy (sequential and/or concurrent), the specific chemotherapeutic drugs, and the dose and intensity of the radiation therapy. Concurrent chemoradiotherapy demonstrates a survival advantage compared to sequential chemoradiotherapy. Initial data suggest that induction chemotherapy prior to concurrent chemoradiotherapy does not further improve survival. The potent radiosensitizer gemcitabine has been evaluated in combination chemotherapy with radiation therapy and appears to be a promising agent, although further trials are needed to define its optimal dose, toxicity and efficacy.

Radiotherapy patterns of care study in lung carcinoma.

PURPOSE: For the first time, a lung Patterns of Care Study was conducted to determine the national patterns of radiation (RT) practice in patients treated for nonmetastatic lung cancer in 1998 to 1999. MATERIALS AND METHODS: A national survey of randomly selected RT institutions in the United States was conducted using two-stage cluster sampling, stratified by practice type. Patients with nonmetastatic lung cancer (Karnofsky performance score [KPS] > or = 60), who received RT as definitive or adjuvant therapy, were randomly selected. To determine national estimates, sample size was weighted by the relative number of institutions per strata and the number of patient records reviewed per the number of patients eligible. Accordingly, 42,335 patient records from 58 institutions were reviewed by trained research associates. The unweighted sample size (or number of patients) was 541. RESULTS: The histologies were small-cell lung cancer (SCLC) in 14.5% of patients versus non-small-cell lung cancer (NSCLC) in 85.5% of patients. The median age was 67 years (range, 29 to 92 years); 61% of patients were male, and 38% were current smokers. Bone scans and brain imaging were not obtained in 34% and 52% of clinical stage (CS) III NSCLC patients, respectively. Regarding treatment strategies, for SCLC and CS III NSCLC, chemotherapy plus RT was used significantly more than RT alone (P <.05); in CS I NSCLC, RT alone was the primary treatment (P <.05). Overall, 58% of patients received systemic therapy. On multivariate analysis, factors correlating with increased use of chemotherapy included younger age, histology (SCLC > NSCLC), increasing CS, increasing KPS, and lack of comorbidities. Only 3% of all patients were treated on prospective clinical trials. CONCLUSION: This study establishes the general patterns of care for lung carcinoma in RT facilities within the United States. As supported by clinical trials, patients with limited-stage SCLC and CS III NSCLC received chemotherapy plus RT more than they received RT alone. Further improvements in staging, smoking cessation, and increased accrual to clinical trials must be encouraged.

Phase I trial of outpatient weekly docetaxel, carboplatin and concurrent thoracic radiation therapy for stage III unresectable non-small-cell lung cancer: a Vanderbilt cancer center affiliate network (VCCAN) trial.

PURPOSE: Docetaxel, an active agent for non-small cell lung cancer (NSCLC), has demonstrated activity as a radiosensitizer in numerous pre-clinical studies. We conducted a phase I trial to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLT) of weekly Docetaxel, Carboplatin with concurrent thoracic radiation therapy (TRT) in patients with unresectable stage III NSCLC. PATIENTS AND METHODS: In this phase I clinical trial, Docetaxel was administered weekly as a 1-h intravenous infusion for 6 weeks with a starting dose of 20 mg/m(2). Docetaxel doses were escalated by 10 mg/m(2) increments in successive cohorts of three patients. DLT was defined as grade >or=3 nonhematologic and hematologic toxicity according to RTOG toxicity criteria. Once the DLT of Docetaxel alone was reached, weekly Carboplatin (AUC 2) was added at a DLT-2 dose of Docetaxel (two dose levels below that of dose limiting toxicity). Docetaxel doses were again escalated at 10 mg/m(2) increments in successive cohorts of three new patients to define further DLT and MTD of Docetaxel/Carboplatin with TRT. TRT was administered to the primary tumor and regional lymph nodes (40 Gy) followed by a boost to the tumor (20 Gy). RESULTS: Fifteen patients were entered onto this study with Docetaxel alone through three dose escalations (from 20 to 40 mg/m(2) weekly). The DLT of weekly Docetaxel/TRT was esophagitis and the MTD was 30 mg/m(2) per week for 6 weeks. Nine more patients were added with the Docetaxel/Carboplatin/TRT regimen. The DLT of weekly Docetaxel/Carboplatin with TRT was esophagitis and the MTD of Docetaxel was 20 mg/m(2) per week with weekly Carboplatin (AUC 2). There were 2 complete responses and 13 partial responses in 25 evaluable patients (RR 60%). CONCLUSIONS: This combination regimen has activity with manageable toxicity in patients with stage III NSCLC. A phase II study is planned to define activity.

The current state of paclitaxel and radiation in the combined-modality therapy of non-small cell lung cancer.

The results of randomized trials have prompted an evolution in the treatment approach to inoperable locally advanced non-small cell lung cancer, from radiotherapy alone to sequential chemoradiotherapy and now to concurrent chemoradiotherapy. The improvement in outcome seen with a concurrent chemoradiotherapy approach may be because of spatial cooperation, enhanced radiosensitization, and/or enhanced cytotoxicity. The taxanes, specifically paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), delivered in combination with radiation have been extensively examined in both preclinical and clinical studies. Several mechanisms have been suggested to explain the enhanced tumor cell kill seen with paclitaxel and radiation, and phase II studies have examined this combination in the setting of inoperable stage III non-small cell lung cancer. This review will explore some of the studies with this treatment approach in locally advanced disease. We also will briefly discuss some of the ongoing trials that are attempting to refine the delivery of concurrent thoracic radiation and paclitaxel-based chemotherapy.

Role of taxanes in the combined modality treatment of patients with locally advanced non-small cell lung cancer.

The plant-derived taxanes have a unique mechanism of cytotoxic action and have shown interesting response and survival data in metastatic non-small cell lung cancer (NSCLC). Based on these results, taxane-based regimens have been investigated in combination with radiotherapy in unresectable NSCLC. Trials with paclitaxel-based concurrent chemoradiotherapy have shown 50-100% tumour response rates, 12-26 month median survivals and 32-52% 2-year survival rates. Trials with concurrent chemoradiotherapy with docetaxel have shown 35-92% tumour response rates, 12-23 month median survivals, and 41-43% 2 year survival rates. Taxane-based concurrent chemoradiotherapy for stage III NSCLC appears promising. Large ongoing randomised trials will define the role of these agents in the treatment of locally advanced NSCLC.

A selective cyclooxygenase-2 inhibitor, NS-398, enhances the effect of radiation in vitro and in vivo preferentially on the cells that express cyclooxygenase-2.

It has been proposed that Cyclooxygenase (COX)-2 inhibitors may be able to enhance the effects of chemotherapeutic or radiation treatment; however, currently few studies have been reported that define the radiation-enhancing effect of COX-2 inhibitors. We conducted in vitro radiation survival experiments using rat intestinal epithelial cells which were stably transfected with COX-2 cDNA in the sense (RIE-S) and antisense (RIE-AS) orientations to investigate the potential radiosensitizing effect of the selective COX-2 inhibitor, NS-398. Apoptosis was measured using 7-aminoactinomycin-D with flow cytometry to investigate underlying mechanisms for the effect of NS-398 on radiosensitivity. The same experiments were repeated with NCI-H460 human lung cancer cells, which express COX-2 constitutively, and HCT-116 human colon cancer cells, which lack COX-2 expression. In vivo tumor growth delay assays were also performed with tumors formed by H460 and HCT-116 cells. No difference was observed in the intrinsic radiation sensitivity of RIE-S and RIE-AS cells exposed to radiation alone. However, 150-400 microM of NS-398 enhanced radiosensitivity in a concentration-dependent manner in RIE-S cells with dose enhancement ratios of 1.2-1.9 at a surviving fraction of 0.25. However, this effect was not shown in RIE-AS cells. NS-398 enhanced radiosensitivity in H460 cells with a dose enhancement ratio of 1.8 but protected HCT-116 cells from the effects of radiation. Radiation-induced apoptosis was enhanced by NS-398 in RIE-S and H460 cells but not in RIE-AS and HCT-116 cells. Additionally, this radiation-enhancing effect in RIE-S cells seemed to be attributable to some mechanisms other than the reversal of radioresistance induced by COX-2. NS-398 (36 mg/kg) enhanced the effect of radiation on H460 tumors in vivo by an enhancement factor of 2.5; however, it did not enhance the radiosensitivity of HCT-116 tumors (enhancement factor = 1.04). These in vitro and in vivo results suggest that selective COX-2 inhibitors enhance the effect of radiation on tumors that express COX-2 but not on COX-2-lacking tumors. This effect may be attributable to enhancement of radiation-induced apoptosis. Thus, selective COX-2 inhibitors may have potential as radiosensitizers for treatment of human cancers.

Repression of deoP2 in Escherichia coli by CytR: conversion of a transcription activator into a repressor.

In the deoP2 promoter of Escherichia coli, a transcription activator, cAMP-CRP, binds at two sites, centered at -41.5 and -93.5 from the start site of transcription, while a repressor, CytR, binds to a space between the two cAMP-CRP complexes. The mechanisms for the cAMP-CRP-mediated transcription activation and CytR-mediated transcription repression were investigated in vitro using purified components. We classified the deoP2 promoter as a class II cAMP-CRP-dependent promoter, primarily by the action of cAMP-CRP at the downstream site. Interestingly, we also found that deoP2 carries an "UP-element" immediately upstream of the downstream cAMP-CRP site. The UP-element overlaps with the DNA site for CytR. However, it was observed that CytR functions with the RNA polymerase devoid of the C-terminal domain of the alpha-subunit as well as with intact RNA polymerase. The mechanism of repression by CytR proposed in this study is that the cAMP-CRP bound at -41.5 undergoes an allosteric change upon direct interaction with CytR such that it no longer maintains a productive interaction with the N-terminal domain of alpha, but instead acts as a repressor to interfere with RNA polymerase acting on deoP2.

The novel taxane analogs, BMS-184476 and BMS-188797, potentiate the effects of radiation therapy in vitro and in vivo against human lung cancer cells.

PURPOSE: To evaluate the novel taxane analogs, BMS-184476 and BMS-188797, as potential radiosensitizers in vitro and in vivo. METHODS AND MATERIALS: Human H460 lung cancer cells were incubated with either paclitaxel or a taxane analog and irradiated at various times. Surviving fractions were then determined using a clonogenic assay. Three different schedules were used: (A) 1-h drug incubation with radiation at t = 8 h, (B) 1-h drug incubation with radiation at t = 24 h, (C) 24-h drug incubation with radiation immediately after. Cell cycle redistribution by taxanes alone was measured with propidium iodide and flow cytometry. Percent apoptosis was also measured using 7-aminoactinomycin D (7-AAD) staining with flow cytometry. For in vivo studies, H460 cell xenografts were used in nude mice. Tumors were grown s.c. on the flank and then treated with BMS-184476 (10 mg/kg i.p. injection, Days 0, 2, and 4) and/or radiation (2 Gy/day, Days 0-4). Tumor growth delay was then measured for each treatment group. RESULTS: The mean in vitro radiation dose enhancement ratios of BMS-184476, BMS-188797, and paclitaxel were 1.76, 1.49, and 1.31 for Schedules A, B, and C, respectively. Isobologram analysis showed that BMS-184476 was synergistic with radiation using Schedule A. Treatment with taxanes caused an increase in the percentage of G2/M cells at the time of irradiation. The mean fold increases in the %G2/M above control values for all three drugs were 5.6, 2.5, and 1.7 for Schedules A, B, and C, respectively. The combined effects of taxanes plus radiation on the induction of apoptosis were additive for all three drugs. In vivo studies showed that BMS-184476 can enhance the effects of fractionated radiotherapy, with an average enhancement factor of 1.66 obtained from three independent experiments. CONCLUSIONS: These results demonstrated that the novel taxane analogs, BMS-184476 and BMS-188797, can enhance the effects of radiation in human lung cancer cells both in vitro and in vivo. These data also support the hypothesis that a G2/M block is involved in the radiosensitization caused by the taxanes.

Induction chemotherapy increases perioperative complications in patients undergoing resection for non-small cell lung cancer.

BACKGROUND: Neoadjuvant chemotherapy before resection is the standard of care for stage IIIA non-small cell lung cancer in many institutions. Further, neoadjuvant therapy is being studied in earlier stage lung cancer and may be applied more broadly in the future. There is little information about the effect of preoperative chemotherapy on the perioperative complications and mortality after lung resection. METHODS: All patients undergoing anatomic resection after neoadjuvant chemotherapy by a single surgeon at a single institution were compared with patients undergoing similar resections without preoperative chemotherapy. Complications were analyzed as life-threatening (pneumonia, emergency surgery, transfer to the intensive care unit, or intubation), major (prolonging hospital stay but not necessarily dangerous), and minor. The incidence of life-threatening complications, major complications, reintubation, tracheostomy, and mortality were analyzed to determine whether neoadjuvant chemotherapy might have an effect on these complications. Mortality was defined as hospital mortality. Two-tailed Student's t test was used to analyze differences in means and chi2 to determine differences in proportions. Differences less than 0.05 were considered significant. RESULTS: Thirty-four patients underwent resection after neoadjuvant chemotherapy, and 67 patients underwent resection without preoperative therapy. No differences between the two groups in age, pulmonary function, or comorbid diseases were found. The patients receiving chemotherapy did have a more advanced stage (2.52 versus 1.55, p < 0.0001). Striking increases were found in incidence of life-threatening complications (6.0% versus 26.5%, p = 0.0036), major complications (19.4% versus 47.1%, p = 0.0037), reintubation (3.0% versus 17.6%, p = 0.0093), and tracheostomy (0% versus 11.8%, p = 0.0042) in those patients who received preoperative chemotherapy. There was no hospital mortality. However, 2 (neoadjuvant) patients died within 90 days after discharge from the hospital of pneumonia and pulmonary embolus. This difference was also significant (0% versus 5.89%, p = 0.045). CONCLUSIONS: Neoadjuvant carboplatin and Taxol increased the perioperative life-threatening complications in this cohort of patients compared with a similar cohort undergoing operations by the same surgeon in the same institution. The most common life-threatening complication in patients receiving induction chemotherapy was the failure to respond to antibiotics given for pneumonia. Strategies to prevent these complications will be important, especially if chemotherapy before resection becomes the standard for earlier stages of non-small cell lung cancer.

Irinotecan and radiation in combined-modality therapy for solid tumors.

Irinotecan (CPT-11, Camptosar) is a camptothecin derivative that is thought to exert its cytotoxic effects by targeting topoisomerase I. It is believed that irinotecan stabilizes a DNA-topoisomerase I cleavable complex, and that interactions between this complex and the replication machinery may lead to cell death. There is a significant volume of in vitro and in vivo data demonstrating that irinotecan acts as a radiosensitizer. The exact mechanism of this radiosensitization is currently unknown. The increasing amount of data demonstrating improved outcomes with concurrent chemoradiation treatment of malignancies like lung cancer and head and neck cancer provide impetus for pursuing the addition of other drugs as radiosensitizers to improve local control further. Irinotecan is undergoing early clinical trials in the combined-modality setting in several disease sites. This article will provide an overview of the current status of irinotecan used concurrently with radiotherapy in the treatment of a variety of solid tumors.

Enhancement of tumor oxygenation and radiation response by the allosteric effector of hemoglobin, RSR13.

Prior studies using pO(2) microelectrodes have shown that RSR13, an allosteric modifier of hemoglobin, increases tissue oxygenation in vivo. Recently, measurements of tissue oxygenation have been performed by many investigators using blood oxygen level-dependent magnetic resonance imaging (BOLD MRI). In this study, we tested the hypothesis that the BOLD MRI signal ratio in tumors will change after administration of RSR13. NCI-H460 human lung carcinoma cells were used as a xenograft in athymic nude mice. Mice with 1-cm(3) tumors in the flank were anesthetized and mounted on the MRI apparatus, and various doses of RSR13 were administered intraperitoneally (i.p.). MR images were then acquired at 10-min intervals for up to 60 min after injection. The effect of RSR13 on tumor response was studied using the same mouse xenograft model with tumor growth delay measurements. RSR13 increased the MRI signal ratio [Intensity(t)/Intensity(t = 0)] in a dose-dependent manner, with maximum increases occurring 30 min after RSR13 was administered. An RSR13 dose of 200 mg/kg proved to be optimum. Since the MRI signal ratio has been shown previously to be linearly related to tissue oxygenation, the changes in the MRI signal ratio can be attributed to changes in tumor oxygen levels. Using a 200-mg/kg dose of RSR13, with a 10-Gy dose of radiation administered to tumors 30 min later, enhancement of radiation-induced tumor growth delay by RSR13 was observed (enhancement factor = 2.8). Thus our MRI results support and verify the previously reported RSR13-induced increase in tumor oxygenation obtained using pO(2) microelectrodes. Based upon these results and other previous studies, the mechanism of enhancement of the effect of radiation by RSR13 probably involves an increase in tumor oxygenation.

Optimizing chemoradiation in locally advanced non-small-cell lung cancer.

Gemcitabine (Gemzar) has demonstrated activity in a broad range of solid tumors with good tolerance. In combined-modality therapy, gemcitabine has achieved response rates ranging between 30% and 60% in patients with non-small-cell lung cancer. Initial trials of gemcitabine and radiation showed that the fields and volume of radiation as well as the dose of gemcitabine should be managed carefully so as to optimize the radiosensitizing properties of this agent. The Cancer and Leukemia Group B conducted a phase III trial in patients with unresectable stage III non-small-cell lung cancer. A total of 187 patients were randomized to one of three cisplatin (Platinol)-based combinations (with gemcitabine, paclitaxel [Taxol], or vinorelbine [Navelbine]) as induction therapy followed by concomitant chemoradiation. At a median follow-up of 9 months, the median survival for all patients was 18 months and the median progression-free survival was 10 months. The trial demonstrated that the combination of gemcitabine and cisplatin could be administered successfully as induction therapy without affecting concurrent administration of gemcitabine/cisplatin with radiation.