Emiko Nakataki

Retreatment of lung adenocarcinoma patients with gefitinib who had experienced favorable results from their initial treatment with this selective epidermal growth factor receptor inhibitor: a report of three cases.

Gefitinib is a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinases, and shows favorable antitumor activity against chemorefractory non-small cell lung cancer (NSCLC). The majority of responders (patients who are sensitive to gefitinib), however, relapse within 1.5 years, indicating an acquired resistance to gefitinib. Here we report three chemotherapy refractory NSCLC patients who were retreated with gefitinib. All three cases were nonsmokers and showed an adenocarcinoma histology. While they had experienced successful control from their initial treatment with gefitinib for more than 12 months, gefitinib therapy was terminated because two cases (cases 1 and 3) relapsed during the therapy and case 2 suffered alveolar hemorrhage. After more than 7 months from the time of discontinuation of the initial gefitinib treatment, they were retreated with gefitinib, as further tumor progression was observed. Of the three cases, cases 1 and 2 were well controlled by retreatment with gefitinib monotherapy for more than 7 months, suggesting sensitivity to retreatment. Case 3 also showed a regression in size of several tumors, while some other lesions progressively enlarged and developed a malignant pleural effusion after 4 months. These observations suggest the possibility that retreatment with gefitinib might be useful when 1) initial treatment shows a favorable clinical response, and 2) there has been a period of time following the termination of the initial gefitinib treatment.

ZD6474, an inhibitor of vascular endothelial growth factor receptor tyrosine kinase, inhibits growth of experimental lung metastasis and production of malignant pleural effusions in a non-small cell lung cancer model.

ZD6474 is a novel, orally active inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase, with some additional activity against epidermal growth factor receptor (EGFR) tyrosine kinase. The purpose of this study was to determine the potential of ZD6474 in the control of established experimental lung metastasis and pleural effusions produced by human non-small cell lung cancer (NSCLC) cells. PC14PE6 (adenocarcinoma) and H226 (squamous cell carcinoma) cells express high levels of EGFR and only PC14PE6 cells overexpress VEGF. Neither ZD6474 nor the EGFR tyrosine kinase inhibitor gefitinib inhibit proliferation of PC14PE6 or H226 cells in vitro. Both PC14PE6 and H226 cells inoculated intravenously into nude mice induced multiple lung nodules after 5-7 weeks. In addition, PC14PE6 cells produced bloody pleural effusions. Daily oral treatment with ZD6474 did not reduce the number of lung nodules produced by PC14PE6 or H226 cells, but did reduce the lung weight and the size of lung nodules. ZD6474 also inhibited the production of pleural effusions by PC14PE6 cells. Histological analyses of lung lesions revealed that ZD6474 treatment inhibited activation of VEGFR-2 and reduced tumor vascularization and tumor cell proliferation. Therapeutic effects of ZD6474 were considered likely to be due to inhibition of VEGFR-2 tyrosine kinase because gefitinib was inactive in this model. These results indicate that ZD6474, an inhibitor of VEGFR-2, may be useful in controlling the growth of established lung metastasis and pleural effusions by NSCLC.

Antitumor Vascular Strategy for Controlling Experimental Metastatic Spread of Human Small-Cell Lung Cancer Cells with ZD6474 in Natural Killer Cell–Depleted Severe Combined Immunodeficient Mice

Background: Small-cell lung cancer is often characterized by rapid growth and metastatic spread. Because tumor growth and metastasis are angiogenesis dependent, there is great interest in therapeutic strategies that aim to inhibit tumor angiogenesis. Methods: The effect of ZD6474, an orally available inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor tyrosine kinases, was studied in experimental multiple-organ metastasis models with human small-cell lung cancer cell lines (SBC-3 or SBC-5) in natural killer cell–depleted severe combined immunodeficient mice. Results: Intravenously inoculated SBC-5 cells produced experimental metastases in the liver, lung, and bone whereas SBC-3 cells produced the metastases in the liver, systemic lymph nodes, and kidneys. Daily oral treatment with ZD6474 (50 mg/kg), started on day 14 (after the establishment of micrometastases), significantly reduced the frequency of large (>3 mm) metastatic colonies (in the liver and lymph nodes) and osteolytic bone lesions. ZD6474 treatment did not significantly reduce the frequency of small (<2-3 mm) metastatic lesions found in the lung (SBC-5) or kidney (SBC-3), consistent with an antiangiogenic mechanism of action. Immunohistochemical analysis of SBC-5 metastatic deposits in the liver showed that ZD6474 treatment inhibited VEGFR-2 activation and induced apoptosis of tumor-associated endothelial cells, resulting in decreasing tumor microvessel density. ZD6474 treatment was also associated with a decrease in tumor cell proliferation and an increase in tumor cell apoptosis. The antitumor effects of ZD6474 were considered likely to be due to inhibition of VEGFR-2 tyrosine kinase because gefitinib, a small-molecule inhibitor of epidermal growth factor receptor tyrosine kinase, was inactive in these models. Conclusions: These results suggest that ZD6474 may be of potential therapeutic value in inhibiting the growth of metastatic small-cell lung cancer in humans. Phase II trials with ZD6474 are currently ongoing in a range of solid tumors.

Effect of High Flow Nasal Cannula on Thoraco-abdominal Synchrony in Adult Critically Ill Patients

BACKGROUND: High-flow nasal cannula (HFNC) creates positive oropharyngeal airway pressure and improves oxygenation. It remains unclear, however, whether HFNC improves thoraco-abdominal synchrony in patients with mild to moderate respiratory failure. Using respiratory inductive plethysmography, we investigated the effects of HFNC on thoraco-abdominal synchrony. METHODS: We studied 40 adult subjects requiring oxygen therapy in the ICU. Low-flow oxygen (up to 8 L/min) was administered via oronasal mask for 30 min, followed by HFNC at 30–50 L/min. Respiratory inductive plethysmography transducer bands were circumferentially placed: one around the rib cage, and one around the abdomen. We measured the movement of the rib-cage and abdomen, and used the sum signal to represent tidal volume (VT) during mask breathing, and at 30 min during HFNC. We calculated the ratio of maximum compartmental amplitude (MCA) to VT, and the phase angle. We assessed arterial blood gas and vital signs at each period, and mouth status during HFNC. We used multiple regression analysis to identify factors associated with improvement in thoraco-abdominal synchrony. RESULTS: During HFNC, breathing frequency significantly decreased from 25 breaths/min (IQR 22–27 breaths/min) to 21 breaths/min (IQR 18–24 breaths/min) (P < .001), and MCA/VT (P < .001) and phase angle (P = .047) significantly improved. CONCLUSIONS: HFNC improved thoraco-abdominal synchrony in adult subjects with mild to moderate respiratory failure.

Novel orthotopic implantation model of human malignant pleural mesothelioma (EHMES-10 cells) highly expressing vascular endothelial growth factor and its receptor.

Malignant pleural mesothelioma (MPM) is closely related to exposure to asbestos, and a rapid increase in the number of MPM patients in Japan is estimated in the years 2010–2050. The purpose of the present study was to establish a clinically relevant animal model that shows human patient‐like progression of MPM. Here, we demonstrate that a human MPM cell line (EHMES‐10) inoculated orthotopically (thoracic cavity) into severe combined immunodeficiency (SCID) mice produces highly vascularized thoracic tumors with pleural dissemination and bloody pleural effusions by 5 weeks, suggesting a patient‐like progression of this cell line after orthotopic inoculation. EHMES‐10 cells overexpressed vascular endothelial growth factor (VEGF), a molecule responsible for malignant effusions, and its receptor. Treatment with cisplatin, but not gemcitabine, significantly inhibited the production of pleural effusions, but it was not effective for thoracic tumors, consistent with chemotherapy refractory characteristics of MPM in patients. Our patient‐like orthotopic model using EHMES‐10 cells overexpressing VEGF and its receptor may be useful for examining the molecular pathogenesis of MPM and may contribute to the development of novel treatment strategies for MPM. (Cancer Sci 2006; 97: 183 –191)

CD9 overexpression suppressed the liver metastasis and malignant ascites via inhibition of proliferation and motility of small-cell lung cancer cells in NK cell-depleted SCID mice.

CD9, a transmembrane protein known as motility-related protein-1, plays a pivotal role in regulating cell adhesion, motility, and proliferation, and has been regarded as an important metastasis-inhibitory factor of various human cancers. However, little information has been obtained regarding the highly metastatic human small-cell lung cancer (SCLC). In the present study, an SCLC cell line (OS3-R5), lacking CD9 expression, was transfected with human CD9 gene to assess the role of CD9 on the metastatic potential of SCLC. CD9 gene transfection into OS3-R5 cells resulted in cell proliferation and motility in vitro. Parental and mock-transfected OS3-R5 cells developed liver metastasis and malignant ascites when they were intravenously inoculated into NK cell-depleted SCID mice. CD9 gene transfection into OS3-R5 cells caused suppression of the liver metastasis and malignant ascites. Immunohistochemical analysis revealed that the number of proliferating tumor cells was significantly fewer in liver lesions produced by CD9 gene-transfected OS3-R5 cells than those produced by parental or mock control OS3-R5 cells. In addition, no detectable levels of CD9 were expressed in metastatic tumor cells in mice bearing CD9 gene-transfected OS3-R5 cells, as well as those in mice bearing parental or mock control OS3-R5 cells. These results suggest that the restored expression of CD9 in SCLC cells may reduce the metastatic spread of SCLC cells via the inhibition of cell proliferation and motility.

Humidification Performance of Two High-Flow Nasal Cannula Devices: A Bench Study

INTRODUCTION: Delivering heated and humidified medical gas at 20–60 L/min, high-flow nasal cannula (HFNC) creates low levels of PEEP and ameliorates respiratory mechanics. It has become a common therapy for patients with respiratory failure. However, independent measurement of heat and humidity during HFNC and comparison of HFNC devices are lacking. METHODS: We evaluated 2 HFNC (Airvo 2 and Optiflow system) devices. Each HFNC was connected to simulated external nares using the manufacturers standard circuit. The Airvo 2 outlet-chamber temperature was set at 37°C. The Optiflow system incorporated an O2/air blender and a heated humidifier, which was set at 40°C/−3. For both systems, HFNC flow was tested at 20, 40, and 50 L/min. Simulating spontaneous breathing using a mechanical ventilator and TTL test lung, we tested tidal volumes (VT) of 300, 500, and 700 mL, and breathing frequencies of 10 and 20 breaths/min. The TTL was connected to the simulated external nares with a standard ventilator circuit. To prevent condensation, the circuit was placed in an incubator maintained at 37°C. Small, medium, and large nasal prongs were tested. Absolute humidity (AH) of inspired gas was measured at the simulated external nares. RESULTS: At 20, 40, and 50 L/min of flow, respective AH values for the Airvo 2 were 35.3 ± 2.0, 37.1 ± 2.2, and 37.6 ± 2.1 mg/L, and for the Optiflow system, 33.1 ± 1.5, 35.9 ± 1.7, and 36.2 ± 1.8 mg/L. AH was lower at 20 L/min of HFNC flow than at 40 and 50 L/min (P < .01). While AH remained constant at 40 and 50 L/min, at 20 L/min of HFNC flow, AH decreased as VT increased for both devices. CONCLUSIONS: During bench use of HFNC, AH increased with increasing HFNC flow. When the inspiratory flow of spontaneous breathing exceeded the HFNC flow, AH was influenced by VT. At all experimental settings, AH remained > 30 mg/L.

A prospective clinical trial on prevention of catheter contamination using the hub protection cap for needleless injection device

BACKGROUND Catheter hub contamination has been recognized as a source of catheter-related bloodstream infections. We have investigated the efficacy of a protection cap for a needleless injection device in preventing intraluminal catheter contamination, compared with a conventional 3-way stopcock. METHODS Adult patients requiring an intravascular catheter placement for at least 48 hours in an intensive care unit were randomly assigned to receive either the needleless injection device with protection cap (test group, n = 31, number of devices = 151) or with a conventional 3-way stopcock (comparator group, n = 33, number of devices = 179). To evaluate intraluminal contamination, we examined the bacteria isolated in the inline bacterial filters, which were attached downstream of the injection ports. RESULTS The incidence of bacterial contamination was significantly different between the groups (test group 2/151 (1.3%) vs comparator group 11/179 (6.2%), P = .04). There was no correlation between the microbial contamination rate and the in situ time of catheter or numbers of injections. CONCLUSION The protection cap for needleless injection devices decreased microbial transfer from the injection port to the intraluminal fluid pathway and lowered the risk of catheter-related bloodstream infections.

Potential Inadequacy of Automatic Tube Compensation to Decrease Inspiratory Work Load After at Least 48 Hours of Endotracheal Tube Use in the Clinical Setting

BACKGROUND: Endotracheal tubes (ETTs) impose a substantial respiratory work load on mechanically ventilated patients. Automatic tube compensation (ATC) should overcome this flow-dependent resistive work load; however, ETT resistance can be increased by tracheal secretions or ETT deformities. Our bench study investigated whether ATC provides effective respiratory work load relief in used ETTs. METHODS: We enrolled 20 critically ill patients requiring mechanical ventilation for longer than 48 hours. After extubation, we collected the used ETTs and measured the pressure-time products (PTPs) by using a bellows-in-a-box lung model that simulated spontaneous breathing, at a respiratory rate of 10 breaths/min, inspiratory time of 1.0 s, and tidal volumes (VT) of 300 mL, 500 mL, and 700 mL. The ventilator was set at ATC 100% with PEEP of 5 cm H2O and FIO2 of 0.21. The flow and airway pressure at the proximal (Paw) and distal (Ptr) ends of the ETT were recorded, and the PTP integrated from Ptr analyzed. RESULTS: PTP values increased with VT during ATC. Even at 100% ATC the ventilator did not completely compensate for the PTP imposed by the ETT. In used ETTs, peak flow and peak Paw were lower and PTP values were greater than in new ETTs. As VT increased, the percentage difference in the PTP values between the new and used ETTs increased. CONCLUSIONS: ATC does not necessarily compensate for an ETT-imposed respiratory work load. ETT configuration changes and tracheal secretions can increase ETT resistance and decrease the ability of ATC to compensate for the increased respiratory work load.

Novel dual targeting strategy with vandetanib induces tumor cell apoptosis and inhibits angiogenesis in malignant pleural mesothelioma cells expressing RET oncogenic rearrangement

Malignant pleural mesothelioma (MPM) is an aggressive malignancy with a poor prognosis, therefore development of novel effective therapies is urgent. In the present study, we investigated the therapeutic efficacy of vandetanib (ZD6474), an inhibitor of VEGFR-2, EGFR and RET tyrosine kinases, in an orthotopic model of MPM. We found that a human MPM cell line, EHMES-10, expressed RET/PTC3 oncogenic rearrangement and a large amount of VEGF. Vandetanib induced the apoptosis and inhibited the proliferation of EHMES-10 cells in vitro (IC(50)=0.3 microM). Once-daily oral treatment with vandetanib inhibited tumor angiogenesis, and reduced significantly the growth of thoracic tumors and the production of pleural effusions, resulting in the prolonged survival of mice in EHMES-10 orthograft model. In contrast, the selective EGFR tyrosine kinase inhibitor, gefitinib, had no effect against EHMES-10 cells both in vitro and in vivo. Our results suggest that using vandetanib to target RET-dependent tumor cell proliferation and survival and VEGFR-2-dependent tumor angiogenesis may be promising against MPM expressing RET oncogenic rearrangement and VEGF.