Low Pulmonary Toxicity Research Articles

Sugemalimab in locally advanced and advanced Chinese NSCLC: A real-world retrospective study.

e20575 Background: Lung cancer is a major cause of cancer deaths in China. Immunotherapy has emerged as a promising treatment approach for advanced NSCLC without sensitive mutations. Sugemalimab, a fully human immunoglobulin G4 monoclonal antibody, retains its Fc function, inducing antibody-dependent cellular phagocytosis. This study aims to evaluate the real-world effectiveness and safety of Sugemalimab in various treatment patterns, particularly with radiotherapy, in Chinese NSCLC patients with locally advanced or metastatic disease. Methods: We retrospectively evaluated locally advanced (LA-) and metastatic (m-) NSCLC patients (pts) treated with Sugemalimab in Cancer Hospital, Chinese Academy of Medical Sciences from Feb. 2022 to Sep. 2023. Demographic characteristics, clinical features, genetic landscape and therapy patterns were collected. We employed descriptive statistics to determine the Objective Response Rate (ORR) and Disease Control Rate (DCR), and used the Kaplan-Meier method for estimating Progression-Free Survival (PFS) and Overall Survival (OS). Safety profiles, including adverse events and immune-related pneumonitis, were similarly analyzed. Results: 76 pts with LA-NSCLC and mNSCLC were enrolled. Majority were male (92.1%) and smokers (84.2%) and ECOG PS 0-1 (78.9%). Median age was 66. Squamous-cell carcinoma was found in 44 pts (57.9%). The main metastatic sites were bone, brain, liver, lung and lymph node for mNSCLC pts. Genetic profiling in 39 pts revealed TP53 mutations in 19 (48.7%) and KRAS mutations in 10 (25.6%). A total of 38 pts (51.3%) received 1L Sugemalimab therapy, while 21 pts (27.6%) receiving 2L. Main treatment pattern was Sugemalimab plus platinum-based chemo. Radiotherapy (RT) was main local therapy approach, concurrent with Sugemalimab in 18 pts. Majority of pts received either volumetric modulated arc therapy or intensity-modulated radiation therapy to thoracic lesions. Tomotherapy was administered to brain metastases in 2 pts. The median follow-up time was 9.18m at this cut-off date. 16 pts receiving Sugemalimab plus chemo achieved objective response (ORR 44.4%) and DCR was 91.5% in 1L therapy. Median PFS (mPFS) has not been reached. PFS rate at 6m, 12m was 75.6%, 62.1% respectively. 1L OS was immature. For pts receiving additional thoracic RT concurrent with 1L systematic therapy, mPFS was still not mature. PFS rate was 82.4% at 6m and 74.9% at 12 m. Common RT-related side effects were radiation pneumonitis, radiation esophagitis and skin injury. None immune-related pneumonitis was found in this population. Only one case of immune-related pneumonitis was observed in a pts without RT. Conclusions: Our study demonstrated Sugemalimab-based therapy provide clinical benefits to LA-NSCLC and mNSCLC with good safety in real-world setting. The combination treatment of Sugemalimab with radiotherapy illustrates low pulmonary toxicity and superior tolerability.

Development and Evaluation of Paclitaxel and Curcumin Dry Powder for Inhalation Lung Cancer Treatment.

Despite the effort to develop efficient targeted drug delivery for lung cancer treatment, the outcome remains unsatisfactory with a survival rate of 15% after 5 years of diagnosis. Inhalation formulation is an ideal alternative that could ensure the direct deposition of chemotherapeutics to the lungs. However, the design of an inhalable formulation that could simultaneously achieve a high local chemotherapeutic dose to the solid tumor and exert low pulmonary toxicities is a challenge, as the presence of 10–30% of chemotherapeutics in the lung is sufficient to induce toxicity. Therefore, this study aimed to develop a simple dry powder inhalation (DPI) formulation containing a model chemotherapeutic agent (paclitaxel, PTX) and a natural antioxidant (curcumin, CUR) that acts to protect healthy lung cells from injury during direct lung delivery. The co-jet-milling of CUR and PTX resulted in formulations with suitable aerosol performance, as indicated in the high fine particle fractions (FPF) (>60%) and adequate mass median aerodynamic diameter (MMAD). The CUR/PTX combination showed a more potent cytotoxic effect against lung cancer cells. This is evident from the induction of apoptosis/necrotic cell death and G2/M cell cycle arrests in both A549 and Calu-3 cells. The increased intracellular ROS, mitochondrial depolarization and reduced ATP content in A549 and Calu-3 cells indicated that the actions of CUR and PTX were associated with mitochondrial oxidative stress. Interestingly, the presence of CUR is crucial to neutralize the cytotoxic effects of PTX against healthy cells (Beas-2B), and this is dose-dependent. This study presents a simple approach to formulating an effective DPI formulation with preferential cytotoxicity towards lung cancer.

Predictive Biomarkers for the Ranking of Pulmonary Toxicity of Nanomaterials.

We analyzed the mRNA expression of chemokines in rat lungs following intratracheal instillation of nanomaterials in order to find useful predictive markers of the pulmonary toxicity of nanomaterials. Nickel oxide (NiO) and cerium dioxide (CeO2) as nanomaterials with high pulmonary toxicity, and titanium dioxide (TiO2) and zinc oxide (ZnO) as nanomaterials with low pulmonary toxicity, were administered into rat lungs (0.8 or 4 mg/kg BW). C-X-C motif chemokine 5 (CXCL5), C-C motif chemokine 2 (CCL2), C-C motif chemokine 7 (CCL7), C-X-C motif chemokine 10 (CXCL10), and C-X-C motif chemokine 11 (CXCL11) were selected using cDNA microarray analysis at one month after instillation of NiO in the high dose group. The mRNA expression of these five genes were evaluated while using real-time quantitative polymerase chain reaction (RT-qPCR) from three days to six months after intratracheal instillation. The receiver operating characteristic (ROC) results showed a considerable relationship between the pulmonary toxicity ranking of nanomaterials and the expression of CXCL5, CCL2, and CCL7 at one week and one month. The expression levels of these three genes also moderately or strongly correlated with inflammation in the lung tissues. Three chemokine genes can be useful as predictive biomarkers for the ranking of the pulmonary toxicity of nanomaterials.

Assessment of Cytokine-Induced Neutrophil Chemoattractants as Biomarkers for Prediction of Pulmonary Toxicity of Nanomaterials.

This work determines whether cytokine-induced neutrophil chemoattractants (CINC)-1, CINC-2 and CINC-3 can be markers for predicting high or low pulmonary toxicity of nanomaterials (NMs). We classified NMs of nickel oxide (NiO) and cerium dioxide (CeO2) into high toxicity and NMs of two types of titanium dioxides (TiO2 (P90 and rutile)) and zinc oxide (ZnO) into low toxicity, and we analyzed previous data of CINCs in bronchoalveolar lavage fluid (BALF) of rats from three days to six months after intratracheal instillation (0.2 and 1.0 mg) and inhalation exposure (0.32–10.4 mg/m3) of materials (NiO, CeO2, TiO2 (P90 and rutile), ZnO NMs and micron-particles of crystalline silica (SiO2)). The concentration of CINC-1 and CINC-2 in BALF had different increase tendency between high and low pulmonary toxicity of NMs and correlated with the other inflammatory markers in BALF. However, CINC-3 increased only slightly in a dose-dependent manner compared with CINC-1 and CINC-2. Analysis of receiver operating characteristics for the toxicity of NMs by CINC-1 and CINC-2 showed the most accuracy of discrimination of the toxicity at one week or one month after exposure and CINC-1 and CINC-2 in BALF following intratracheal instillation of SiO2 as a high toxicity could accurately predict the toxicity at more than one month after exposure. These data suggest that CINC-1 and CINC-2 may be useful biomarkers for the prediction of pulmonary toxicity of NMs relatively early in both intratracheal instillation and inhalation exposure.

Present Situation and Future Progress of Inhaled Lung Cancer Therapy: Necessity of Inhaled Formulations with Drug Delivery Functions.

Inhaled lung cancer therapy is promising because of direct and noninvasive drug delivery to the lungs with low potential for severe systemic toxicity. Thus chemotherapeutic drugs have been administered clinically by nebulization of solution or suspension formulations, which demonstrated their limited pulmonary absorption and relatively mild systemic toxicity. In all these clinical trials, however, there was no obviously superior anticancer efficacy in lung cancer patients even at the maximum doses of drugs limited by pulmonary toxicity. Therefore methods that deliver both higher anticancer efficacy and lower pulmonary toxicity are strongly desired. In addition to the worldwide availability of pressured metered dose inhalers (pMDIs) and dry powder inhalers (DPIs) to treat local respiratory diseases, recent innovations in medicines and technologies are encouraging next steps toward effective inhaled lung cancer therapy with new therapeutic or drug delivery concepts. These include the discovery of target cells/molecules and drug candidates for novel cancer therapy, the development of high-performance inhalation devices for effective pulmonary drug delivery, and the establishment of manufacturing technologies for functional nanoparticles/microparticles. This review highlights the present situation and future progress of inhaled drugs for lung cancer therapy, including an overview of available inhalation devices, pharmacokinetics, and outcomes in clinical trials so far and some novel formulation strategies based on drug delivery systems to achieve enhanced anticancer efficacy and attenuated pulmonary toxicity.

P1.18-16 Is Tumor Shrinking During Chemoradiation for LA-NSCLC a Biomarker for Outcome?

Adaptation of dose distribution to tumor reduction during radiotherapy is an innovative approach. Even if the advantage for lung toxicity is intuitive, some concerns exist about the risk of tumor recurrences in the area of target reduction. Recent data reported no increased local relapse and low pulmonary toxicity so, waiting for the ongoing phase III trial investigating this issue (RTOG 1106-ACRIN 6697), the aims of this study is to compare the long term outcome for patients treated or not with the adaptive approach. LA- NSCLC patients enrolled in a prospective study, where they were treated with concomitant chemoradiation and underwent to replanning in case of tumor shrinkage, have been compared with patients without tumor shrinkage treated with the concurrent treatment in the same period. Toxicity was evaluated with the RTOG/EORTC scale. The differences between groups were compared by Fisher’s exact test (two tail) or χ2 when appropriate. The “time to event” curve was calculated with the Kaplan-Meier method, and log-rank test was used to perform between-group comparisons. Patients in the adaptive group (AG) were more likely to receive a total radiation dose equal or higher than 59.4Gy (58% vs 27%, p=0.003). No statistical differences were reported in local recurrences, even if in non-adaptive (NAG) and AG were 48% and 31%, respectively. Distant recurrences were documented in the 55% and 46% of patients. Acute ≥G2 esophageal and pulmonary toxicity was similar, but G3 acute lung toxicity was lower than a third in AG (2% vs 7%) and G3 chronic lung damage reduced by half (7.5% vs 4%). Median follow up for alive patients was 57.8 months. Median OS were 26,6 and 30,5 months and PFS 7,6 and 8.3 months between NAG and AG, respectively. Survival was affected by the rate of shrinking with better result for patients reducing 25-50% of the initial volume (median not reached) in comparison with no-reduction or until 25% patients (median 25 months) (p=0.016). An apparent contra-intuitive result was the lower survival in case of reduction >50% (median 23 months). PFS reflects the same observation with median values of 7,5 and 7,4 months for patients shrinking 0-25% and >50%, respectively and 13,8 months for patients reporting a tumor reduction in the range of 25-50%. Waiting for randomized phase III results, adaptive approach confirms its role in escalating dose and reducing toxicity without compromise outcome. The worse outcome in patients with >50% reduction could be explained by high proliferating aggressive tumor behavior. The value of the shrinking rate as a biomarker for survival deserves to be investigated in future trials at the aim to intensify treatment in selected population.

Autologous Stem Cell Transplantation with Bendaeam (Bendamustine, Etoposide, Cytarabine, Melphalan) As Conditioning Regimen for Non-Hodgkin’s Lymphoma and Hodgkin’s Lymphoma

Background: High dose chemotherapy followed by autologous stem cell transplantation (ASCT) remain standard of care in patients with relapsed non Hodgkin’s lymphoma (NHL) and Hodgkin’s lymphoma (HL). This regimen is also proposed as consolidation therapy in patients with poor prognosis aggressive NHL and mantle cell lymphoma in first complete remission (CR). BEAM (BCNU, etoposide, cytarabine, melphalan) is the standard protocol chemotherapy used as conditioning regimen. A few previous studies with Bendamustine replacing BCNU have been reported with promising results. BendaEAM seems to show less toxicity and might improve results in relapsed Hodgkin/non-Hodgkin’s lymphoma (R-HL/NHL) patients.Method: From January 2014 to July 2014, patients with NHL and HL were enrolled in this study. Previous therapy consisted in Rituximab (R)-CHOP (cyclophosphamide, doxorubicine, vincristine, prednisone) for all NHL patients transplanted in first CR. Patients with relapsed NHL and HL received high-dose cytarabine based salvage regimen. No patient presented significative comorbidity. Functional pulmonary test and cardiac evaluation were performed for all patients. with the conditioning regimen consisted in Bendamustine on day -7 and -6 (200 mg/m²/d), cytarabine daily from day -5 to day -2 (200 mg/m²/d), etoposide daily from day -5 to day -2 (200 mg/m²/d) and melphalan on day -1 (140 mg/m²). Autologous stem cells were infused on day 0. Prophylactic use of colony-stimulating factors was not allowed except for patients with less than 2x106 in the apheresis product. Patients received antimicrobial prophylaxis with oral fungizone. Red cells and platelets transfusions were administered to maintain hemoglobin level >8g/dl and a platelet count (PLT) >10x109/l. Broad spectrum antibiotics were delivered when fever developed.Results: There were 25 patients: 10 patients with diffuse large-B cell lymphoma and high international prognostic score (IPI) score in first CR, 5 patients with relapsed NHL or HL, 4 patients with mantle cell lymphoma in first CR, 5 patients with relapsed follicular lymphoma, and 1 patient with peripheral T cell lymphoma. A median number of 4,1x106 (range: 1.5-8.1) CD34 cells/kg was infused. All patients fully engrafted after a median time of 19.5 days (range: 14-24). Median times to PLT>20x109/l and PLT>50x109/l were 20 days (range: 16-52) and 22 days (range: 18-52) respectively. All patients experienced grade 3-4 fever with a documented infection in 9 cases Five patients were admitted in intensive care unit for septic shock and one patient died. One patient presented a total resolutive grade 4 renal failure. Three patients (12%) developed grade 3 cardiotoxicity (atrial fibrillation). No pulmonary toxicity was observed. Median time to hospital discharge was 23 days (range: 18-77). With a median follow-up of 2 months (range: 1-6) 24 patients are alive in CR.Conclusion: BendaEAM as conditioning regimen followed by ASCT is feasible in patients with NHL and HL. Toxicity of this chemotherapy is acceptable and seems comparable to that observed with the standard BEAM regimen (data will be presented). While the follow-up remains short, results are encouraging in patients with NHL or HL, as well as in first CR or subsequent CR.Thus, the use of bendamustine in lymphoma conditioning regimen can be recommended on the basis of its high anti-lymphoma activity, but also according to the safety of the drug with a lower pulmonary toxicity. DisclosuresNo relevant conflicts of interest to declare.

Dose Dense/Dose Intense ABVD without Radiotherapy: A New Early Intensification Treatment Approach in Advanced-Stage Hodgkin Lymphoma. Ten Years Experience and Analysis of a Consecutive Series of 172 Previously Untreated Classic Hodgkin’s Lymphoma Patients

Despite impressive cure rates obtained with modern chemotherapy, the optimal therapeutic strategy in advanced classic Hodgkin Lymphoma (HL) is still debated due to some remaining open issues. These involve the best choice of upfront chemotherapy, the duration and intensity of frontline treatment, the value of consolidation radiotherapy, the role of functional imaging in treatment planning and monitoring and the adequacy of risk stratification tools. These observations have led us to investigate whether intensification of front-line ABVD would be possible while maintaining acceptable levels of toxicity and improving the performance of the schedule. We designed a dose-dense three-weekly version of the ABVD regimen (six cycles), which was also dose intensified, in the first four cycles, by escalating doxorubicin dose from 50 to 70 mg/m2 per cycle, in the absence of consolidation RT. A series of 172 patients (advanced-stage=124, intermediate-stage=48) was studied. Apart from pre- and post-Tx staging, all patients also underwent 18F-FDG-PET imaging after the 2nd cycle (PET2); in case of pathologic uptake at PET2, a new scan was performed after the 4th cycle (PET4). Open-label phase study began I June 2004; specifications are contained in the published article (Russo F BHJ 166,1118,2014) focused on feasibility and toxicity in 82 patients. The demographics and clinical characteristics are in Tab1.Ninety-five percent of patients completed the planned six cycles (median duration time=16.7 weeks). Median actual dose intensities were 20.94 (23.12 cycles1-4), 6.69, 3.96 and 245 mg/m2/week for doxorubicin, bleomycin, vinblastine and dacarbazine, respectively. This corresponded to a 66.9% (85.0%, cycles 1-4) increase in dose intensity for doxorubicin, (total dose 380 mg/m2) and of 32% for the other agents, over standard ABVD. Intensified ABVD was highly tolerated with low rates of hospitalization during treatment, a low incidence of G3/ G4 events, low post-treatment cardiac and pulmonary toxicities and a very low rate of gonadic toxicity. Only two cases of second cancer have been recorded. PET2 was negative in 87% of patients (85% ADV,92%INT). Remarkably a CR rate of 94% (93% ADV, 98% INT) was achieved and EFS and OS at 7-years were 85% (79%ADV, 91% INT) and 96% (93%ADV, 98%INT) respectively (Tab2, Fig1). At univariate analysis (factors: Age, sex, LDH, IPS,B-symptoms, mediastinal bulky disease (MBD), E-disease, PET2, stage IV) the predictive factors of low CR rate were IPS≥3 (CR 89% vs 97%, p=0.03), and PET2pos (CR 65% vs 99%p<0.001). At multivariate analysis PET2 positivity (p<0.001) was the only independent risk factor predictive of low CR rate. Kaplan-Meyer 7yr-EFS was 77 and 78% (Log Rank 1.1, p=0.28) in MBD and no-MBD subsets, respectively. 7yr-EFS was significantly better in patients with PET2neg (87% vs 52% , log rank 24.7, p<0.001) and in patients with IPS 0-2 (88% vs 71% log rank 4.9, p=0.02). At Cox regression analysis PET2 was the only independent factor predictive of Event Free Survival.Intensified ABVD without radiotherapy seems to be adequately powered to exploit early disease chemo-sensitivity yielding high percentage of early negative PET2, high rate of response and survival, without new severe or critical short and long-term toxicities. Table 1TAB 1Advanced-stage(n=124)Intermediate-stage (n=48)CharacteristicsNo.%No.%Age, yearsmedian3229range15-7715 - 62>45 years2319510Gender, male64521837Ann Arbor stageII322648100III4032IV5242B symptoms88711531Mediastinal bulk5645919Extramediastinal bulk ≥10cm6524≥ 3 nodal areas involved99803675Spleen involvement2319Extranodal (stage II-III)8624Extranodal (stage IV )5141ESR (>50 mm/h)60481531IPS ≥ 3614948LDH ratio>151411225Histologic subtypeNodular sclerosis102824083Lymphocyte rich108510Mixed celluarity6536NOS6500Table 2Advanced stageIntermediate stageTab 2N%95%C.I.N%95%C.I.Final treatment response12310048100CR1159388 - 97479894–100NearCR/PR64.912.1Progression21.600Cycle 2 PET12410048100negative106854492positive181548Cycle 4 PET181004100negative1161375positive739125Events222148<CR6512progression2200early relapse 3-128624late relapse>12 months32122nd tumor22001st line treatment-related death11001-yr EFS8583-949594–1002-yr EFS8376-909183-994-yr EFS8274-897-yr EFS7970-889183-997-yr OS9386-1009793–100 [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The effect on patients with pulmonary fibrosis (PF) and advanced non small cell lung cancer (NSCLC): A prospective, feasibility study of S-1 and carboplatin.

e19583 Background: PF is commonly concomitant disorder with lung cancer. Because PF sometimes deteriorates and results unfavorable clinical course, patients with PF are excluded from most cancer clinical trials. S-1 is a novel active oral fluoropyrimidine anticancer agent consisting of tegafur, gimeracil and oteracil potassium. Although most anti-cancer agent have pulmonary toxicity, post marketing surveillance reported S-1 has lower pulmonary toxicity incidence. We have conducted feasibility study of S-1 and carboplatin combination for patients with advanced or ineligible for other treatment modality of NSCLC patients. Methods: Patients with histologically or cytologically confirmed NSCLC, clinically diagnosed pulmonary fibrosis, aged 80 years old or younger, performance status 0-2 and chemo naive were eligible for the study. Carboplatin (AUC 5) was administered on day 1 and S-1 (80mg/m2/day) on day 1 to 14 for four to six cycles. Endpoints were response rate, common safety profiles and effect to PF. Results: From March 2009 to December 2011, 21 pts (19 males/ 2 females, median age 67 years old, ranged 55 to 77, 10 adenocarcinoma, 10 squamous, 1 adenosquamous, stage IIA: 1, IIIA: 3, IIIB: 9, IV: 4, recurrence: 4) were enrolled. All patients had moderate or severe PF. Treatment delivery; 1 cycle: 3pts, 2: 3pts, 3: 3pts, 4: 10pts, 5; 1pts, 6: 1pts. Partial responses were observed in 7 patients (RR; 33%). The median progression free survival duration was 4.0 months and the median overall survival duration in 10.4 months. During the treatment, 2 patient experienced moderate deterioration of pulmonary fibrosis, 1 experienced infectious pneumonia, all three patients recovered from the event. There was no treatment related death. Besides pulmonary toxicity, most common adverse events were myelotoxicities. Conclusions: This is the first trial of S-1 and carboplatin combination for patients with PF and NSCLC. The study revealed S-1 and carboplatin combination was feasible and active even in patients with PF and NSCLC who are usually excluded from cancer clinical trials.

Chitosan nanoparticles show rapid extrapulmonary tissue distribution and excretion with mild pulmonary inflammation to mice

Pulmonary delivery of nanoparticles (NP) conjugated with therapeutic agents has been considered recently for both lung disorders and systemic circulation. Hydrophobically modified glycol chitosan (HGC) NP have previously shown excellent deposition to the tumor site and non-destructive intracellular release. Here, we evaluated the kinetics and toxicity of HGC NP by intratracheal instillation to mice. HGC NP showed a positive charge and average hydrodynamic size was around 350 nm. The half-life of NP in the lung was determined as 131.97 ± 50.51 h. NP showed rapid uptake into systemic circulation and excretion via urine which was peaked at 6 h after instillation. Although HGC NP were distributed to several extrapulmonary organs, the levels were extremely low and transient. HGC NP induced transient neutrophilic pulmonary inflammation from 6 h to day 3 after instillation. Expression of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and chemokine (MIP-1α) in lung showed an increase from 1 h to 24 h after instillation and recovered thereafter. Our findings suggest that HGC NP can be successful candidates for use as pulmonary delivery vehicles, owing to their excellent biocompatibility, transiency, and low pulmonary toxicity, and property of rapid elimination without accumulation.

Radiographic Pneumonitis Patterns and Low Pulmonary Toxicity After Helical Tomotherapy

AJR 2010; 194:W459 0361–803X/10/1945–W459 © American Roentgen Ray Society Radiographic Pneumonitis Patterns and Low Pulmonary Toxicity After Helical Tomotherapy We read with interest the recent article by Park et al. [1] describing early CT pneumonitis patterns after thoracic radiotherapy via helical tomotherapy. This retrospective study reported on 77 target lesions in 25 patients treated from 2005 to 2007 for either primary lung cancer or metastases with doses of 40 to 50 Gy in 3 to 20 fractions. Only five patients developed grade 2 pneumonitis requiring steroids, and no grade 3 toxicities were observed. The distribution of pneumonitis was commonly peripheral to the target, with skip areas and a centrifugal pattern. Radiation-induced lung parenchymal changes occur adjacent to high-dose areas, irrespective of technique. A small study from Japan detailed the radiographic changes that may occur with multiple-field arrangements at doses less than 20 Gy. Lung density changes were not seen outside the portals of the static beams [2]. The volume of lung receiving greater than 20 Gy has been shown to correlate with clinical development of pneumonitis using conventional fractionation [3]. The shape of these radiographic changes after tomotherapy differs from 3D conformal conventional fields, which produce predictable changes mostly along the perihilar regions because of the use of anteroposterior and oblique portals (Fig. 1). The helical nature of tomotherapy delivers the dose via 360°, and the inverse planning involved in beamlet arrangement makes the shape of these changes unique. The significance of the radiographic changes, in our experience, is not clinically relevant. The University of Wisconsin dose-escalation study suggests that the increased conformality of tomotherapy allows higher total lung tumor dose without significant (≥ grade 3) toxicity [4]. We have seen radiographic changes similar to those described by Park et al. [1], and only 13% of our patients required temporary steroids for clinical grade 2 pneumonitis. None developed grade 3 pneumonitis in spite of significant dose escalation. Importantly, nonpulmonary toxicity, such as esophagitis, also may be reduced with tomotherapy. We believe that tomotherapy represents a safe technology for delivery of thoracic intensity-modulated radiotherapy. We agree that the radiographic changes observed after treatment must be interpreted differently than those with conventional 3D conformal radiotherapy. Jarrod B. Adkison Minesh Mehta University of Wisconsin Madison, WI

Dronedarone: an emerging therapy for atrial fibrillation

Atrial fibrillation (AF) is a common arrhythmia, with a prevalence ranging from 0.1% to 9.0% at different ages, and is associated with increased cardiovascular events and mortality. A significant increase in the prevalence of the disease is expected to occur in the coming years as a consequence of the aging of the population and advances in the management of coronary artery disease and heart failure. Effective rhythm control may be difficult to obtain in a significant proportion of patients with AF. The limited efficacy and the possible adverse effects of antiarrhythmic drugs has led researchers to focus their attention on new molecules, in a search of compounds with antiarrhythmic efficacy and a more favourable safety profile. Among several new drugs developed for the management of AF, dronedarone, a benzofuran derivative that shares many of the antiarrhythmic properties of amiodarone, but with a more favourable safety profile, seems particularly promising. The drug is noniodinated, has less lipophilicity, reaches therapeutic concentrations over a shorter period of time and has lower tissue accumulation. Dronedarone, similarly to amiodarone, exhibits electrophysiologic characteristics of all 4 Vaughan Williams classes. Clinical studies have shown that dronedarone effectively reduces ventricular rate, may prevent or delay the recurrence of AF, and may reduce cardiovascular morbidity and mortality in patients with AF or atrial flutter. The drug has an overall good safety profile, in particular with low pulmonary and thyroid toxicity. An important exception is represented by patients with unstable haemodynamic conditions, in which the use of dronedarone has been found to be associated with an increase in mortality. Dronedarone has been recently approved for clinical use by the Food and Drug Administration and by the European Medicines Agency. Further results from trials and clinical use will better define the efficacy and safety profile of dronedarone in AF compared with other antiarrhythmic drugs and its role in the management of patients with AF.

Pulmonary toxicity and translocation of nanodiamonds in mice

Because of the possible health threat of nanodiamonds (NDs) to organisms, the pulmonary toxicity and translocation of NDs in different sizes in mice were investigated after intratracheal instillation administration. Biochemical assays, ultrastructural and histopathological evaluations of the lungs of the control and the ND exposed mice were carried out at 1, 7, 14 or 28 days post-exposure. Exposure to 1.0 mg/kg NDs with an average diameter of 4 nm produced a temporary lung index increase at 1 day post-exposure. NDs did not have evident adverse effects in the lungs within the studied period according to histopathological and ultrastructural investigations. Furthermore, no lipid peroxidation of the lung was observed. On the whole, intratracheally instilled NDs are of low pulmonary toxicity. In addition, the amount of NDs in alveolar decreased with time elapsed and the macrophages burdened with NDs were clearly observed in the bronchia from 1 day to 28 days post-exposure. Thus we affirm the critical role of alveolar macrophages in the main excretion pathway of NDs from the lungs, i.e. they engulf the NDs, migrate upward to the trachea by escalator/mucociliary system and finally enter the pharynx.

Rosette nanotubes show low acute pulmonary toxicity in vivo.

Nanotubes are being developed for a large variety of applications ranging from electronics to drug delivery. Common carbon nanotubes such as single-walled and multi-walled carbon nanotubes have been studied in the greatest detail but require solubilization and removal of catalytic contaminants such as metals prior to being introduced to biological systems for medical application. The present in vivo study characterizes the degree and nature of inflammation caused by a novel class of self-assembling rosette nanotubes, which are biologically inspired, naturally water-soluble and free of metal content upon synthesis. Upon pulmonary administration of this material we examined responses at 24 h and 7d post-exposure. An acute inflammatory response is triggered at 50 and 25 microg doses by 24 h post-exposure but an inflammatory response is not triggered by a 5 microg dose. Lung inflammation observed at a 50 microg dose at 24 h was resolving by 7d. This work suggests that novel nanostructures with biological design may negate toxicity concerns for biomedical applications of nanotubes. This study also demonstrates that water-soluble rosette nanotube structures represent low pulmonary toxicity, likely due to their biologically inspired design, and their self-assembled architecture.

Combination of bleomycin, etoposide, and cisplatin for the treatment of advanced ovarian granulosa cell tumors

The objective is to investigate the activity and toxicity of bleomycin, etoposide, and cisplatin (BEP) regimen in ovarian granulosa cell tumors (OGCTs). Twenty consecutive patients with initial metastatic (5 patients) or recurrent (15 patients) OGCT were treated; BEP regimen: B: 30 mg intravenously or intramurally on days 1, 8, and 15; E: 100 mg/m2/day on days 1-5; and P: 20 mg/m2/day on days 1-5. Median age: 42 years (range: 17-60); median follow-up: 45 months (range: 3-112). The overall response rate is 90% (nine clinical complete response [CR], nine clinical partial response) with a median duration of 24 months (range: 4-77). A second-look laparotomy performed in 11 patients showed a pathologic CR in 7 cases and microscopic disease in 1 case. Seven patients remain free of disease (at 4-84 months); 11 patients relapsed (median: 24 months, range: 13-58), 12 patients are still alive, and 9 patients are without disease (2 patients in second CR). At 4 years, overall survival and event-free survival are respectively 58% and 30%. Toxicity is evaluable for 19 patients (48 cycles). A grade 4 neutropenia occurred in 15% of cycles (in seven patients) with a febrile neutropenia in four patients. Five patients experienced a low bleomycin pulmonary toxicity. BEP regimen appears to be an active regimen for OGCT in first-line chemotherapy.

P53 Aerosol Formulation with Low Toxicity and High Efficiency for Early Lung Cancer Treatment

To develop an optimal nonviral aerosol formulation for locoregional treatment of early lung cancer. The formulation was made of polylysine/protamine combination (AND) as the carrier and p53 gene (p53sm) as therapeutic agent. To estimate the aerosol deposition, the aerodynamic size of the AND-p53sm was measured with extrusion-precipitation method. To accurately determine the dose, the aerosol efficiency in mice was measured with a fluorescent dye. The transfection efficiency and DNA protection function of the aerosolized formulation in cultured cells and mouse lungs were detected with reporter gene assays and/or reverse transcription-PCR. The preclinical safety and efficacy of AND-p53sm were studied in healthy mice and mice bearing orthotopic human non-small-cell lung cancer (NSCLC) xenograft. After aerosolization, AND is 3- to 17-fold more effective than commonly used PEI or cationic lipid formulations in transfecting the NSCLC cells (relative light units, 1,494 versus 534 and 86; P < 0.003). Aerodynamic size of AND-p53sm ranged 0.2 to 3 mum is the optimal aerosol droplets for deposition in the entire human respiratory tract. Significant gene expression was detected in the lungs of mice given aerosolized AND-p53sm and AND-luciferase. Aerosolized AND-p53sm significantly prolonged the life of mice bearing orthotopic human NSCLC xenografts, and it was more effective than an optimal i.v. cisplatin chemotherapy (increased life span, 93% versus 25%; P = 0.014). Inhalation of AND produced low and reversible pulmonary toxicity and no systemic toxicity. This optimal formulation is suitable for delivering biological materials to human lung with aerosol administration. This therapeutic strategy is an option for patients with early lung cancer and bronchoalveolar carcinoma.

Activity of boanmycin against colorectal cancer

Boanmycin (Bleomycin A6, BAM), a new antitumor antibiotic, was isolated from many components of bleomycin (BLM) produced by streptomyces pingyangensis which were obtained from a soil sample collected in Pingyang County, Zhejiang Province, China. Boanmycin has a similar chemical structure to that of BLM, but the terminal amine moiety is different[1]. Pingyangmycin (bleomycin A5), one of multicomponent bleomycin complex produced by the strain, was found to have a high activity against a wide spectrum of murine transplantable tumors, but have a relatively low pulmonary toxicity in mice[2-4]. Pingyangmycin, as a single agent, shows marked inhibition on the growth of human colon cancer, stomach cancer and nasopharyngeal cancer xenografts in nude mice[5-7]. It has been widely used clinically in the treatment of tumors since 1979 in China[8]. Because of a good antitumor efficacy of pingyangmycin as a single agent and low marrow toxicity, attempts have been made to develop new superior bleomycin derivatives[9]. BAM, a minor component of bleomycin complex, was also found to be highly active against murine tumors, human liver cancer and colorectal xenografts in nude mice, and markedly inhibit the spontaneous pulmonary metastasis of Lewis carcinoma in mice[10-14]. BAM-monoclonal antibody immunoconjugates were highly effective against related human tumor in vivo and in vitro[15-19]. BAM also reached a higher concentration and remained for a longer time in murine transplantable carcinomas as compared with other bleomycin components[3]. As observed under electron microscopy, the pulmonary toxic damage caused by BAM was less than that induced by bleomycin[20]. Phase I clinical study of BAM showed no myelosuppression and cardiac toxicity, and its major adverse reactions were fever, gastrointestinal reactions and hardening at the site of i.m. injection. All adverse effects disappeared after discontinuation of the therapy[21]. An ideal animal model for cancer is one that mimics human disease in every respect. Most tumor xenograft studies, including colorectal tumor, for the evaluation of antitumor activity of drugs used subcutaneous implantation system due to its convenience and access to direct detection and therapeutic effect. However, those models have limitations for the study of interaction of tumor cells with their relevant organ environment or or gan distribution of drugs. Alteration of microenvironment surrounding tumor tissue will not only influence growth and spread of tumor but also is important for drug delivery[22-24]. Recently, use of orthotopic models for the growth of tumors in mice or rat has aroused more interest, including lung cancer, colorectal cancer, breast cancer, pancreatic cancer, etc[25-30]. However, whether such orthotopic colorectal tumor models apply to the evaluation of new anticancer agents remains unknown. In the present study, human colorectal tumor xenograft model in nude mice and the orthotopic model of murine colon cancer were used to clarify the antitumor effect of BAM in comparison with that of mitomycin C and 5-fluorouracil, drugs commonly used in clinics against colorectal cancer. We attempted to determine the effect of BAM against colorectal cancer and whether the organ microenvironment could influence the response of a murine colon cancer to systemic therapy with BAM.

Peripheral markers (Clara cell protein and alpha-glutathione S-transferase) and lipidoperoxidation (malondialdehyde) assessment in Sprague-Dawley rats instilled with haematite and benzo[a]pyrene.

The literature suggests that the concomitant exposure to polycyclic aromatic hydrocarbons (PAH) and ferric oxide particles could enhance lung cancer incidence in environmental and occupational settings. High levels of tracheobronchial tumours were obtained in hamsters exposed to benzo[a]pyrene (B[a]P) adsorbed onto ferric oxide carrier particles. Therefore, we have assessed the toxic effects of exposure to haematite (Fe2O3) and B[a]P in male Sprague-Dawley rats. Animals were instilled with the chemicals alone (3 mg of Fe2O3 or B[a]P) or in combination (3 mg Fe2O3 + 3 mg B[a]P). Bronchoalveolar lavages (BAL) and biological samples (serum and urine) were collected 48 h after the intoxication. Clara cell protein (CC16) and alpha-glutathione S-transferase (alpha-GST), as peripheral markers of both tracheobronchial epithelial cell integrity and renal dysfunction, were determined in BAL fluid, serum and urine. Malondialdehyde (MDA), a marker of lipid peroxidation, was measured in BAL fluid and serum. We observed a significant increase of CC16 concentrations in BAL fluid after Fe2O3 + B[a]P instillation (p < 0.05) in serum after Fe2O3 and Fe2O3 + B[a]P exposure (p < 0.01) and in urine after B[a]P administration (p < 0.01). Instillation of Fe2O3 + B[a]P produced an increased amount of alpha-GST in BAL fluid (p < 0.01), whereas B[a]P alone caused a significant elevation of alpha-GST in serum and urine (p < 0.01). Moreover, Fe2O3 or Fe2O3 + B[a]P instillation induced a significant increase in MDA levels in BAL fluid (p < 0.01 and p < 0.05). In conclusion, Fe2O3 may have a low pulmonary toxicity. However, B[a]P manifested a rapid and high toxicity in the respiratory tract and kidneys. When B[a]P was adsorbed on haematite particles, both its retention in the respiratory tract and pulmonary toxicity increased.

Improvement of the Pulmonary Absorption of (Asu1,7)-Eel Calcitonin by Various Absorption Enhancers and Their Pulmonary Toxicity in Rats

□ The effects of absorpti on enhancers on the pulmonary absorption of (Asu1,7)-eel calcitonin (ECT) and their pulmonary toxicity were examined by means of in situ pulmonary experiments. The absorption of ECT from the lungs was estimated by its hypocalcemic effect. The pulmonary membrane toxicity of absorption enhancers was evaluated by the leakage of Evans Blue from the plasma into the lungs. in the absence of absorption enhancers, a slight hypocalcemic effect was obtained following intrapulmonary administration of ECT. However, we found significant hypocalcemic effects after the ECT administration with 10mM n-lauryl β-D-maltopyranoside (LM), 10mM sodium glyco- cholate (NaGC), and 10mM linoleic acid-HCO60 (hydrogenated caster oil) mixed micelle (MM). The plasma calcium levels decreased as the amount of LM coadministered with ECT increased. In contrast, 10mM EDTA did not improve the pulmonary absorption of ECT. Overall, a correlation between the pulmonary absorption of ECT and local toxicity was observed in the presence of these additives. However, 1mM LM, 10mM NaGC, and 10mM MM improve the pulmonary absorption of ECT with low pulmonary toxicity. These findings suggest that the use of these adjuvants would be a useful approach for improving the pulmonary absorption of ECT.

微粒子活性炭をｃａｒｒｉｅｒとしたｔａｒｇｅｔｉｎｇ化学療法

Activated carbon particles adsorbing anticancer drugs release the anticancer components at designated levels for a long period at the target tissues, while distribute at a low level to the whole body. Moreover, the particles target the car-cinomatous tumor because of the tendency to adhere the tumor surface. In animal experiments, relatively large particles of activated carbon adsor-bing mitomycin C(MMC-CH)decreased the toxiaty into 18.5%, and its therapeutic efficacy on carcinomatous effusion(LD50/ED50)was 3 times, as compared with those in mitomycin C aqueous solution. Intraperitoneal MMC-CH extended the survival time of rabbits with peritoneal carcinomatosis longer than mitomycin C aqueous solution did. In clinical trials, 51 of 81 patients with carcinomatous effusion(63%)responded well to the MMC-CH therapy. The survival time of the patients with gastric cancer invading into the peritoneum was increased by intraoperative MMC-CH therapy statistically significantry higer than that of historical control group. Very small activated carbon particles adsorbing peplomycin(PEP-CH) showed superior therapeutic effects on lymphatic metastases and a low pulmonary toxicity, as compared with peplomycin aqueous solution. Seven inoperative patients underwent local injection of PEP-CH against esophagael cancer. The response rate was 86% and the mean survival time was 14.3 months.