A preclinical research platform to evaluate photosensitizers for transbronchial localization and phototherapy of lung cancer using an orthotopic mouse model.

BACKGROUND: Establishing the efficacy of novel photosensitizers (PSs) for phototherapy of lung cancer requires in vivo study prior to clinical evaluation. However, previously described animal models are not ideal for assessing transbronchial approaches with such PSs. METHODS: An ultra-small parallel-type composite optical fiberscope (COF) with a 0.97 mm outer diameter tip. The integration of illumination and laser irradiation fibers inside the COF allows simultaneous white-light and fluorescence imaging, as well as real-time monitoring of tip position during laser phototherapy. An orthotopic lung cancer mouse model was created with three human lung cancer cell lines transbronchially inoculated into athymic nude mice. The COF was inserted transbronchially into a total of 15 mice for tumor observation. For in vivo fluorescence imaging, an organic nanoparticle, porphysome, was used as a PS. Laser excitation through the COF was performed at 50 mW using a 671 nm source. RESULTS: The overall success rate for creating orthotopic lung tumors was 71%. Transbronchial white light images were successfully captured by COF. Access to the left main bronchus was successful in 87% of mice (13/15), the right main bronchus to the cranial lobe bronchus level in 100% (15/15), and to the right basal trifurcation of the middle lobe, caudal lobe and accessory lobe in 93% (14/15). For transbronchial tumor localization of orthotopic lung cancer tumors, PS-laden tumor with the strong signal was clearly contrasted from the normal bronchial wall. CONCLUSIONS: The ultra-small COF enabled reliable transbronchial access to orthotopic human lung cancer xenografts in vivo. This method could serve as a versatile preclinical research platform for PS evaluation in lung cancer, enabling transbronchial approaches in in vivo survival models inoculated with human lung cancer cells.

The positive effect of student-oriented clinical clerkship rounds employing role-play and peer review on the clinical performance and professionalism of clerkship students.

Background: Role-play (RP) and peer review (PR) are occasionally used in training and evaluating communication skills in clinical clerkship (CC). Thus, we evaluated the effect of combining RP and PR during student-oriented CC rounds.Methods: Clerkship students conducted medical interviews with and performed physical examinations on their patients, which were reviewed by five peer students who observed their performance while role-playing as senior physicians or patients' families. The peer reviewers then provided feedback to the students. The performance of the students was evaluated based on a mini-clinical evaluation exercise (Mini-CEX) and a professionalism mini-evaluation exercise (P-MEX) before and after the rounds by two attending physicians. After the CC, the students responded to questionnaires about the rounds.Results: Seventy-five students completed the rounds, and the duration of each round was 41.7 ± 7.1 min. Their communication skills and professionalism abilities on Mini-CEX and P-MEX showed significant improvement after the rounds. Improvements in medical interviewing and physical examinations were also noted. Additionally, the students recognized the importance of multiple viewpoints in patient care through experiences of the rounds.Conclusions: Combining RP and PR with CC rounds improves the students' clinical performance and professionalism and promotes their awareness of the importance of multiple viewpoints in patient care.

Adverse events in patients with ulcerative colitis treated with indigo naturalis: a Japanese nationwide survey.

BACKGROUND: Although indigo naturalis (IN) is effective for patients with active ulcerative colitis (UC), IN was associated with adverse events (AEs), including pulmonary arterial hypertension (PAH). Our aim was to evaluate the occurrence of IN-associated AEs and to evaluate any IN dose-effect on AEs. METHODS: A nationwide survey, using questionnaires, was conducted by conducted by the research group funded by the Ministry of Health, Labour and Welfare of Japan, between June 2017 and September 2018. A first questionnaire determined the occurrence of AEs associated with the therapeutic use of IN or herbal medicines containing IN in patients with UC. A second survey identified the clinical characteristics of patients who developed IN-associated critical AEs, namely, liver dysfunction, PAH, and intussusception. RESULTS: Across 337 participating institutions, 49,320 patients with UC were identified, with IN used in 877 (1.8%). AEs were reported in 91 patients (107 events), including liver dysfunction (n = 40), gastrointestinal symptoms (n = 21), headache (n = 13), and PAH (n = 11). No dose-effect relationship between IN and AEs was identified. Liver dysfunction tended to be mild and reversible. Ten cases of intussusception were reported, with 40% of these patients requiring surgical resection. IN-induced PAH was recovered in patients who discontinued to use IN. No IN-associated deaths were reported. CONCLUSIONS: IN-associated AEs were identified among patients with UC, with liver dysfunction often being reversible, while surgical resection was required in a high proportion of patients who developed intussusception. Both healthcare workers and patients should adequately recognize the potential for AEs with the use of IN.

Safety of a short hydration method for cisplatin administration in comparison with a conventional method-a retrospective study.

OBJECTIVE: Cisplatin is administered in combination with massive hydration to avoid renal toxicity, making its administration difficult in an outpatient setting. Although a short hydration protocol for cisplatin has been recently developed, its safety is not fully understood. METHODS: Consecutive patients with lung or other cancer and an Eastern Cooperative Oncology Group performance status of 0-2 who were receiving chemotherapy containing cisplatin at a dose of ≥60 mg/m(2) in a single administration were evaluated. Seventy-four patients were treated with a short hydration protocol consisting of 1750-2250 ml of hydration with mannitol and magnesium supplementation over a period of 3.75-4.75 h on Day 1. Sixty-nine patients were treated with a conventional hydration protocol consisting of 2100-2600 ml of hydration over 6.5-7.5 h on Day 1 with pre- and post-hydration on Days 0, 2 and 3. Toxicity was then compared between the two groups. RESULTS: An elevated serum creatinine level ≥grade 1 was significantly less frequent in the group receiving the short hydration protocol than in the group receiving conventional hydration. Other toxicities were similar between the two groups. Consequently, the completion rate for the planned treatment in the short hydration group (73.0%, 54/74) was significantly higher than that in the conventional hydration group (53.6%, 37/69). CONCLUSIONS: Short hydration is safe, making cisplatin-containing chemotherapy easier to perform.

Home-based pulmonary rehabilitation in patients with inoperable or residual chronic thromboembolic pulmonary hypertension: a preliminary study.

BACKGROUND: Management of chronic thromboembolic pulmonary hypertension (CTEPH) has recently improved because of advances in pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA), and disease-targeted medications. However, patients with inoperable CTEPH or persistent pulmonary hypertension (PH) after these interventions continue to exhibit impaired exercise capacity and limited quality of life (QOL). METHODS: Eight patients with inoperable or residual CTEPH (mean age, 64±12 years; WHO functional class II/III, 6/2; mean pulmonary artery pressure, 47±13 mmHg) in stable condition and receiving disease-targeted medications participated in a 12-week home-based pulmonary rehabilitation program (muscle strength training, respiratory exercises, and walking) with supervised hospital sessions from March 2012 to January 2014. Efficacy parameters were prospectively evaluated at baseline and at completion of the 12-week program. RESULTS: After completion of the pulmonary rehabilitation program, the 6-minute walking distance (6MWD) (33.3±25.1 m), St. George׳s Respiratory Questionnaire activity score, quadriceps force, and 7-day physical activity level were significantly improved compared with baseline. All subjects completed the rehabilitation program. Although one patient experienced presyncope during the in-hospital exercise sessions, no other severe adverse events or complications of pulmonary rehabilitation were observed. CONCLUSIONS: These findings suggest that home-based pulmonary rehabilitation with closely supervised sessions may safely improve exercise capacity, leg muscle strength, general activity in daily life and health-related QOL in CTEPH patients.

Spontaneously remitted pulmonary arterial hypertension associated with the herbal medicine "bofutsushosan".

Although the link between pulmonary arterial hypertension (PAH) and exposure to certain drugs has already been identified, we herein present the first case of herbal medicine-associated PAH in which the patient demonstrated spontaneous remission. A 38-year-old woman took the herbal medicine "bofutsushosan" for two weeks then stopped taking it due to exertional dyspnea. However, her dyspnea continued, and right heart catheterization revealed a mean pulmonary arterial pressure of 41 mmHg with a normal wedge pressure. Several months after treatment with oxygen therapy, the patient's dyspnea disappeared, and her pulmonary arterial pressure normalized. Further studies focusing on susceptibility factors to drug-induced pulmonary arterial hypertension are needed.

Identification of annexin 1 as a novel autoantigen in acute exacerbation of idiopathic pulmonary fibrosis.

Consistent with the hypothesis that pulmonary epithelial apoptosis is the key to the acute exacerbation of idiopathic pulmonary fibrosis (IPF), we conducted serological identification of Ags by recombinant expression cloning (SEREX) analysis using type II alveolar cell carcinoma (A549) cell lines to identify disease-related Abs. In a survey of Abs to the recombinant autoantigens identified by SEREX analysis, five Abs were identified as novel candidates for the acute exacerbation of IPF. Abs to annexin 1 were detected in 47 and 53% of the sera and bronchoalveolar lavage materials from patients with acute exacerbation of IPF. Some identical TCR Vbeta genes were identified in sequential materials obtained at 1-3 mo in all 10 acute exacerbation IPF cases, suggesting that some infiltrating CD4-positive T cells sharing limited epitopes expand by Ag-driven stimulation during disease extension. The CDR3 region of these identical TCR Vbeta genes showed high homology with the N-terminal portion of annexin 1, including in the HLA-DR ligand epitopes predicted by TEPITOPE analysis. By Western blotting analysis and observation of the CD4-positive T cell responses in bronchoalveolar lavage samples, the N-terminal portion of annexin 1 was cleaved and found to induce marked proliferative responses of CD4-positive T cells in three patients. Our study demonstrates that annexin 1 is an autoantigen that raises both Ab production and T cell response in patients with acute exacerbation of IPF, and that the N-terminal portion of annexin 1 plays some role in the pathogenesis of acute exacerbation in IPF patients.

Thermoradiotherapy for local control of chest wall invasion in patients with advanced non-small cell lung cancer.

BACKGROUND: We tested the feasibility of hyperthermia combined with concurrent radiotherapy (thermoradiotherapy) for pain relief and local control of non-small cell lung cancer (NSCLC) invading to the chest wall. METHODS: Thirteen patients with advanced NSCLC (eight stage IIIB and five stage IV) and severe pain caused by chest wall invasion of tumor were treated with thermoradiotherapy. During the conventional fractionated radiotherapy period, 8-MHz radiofrequency capacitive hyperthermia was administered once or twice per week for a total of three to nine treatment sessions. Pain relief, objective tumor response, thermometry, and toxicity were evaluated. RESULTS: Twelve of the 13 patients (92%) experienced satisfactory pain relief, and objective tumor shrinkage was observed in 11 of the 13 patients (85%), including complete regression in two. The thermometry parameters of minimum and maximum intratumor temperatures, mean of all intratumor temperatures, and rate of the time during which intratumor temperature was 41 degrees C or higher were 37.6 +/- 0.8 degrees C, 42.4 +/- 0.7 degrees C, 40.3 +/- 0.3 degrees C, and 80.1 +/- 8.6%, respectively. Adverse reactions included local transient skin pain in three patients, but no major toxicity was observed. CONCLUSION: Concurrent thermoradiotherapy for chest wall invasion by advanced NSCLC was feasible, with tolerable toxicity, and it may be effective for pain relief and local tumor control. Further studies comparing thermoradiotherapy and radiotherapy alone for such patient populations are warranted.