Hiroyuki Sakashita

Dihydrofolate reductase gene polymorphisms in Pneumocystis carinii f. sp. hominis in Japan

This study examined polymorphisms in the dihydrofolate reductase (DHFR) gene of Pneumocystis carinii isolates from 27 patients with P. carinii pneumonia (PCP) in Japan. Four substitution sites with two synonymous and two non-synonymous changes were found. Two synonymous substitutions at nucleotide positions 540 and 312 were identified in one and 13 patients, respectively. Two amino acid substitutions (Ala67Val, Cysl66Tyr) were found in two different patients. No linkage of amino acid substitutions in DHFR to those in dihydropteroate synthase was observed. The two patients whose isolates showed non-synonymous DHFR mutations were not exposed to DHFR inhibitors before they developed PCP and were treated successfully with co-trimoxazole.

First Report of Trichosporon ovoides Isolated from the Home of a Summer-Type Hypersensitivity Pneumonitis Patient

Trichosporon species have been known to cause summer‐type hypersensitivity pneumonitis (SHP). During the isolation of yeasts from an SHP patients house, we recovered a strain belonging to the genus Trichosporon. Morphologically, the isolate produced rectangular arthroconidia when grown on corn meal agar. DNA‐DNA hybridization experiments identified the isolate as T. ovoides. A slide agglutination test using specific factor sera demonstrated that the serotype of the strain was type II. Previously, T. asahii, a serotype II species, was considered to be the major antigen of SHP, but it is possible that T. ovoides may also be responsible for SHP. This is the first report of T. ovoides isolated from an SHP patients home environment.

Serodiagnosis of Mycobacterium avium Complex Pulmonary Disease in Rheumatoid Arthritis

Background:Mycobacterium avium complex (MAC) pulmonary disease (PD) is often difficult and complicated to diagnose or to discriminate from follicular bronchitis, bronchiectasis, or other conditions associated with rheumatoid arthritis (RA) lung in the clinical setting. Objective: We investigated whether a serologic test for anti-glycopeptidolipid (GPL) antibody was useful for distinguishing MAC-PD from RA lung in diagnosis. Methods: Serum IgA antibody to MAC-specific GPL core antigen was measured by an enzyme immunoassay. Antibody levels were measured in sera from 14 RA patients with MAC-PD (RA + MAC), 20 RA patients with bronchial or bronchiolar lesions without MAC-PD (RA w/o MAC), 20 RA patients without pulmonary lesions (RA only), and 25 healthy volunteers (HV). Results: The levels of serum anti-GPL antibodies were higher in the RA + MAC group than in the RA w/o MAC, RA-only, and HV groups (2.87 ± 2.83 vs. 0.50 ± 0.45, 0.31 ± 0.24, and 0.38 ± 0.10 U/ml, respectively; p < 0.001). With the cutoff point in receiver-operating characteristic analysis set at 0.7 U/ml, the serologic test differentiated RA + MAC from RA w/o MAC with a sensitivity of 100% and specificity of 90%. Conclusions: This serologic test for anti-GPL antibody is useful for diagnosing MAC-PD in RA.

Vesicocutaneous fistula formation during treatment with sunitinib malate: Case report

BackgroundThe oral multi-kinase inhibitor sunitinib malate improves the survival of patients with gastrointestinal stromal tumors (GIST) after the disease progresses or intolerance to imatinib mesylate develops. Urinary fistulae arising during treatment with sunitinib for GIST have not been described.Case presentationWe describe a 62-year-old female patient diagnosed with unresectable GIST that involved the abdominal wall, urinary bladder wall, bowel, mesentery and peritoneum in the pelvic cavity. Intestinocutaneous fistulae developed on a surgical lesion after orally administered imatinib was supplemented by an arterial infusion of 5-flurouracil. Sunitinib was started after the patient developed resistance to imatinib. On day 4 of the fourth course of sunitinib, a widely dilated cutaneous fistula discharged large amounts of fluid accompanied by severe abdominal pain. Urinary communication was indicated based on the results of an intravenous injection of indigo carmine. Computed tomography findings suggested a small opening on the anterior urinary bladder wall and fistulous communication between the bladder and abdominal walls bridged by a subcutaneous cavity. The fistula closed and the amount of discharge decreased when sunitinib was discontinued. Therefore, sunitinib might have been associated with the development of the vesicocutaneous fistula in our patient.ConclusionThis is the first description of a vesicocutaneous fistula forming while under sunitinib treatment. Clinicians should be aware of the possible complication of vesicocutaneous fistula formation during treatment with molecular targeting agents in patients with extravesical invasion and peritoneal dissemination of GIST.

Antigen avoidance tests for diagnosis of chronic hypersensitivity pneumonitis

BACKGROUND Chronic hypersensitivity pneumonitis (HP) is induced by the inhalation of specific antigens. Patients with chronic HP may be able to improve their prognosis by avoiding these antigens. Chronic HP is often difficult to distinguish from idiopathic interstitial pneumonias (IIPs). OBJECTIVE This study was performed to find out how antigen avoidance tests contribute to the diagnosis of chronic HP. METHODS A retrospective analysis was conducted on 265 patients who underwent 2-week antigen avoidance tests between April 2002 and March 2012. The patients were classified into the following categories: acute HP, chronic HP, collagen vascular disease-associated interstitial pneumonia (CVD-IP), lung dominant connective tissue disease (LD-CTD), and IIPs. The following seven clinical parameters were evaluated: vital capacity, alveolar-arterial oxygen pressure difference, Krebs von den Lungen-6, surfactant protein-D, white blood cell count, C-reactive protein, and body temperature. These parameters were compared between the chronic HP group and a control group consisting of CVD-IP, LD-CTD, and IIPs. RESULTS One-hundred and ninety-six patients with chronic HP and 43 control subjects were evaluated. All clinical parameters improved significantly in the chronic HP group but showed no significant changes in the control group. Four of the parameters changed significantly compared with the control group. Diagnostic criteria established using these data had a sensitivity of 51.0% and a specificity of 80.7%. CONCLUSIONS It was difficult to diagnose chronic HP based solely on 2-week antigen avoidance tests; however, improved clinical parameters among patients supported the diagnosis of HP.

Alectinib for Patients with ALK Rearrangement–Positive Non–Small Cell Lung Cancer and a Poor Performance Status (Lung Oncology Group in Kyushu 1401)

Introduction: Alectinib has shown marked efficacy and safety in patients with anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangement–positive NSCLC and a good performance status (PS). It has remained unclear whether alectinib might also be beneficial for such patients with a poor PS. Methods: Eligible patients with advanced ALK rearrangement–positive NSCLC and a PS of 2 to 4 received alectinib orally at 300 mg twice daily. The primary end point of the study was objective response rate (ORR), and the most informative secondary end point was rate of PS improvement. Results: Between September 2014 and December 2015, 18 patients were enrolled in this phase II study. Of those patients, 12, five, and one had a PS of 2, 3, or 4, respectively, whereas four patients had received prior crizotinib treatment. The ORR was 72.2% (90% confidence interval: 52.9–85.8%). The ORR did not differ significantly between patients with a PS of 2 and those with a PS of 3 or higher (58.3% and 100%, respectively [p = 0.114]). The PS improvement rate was 83.3% (90% confidence interval: 64.8–93.1%, p < 0.0001), with the frequency of improvement to a PS of 0 or 1 being 72.2%. The median progression‐free survival was 10.1 months. Toxicity was mild, with the frequency of adverse events of grade 3 or higher being low. Neither dose reduction nor withdrawal of alectinib because of toxicity was necessary. Conclusions: Alectinib is a treatment option for patients with ALK rearrangement–positive NSCLC and a poor PS.

Feasibility study of adjuvant chemotherapy of S-1 and carboplatin for completely resected non-small cell lung cancer.

Background: The purpose of this study was to evaluate the feasibility and compliance of adjuvant chemotherapy of S-1 plus carboplatin for patients with completely resected non-small cell lung cancer (NSCLC) of pathological stage IB-IIIB. Methods: S-1 was given orally at a dose of 80 mg/m2/day for 2 weeks, followed by a 2-week period of no treatment. Carboplatin was given intravenously on day 8 at an area under the curve of 6. This regimen was repeated for four to six 28-day courses. Results: Seventeen patients were enrolled in this study. Fourteen of them completed at least 4 cycles of chemotherapy. Nine patients had grade 2 and three patients had grade 3 thrombocytopenia, respectively. Severe nonhematologic toxicities were uncommon. Treatment was delayed in a few patients because of prolonged thrombocytopenia. Conclusion: We concluded that the regimen was feasible and tolerable for patients with completely resected NSCLC as adjuvant chemotherapy.

Bronchopleural Fistula Successfully Treated With Surgical Sponge

Abstract:A 53-year-old man was admitted because of empyema associated with bronchopleural fistula resulting from Streptococcus milleri. He had been taking prednisolone intermittently for the last 5 years because of Behcet disease. Initially, he was treated unsuccessfully with antibiotics and tube dr

Lung Cancer Diagnosed More Than Five Years after the Development of Polymyositis/Dermatomyositis

Background. The patients with polymyositis (PM) and dermatomyositis (DM) often develop the malignancies in their clinical course. The incidence of cancer is estimated at about 15%. The risk of cancer is the highest within the first year of myositis diagnosis and drops substantially thereafter. The patients with lung cancer diagnosed more than 5 years after the onset of PM or DM are the minority. Methods and Patients. We surveyed the medical records of patients with lung cancer over the period from 1995 to 2011. Results. We found five patients who developed lung cancer more than 5 years after the diagnosis of PM/DM. Three patients were male, and two were female. The median age was 61.2 (±11.7). Histological types were diverse. The clinical stages ranged from IA to IV. Three patients had smoking histories. Four patients suffered from DM, and one suffered from PM. All patients received oral corticosteroid therapy. Two patients also received ciclosporin, and another two received azathioprine. Anti-Jo-1 antibody was positive in one patient. Four patients were complicated with interstitial pneumonia (IP). Conclusion. These lung cancers diagnosed more than 5 years after the onset of PM/DM were probably related to IP or smoking but might not be comorbid with PM/DM.

Cancer Stem Cells (CSCs) in Lung Cancer

The cancer stem cell model for tumor progression is the first model of its type to suggest that only one subpopulation of cancer cells is capable of proliferating indefinitely. These cells resemble normal stem cells in their capacity for self-renewal and multi-potential differentiation, and can both initiate and maintain tumors. The prevailing names for these cells are “cancer stem cells (CSCs)” and “cancer initiating cells (CICs).” The CSC model implies a hierarchical organization within the tumor in which a limited number of CSCs represents the apex of the hierarchy. CSCs are chemo-resistant, radio-resistant, and quiescent, and have been shown to cause both metastasis and relapse. CSCs were first described in patients with acute myeloid leukemia (AML) by Dick et al. (Lapidot et al., 1994). As to be expected from leukemia stem cells, these CSCs exhibited the properties of self-renewal, proliferation and multipotency. The frequency of these leukemiainitiating cells in the peripheral blood of those AML patients was one engraftment unit in 250,000 cells. Dick et al. identified the leukemia-initiating cells as CD34+CD38-. In the years since, CSCs have been identified in cancers of the breast(Al-Hajj et al., 2003), brain (Singh et al., 2003) and prostate, pancreas and lung (Eramo et al., 2008). In this chapter we review CSCs in lung cancer.