Junkichi Yokoyama

Interleukin-15 effectively potentiates the in vitro tumor-specific activity and proliferation of peripheral blood γδT cells isolated from glioblastoma patients

AbstractγδT cells play a regulatory role in both primary and metastatic tumor growth in humans. The mechanisms responsible for the activation and proliferation of circulating γδT cells should be fully understood prior to their adoptive transfer to cancer patients. We have examined in vitro functional effects of interleukin-15 (IL-15) on highly purified γδT cells isolated from glioblastoma patients. γδT cells constitutively express the heterotrimeric IL-2 receptor (IL-2R) αβγ, but the levels of IL-2Rβ or γ expression were not increased by incubation with saturating amounts of IL-15. IL-15 was shown to induce a maximal γδT cell proliferation, although at much higher concentrations (at least 2000 U/ml) than IL-2 (100 U/ml). Submaximal concentrations of IL-15 plus low concentrations of IL-2 produced an additive proliferative response. In contrast to the IL-2-induced response, this activity was completely or partially abrogated by anti-IL-2Rβ, or anti-IL-2Rγ antibodies, but not by anti-IL-2Rα antibodies. Incubation of γδT cells in the presence of IL-15 resulted not only in the appearance of NK and LAK activity, but also in specific autologous tumor cell killing activity, an additive effect being seen with IL-15 and IL-2. This IL-15-induced tumor-specific activity could be significantly blocked by anti-IL-2Rγ and anti-IL-2R-β mAb, but not by anti-IL-2Rα mAb. Thus, in contrast to IL-2, IL-15 activates tumor-specific γδT cells through the components of IL-2Rβ and IL-2Rγ, but not IL-2Rα. These enhanced in vitro tumor-specific and proliferative responses of γδT cells seen with IL-15 suggest a rational adjuvant imunotherapeutic use of γδT cells in cancer patients.

Rapid Diagnosis of Cervical Tuberculous Lymphadenitis by Application of DNA Probe

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Successful application of intra-arterial chemotherapy for advanced lacrimal sac carcinoma: a report of two cases

Objectives: Malignant lacrimal sac tumors are rare. The therapeutic methods are decided depending on the tumor status and general condition. A multidisciplinary approach may be needed. When necessary, orbital exenteration may be performed. To maintain the quality of life in patients, we applied intra-arterial infusion chemotherapy for locally advanced lacrimal sac squamous cell carcinoma cases. Patients and methods: Two patients with lacrimal sac squamous cell carcinoma who were treated by intra-arterial chemotherapy were included in this study. Intraarterial chemotherapy was administered at 150 mg/m2 of CDDP and 15 mg/m2 of DTX. Radiotherapy in combination with intra-arterial chemotherapy was performed for one patient. A Cyberknife was used for the other patient. Result: In both cases, the tumor was considered to have disappeared judging from the PET scan. Furthermore, the eyes of these patients were spared and the visual function was preserved. Conclusion: Multidisciplinary management should be applied for malignant lacrimal sac tumor. Intra-arterial chemotherapy can play an important role in organ preservation therapy for locally advanced lacrimal sac squamous cell carcinoma. Correspondence to: Dr. Shinichi Ohba, Department of OtorhinolaryngologyHead and Neck Surgery, Juntendo University Faculty of Medicine, Tokyo, Japan; Tel:+ 81-3-3813-3111; Fax: 81-3-5840-7103; E-mail: sooba@juntendo.ac.jp Received: September 30, 2016; Accepted: October 31, 2016; Published: November 03, 2016 Introduction Malignant lacrimal sac tumors are rare. The most common malignant tumors are of epithelial origin, with squamous cell carcinoma. The management of malignant tumors includes local resection or extensive wide resection with orbital exenteration followed by adjuvant therapy. However, orbital exenteration decreases the quality of life in such patients. This is the first report describing the application of superselective intra-arterial chemotherapy for locally advanced lacrimal sac carcinoma. This procedure could be a useful treatment for functional preservation of the orbit. Patients and methods Two patients with locally advanced lacrimal sac squamous cell carcinoma were treated with superselective intra-arterial chemotherapy. In these patients, 150 mg/m2 of CDDP and 15 mg/m2 of DOC were superselectively administered weekly to each feeding artery including the internal carotid artery. CT angiography was performed to confirm that the entire tumor was stained by contrast agents via the femoral approach. The one patient was treated with concomitant chemo-radiation and the other subsequently underwent Cyber knife treatment. Results Case 1 A 72 year-old female presented with right exophthalmous and diplopia. She had been treated for dacryocystitis for two years. On clinical examination, she was noted to have a firm mass inferior to the right medial canthas. The tumor was also easily visible in the right inferior nasal meatus (Figure1A). CT of the sinuses revealed an enhanced mass in the right lacrimal sac extensively involving the right orbit. There was also extension of the mass into the nasal cavity, the ethomoid sinus (Figure1B). Transnasal biopsy revealed moderately differentiated squamous cell carcinoma. Figure 1A. A tumor was confirmed in the right inferior nasal meatus (arrows). Trans nasal biopsy was performed, which revealed moderately differentiated squamous cell carcinoma. Hibiya R (2016) Successful application of intra-arterial chemotherapy for advanced lacrimal sac carcinoma: a report of two cases Volume 2(1): 128-130 Otorhinolaryngol Head Neck Surg, 2016 doi: 10.15761/OHNS.1000132 To avoid orbital exenteration, intra-arterial chemotherapy with concurrent radiotherapy was conducted five times. All of the cancer area was enhanced by contrast agent in the CT angiography, not only the external carotid artery but also the internal carotid artery (Figure 2). 200 mg of cisplatin and 20 mg of docetaxel were administered weekly five times. During the infusion of CDDP, sodium thiosulphate (STS) at 200 fold the dose of CDDP was injected to the brachiocephalic vein to neutralize the CDDP. The procedure was performed weekly for five times. The primary tumor was irradiated for a total 60Gy in 30 fractions. Two months after the treatment, MRI and 18F-FDG PET/CT showed no evidence of residual disease (Figure 3A and 3B). There were no complications related to the ICA infusion. The visual acuity was unchanged after treatment and the diplopia was also improved. Case 2 A 68-year-old-man was referred to our hospital with a hard mass in the left medial canthus and tearing. He had been diagnosed with maxillary sinus cancer at the age of 40 years and received chemoradiotherapy followed by partial maxillectomy at that time. He had also undergone coronary artery bypass surgery. Physical examination revealed a firm and fixed mass in the left internal canthus. An otolaryngologic rigid nasal/sinus endoscopy showed a firm mass under the normalappearing mucosa just in front of the uncinate process (Figure 4A). Transnasal biopsy revealed moderately differentiated squamous cell carcinoma that was considered to be a radiation-induced cancer. A sinus CT demonstrated a massively enlarged left lacrimal sac with bone loss. There was also extension of the mass into the orbit (Figure 4B). The patient’s visual acuity was 20/20 and 20/20. The patient was treated with super-selective intra-arterial chemotherapy followed by Cyberknife therapy (an-image guided, robotic radiotherapy) as an organ preservation technique. Most of the tumor was fed by the internal carotid artery (ICA) (Figure 5). 125 mg of CDDP and 10 mg of DOC were administered weekly four times (day 1,8,15 and 22) via the superficial temporal artery. The cyberknife therapy (3 treatments; maximum dose, 3703 cGy) was performed a month after the chemotherapy. The post treatment PET scan taken after 2 months revealed there was no residual tumor (Figure 6). There was no adverse event related to the ICA infusion and the visual acuity was preserved at 20/20 and 20/20. Discussion A variety of neoplasms may affect the lacrimal drainage system, with approximately 70% malignant in nature [1]. The most common type of cancer is squamous cell carcinoma followed by transitional cell carcinoma [2,3]. Lacrimal sac carcinoma is often mistaken for Figure 1B. Appearance of tumor on CT scan: axial CT scan shows enhancement of this lesion extending to the right orbit; coronal CT revealing the enhanced mass widely involving the orbit with bone destruction. Figure 2. CT angiographies of the right internal carotid artery. The cancer area that was not stained by the maxillary artery was covered by infusion of the right internal carotid artery. A B Figure 3. CT scan [Figure 3A] and FDG-PET/CT [Figure 3B] at two months after treatment showing no significant accumulation in the right lacrimal sac.