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We conducted a post-marketing surveillance of Zykadia® in patients with ALK-positive unresectable, advanced or recurrent non-small cell lung cancer. There were 573 patients included in the safety analysis, of which 54.62% were female, and their mean age was 59.9 years. Overall, 473 patients(82.55%)experienced side effects, which were mainly diarrhea in 43.46%, nausea in 34.38%, vomiting in 18.67%, and hepatic dysfunction in 16.40%. Side effects led to treatment discontinuation in 24.78%. Among 455 patients included in the efficacy analysis, the response rate was 30.99%. The median progression- free survival was approximately 4 months. The safety and efficacy were similar to those of previous reports, and this study confirmed that there are no problems requiring additional precautions in clinical use of Zykadia®.

Therapeutic landscape of lung cancer has undergone a dramatic shift due to the better understandings of disease biology and the identification of oncogenic driver alterations. Consequently, the new classification paradigm of non-small-cell lung cancer is further characterized by molecularly defined subsets, and making the therapeutic landscape increasingly complex. Driver gene mutations have been found in approximately 75% of Japanese non-squamous, non-small-cell lung cancers. Among these, the gene mutations for which molecularly-targeted therapies are being developed include EGFR mutations, ALK fusion gene, ROS1 fusion gene, BRAF V600E mutation, MET exon 14 skipping mutation, KRAS G12C mutation, RET fusion gene, and NTRK fusion gene. When limited to fusion genes, as of June 2022, crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are approved for the ALK fusion gene; crizotinib and entrectinib for the ROS1 fusion gene; selpercatinib for the RET fusion gene; entrectinib and larotrectinib for the NTRK fusion gene have been approved in Japan. This article summarizes the therapeutic development of each fusion gene mutation, as well as the therapeutic outcomes and adverse events of the approved drugs.

An 89-year-old female who had been clinically diagnosed with primary lung cancer underwent right upper lobectomy and lymph node dissection(ND2a-2). Postoperative pathological staging revealed a stage ⅡA(pT1bN1M0)adenocarcinoma that was negative for an EGFR mutation. Nineteen months after surgery, the patient developed a mediastinal lymph node metastasis, and radiotherapy was prescribed. Thirty-eight months later, she developed new mediastinal/hilar lymph node metastases and was prescribed pemetrexed(500 mg on day 1 of each of 3 weeks)as the first-line therapy. A complete response was evident after 10 courses. However, she developed grade 3 nausea, and pemetrexed was discontinued. During 10 months of follow-up, no new lesion appeared; therefore, follow-up was discontinued. Ninety-three months after surgery, she was referred to our hospital because an abnormal shadow was apparent on chest roentgenography. A thorough examination revealed pleural dissemination, pulmonary metastases, mediastinal/hilar lymph node metastases, an adrenal metastasis, and bone metastases. Although her performance status(PS)was poor(grade 4), as the diagnosis was ALK fusion gene-positive adenocarcinoma, alectinib(600 mg once daily)was commenced as the second-line therapy. Complete response was achieved 14 months later(ie, 108 months after surgery and 89 months after postoperative recurrence). Thus, an octogenarian patient with poor PS and ALK fusion gene-positive adenocarcinoma exhibited a complete response after treatment with alectinib.

A 44-year-old woman was diagnosed with anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) with clinical stage IVA (nodal and bladder involvement). Complete response (CR) was achieved after the CHOP chemotherapy; however, 12 months after the last course of chemotherapy, ALCL relapsed in the form of skin lesions without nodal involvement. After achieving a second CR with chemotherapy, autologous stem cell transplantation was performed. Two months after transplantation, the disease again relapsed as multiple skin lesions. Electron beam irradiation was performed; however, other skin lesions appeared thereafter and spontaneously disappeared. At present, 3.4 years after the transplantation, the patient is free from disease. ALK-positive ALCL relapsing as skin lesions may behave differently from the nodal relapse. An accumulation of cases is required to elucidate ALCL characteristics relapsing as skin lesions.

While lung cancer is the leading cause of cancer deaths worldwide, the molecular mechanism underlying its carcinogenesis is mainly unknown. We have discovered a small, fusion-type tyrosine kinase EML4-ALK that is generated through a tiny inversion within the short arm of human chromosome 2. Transgenic mice expressing EML4-ALK in lung developed hundreds of lung cancer nodules soon after birth, but such nodules were readily eradicated upon treatment with an ALK inhibitor. Clinical trials for EML4-ALK-positive lung cancer with an ALK inhibitor is ongoing, with its interim results being highly promising.

Protein kinases play essential roles in the regulation of cell proliferation. Point mutations or/and fusions of protein kinases are frequently identified in human cancers, and targeting such activated kinases provides us with a chance to eradicate tumor cells. This was first proved by imatinib mesylate that inhibits ABL tyrosine kinase and, thereby, efficiently kills malignant cells in chronic myeloid leukemia. In addition, other clinical trials are ongoing for kinase inhibitors against EML4--ALK in lung cancer, JAK2 in myeloproliferative disorders and BRAF in malignant melanoma. Early reports indeed reveal that such targeting compounds are promising drugs for human cancers with activated kinases.

A 56-year-old Japanese woman was admitted to our hospital with upper abdominal pain. Gastroendoscopy revealed a Borrmann III type tumor which was diagnosed from the biopsied specimen as an anaplastic large cell lymphoma (ALCL). CT scan revealed para-aortic and left-supra clavicular lymph node swelling, so her clinical stage was defined as IIIE according to the Ann Arbor classification. The patient first of all received CHOP therapy, however her lymphoma lesions increased in size. Therefore she underwent salvage chemotherapy regimens and autologous peripheral blood stem cell transplantation (APBSCT). She has remained in complete clinical remission (CCR) for eleven months after the APBSCT.

A 52-year-old house wife presented with pain on urination. Cystoscopy and magnetic resonance imaging revealed solid and sessile tumor of 3 cm in diameter invading the bladder wall. Pathological examination of the transurethral resection specimen showed proliferation of spindle cells and epithelial cells. Since both types of cells were positive for cytokeratin immunostaining, sarcomatoid carcinoma was highly suspected. She underwent anterior pelvic exenteration and construction of continent reservoir (Penn Pouch). Since the tumor cells showed spindle cell proliferation alone without epithelial growth and positive staining for anaplastic lymphoma kinase, we corrected the final diagnosis as an inflammatory myofibroblastic tumor of the urinary bladder. She has been doing well without recurrence for 1 year.

A 33-years-old man was diagnosed as having undifferentiated carcinoma presenting with right neck lymphadenopathy in December 2000. He obtained complete remission (CR) following chemotherapy, radiation and lymphadenectomy on the right neck. He had multiple para-aorta lymphadenopathy and splenomegaly in December 2001. An open-abdominal lymph node biopsy was performed from which a diagnosis of anaplastic large cell lymphoma was made. CR was achieved with biweekly CHOP, however, the patient suffered from a relapse twice. He underwent allogeneic peripheral blood stem cell transplantation (PBSCT) from his HLA-matched sister while in non-CR in November 2002. Engraftment was achieved on day 14, and at the same time, complete chimerism was confirmed. Acute grade III graft-versus-host disease (GVHD) developed and was controlled with cyclosporine A and prednisolone. Extensive chronic GVHD was subsequently observed and required systemic immunosuppression. His condition returned to CR after the PBSCT and he sustained complete chimerism. He suddenly died of fulminant thrombotic microangiopathy seven months after the PBSCT. The tumor cells were ALK-positive, CD30-negative and JH rearrangement was detected, and were therefore classified as diffuse large B-cell lymphoma with expression of ALK according to the WHO classification, though they differed from this subtype in some points. Although this case was refractory for chemotherapy with a complex karyotype, the graft-versus-lymphoma effect might have contributed to the sustained CR following the PBSCT.

The genes implicated in thyroid carcinoma can be categorized as oncogenes or tumor-suppressor genes. The RET oncogene has well-established roles in the development of both medullary and papillary thyroid carcinoma (PTC). Genetic testing for the germline RET mutation is commonly performed, and prophylactic thyroidectomy is carried out at an early stage. The demonstration of a RET rearrangement in a PTC patient may be prognostic factor. TSH-R and Gs alpha are associated with the development of toxic thyroid adenoma (AFTN). The ras oncogene is implicated in the early stages of development of several tumor types. In conclusion, germline screening for RET mutations is now commonly undertaken in patients with medullary thyroid carcinoma.

The origin of rhythmicity in gastrointestinal motility was long thought to involve the activity of interstitial cells of Cajal (ICC) that locate in close association with enteric neurons and smooth muscle cells. We have demonstrated that significant decrease in the number of cells immunopositive to c-Kit, a type of tyrosine kinase receptor, in the gastrointestinal tract of mice mutated at the W/c-kit locus and BALB/c mice administered with neutralizing c-Kit antibody leads to the impaired autonomic motility of the gastrointestinal tract. It is also demonstrated that ICC express c-kit which plays important roles in development and maintenance of the ICC network in the gastrointestinal tract. ICC, derived from mesenchymal cells, are classified into smooth muscle type and fibroblast type by their morphology and tissue location. The ligand for c-Kit, Sl factor (SLF), has shown to be expressed in enteric neurons and gastrointestinal smooth muscle cells. Studies with mutant mice and transgenic mice have suggested that functional c-Kit/SLF is required for the differentiation and proliferation of ICC as pacemakers and mediators of neural regulation in gastrointestinal motility. Here we review the genetic basis of autonomic gastrointestinal motility and the pathophysiological models.

Retinal ischemia promotes retinal neovascularization. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are important growth factors for neovascularization. We did experimental retinal vein occlusion (RVO) and examined the expression of basic FGF and FGF receptor 1(one of the basic FGF receptors) by in situ hybridization. We used adult pigmented rats (Brown-Norway strain). Dye laser photocoagulation (577 nm) was applied to the retinal arteries and veins within two disc diameters of the optic nerve head to injure the retinal vessels. After one week, laser photocoagulation was applied to only the retinal veins to occlude them (RVO model). As a control, laser photocoagulation was applied to the posterior retina avoiding the retinal vessels. After treatment, the eyes were removed and 10 microns thick cryostat-cut chorioretinal section were used for in situ hybridization with probes as mentioned above. In the RVO model, expression of messenger RNA of basic FGF (b-FGF) and FGF receptor 1 increased in the inner nuclear layer and the inner segment of the photoreceptors, and appeared in the retinal vessel wall in the early stage. This shows that b-FGF and FGF receptor 1 increased in the ischemic retina, and were produced on the retinal vessel wall. This suggests that b-FGF may be involved in protection, regeneration, and proliferation of the retinal vascular endothelial cells in retinal circulatory disturbance.

Fibroblast growth factor (FGF) is an important factor for neovascularization in vivo. In order to clarify the role of FGF in experimentally produced choroidal neovascularization, we demonstrated mRNA for FGF receptor 1 in situ hybridization. Krypton laser photocoagulation was applied to the posterior retina of colored rats to produce choroidal neovascularization experimentally. These eyes were removed at several different intervals after photocoagulation. Chorioretinal section were used for in situ hybridization. FGF receptor 1 cDNA fragment was used to make antisense and sense probes for in situ hybridization. In normal chorioretinal tissue, staining indicating the existence of FGF receptor 1 mRNA was seen in the ganglion cell layer and inner nuclear layer. After the photocoagulation, the staining was seen in the retinal pigment epithelial cells, melanocytes in the choroid, and choroidal blood vessel wall in the photocoagulated lesions. FGF receptor 1 mRNA was expressed through the development of choroidal neovascularization, and it appears that FGF is necessary for development of choroidal neovascularization. Previous workers showed that the capillary endothelial cells and retinal pigment epithelial cells produce basic FGF in vitro. It seems that FGF effects those cells in an autocrine or paracrine manner in vivo.

To reveal the expression pattern of fibroblast growth factor receptor 2 (FGFR2) gene during chick eye development, in situ hybridization was performed on sections of chick embryos from stage 8 to 28. At stage 8 and 10 when the primary optic vesicle is formed, transcripts of FGFR2 were observed diffusely over the embryo. At stage 17 when the optic cup develops and afterwards, FGFR2 expression was predominantly detected in the periocular mesenchyme and parts of the diencephalon. At stage 28, FGFR2 was also expressed in the corneal epithelium and endothelium, but it was not observed in blood cells or the endothelium of the cephalic vein. FGFR2 expression was not observed in the lens or the optic cup where FGFR1 is expressed. I suggest that FGFR2 expression is involved in development of the corneal epithelium and the periocular mesenchyme, which is derived from the cephalic neural crest cells.

To reveal the expression pattern of fibroblast growth factor receptor 1 (FGFR1) gene during chick eye development, in situ hybridization was performed on sections of chick embryo from stage 8 to 28. At stage 8 and 10, transcripts of FGFR1 were observed over the whole embryo and they were located at the optic cup, the lens vesicle, the orbital mesenchyme and the neuroepithelium of the diencephalon at stage 17. In the inner layer of the optic cup at stage 21, the expression was restricted to the anterior portion. It was suggested that FGFR1 expression was involved in chick eye development, especially in determination of anterior-posterior axis of the eye.

We have been developing a new treatment for patients with rheumatoid arthritis (RA) by using intradermal injection of carbohydrate molecule complex. Among them, tumor cell associated glycoconjugate (TCA), the membrane structure of Kato III is one of the effective molecules. We studied the immunomodulatory effect of TCA on the autologous mixed lymphocyte reaction (AMLR) using PWM-mitogen induced lymphoblasts as stimulator cells and peripheral blood mononuclear cells (PBMC) as responder cells. In the kinetic study of the AMLR, its maximum proliferation was observed on days five through seven and responding CD4 cells highly expressed HLA-DR antigen. Studied AMLR in 10 patients with RA, proliferative responses of AMLR in these patients were divided into two types, high and low AMLR types. In vitro examination of TCA on AMLR showed that TCA at a concentration of 250 ng/ml significantly suppressed the AMLR response (p less than 0.01, paired T-test) and this phenomenon was found more frequently in high AMLR type patients than in low AMLR type patients. The suppressive effect of TCA on AMLR had a tendency to correlate with the efficacy of TCA therapy in patients studied. These results suggest that TCA may play a role in regulating the function of autoreactive lymphocytes of patients with RA.