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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®.

A 28-year-old male patient presented with multiple lymphadenopathies and extranodal masses. He was diagnosed with stage IVB ALK-positive anaplastic large cell lymphoma after the right axillary lymph node biopsy. A partial metabolic response with fluorodeoxyglucose accumulation was observed in the residual disease of the upper left hilar lymph node after eight courses of brentuximab vedotin, cyclophosphamide, adriamycin, and prednisolone. We started alectinib at 600 mg daily, which achieved a complete metabolic response (CMR) after three months. The CMR was maintained and alectinib was continuously administered without adverse events at the last follow up. Alectinib showed high efficacy and tolerability, though the optimal period and long-term adverse effects of administration remain unclear. Therefore, further studies are necessary.

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.

Few cases of lung mucoepidermoid carcinomas with anaplastic lymphoma kinase (ALK) fusion have been reported. A 35-year-old woman was found to have an abnormal chest X-ray. A tumor and obstructive pneumonitis in her left upper lobe was detected using computed tomography (CT). She was admitted to our hospital, and was diagnosed with mucoepidermoid carcinoma by transbronchial biopsy. Left pneumonectomy and lymphadenectomy were performed for lung mucoepidermoid carcinoma and a mediastinal lymph node metastasis (pT2aN2M0, stage ⅢA). Postoperative radiotherapy (50 Gy) to the mediastinum and chemotherapy were performed followed by several radiotherapies for cervical and mediastinal lymph node and right ischium metastases. Since then, further radiotherapy was impossible. However, we detected ALK fusion in the resected specimen and the cancer responded to alectinib hydrochloride.

The advent of anaplastic lymphoma kinase(ALK)inhibitors has revolutionized treatment of ALK fusion gene-positive nonsmall cell lung cancer(NSCLC). Nevertheless, it has become clear that cases refractory and resistant to ALK inhibitors occur at a certain incidence, and how to treat such cases is a current issue. Following crizotinib and alectinib, ceritinib(Zykadia® capsules)is the third ALK inhibitor approved in Japan, and it is expected to be useful for patients who have developed crizotinib resistance. However, ceritinib has been pointed out to have a high incidence of gastrointestinal adverse events that impact patients' quality of life. Accordingly, in this paper, we report the clinical results and incidence of gastrointestinal adverse reactions with ceritinib in treatment of ALK-positive NSCLC patients. We also present management methods of the adverse events.

There have been 23 reports of primary central nervous system anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma in the literature. Here we report the 24th case of a 40-year-old man who presented with occipital headache for one month. His contrast-enhanced brain MRI showed enhancement around the right temporal lobe, which suggested a diagnosis of hypertrophic pachymeningitis. He improved with steroid therapy. After discharge, however, he was readmitted with generalized convulsive seizures. Finally, he was diagnosed as primary central nervous system ALK-positive anaplastic large cell lymphoma by brain biopsy. Primary central nervous system lymphoma invading dura matter can rarely manifests as a unilateral pachymeningitis. Therefore, in case of pachymeningitis, we should pay attention to the possibility of infiltration of lymophoma with meticulous clinical follow-up.

The patient was a 54-year-old woman with anaplastic lymphoma kinase-positive stage III B lung cancer. She received 4 courses of carboplatin(CBDCA)plus paclitaxel(PTX)plus bevacizumab(Bev)chemotherapy and crizotinib. Chemotherapy reduced the size of the primary site and mediastinal lymphadenopathy; however, the right supraclavicular and subcarinal lymph nodes were enlarged again during crizotinib treatment. Because it was an oligo-recurrence, we performed radiotherapy for these lymph nodes and changed systemic chemotherapy to alectinib. After 16 months, the patient exhibited esophageal stenosis due to subcarinal lymphadenopathy. We performed a subtotal esophagectomy, which improved the quality of life, and she was continued on an oral treatment of alectinib. Therefore, we suggest that an invasive surgical treatment is useful for oligo-recurrence cases.

A 59-year-old woman with anaplastic large cell lymphoma (ALCL), ALK-negative, was treated with brentuximab vedotin (BV) against relapse after 6 regimens of systemic chemotherapy and radiation. Despite achieving an initial response, skin lesions worsened after 11 courses. A skin biopsy after the development of resistance to BV confirmed loss of CD30 expression by the tumor cells, suggesting a possible cause of resistance. This case shows that down-regulation of CD30 does occur during BV treatment, resulting in resistance to this drug. Because of this possibility, in the future, expression of CD30 should be carefully monitored with extended use of BV against ALCL.

Companion diagnostics (CoDx) will likely continue to rapidly increase in number and application to disease areas including solid tumors, for example EGFR for gefitinib and ALK fusion gene for crizotinib in non-small-cell lung cancer; KRAS against the use of cetuximab and panitumumab in colorectal cancer; HER2 for trastuzumab in breast cancer. CoDx are an indispensable part of personalized medicine and pharmacogenomics. In CoDx development, there are still many challenges, such as the business model promoting cooperation between diagnostics and pharmaceutical companies, and also the regulations related to CoDx. The FDA notice on the development of CoDx in 2011 recommended the co-development of a new drug and CoDx as the best practice, and the Ministry of Health, Labour and Welfare in Japan also issued a statement in 2013. In addition, the recent discovery of many novel variants in the DNA sequence, advances in sequencing and genomic technology, and improved analytic methods have enabled the impact of germline and somatic mutations to be determined using multiplex diagnosis. The complex challenges to develop CoDx necessitate a close collaboration among academic institutions, regulatory authorities, and pharmaceutical companies. [Review].

A 77-years-old man who underwent middle lobectomy for lung adenocarcinoma in our hospital 19 years ago. p-Stage IA was pointed out multiple nodules in bilateral lung fields on a medical examination. Computed tomography scan revealed a tumor measuring 34×34 mm in size in the right lower lung and other 40 small pulmonary nodules. Characteristic pattern of metastatic adenocarcinoma from the previous lung cancer was pathologically demonstrated. Immunostaining revealed anaplastic lymphoma kinase (ALK) positivity of the both specimens, which determined the diagnosis of recurrence. Long-team postoperative follow-up for ALK positive lung cancer patients is considered to be necessary especially for younger patients.

Several driver oncogenes, including EGFR mutations and ALK rearrangement, have been identified in lung cancer. The EGFR tyrosine kinase inhibitors (TKIs) and ALK-TKIs show dramatic effects against lung cancer with EGFR activating mutations and ALK rearrangements, respectively. However, 20% of EGFR mutant lung cancer patients show intrinsic resistance, and the responders almost invariably acquire resistance to EGFR-TKIs within several years. Several mechanisms, including secondary mutations in EGFR or ALK, activation of alternative pathway, have been reported to contribute to resistance to EGFR-TKIs and ALK-TKIs. New generation TKIs for overcoming resistance to EGFR-TKI or ALK-TKI are being evaluated in clinical trials. Further investigations to develop optimal therapy based on accurate diagnosis of resistant mechanism are warranted to improve the success of treatment with targeted drugs in lung cancer.

Personalized medicine is expected to provide patients with safe and effective treatment compared to conventional medical care in which patients are treated based on the diagnosis and/or histology. In personalized medicine, patients are treated based on their genetic makeup and genetic characteristics of tumor tissues in the case of cancer chemotherapy. Genomic biomarker tests are used to molecularly characterize host and tumor tissues and stratify patients for the appropriate drugs. Drugs targeting the causative genetic changes have been developed along with companion diagnostics to test such genetic changes. In this paper, I introduce the technical guidance for companion diagnostics and related drugs issued by the Pharmaceutical and Medical Devices Agency of Japan, and discuss how to carry out a concordance study of diagnostic tests for the ALK fusion gene when new ALK inhibitors are approved. The regulations for companion diagnostics should be revised frequently to keep up with advances in this area.

In recent anti-cancer drug treatment, personalized medicine has become popular with the development of many molecularly-targeted drugs. Companion Diagnostics (CDx) identify and detect biomarkers to predict whether a drug will work or have adverse effects on patients. We developed two CDx with FISH assays, the PathVysion HER-2 DNA Probe Kit and Vysis ALK Break Apart FISH Probe Kit. The PathVysion HER-2 DNA Probe Kit is a test to detect amplification of the HER2 gene in tissue samples from breast cancer patients to aid in determining and identifying patients eligible for treatment with Trastuzumab. The Vysis ALK Break Apart FISH Probe Kit is a test to detect rearrangements involving the ALK gene in tissue samples from non-small cell lung cancer (NSCLC) patients to aid in identifying patients eligible for treatment with Crizotinib. In this article, we review the CDx, focusing on HER2 gene and ALK fusion testing.

Patients with SCLC (Small cell lung cancer) have been treated differently from those with NSCLC (New-small cell lung cancer) as a different disease. Recently, even patients with NSCLC are treated differently according to histological subtypes. This change is associated with the development of new drugs, particularly molecular-targeted drugs. Because Bevacizumab can cause serious adverse effects, patients with squamous cell carcinoma histology and a history of hemoptysis are contraindicated for this drug. Pemetrexed has been approved with an anti-mesothelioma drug and was confirmed to be effective for NSCLC. However, its efficacy was not equally proved among the histological subtypes; only adenocarcinoma patients showed shorter progression-free and prolonged survival periods. Regarding tyrosine kinase inhibitors, the targeted gene alterations occur specifically in adenocarcinoma. Based on these findings, the current therapeutic strategy for NSCLC is based on the histological subtype and mutational status of EGFR and ALK. In this article, transition of the therapeutic strategy for NSCLC, characteristics of targeted gene alterations and efficacies of the targeted therapy are reviewed.

Recent advances in lung cancer research have enabled significant progress in our understanding of the molecular pathogenesis and treatment for lung cancer. For example, EGFR tyrosine kinase inhibitors have been developed, and a subset of patients show marked therapeutic responses to this treatment. Subsequently, this super-response was revealed to be associated with an EGFR mutation that was identified in 2005. Currently, EGFR tyrosine kinase inhibitors are available for first-line treatments of patients with advanced non-small-cell lung cancer when the tumor is positive for an EGFR mutation. More recently, similar marked responses to an ALK inhibitor in patients with ALK fusion lung cancers were demonstrated. In this article, we review such recent advances in lung cancer, focusing on EGFR mutation and ALK fusion..

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.