Nodoka Sekiguchi

STAT3 gene mutations and their association with pure red cell aplasia in large granular lymphocyte leukemia

Large granular lymphocyte leukemia (LGL L) has been morphologically characterized as a group of lymphoproliferative diseases that include T‐cell large granular lymphocytic leukemia (T‐LGL L) and chronic lymphoproliferative disorders of natural killer cells (CLPD‐NK). We investigated mutations in the Src homology 2 (SH2) domain of the signal transducer and activator of transcription 3 (STAT3) gene in Asian cohorts of T‐LGL L and CLPD‐NK (n = 42 and 11, respectively). Two mutations, Y640F and D661Y, were identified using direct sequencing or allele‐specific (AS) PCR. Y640F and D661Y mutations were found in seven and 18 patients, respectively. Two patients were positive for both mutations. Frequencies of STAT3 mutations in T‐LGL L and CLPD‐NK were 47.6% and 27.2%, respectively. Pure red cell aplasia (PRCA) was associated with the mutations (P = 0.005). The mutations were persistently found at stable levels in some patients after more than 5 years using AS‐quantitative PCR. The results of the present study indicate that the SH2 domain of the STAT3 gene is frequently mutated in Asian T‐LGL L and CLPD‐NK, and that PRCA is closely correlated with the mutations.

Successful treatment of crizotinib-induced dysgeusia by switching to alectinib in ALK-positive non-small cell lung cancer.

We describe a case of dysgeusia that developed gradually over one week after initiation of crizotinib administration for treatment of ALK-positive non-small cell lung cancer, necessitating discontinuation of the agent. The symptom was accompanied by progressive loss in appetite and body weight. Alectinib, a novel alternative ALK inhibitor, was administered and has been successfully continued without any toxicity, including dysgeusia. The present case indicates that dysgeusia is an important toxicity associated with crizotinib, which could adversely affect nutritional condition and quality of life. We describe the clinical course and present a review of crizotinib-induced dysgeusia.

Screening Tests Using Serum Tissue Transglutaminase IgA May Facilitate the Identification of Undiagnosed Celiac Disease among Japanese Population

The prevalence of celiac disease (CD) among Japanese population has been unknown, whereas it has been increasingly recognized in the US and in the European countries. The aim of the present study is to identify possible cases with CD among Japanese population and clarify the relevance of screening for the disease. We conducted a serologic screening for the disease among 710 Japanese patients and 239 healthy volunteers at a local tertiary teaching hospital, using an anti-tissue transglutaminase IgA (TTG-IgA) test, and histological examination of the small intestines from the TTG-IgA positive subjects. There were no TTG-IgA positive sera among the healthy volunteers. Twenty of the patients (2.8%), including eight with malignant lymphoma, were tested positive for TTG-IgA. The histological examination of the eleven patients among those with positive TTG-IgA, seven showed villous atrophy and partial lymphocytes infiltration in the mucosa, which could be compatible to mucosal changes observed in CD. Five of them had non-Hodgkin lymphoma in the gastrointestinal tracts. Serologic tests using TTG-IgA might be relevant to screen for those with undiagnosed CD among Japanese population.

Two Cases of Thymic Carcinoma Initially Presenting as Bone Metastasis: A Clinical Report and the Usefulness of CD5 Immunohistochemistry for Assessing Bone Lesions.

Thymic carcinoma frequently spreads to the pleural space, regional lymph nodes, liver and lungs. However, an initial clinical presentation involving spinal or multiple bone metastases in patients with thymic carcinoma is extremely rare. We experienced two cases of thymic carcinoma that initially presented with spinal compression and severe pain due to multiple bone metastases, respectively. Both patients were histologically diagnosed with metastatic thymic squamous cell carcinoma based on the findings of specimens resected from the metastatic bone lesions. We herein describe the clinical courses of these cases and review the characteristics of bone metastasis of thymic carcinoma.

Late relapse of extranodal natural killer/T cell lymphoma, nasal type, after more than ten years

Extranodal NK/T cell lymphoma, nasal type (ENKL) is a malignant lymphoproliferative disorder of NK cells characterized by an invasive nature with vascular damage and necrosis [1–3]. The upper aerodigestive tracts, especially nasal cavities, are commonly involved (the nasal type), and in minor populations, other sites such as the skin, intestines, or soft tissues other than the aerodigestive tracts are the main invasive sites (extranasal type). ENKL is more prevalent in Asians and Central Americans, and a lower incidence among Caucasians is recognized. ENKL is also characterized by a strong association with Epstein-Barr virus (EBV). The clinical outcome of ENKL varies depending on the involved site and clinical stage, and the prognosis is considerably worse than that of other lymphomas, although the recent therapeutic progress including in concurrent chemoand radiotherapy against limited-stage nasal type ENKL and the introduction of hematopoietic cell transplantation (HCT) might improve the outcome [4–6]. Some cases of ENKL have been known to relapse after a long duration of complete response [7,8]; however, the biological mechanisms of ENKL including those of such cases are still unknown. Here, we report three Japanese cases of ENKL who relapsed after a period of longer than 10 years of complete response after the initial treatment. Case one was a 44-year-old male who had suffered from intermittent nasal discharge and was diagnosed with non-Hodgkin lymphoma, diffuse pleomorphic type, with clinical stage IIE in 1991. He had received combination chemotherapy of methotrexate (MTX), doxorubicin (ADR), cyclophosphamide (CY), vincristine (VCR), and bleomycin (MACOP-B) and local irradiation. He achieved complete response (CR) and had been well until 2007, when he noticed hoarseness and was found to have a paralaryngeal tumor. The tumor was diagnosed as ENKL with positivity for cytoplasmic CD3, CD56, TIA1, granzyme B, and EBV by immunohistochemical studies and in situ hybridization, respectively. He needed trachostomy for bronchial obstruction, and multiple skin lesions also developed. He was administered carboplatin, etopside, ifosdamide (IFO), and dexamethasone, with no improvement, so he was also given cytosine arabinoside, IFO, MTX, and L-asparaginase. He reached CR after three courses of chemotherapy. Months later, he died of exacerbation of his ENKL. Re-examination of the histological specimen of the primary lesion taken in 1991 revealed identical morphological features and the same immunophenotypes and EBV positivity as the relapsed lesions. He was clarified as having had a relapse of ENKL after 16 years. The second case was a 36-year-old female who was diagnosed with, diffuse, medium sized, NHL, which was positive for CD45RO and negative for CD20, in a right nasal tumor in 1989. She received four courses of MACOP-B and 50 Gy involved field irradiation (IFR). She had maintained a CR until

Primary Malignant Lymphoma of the Trigeminal Nerve: Case Report and Literature Review

BACKGROUND Primary lymphomas of the cranial nerves are extremely rare except for optic nerve lymphoma, and it is difficult to make a correct diagnosis in the initial stage. Here, we report a case of primary malignant lymphoma of the left trigeminal nerve that presented as trigeminal nerve disorder. CASE DESCRIPTION A 47-year-old man presented with aggravating left facial pain and hypesthesia within all three divisions of the trigeminal nerve. Magnetic resonance imaging (MRI) revealed a swollen left trigeminal nerve with gadolinium homogenous enhancement. An open biopsy had to be taken from two different locations of the tumor via the lateral suboccipital approach followed by subtemporal approach because adequate specimen volume was not obtained for definitive diagnosis at the first surgery. Histopathological examinations with flow cytometric analysis revealed diffuse large B cell lymphoma. Chemotherapy followed by whole-brain radiation therapy was effective. No recurrence was observed during a 15-month follow-up period. CONCLUSIONS This is a rare clinical presentation of malignant lymphoma of the trigeminal nerve. It is difficult to establish a correct diagnosis of trigeminal nerve lesions during the initial stages without biopsy. Therefore it is important that a sufficient specimen should be taken for biopsy without hesitation in order to diagnose and treat rapidly. The most suitable operative approach must be selected in trigeminal nerve lesions considering functional preservation, operative difficulty, preference of each surgeon, and quantity of specimen to be removed.

Alectinib-Induced Alopecia in a Patient with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer

Alectinib, a novel alternative anaplastic lymphoma kinase (ALK) inhibitor, is highly effective against ALK-positive non-small cell lung cancer (NSCLC) and is well tolerated. Molecular targeted agents generally have little contribution to alopecia. We encountered a case of alopecia that developed gradually over 2 months after initiation of alectinib administration for the treatment of ALK-positive NSCLC. The patient had no history of alopecia in previous treatments of cisplatin + pemetrexed and crizotinib. The present case indicates that alopecia should be taken into consideration as toxicity during alectinib treatment, which could adversely affect the psychological and emotional condition and quality of life even in patients treated with specific molecular targeted agents.

Cell size variations of large granular lymphocyte leukemia: Implication of a small cell subtype of granular lymphocyte leukemia with STAT3 mutations

Large granular lymphocyte leukemia (LGL-L) has been morphologically defined as a group of lymphoproliferative disorders, including T-cell large granular lymphocytic leukemia (T-LGL-L), chronic lymphoproliferative disorders of NK cells (CLPD-NK) and aggressive NK cell leukemia. We investigated the morphological features of LGL leukemic cells in 26 LGL-L patients in order to elucidate relationships with current classifications and molecular backgrounds. LGL-L cells were mostly indistinguishable from normal LGL. Patients with STAT3 SH2 domain mutations showed significantly smaller cells compared with patients without STAT3 mutations. Four patients with T-LGL-L showed smaller granular lymphocytes with a median diameter of less than 13μm, which were rarely seen in normal subjects. This small subtype of T-LGL-L was recognized among rather young patients and was associated with D661Y mutations in the STAT3 gene SH2 domain. In addition, all of them showed anemia including two cases with pure red cell aplasia. These results suggest the heterogeneity of T-LGL-L and a specific subtype with small variants of T-LGL-L.

Effectiveness of Imatinib Mesylate Treatment in a Patient with Dermatofibrosarcoma Protuberans with Pulmonary and Pancreatic Metastases.

We herein encountered a case of abdominal wall dermatofibrosarcoma protuberans (DFSP) that developed pulmonary and pancreatic metastases 5 years after complete resection. Because specific rearrangements of the platelet-derived growth factor beta (PDGFB) locus by a novel fluorescence in situ hybridization method was detected, the patient was treated with imatinib mesylate at 400 mg/day. A partial response was achieved by imatinib without any specific toxicity. Although metastatic DFSP is an extremely rare disease, an evaluation of PDGFB fusion is essential and imatinib mesylate should be considered as an optimal therapeutic choice in patients with metastatic or locally advanced DFSP.

Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target

Aggressive natural killer-cell (NK-cell) leukemia (ANKL) is an extremely aggressive malignancy with dismal prognosis and lack of targeted therapies. Here, we elucidate the molecular pathogenesis of ANKL using a combination of genomic and drug sensitivity profiling. We study 14 ANKL patients using whole-exome sequencing (WES) and identify mutations in STAT3 (21%) and RAS-MAPK pathway genes (21%) as well as in DDX3X (29%) and epigenetic modifiers (50%). Additional alterations include JAK-STAT copy gains and tyrosine phosphatase mutations, which we show recurrent also in extranodal NK/T-cell lymphoma, nasal type (NKTCL) through integration of public genomic data. Drug sensitivity profiling further demonstrates the role of the JAK-STAT pathway in the pathogenesis of NK-cell malignancies, identifying NK cells to be highly sensitive to JAK and BCL2 inhibition compared to other hematopoietic cell lineages. Our results provide insight into ANKL genetics and a framework for application of targeted therapies in NK-cell malignancies.Aggressive natural killer-cell leukemia (ANKL) has few targeted therapies. Here ANKL patients are reported to harbor STAT3, RAS-MAPK pathway, DDX3X and epigenetic modifier mutations; and drug sensitivity profiling uncovers the importance of the JAK-STAT pathway, revealing potential ANKL therapeutic targets.