Multicenter retrospective study of nivolumab for recurrent/metastatic oral squamous cell carcinoma.

OBJECTIVES: Immunotherapy with nivolumab for patients with recurrent/metastatic oral squamous cell carcinoma has not been evaluated. Here, we aimed to examine the efficacy, safety, and prognostic factors of nivolumab in these patients. MATERIALS AND METHODS: This multicenter retrospective observational study involved patients who received nivolumab between April 2017 and June 2019. The patient characteristics were evaluated for association with progression-free and overall survival. Progression-free and overall survival rates were calculated; parameters that were significant in the univariate analysis were used as explanatory variables. Independent factors for progression-free and overall survival were identified using multivariate analysis. RESULTS: Totally, 143 patients were included. The overall response and disease control rates were 27.3% and 46.2%, respectively. The median, 1- and 2-year progression-free survival rates were 2.7 months, 25.4%, and 19.2%, respectively; those for overall survival were 11.2 months, 47.3%, and 33.6%, respectively. The independent factors affecting progression-free survival were performance status and immune-related adverse event occurrence, whereas those affecting overall survival were performance status, target disease, and number of previous lines of systemic cancer therapy. Eight patients reported grade ≥3 immune-related adverse events. CONCLUSION: Nivolumab was effective for recurrent/metastatic oral squamous cell carcinoma treatment and was well tolerated by patients.

Four cases of medullary thyroid carcinomas associated with multiple endocrine neoplasia 2B with rearranged during transfection codon M918T mutation in the same family.

Multiple endocrine neoplasia (MEN) with medullary thyroid carcinoma (MTC) is associated with rearranged during transfection (RET) mutations. The authors encountered four cases of MTC-related MEN type 2B (MEN2B) with RET codon M918T mutation in one family. Case 1 included a 19 year-old male diagnosed with MTC with lung metastases. Genetic testing revealed an RET codon M918T mutation, which indicated MEN2B. The patient responded partially to vandetanib and the disease has shown no progression in 25 months. Case 2 involved the mother of the patient in Case 1. She underwent total thyroidectomy (TT) when diagnosed with MTC-related MEN2B at 12 years of age, but was not counseled adequately. Cases 3 and 4 involved the sisters of the Case 1 patient and were assessed after Case 1 was diagnosed. Genetic testing revealed the same mutation. Case 3 was diagnosed with MTC and underwent TT. Case 4 was asymptomatic but underwent prophylactic TT; histopathologic examination revealed MTC tissue. Prophylactic TT prevented MTC from being detected at an advanced state. Genetic counseling is essential in treating MEN2B. The mother was uninformed about the genetic characteristics of MEN2B, delaying the detection of MTC in her children. The present study reaffirms the importance of family history and screening.

Current Status of Next-Generation Sequencing-Based Cancer Genome Profiling Tests in Japan and Prospects for Liquid Biopsy.

Next-generation sequencing-based comprehensive genome profiling (CGP) testing, OncoGuide NCC Oncopanel System, and FoundationOne CDx Cancer Genomic Profile have been covered by the Japanese national health insurance system since June 2019. Because CGP was initially developed to enroll patients into an early-phase clinical trial for solid tumors, its approved indications have been limited to patients who have completed the standard chemotherapy treatment. Approximately 14,000 cases have been registered with the Center for Cancer Genomics and Advanced Therapeutics as of March 2021. Measuring the drug access rate is not enough due to patients' deteriorating condition during CGP analysis and due to the limited number of ongoing clinical trials available, although tumor-agnostic therapies, such as the use of pembrolizumab in high microsatellite-instable solid tumors and in conditions with a high tumor mutational burden (≥10 mut/Mb) as well as the use of entrectinib and larotrectinib in NTRK fusion-positive tumors have been approved in Japan. Moreover, since this analysis is performed using DNA derived from tumor tissue, it is difficult to perform CGP in cases in which an insufficient amount of tissue exists. Thus, noninvasive blood-based assays have been developed, and CGP panels using circulating tumor DNA from blood were approved in March 2021. However, cost, timing, and the number of tests allowed by the health system have not yet been determined. Therefore, in this review, we outline the current status and issues of CGP testing using tumor tissues as well as the expectations and limitations of liquid biopsy for use in Japanese clinical practice.

Anaplastic thyroid cancer with long-term survival with lenvatinib therapy and preservation of laryngeal function after one-stage reconstruction: A case report.

Laryngotracheal reconstruction is performed to treat locally advanced thyroid carcinoma invading the larynx and/or trachea. The reconstructive technique varies. The present report describes the case of a 71-year-old female patient who underwent surgery for thyroid carcinoma involving the larynx. Reconstructive surgical techniques were employed to maintain laryngeal structure and function. An anterolateral thigh flap with free rib cartilage grafts was used to compensate for laryngeal defects. Although a temporary tracheal stoma was constructed, it closed spontaneously after decannulation. Therefore, one-stage laryngeal reconstruction was accomplished. Post-operative histopathological examination revealed focal anaplastic changes in the lesion, which mainly consisted of papillary components. Post-operative positron emission tomography/computed tomography indicated early recurrence in the left side of the neck. Therefore, lenvatinib was started as adjuvant therapy. Complete response was observed with lenvatinib therapy. The patient was alive and had good laryngeal function 26 months after the operation. One-stage laryngeal reconstruction can reduce burden and improve quality of life in patients with thyroid carcinoma involving the larynx. Lenvatinib may be useful for treating early recurrence of anaplastic thyroid carcinoma after reconstructive surgery with a free flap.

Non-viral derivation of a transgene-free induced pluripotent stem cell line from a male beagle dog.

We previously reported the non-viral derivation of transgene-free induced pluripotent stem cells (iPSCs) from somatic fibroblasts of a female beagle dog using an optimized induction medium and integration-free episomal vectors. Here, we report novel derivation of a male canine iPSC line OF35Y-iPS, which showed standard characteristics of pluripotency such as a strong gene expression profile of pluripotency markers, differentiation potential into all three germ layers, and normal karyotype (78XY). Furthermore, we demonstrated targeted integration of 2A-EGFP into the canine NANOS3 locus. The novel iPSC line would be a useful resource for stem cell research and regenerative veterinary medicine.

Rituximab prolongs the time to relapse in patients with immune thrombotic thrombocytopenic purpura: analysis of off-label use in Japan.

Immune thrombotic thrombocytopenic purpura (iTTP) is caused by ADAMTS13 deficiency due to anti-ADAMTS13 autoantibodies. Rituximab, an anti-CD20 monoclonal antibody, is often used to suppress these autoantibodies. This retrospective study, conducted in an iTTP cohort in Japan, evaluated the long-term efficacy of rituximab as off-label treatment for refractory or relapsed cases. A total of 252 iTTP patients with severe ADAMTS13 deficiency (< 10%) and its inhibitor were enrolled, and 169 episodes in 156 patients were analyzed. Sixty-five episodes with relapse or resistance to conventional treatment were treated with rituximab, while 104 episodes received conventional treatment only. The rituximab group had a significantly higher inhibitor titer than the rituximab-untreated group. During the median follow-up period of 3.9 years, there were 8 relapses in the rituximab group and 17 relapses in the rituximab-untreated group. The median time to relapse in the rituximab group (2.9 years) was significantly longer than that in the rituximab-untreated group (1.2 years). Relapse-free survival at 2 years was significantly higher in the rituximab group than in the rituximab-untreated group. The incidence of relapse at 5 years did not differ between the 2 groups. Rituximab reduced the risk of relapse in refractory or relapsed iTTP patients for 2 years.

Implementation of a rapid assay of ADAMTS13 activity was associated with improved 30-day survival rate in patients with acquired primary thrombotic thrombocytopenic purpura who received platelet transfusions.

BACKGROUND: Platelet (PLT) transfusions are probably harmful in patients with acquired idiopathic thrombotic thrombocytopenic purpura (aTTP). Introduction of a rapid assay for ADAMTS13 activity should reduce the time to definite diagnosis of aTTP, reduce the amount of inappropriately transfused PLT concentrates, and improve mortality and morbidity. STUDY DESIGN AND METHODS: We selected 265 aTTP patients with severe ADAMTS13 deficiency. Of these, 91 patients were diagnosed by March 2005 (Period 1), when ADAMTS13 activity was measured by von Willebrand factor multimer assay, which took 4 to 7 days until the result was reported. An additional 174 patients were diagnosed after April 2005 (Period 2), when the activity was measured by a chromogenic enzyme-linked immunosorbent assay, which took 1 to 2 days. RESULTS: We found no significant differences in 30-day survival rate between the two periods. Overall, 48 patients received PLT transfusions. Mortality was slightly greater between patients with (22.9%) versus without PLT transfusion (17.7%), but not significant. In Period 1, Cox proportional hazards regression analysis showed that older age (≥60 years) and PLT transfusion administration were independent factors associated with higher risks of 30-day mortality. In contrast, in Period 2, lower Rose-Eldor TTP severity score and use of plasma exchange and corticosteroid therapy were independent factors associated with higher survival rates while nonadministration of PLT transfusions was not. CONCLUSION: Our results indicate that PLT transfusions are harmful for aTTP patients when the definite diagnosis of severe ADAMTS13 deficiency is delayed. If it can be done as soon as possible, PLT transfusions for severe bleeding or surgical interventions might be allowed with subsequent plasmapheresis.

A retrospective study of patients with follicular lymphoma (FL): identification of in situ FL or FL-like B cells of uncertain significance in lymph nodes resected at the time of previous surgery for carcinomas.

BACKGROUND AND AIMS: In situ follicular lymphoma (iFL)/intrafollicular neoplasia and follicular lymphoma (FL)-like B cells of uncertain significance represent proliferation of Bcl-2/t(14;18)-positive B cells solely in the germinal centres. The condition is interpreted as an early event in the multi-step lymphomagenesis of FL. The aim of this study is to examine the issue more specifically. METHODS: We reviewed medical history of FL patients in whom thoracoabdominal surgery with lymphadenectomy had been performed for management of carcinomas. These previously resected lymph nodes as well as the current FL nodes were analysed by immunohistochemistry, fluorescent in situ hybridisation, and PCR amplification with direct sequencing. RESULTS: We studied four such FL patients from a total of 150 patients with FL; all had iFL in the previously resected lymph nodes. Clonal relation was verified and suggested in one case each. The time from lymphadenectomy to the diagnosis of FL was 23-120 months. There appeared to be a reverse correlation between the rate of Bcl-2-positive follicle proliferation and the time from surgery to diagnosis of FL. CONCLUSIONS: Although the rate for development of FL in individuals having iFL has been reported to be low from prospective studies, the present data indicate that follow-up studies for a longer period is necessary; the rate of Bcl-2-positive follicle proliferation could be a factor to predict development of FL in prospective studies. Such a retrospective study may contribute to elucidate mechanism(s) involved in lymphomagenesis of FL.

Primary diffuse large B-Cell lymphoma of the prostate presenting with urinary retention and dyschezia for which rituximab-combined CHOP therapy was effective-a case presentation.

We report the case of a 66-year-old man with primary diffuse large B-cell lymphoma of the prostate presenting with urinary retention and dyschezia as first manifestation. Although a colostomy was needed due to rectal obstruction, rituximab-combined chemotherapy resulted in complete remission. He underwent stoma closure safely and has remained in complete remission for over 3years. Primary prostatic lymphoma is extremely rare, presenting as 0.1% of newly diagnosed lymphomas, but rituximab-containing chemotherapy seems to be as effective as for nodal lymphoma.

[Late appearing Philadelphia chromosome as another clone in a patient with myelodysplastic syndrome harboring der(5;12)(q10;q10) at diagnosis].

A 61-year-old man was referred to our hospital for leukocytosis and thrombocytopenia. Bone marrow examination showed hypercellular bone marrow accompanied by dysplasia, and the karyotype of his bone marrow cells was 46,XY, der(5;12)(q10;q10), +mar,inc[3]/46,XY[12]. A diagnosis of myelodysplastic syndrome, unclassifiable, was made. Analysis of major BCR/ABL1 chimeric RNA by real-time polymerase chain reaction method was positive, and then Ph chromosome was observed afterward. His Ph chromosome was seen in der(5;12)-negative cells analyzed by FISH, which suggested the late-appearing Ph chromosome evolved into another clone. Despite treatment containing imatinib, hydroxyurea, and cytosine arabinoside, he died due to respiratory dysfunction 5 months after the initial diagnosis. The autopsy revealed massive pulmonary infiltration by Ph-negative cells, suggesting MDS-derived clones. It has been reported that the late appearance of Ph chromosome associates with leukemic progression. Although the incidence of late-appearing Ph chromosome is estimated to be relatively low, further accumulation of cases is necessary for the evaluation of its impact on prognosis and disease progression.

Precursor B-lymphoblastic lymphoma involving an intracardiac mass and myocardial infiltration: a case report.

We report the case of a 17-year-old man with precursor B-lymphoblastic lymphoma involving an intracardiac mass and myocardial infiltration. Intensified chemotherapy followed by autologous peripheral blood stem cell transplantation resulted in long-term complete remission for over 5 years. As the most frequent sites of B-lymphoblastic lymphoma involvement are the skin, soft tissue, bone, and lymph nodes, reports of cases harboring cardiac involvement are relatively few. This is a rare case of B-lymphoblastic lymphoma displaying cardiac involvement, in which cardiac infiltration was one of the initial manifestations.

A Rare t(9;22;16)(q34;q11;q24) Translocation in Chronic Myeloid Leukemia for Which Imatinib Mesylate Was Effective: A Case Report.

The t(9;22)(q34;q11) translocation is found in about 90% of chronic myeloid leukemia (CML) patients. About 5-10% of CML patients have complex variant translocations involving a third chromosome in addition to chromosomes 9 and 22. Herein, we describe a CML-chronic phase male with a complex translocation involving chromosome 16, t(9;22;16)(q34;q11;q24). First, he was treated with interferon-alpha and intermittent hydroxyurea, but only a partial cytogenetic response was attained. Subsequently, the patient was treated with imatinib mesylate because of an additional chromosome abnormality, trisomy 8. A major molecular response was obtained after one year's imatinib therapy, and the follow-up chromosomal analysis performed 4 years and 3 months after the initiation of imatinib therapy displayed a normal karyotype of 46,XY.