Genetic Analysis of Melanoma Types Using Japanese Genomic Database.

OBJECTIVES: The purpose of this study is to compare genetic mutations, tumor mutation burden (TMB), and the effects of molecular targeted drugs and immune checkpoint inhibitors (ICIs) in head and neck mucosal melanoma (HNMUM) with those in skin melanoma (SKM) and ocular melanoma (OM). METHODS: Data were analyzed for 72 consecutive patients with HNMUM, including 366 with SKM and 31 with OM, registered at the Japan National Cancer Center, Center for Cancer Genomics and Advanced Therapeutics (C-CAT) between June 2019 and October 2023. Genetic alterations and TMB were determined by FoundationOne CDx next-generation sequencing. RESULTS: The top 10 mutations in HNMUM were RAD21 (47.2%), NBN (45.8%), MYC (40.3%), LYN (31.9%), NRAS (29.1%), IRF4 (23.6%), DAXX (22.2%), KIT (22.2%), NOTCH3 (20.8%), and DDR1 (19.4%), with 16.6 ± 0.8 (mean ± SEM) mutations/individual. In SKM, BRAF (p = 0.04) mutation was associated with a significantly better prognosis. The TMB values were 5.7 ± 2.1 (mean ± SEM) in HNMUM, 4.1 ± 0.2 in SKM, and 3.4 ± 0.9 in OM, with no significant differences among the three groups. The median survival time for patients with distant metastases was 803 (95% confidence interval: 539-NA) days for HNMUM, 1413 (831-2172) days for SKM, and 1138 (438-NA) days for OM. CONCLUSIONS: The top 10 mutations in HNMUM are closer to those in OM than those in SKM. There was no significant difference in TMB values or survival rates with regard to the therapeutic effect of ICIs among the diseases, which suggests that current treatment of HNMUM with ICIs is appropriate. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Adult T-cell Leukemia/Lymphoma (ATL) in the Nasal and Paranasal Cavity: Four Cases Report.

Adult T-cell leukemia/lymphoma (ATL) is a form of leukemia caused by the human T-cell leukemia virus type I (HTLV-1). Otolaryngologists often diagnose ATL based on cervical lymphadenopathy or Waldeyer ring lesions. However, there are few reports of ATL occurring in the nasal and paranasal cavity. Here, we report four such cases of ATL. Case 1: An 82-year-old man diagnosed with acute-type ATL with a tumor in the nasal cavity underwent 5 courses of THP-COP, but died after 36 months due to ATL. Case 2: A 62-year-old woman diagnosed with lymphoma-type ATL with a tumor in the frontal sinus was treated with 5 courses of VCAP-AMP-VECP, and has survived for more than 10 years. Case 3: A 64-year-old man diagnosed with lymphoma-type ATL with a tumor in the maxillary sinus underwent 8 courses of VCAP-AMP-VECP and 2 courses of mogamulizumab, but died after 34 months due to ATL. Case 4: A 52-year-old woman diagnosed with lymphoma-type ATL with tumors in both ethmoid sinuses received 2 courses of CHOP, 2 courses of DeVIC, radiotherapy (32 Gy) and 2 courses of mogamulizumab, but died after 9 months due to ATL.

Construction of a T7 phage random peptide library by combining seamless cloning with in vitro translation.

T7 phage libraries displaying random peptides are powerful tools for screening peptide sequences that bind to various target molecules. The T7 phage system has the advantage of less biased peptide distribution compared to the M13 phage system. However, the construction of T7 phage DNA is challenging due to its long 36 kb linear DNA. Furthermore, the diversity of the libraries depends strongly on the efficiency of commercially available packaging extracts. To address these issues, we examined the combination of seamless cloning with cell-free translation systems. Seamless cloning technologies have been widely used to construct short circular plasmid DNA, and several recent studies showed that cell-free translation can achieve more diverse phage packaging. In this study, we combined these techniques to construct four libraries (CX7C, CX9C, CX11C and CX13C) with different random regions lengths. The libraries thus obtained all showed diversity > 109 plaque forming units (pfu). Evaluating our libraries with an anti-FLAG monoclonal antibody yielded the correct epitope sequence. The results indicate that our libraries are useful for screening peptide epitopes against antibodies. These findings suggest that our system can efficiently construct T7 phage libraries with greater diversity than previous systems.

Dysphonia in Polymyositis/Dermatomyositis in Adults.

The purpose of this study was to examine clinical dysphonia in patients with polymyositis (PM)/dermatomyositis (DM). The subjects were 21 Japanese patients with PM/DM (11 females, 10 males; mean age ± SD, 61.4 ± 16.2 years) who visited our department between April 2009 and March 2020. Dysphonia was evaluated by laryngoscopy and histopathological examination. Eight (38.1%) patients were aware of dysphonia. These patients included one with PM and 7 with DM, 5 were male and 3 were female, and the mean age at diagnosis was 62.0 (range 48 to 72) years. White lesions on the vocal cords were found in 7 of the patients with dysphonia. The patient without these white lesions had regurgitation into the nasal cavity. Histopathological examination revealed inflammation of lamina propria in the laryngeal white lesions. White lesions on the vocal cords were found in patients with dysphonia in patients with polymyositis (PM)/dermatomyositis (DM). Histopathological examination revealed fiber necrosis and inflammatory cell infiltration in lamina propria of the laryngeal lesions. White lesions on the vocal cords were relieved by treatment. Level of Evidence 2b (Individual retrospective cohort study).

Sudden death after operation, radiotherapy or chemoradiotherapy for head and neck cancer.

OBJECTIVE: The purpose of this report to determine sudden death following operation, radiotherapy (RT) or chemoradiotherapy (CRT) for head and neck cancer. STUDY DESIGN: Retrospective, observational, single-center. METHODS: Data from 729 consecutive patients diagnosed with head and neck cancer (confirmed using multiple modalities) who underwent operation, RT or CRT at Kagoshima University Hospital between April 2011, and March 2020 were analyzed. A total of 199 patients underwent operation, 223 patients underwent RT and 307 underwent CRT. 175 patients who received operation, 118 patients who received RT and 190 who received CRT had a complete response. RESULTS: There were 13 cases of sudden death reported in 10 years. 12 were male and one was female.Sudden death occurred in 3/175 patients (1.7%) who received operation, in 4/118 patients (3.4%) who had received RT and in 6/190 (3.1%) who had received CRT. CONCLUSIONS: We present the first report on cases of sudden death after operation, RT and CRT for head and neck cancer. Otolaryngologists should still follow these patients carefully after such treatment given that sudden death does occur in some patients.

Impacts of Inflammation-Based Prognostic Scores on Survival in Patients With Hypopharyngeal Squamous Cell Carcinoma.

OBJECTIVE: To investigate the predictive accuracies of the modified Glasgow Prognostic Score (mGPS), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR) as prognostic factors for patients with hypopharyngeal squamous cell carcinoma (HSCC). STUDY DESIGN: Retrospective study. SETTING: University hospital. METHODS: The records of 106 patients who were histologically diagnosed with HSCC between January 2007 and December 2017 were reviewed. mGPS, NLR, and PLR were analyzed; univariate and multivariate analyses were performed to evaluate the prognosis of overall survival (OS). RESULTS: The overall 5-year survival rates of patients with mGPS0, mGPS1, and mGPS2 were 82.0%, 41.9%, and 13.5%, respectively. The overall 5-year survival rates of patients with low and high NLRs and with low and high PLRs were 83.8%, 46.2%, 57.0%, and 59.1%, respectively. mGPS (P < .001) and NLR (P < .05) were independently associated with OS, whereas PLR was not. For stage IV HSCC, only mGPS was independently associated with OS (P = .004). CONCLUSION: mGPS is an excellent prognostic factor for patients with HSCC.

Lenalidomide as a Beneficial Treatment Option for Renal Impairment Caused by Light Chain Deposition Disease.

Light chain deposition disease (LCDD) is a rare systemic disorder caused by the deposition of light chain immunoglobulins, which often results in renal impairment associated with either nephrotic syndrome or asymptomatic proteinuria. B-cell neoplasms, such as multiple myeloma and lymphoproliferative disorders, are well-known underlying diseases in LCDD. Some chemotherapy regimens have been reported, but both evidence-based treatment and management for LCDD have yet to be established. We herein report three cases of LCDD treated with lenalidomide-based therapy, resulting in hematologic responses accompanied by a significant reduction in proteinuria and improvement in the renal function. We recommend lenalidomide-based therapy for renal impairment caused by LCDD.

Persistent complete remission of acute leukemic-phase CCR4-positive gamma-delta peripheral T-cell lymphoma by autologous stem cell transplantation with mogamulizumab.

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), frequently shows a poor outcome. Especially, expressions of CC chemokine receptor 4 (CCR4) and γδ T-cell receptor (TCR) are associated with worse prognosis in PTCL-NOS. We here report successful treatment with autologous peripheral blood stem cell transplantation (auto-PBSCT) combined with anti-CCR4 antibody mogamulizumab for a very rare case of CCR4+γδTCR+ PTCL-NOS that coexisted with Hodgkin's lymphoma. PTCL-NOS in this patient progressed to leukemic phase, whereas Hodgkin's lymphoma disappeared with standard chemotherapies within 4 years of the initial diagnosis. Leukemic-phase PTCL-NOS was refractory to several chemotherapies. However, auto-PBSCT following high-dose chemotherapy combined with pre- and post-transplant mogamulizumab, which is a humanized monoclonal antibody to CCR4, provided persistent complete remission of PTCL-NOS, despite residual γδTCR+ in the transplanted stem cell product, suggesting a purging effect of mogamulizumab. At 15 months after transplantation, we also found markedly fewer effector regulatory T cells, which may have contributed to prolonged remission. This case suggests that autologous stem cell transplantation combined with mogamulizumab may have a potential to cure T-cell neoplasms that express CCR4 including leukemic-phase PTCL-NOS.

Efficacy of 1.0% chlorhexidine-gluconate ethanol compared with 10% povidone-iodine for long-term central venous catheter care in hematology departments: a prospective study.

The efficacy of 1% chlorhexidine-gluconate ethanol and 10% povidone-iodine for skin antisepsis of central venous catheter (CVC) sites were compared among hematology patients. The CVC site colonization rates of those groups were 11.9% and 29.2%, respectively, and the catheter-associated blood stream infections were 0.75 and 3.62 per 1,000 catheter-days, respectively. One percent chlorhexidine-gluconate ethanol was superior to povidone-iodine to reduce skin colonizers at CVC sites even when catheters were used for long duration.

A Japanese case of chronic lymphocytic leukemia with t (1;6).

Chronic lymphocytic leukemia (CLL) rarely exhibits an aggressive clinical course and its patients often have chromosomal deletions or additions. Furthermore, reciprocal translocations are barely observed in CLL. There have only been a few reports of CLL with t(1;6), and here we report the first Asian case of CLL with reciprocal translocation t(1;6). Since our case and previously reported CLL patients with t(1;6) consistently showed aggressive clinical course, t(1;6) may define a distinct type of CLL.

Impaired regulatory T cell reconstitution in patients with acute graft-versus-host disease and cytomegalovirus infection after allogeneic bone marrow transplantation.

To elucidate the correlation between regulatory T cells (Tregs) and acute graft-versus-host disease (aGVHD) or cytomegalovirus infection following allogeneic bone marrow transplantation (allo-BMT), we evaluated either CD4⁺CD25(high) or FOXP3⁺ Treg-enriched cells in peripheral blood (PB) from 20 patients who received allo-BMT, and in biopsies of skin with aGVHD. Proportions of CD4⁺CD25(high)FOXP3⁺ cells in total lymphocytes, but not other types of T cells, were lower in patients who eventually developed grades II-IV aGVHD (n = 13) than in others (n = 7, P < 0.001). Proportions of CD62L⁺ cells in CD4⁺CD25(high) cells at day +30 were lower (P < 0.01) in patients who eventually showed cytomegalovirus viremia (n = 6) than in others (n = 14). Incidence of aGVHD (P < 0.05) or cytomegalovirus viremia (P < 0.05) was higher in patients without these complications, but with lower proportions of PB CD4⁺CD25(high)FOXP3⁺ cells at day +30 (n = 8) than in others (n = 8). However, in skin with aGVHD (n = 5), there was marked or slightly increased infiltration of CD8⁺ cells (P < 0.001) or CD3⁺FOXP3⁺ cells (P < 0.05), respectively, when compared with control (n = 5), resulting in threefold higher ratio of CD8⁺/CD3⁺FOXP3⁺ cells in aGVHD relative to controls (P < 0.05). Thus, impaired reconstitution of Tregs may be associated with aGVHD and CMV infection. Moreover, imbalance of Tregs and CD8⁺ cells may play a role in aGVHD tissue.

Total anomalous pulmonary vein drainage: report of an autopsy case associated with atresia of the common pulmonary vein and left superior pulmonary vein.

We describe the clinicopathological features of a case of total anomalous pulmonary vein drainage (TAPVD) associated with atresia of the common pulmonary vein (ACPV). A male Japanese infant born at 37 weeks of gestation demonstrated apnea and severe respiratory acidosis immediately after delivery. The patient died of hypoxemic respiratory failure 6 days after birth despite the initiation of artificial ventilation and administration of a surfactant. Autopsy showed the bilateral inferior pulmonary veins joined with a blind confluence, representing ACPV, accompanied by atresia of the left superior pulmonary vein. Moreover, the anomalous and small right superior pulmonary vein drained into the superior vena cava, consistent with partial and supracardiac type TAPVD. A histological examination of the lungs exhibited diffuse dilation of the lymphatic channels in the peribronchial, interlobular, hilar and focally, subpleural areas. The channels were lined with flattened endothelium which was immunohistochemically positive for D2-40. These findings conformed to a secondary form of pulmonary lymphangiectasis due to the congenital cardiovascular anomalies, including TAPVD and ACPV. To the authors' knowledge, this is the first case of TAPVD associated with ACPV, atresia of left superior pulmonary vein and pulmonary lymphangiectasis.

Hematopoietic stem cell transplantation in the Department of Hematology, Fukushima Medical University.

From 1996 to the end of 2009, a total of 114 cases of hematopoietic stem cell transplantation were performed in the Department of Hematology, Fukushima Medical University. We report here a general overview of our results. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed in 37 cases of acute leukemia, 10 of myelodysplastic syndrome, 5 of aplastic anemia, and 5 others. The 5-year survival rate with allo-HSCT was 51.1%. Autologous hematopoietic stem cell transplantation (auto-HSCT) was performed in 34 cases of malignant lymphoma, 15 of multiple myeloma, and 8 others. The 5-year patient survival rate was 75.2% with malignant lymphoma and 46.7% with multiple myeloma. These results are comparable to those from a nationwide survey in Japan, confirming that our hospital has attained a creditable level as a transplantation center.

A long-term remission of renal amyloidosis with nephrotic syndrome after autologous peripheral blood stem-cell transplantation.

Renal amyloidosis is typically characterized by nephrotic syndrome, often with massive proteinuria and refractory peripheral edema. We report the case of a patient with renal amyloidosis associated with nephrotic syndrome who maintained remission for 6 years after undergoing high-dose chemotherapy followed by autologous peripheral blood stem-cell transplantation (auto-PBSCT). The patient was a man aged in his 50s who had developed nephrotic syndrome. Bone marrow aspiration and kidney biopsy determined that the cause of the nephrotic syndrome was renal amyloidosis due to multiple myeloma, and the patient was admitted to our department in July 2003. After one course of chemotherapy, auto-PBSCT was performed in March 2004. Following transplantation, serum M-protein was no longer detectable from March 2005, and the patient achieved complete hematological remission. Subsequently, proteinuria decreased, serum albumin levels normalized, and nephrotic syndrome improved. As of 6 years after transplantation, in March 2010, the patient remained in remission, meaning that auto-PBSCT proved extremely effective as a treatment for renal amyloidosis in this case.

Microvascular thrombosis in the hepatic vein of a patient with paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated hemolysis, venous thrombosis, and bone marrow failure. In May 2003, a 33-year-old man was admitted to a hospital with right hypochondralgia and fever. He had a history of aplastic anemia. The patient's diagnosis of diffuse microvessel thrombosis in the hepatic vein due to an unknown cause was derived from the findings of a contrast-enhanced computed tomography examination of the abdominal region, angiographic evaluation of abdominal vessels, and pathohistologic examination of a liver biopsy sample. The patient was subsequently treated with warfarin. The abdominal pain and fever continued, however, and anemia gradually appeared. In April 2004, the patient was referred to our hospital to examine the cause of the thrombosis. On admission, slight anemia and a low serum haptoglobin level were observed. A flow cytometry evaluation of CD55 and/or CD59, CD59, and CD48 expression in erythrocytes, granulocytes, and monocytes, respectively, showed that the respective proportions of negative populations were 5.6%, 97.1%, and 96.2%. The patient then received a diagnosis of aplastic anemia/PNH syndrome, which had caused the hemolytic anemia and thrombosis, although no hemoglobinuria had been observed during his clinical course. This patient is, to our knowledge, the first reported case of a PNH patient with thrombosis present only in hepatic microvessels and not in hepatic large vessels, in spite of the presence of few hemolytic events.

Synergetic antioxidant and vasodilatory action of carbon monoxide in angiotensin II - induced cardiac hypertrophy.

The aim of this study was to determine the effects of carbon monoxide (CO) at a nontoxic low concentration on the cardiac and vascular hypertrophic response and reactive oxygen species generation, compared with the action of a vasodilator, hydralazine. Twelve- to 16-week-old low-density lipoprotein receptor knockout mice were subjected to angiotensin II (Ang II) infusion using osmotic minipumps (Ang II group; n=11) for 2 weeks. Controls were administered saline (n=10). Animals were exposed to CO in a chamber at 60 ppm for 2 hours per day with or without Ang II infusion (Ang II+CO group, n=10; CO group, n=9). Hydralazine was administered with Ang II infusion (n=10). Animals exhibited elevated arterial carboxyhemoglobin after CO exposure. Although the CO exposure did not affect systolic blood pressure without Ang II infusion, the hypertensive response after Ang II infusion was significantly attenuated by CO. Accordingly, the mice in the Ang II+CO group showed lesser left ventricular hypertrophy compared with those in the Ang II group. CO treatment also attenuated aortic hypertrophy. Interestingly, these changes were accompanied by the reduction of reactive oxygen species production, p47(phox) and p67(phox) subunit expressions of reduced nicotinamide-adenine dinucleotide phosphate oxidase, and Akt phosphorylation. Although hydralazine showed stronger antihypertensive action, superior inhibition on cardiac hypertrophy was obtained by CO (P<0.05). Furthermore, Ang II-dependent myocardial reactive oxygen species generation was more effectively suppressed by CO. Low-dose exogenous CO treatment attenuates Ang II-dependent reactive oxygen species generation, suggesting that appropriate CO administration alleviates hypertension and reduces organ hypertrophy mediated by Ang II.