Association between human papillomavirus particle production and the severity of recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) has a wide range of severity. We investigate the relationship between human papillomavirus (HPV) particle production and severity of RRP. From September 2005 to June 2021, 68 RRP samples (from 29 patients) were included. HPV type was determined. HPV viral load, physical status, and demographic and clinical characteristics were assessed. Immunohistochemistry (IHC) was performed for p16, Ki-67, L1, and E4. We used NanoSuit-CLEM (correlative light and electron microscopy) and transmission electron microscopy (TEM) to examine the samples. The total number of surgeries in HPV-positive and HPV-negative cases were 3.78 (n = 55/68, range: 1-16) and 1.30 (n = 13/68, range: 1-3), respectively (p = 0.02). IHC showed that L1 and E4 were correlated and expressed on the tumour surface. NanoSuit-CLEM and TEM revealed HPV particles in L1-positive nuclei. L1 IHC-positive cases had a shorter surgical interval (p < 0.01) and more frequent surgeries (p = 0.04). P16 IHC, viral load, and physical status were not associated with disease severity. This study visualised HPV particle production in RRP for the first time. Persistent HPV particle infection was associated with severity. We suggest L1 IHC for evaluating RRP severity in addition to the Derkay score.

An infant case of pseudohypoaldosteronism type1A caused by a novel NR3C2 variant.

Pseudohypoaldosteronism type1A (PHA1A) is the renal form of pseudohypoaldosteronism with autosomal dominant inheritance. PHA1A is caused by haploinsufficiency of the mineralocorticoid receptor, which is encoded by NR3C2. We encountered an infant who was diagnosed with PHA1A due to hyponatremia, hyperkalemia, and poor weight gain in the neonatal period. She carried a novel heterozygous mutation (NM_000901.5: c.1757 + 1 G > C) in the splice donor site of IVS-2 in NR3C2.

Differences in the neuronal correlation between the central and peripheral vision in the cat early visual cortex.

Significant surround modulation was reported in the cortical areas corresponding to the periphery of the visual field, whereas no clear surround modulation was reported in the center. To understand the neural bases underlying the differences of the functions between the cortical areas corresponding to the center and periphery of the visual field, responses of the cells in the cat early visual cortex with their receptive fields in the center and periphery of the visual field were recorded by using multichannel electrodes, and cross-correlations of the spikes in the responses to the full-field stimuli, and the center-surround stimuli, which contained a grating in a central patch and a surround grating, were analyzed. Percentages of the cell pairs showing significant cross-correlation were larger in the cortical areas corresponding to the periphery than the center. In the center of the visual field, the percentages of the cell pairs showing significant cross-correlation significantly decreased as the separation of the recording points increased, and the time lags of the peaks of the cross-correlogram distributed around zero. In the periphery of the visual field, the time lags of the peaks of the cross-correlogram distributed more widely and increased as the separation of the recording points increased. In the responses to the center-surround stimuli in the preferred orientation of each cell, percentages of the cell pairs showing significant cross-correlation were larger in the periphery than the center. These results suggest that more lateral interactions occur in the cortical areas corresponding to the periphery than the center of the visual field.

Object discrimination performance and dynamics evaluated by inferotemporal cell population activity.

We have previously reported an increase in response tolerance of inferotemporal cells around trained views. However, an inferotemporal cell usually displays different response patterns in an initial response phase immediately after the stimulus onset and in a late phase from approximately 260 ms after stimulus onset. This study aimed to understand the difference between the two time periods and their involvement in the view-invariant object recognition. Responses to object images with and without prior experience of object discrimination across views, recorded by microelectrodes, were pooled together from our previous experiments. With a machine learning algorithm, we trained to build classifiers for object discrimination. In the early phase, the performance of classifiers created based on data of responses to the object images with prior training of object discrimination across views did not significantly differ from that based on data of responses to the object images without prior experience of object discrimination across views. However, the performance was significantly better in the late phase. Furthermore, compared to the preferred stimulus image in the early phase, we found 2/3 of cells changed their preference in the late phase. For object images with prior experience of training with object discrimination across views, a significant higher percentage of cells responded in the late phase to the same objects as in the early phase, but under different views. The results demonstrate the dynamics of selectivity changes and suggest the involvement of the late phase in the view-invariant object recognition rather than that of the early phase.

Sarcopenia and obesity in long-term survivors of childhood leukemia/lymphoma: a report from a single institution.

BACKGROUND: The incidence and background factors of sarcopenia and obesity in long-term survivors of childhood leukemia/lymphoma were not clear in Japan. METHODS: Between August 2018 and September 2019, we recruited adults aged ≥18 years who had childhood leukemia/lymphoma. Blood sampling, body composition measurement by bioelectrical impedance analysis and grip strength test were performed. RESULTS: Among 81 adult survivors (34 men and 47 women) with a median age of 25.0 years, 9 (11%) had sarcopenia and 10 (12%) had obesity, of whom, 3 had metabolic syndrome. Sarcopenia was observed in 7 (21%) of 33 survivors with hematopoietic stem cell transplantation (HSCT) and 2 (4%) of 48 survivors without hematopoietic stem cell transplantation (P = 0.012). The incidence of obesity was significantly higher in the cranial radiotherapy (P = 0.021) and non-transplanted cases (P = 0.042). Univariate logistic regression analysis revealed that hematopoietic stem cell transplantation for sarcopenia (odds ratio, 6.19; 95% confidence interval, 1.2-32.0; P = 0.03) and cranial radiotherapy for obesity (odds ratio, 5.6; 95% confidence interval, 1.4-22.4; P = 0.015) were significantly associated. Hypertension was more prevalent among the obese survivors, and higher transaminase levels were found more in both the sarcopenia and obese survivors than in others. CONCLUSIONS: Young adult survivors of childhood leukemia/lymphoma could be at risk of developing sarcopenia after hematopoietic stem cell transplantation and obesity after cranial radiotherapy. Further studies are required to assess the body composition of long-term survivors to find detailed risk factors of sarcopenia and metabolic syndrome.

An intrinsic algorithm for viewing angle tolerance of object discrimination in human subjects.

Prevailing theories suggest that view-invariant object recognition is accomplished via spatiotemporal correlations of multiple views that bind different views to the same object. However, it is unknown how the exposure to multiple views without association affects view-invariant recognition generating. Behavioural studies have shown that monkeys acquired view-invariant object recognition capability in a range of the viewing angles of 30° to 60° after experiencing discrimination of similar objects at each of several viewing angles without associating different views, but the monkeys could not discriminate novel objects from similar distractors when the viewing angle changed. In the present study the development of the view invariance was tested in the human subjects and compared with the results of the monkeys previously reported. The view-invariant object recognition capability of human subjects was tested using either familiar objects that the subjects experienced in a preparatory object discrimination task at the same viewpoints or novel objects that the subjects had never experienced. In the viewing angle range of 30°, human subjects showed significant object discrimination capability across views, with no need for prior experience of the objects. Prior discrimination experience within the same viewpoints endowed the human subjects with broadening of the viewing angle tuning, because an object discrimination test immediately after the prior discrimination experience at a single view showed wider viewing angle tuning than a test without prior experience. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Management of elderly patients with head and neck carcinoma: analysis of outcomes for radical versus palliative treatment.

BACKGROUND: There are no universally accepted treatment recommendations for elderly patients with head and neck carcinomas. This study investigated whether radical treatment in elderly patients resulted in better survival compared with palliative treatment. METHODS: We retrospectively reviewed the medical records of 724 patients aged > 60 years who underwent treatment for primary head and neck carcinomas at Hamamatsu University Hospital. We evaluated the impact of the following: age, sex, the clinical stage, smoking history, alcohol use history, primary tumor site, performance status, and Osaka Head and Neck Comorbidity Index score on overall survival using a Cox proportional hazards model. RESULTS: The 5-year overall survival rate was significantly greater for the 646 patients initially treated with radical (curative) therapy than for the 78 patients treated with palliative therapy (p < 0.01). Patients who received palliative treatment in all age groups were more likely to die than were those in the radical treatment group, after controlling for age, sex, and clinical stage of the cancer. Information on the survival status of patients was obtained after a mean follow-up period of 46 months (range 6-205 months). CONCLUSIONS: In the absence of contraindications associated with comorbidities, radical treatment protocols should be recommended for elderly patients with head and neck carcinomas because they confer better survival.

Porfimer sodium-mediated photodynamic therapy in patients with head and neck squamous cell carcinoma.

BACKGROUND: Photodynamic therapy is a less invasive therapeutic procedure for carcinomas. The goal of this study was to evaluate the utility of Photofrin (porfimer sodium)-mediated photodynamic therapy in patients with head and neck squamous cell carcinoma. METHODS: Forty-two head and neck squamous cell carcinoma patients who underwent Photofrin-mediated photodynamic therapy were treated by intraoperative light activation at 630 nm via a fiber optic microlens, 48 h after injection. We evaluated the impact of age, sex, tumor stage, primary site, light dose, and cancer history on overall survival using a Cox proportional hazards model. Information on the survival status of patients was obtained after a mean follow-up period of 51 months (range, 6-180 months). RESULTS: The 5-year overall survival for all patients was 57.8 % (95 % confidence interval of the survival rate: 39.8 %-72.1 %). The complete response rate was 69.0 %, and the efficacy (complete response + partial response) was 97.6 %. Earlier tumor stage was associated with increased survival (p = 0.012). Diseases of the respiratory tract also showed significant association with survival as compared to those of the alimentary tract (p = 0.01). CONCLUSIONS: Photofrin-mediated photodynamic therapy is useful for treating head and neck squamous cell carcinomas, and provides an improved quality of life in patients with recurrent or residual disease.

Relevance of Level IIb Neck Dissection in Patients with Head and Neck Squamous Cell Carcinomas.

BACKGROUND: Cervical nodal metastasis is the most important prognostic factor in patients with head and neck cancers. Unfortunately, nodal dissection at level IIb carries a risk of damage to the spinal accessory nerve. We aimed to determine the prevalence of level IIb metastasis and the relevance of nodal dissection at level IIb in patients with head and neck squamous cell carcinomas. METHODS: During neck dissection, level IIb lymph nodes obtained from 181 patients with head and neck squamous cell carcinomas were removed, processed, and histopathologically examined. All specimens were divided into two groups according to the side (affected and unaffected sides). The number of dissected lymph nodes and prevalence of level IIb metastasis in each group were then determined and compared according to the preoperative clinical N stage (cN0 and cN+). RESULTS: The study included 158 men and 23 women with a median age of 65 years (range, 17-89 years). The prevalence of pathologically confirmed level IIb metastasis was 0% for clinically node-negative (cN0) necks on the unaffected side and 10.34% for clinically node-positive necks (cN+), with an overall prevalence of 2.4%. There was a significant association between clinically determined and pathologically confirmed node negativity at level IIb. CONCLUSION: Our findings suggest that level IIb neck dissection in patients with head and neck squamous cell carcinomas may be required only if preoperative examination reveals multilevel or level IIa metastasis or suspicious level IIb metastasis.

Risk Factors and Prognostic Factors of Hearing Impairment in Neonatal Intensive Care Unit-Treated Infants.

BACKGROUND: Infants admitted to the neonatal intensive care unit (NICU) have a higher incidence of congenital hearing loss compared with the healthy newborn population. OBJECTIVES: To clarify the relationship between risk factors for hearing impairment in NICU-treated infants and deterioration of the auditory brainstem response (ABR) threshold during childhood. METHOD: We screened 1,071 high-risk infants admitted to the NICU for hearing impairment. One-hundred forty-eight infants exhibited an abnormal ABR threshold of ≥40 dB nHL. We analyzed the correlation of change in ABR threshold with risk factors for future hearing impairment. RESULTS: Among infants treated in the NICU, 148 (13.8%) exhibited an ABR threshold of ≥40 dB nHL; 107 of these 148 (72.3%) showed hearing change in the process (102 showed improvement to normal hearing level, whereas 5 showed further deterioration). Our analysis showed that the factors contributing to the elevation of ABR threshold were oxygen administration and chromosomal aberrations. CONCLUSIONS: Factors related to the elevation of ABR threshold were oxygen administration and the presence of chromosomal aberrations. Awareness of risk factors that are more likely to cause hearing loss in infants may aid in follow-up treatment of these children.

A multicenter phase I study of inebilizumab, a humanized anti-CD19 monoclonal antibody, in Japanese patients with relapsed or refractory B-cell lymphoma and multiple myeloma.

This multicenter, phase I, open-label dose escalation study evaluated safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of inebilizumab in Japanese patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), or multiple myeloma (MM) who were ineligible for hematopoietic stem cell transplantation. Patients received inebilizumab 2, 4, or 8 mg/kg intravenously on days 1 and 8 of the first 28-day cycle, and once every 28 days thereafter, with a 12 mg/kg cohort added. Twenty patients (11 FL, six DLBCL, two CLL, and one MM) received inebilizumab at four dose levels (2 mg/kg cohort, n = 3; 4 mg/kg cohort, n = 7; 8 mg/kg cohort, n = 4; 12 mg/kg cohort, n = 6). Three patients experienced dose-limiting toxicities: grade 4 neutropenia/grade 3 leukopenia (n = 1, 12 mg/kg) and grade 3 infusion reaction (n = 1 each, 4 mg/kg and 12 mg/kg); the maximum tolerated dose was 8 mg/kg. Four (three FL and one DLBCL) patients achieved complete response; eight (six FL and two DLBCL) achieved partial response. Overall response rate was 60%. Over the dose ranges evaluated, the pharmacokinetic profile of inebilizumab in Japanese patients was generally dose proportional. This phase I study showed acceptable toxicity and preliminary and promising efficacy of inebilizumab in patients with relapsed/refractory FL and DLBCL.

Maintenance of long remission in adult T-cell leukemia by Tax-targeted vaccine: A hope for disease-preventive therapy.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive lymphoproliferative disease caused by human T-cell leukemia virus type 1 (HTLV-1). Multi-agent chemotherapy can reduce ATL cells but frequently allows relapses within a short period of time. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) following chemotherapy is now a standard therapy for ATL in Japan as it can achieve long-term remission in approximately one-third of recipient ATL patients; however, it also has a risk of treatment-related mortality. Allo-HSCT often induces HTLV-1 Tax-specific cytotoxic T cells (CTL) as well as graft-versus-host (GVH) response in ATL patients. This observation led to development of a new therapeutic vaccine to activate Tax-specific CTL, anticipating anti-ATL effects without GVH response. The newly developed Tax-DC vaccine consists of autologous dendritic cells pulsed with Tax peptides corresponding to CTL epitopes that have been identified in post-allo-HSCT ATL patients. In a pilot study of Tax-DC therapy in three ATL patients after various initial therapies, two patients survived for more than 4 years after vaccination without severe adverse effects (UMIN000011423). The Tax-DC vaccine is currently under phase I trial, showing a promising clinical outcome so far. These findings indicate the importance of patients' own HTLV-1-specific T-cell responses in maintaining remission and provide a new approach to anti-ATL immunotherapy targeting Tax. Although Tax-targeted vaccination is ineffective against Tax-negative ATL cells, it can be a safe alternative maintenance therapy for Tax-positive ATL and may be further applicable for treatment of indolent ATL or even prophylaxis of ATL development among HTLV-1-carriers.

Difference in the generalization of response tolerance across views between the anterior and posterior part of the inferotemporal cortex.

The inferotemporal cortex consists of an anterior (cytoarchitectonic area TE) and a posterior (area TEO) part, which together constitute the final areas of the ventral visual stream, which is critical for object discrimination. Area TE receives dense projections from area TEO. We have previously identified a response tolerance in the cells in area TE in monkeys to a range of viewing angles after object discrimination at each of several views. To investigate the contribution of area TEO to the establishment of such a response tolerance in area TE, we conducted electrophysiological recordings of the responses of the single cells in area TEO after performance saturation of object discrimination at several independent views, without any association across views, and compared them with those obtained from the TE cells. The cells in area TEO showed responses to the experienced object views, but not to nearby views. Comparisons of the tunings of the TE and TEO cells to different viewing angles for the same object sets in the same animal showed that cells in area TEO had a significantly narrower tuning width, whereas the response tolerance was usually observed in the TE cells across viewing angles up to 60°. Our findings revealed a significant difference in the representation of the object views between areas TE and TEO, and suggested that such a representation in area TE may be completed through neuronal mechanisms within area TE, which is not a property of the earlier stages of the ventral visual stream.

Secondary bone/soft tissue sarcoma in childhood cancer survivors: a nationwide hospital-based case-series study in Japan.

BACKGROUND: Secondary cancer is the most life-threatening late effect of childhood cancer. We investigated the clinical features of secondary bone/soft tissue sarcoma among childhood cancer survivors (CCSs). METHODS: We conducted a retrospective case-series study of 10 069 CCSs newly diagnosed with cancer between 1980 and 2009 across 15 Japanese hospitals. Twenty-one cases of pathologically diagnosed secondary bone/soft tissue sarcoma were selected, and the respective clinical courses were determined using additional questionnaires. RESULTS: The primary cancers included retinoblastoma (n = 7), acute lymphoblastic leukemia (n = 5), lymphoma (n = 5), osteosarcoma (n = 1), rhabdomyosarcoma (n = 1), brain tumor (n = 1) and Langerhans cell histiocytosis (n = 1). The median age at the primary cancer diagnosis was 2.9 years, and the male-to-female ratio was 16:5. The histological classifications of the secondary sarcoma included osteosarcoma (n = 10), malignant peripheral nerve sheath tumor (n = 4), rhabdomyosarcoma (n = 3), Ewing's sarcoma (n = 3) and primitive neuroectodermal tumor (n = 1). The median latency period to the secondary sarcoma was 10.2 years. Significant risk factors for secondary sarcoma in the multivariate Cox regression model included a history of retinoblastoma as the primary cancer (hazard ratio [HR], 20.9; 95% confidence interval [CI], 5.70-76.5) and autologous stem cell transplantation (SCT) (HR, 2.56; 95% CI, 1.08-6.03). Seventeen CCSs with secondary sarcoma underwent radiation, and nine, hematopoietic SCT. Twelve CCSs with secondary sarcoma achieved disease-free survival, while CCSs with hematological cancer or relapsed primary cancer who developed secondary sarcoma had the worst prognoses. CONCLUSION: The prognoses of CCSs with secondary sarcoma may depend on the primary cancer or prior relapse of primary cancer.

Secondary cancer after a childhood cancer diagnosis: viewpoints considering primary cancer.

BACKGROUNDS: Multidisciplinary therapy has increased the risk of subsequent late effects, but detailed analyses on secondary cancers in childhood cancer survivors (CCSs) are limited in Asian countries. METHODS: This was a retrospective cohort study comprising 10,069 CCSs who were diagnosed between 1980 and 2009 across 15 Japanese hospitals. We conducted secondary analyses to estimate the incidence of secondary cancer according to each primary malignancy and to elucidate the association between primary and secondary cancers. We also explored the risk factors for the development of secondary cancer in each independent primary malignancy. RESULTS: The cumulative incidence of secondary cancer at 20 years varied among primary cancers: hematological malignancy, 3.1% (95% CI 2.2-4.3); retinoblastoma, 6.6% (95% CI 1.5-16.8); pediatric solid tumor, 2.5% (95% CI 1.3-4.2); brain tumors, 5.2% (95% CI 1.7-11.8) bone/soft tissue sarcoma, 5.2% (95% CI 2.3-10.1); and others, 3.3% (95% CI 1.6-6.0) (p = 0.015). The cumulative incidence of secondary cancers is highest in those with osteosarcoma (13.1%) followed by those with hepatoblastoma (8.4%) and retinoblastoma (6.6%). Close association between the primary and secondary cancer diagnoses was found. The risk factors for secondary cancer development depended on the primary cancer, but autologous/allogeneic stem cell transplantation was a relatively common risk factor. CONCLUSION: The cumulative incidence of secondary cancer varied among primary cancers. The primary cancer was closely associated with the secondary cancer but stem cell transplantation was a common risk factor for secondary cancers among CCSs.

Photodynamic therapy in patients with head and neck squamous cell carcinoma.

BACKGROUND: Photodynamic therapy (PDT) is a minimally invasive treatment for malignant tumors. The aim of this study was to determine the efficacy of PDT in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: Thirty-three patients with HNSCC were treated with porfimer sodium-mediated PDT followed by intraoperative light activation at 630 nm via fiber optic microlens delivered after 48 hours of injection. RESULTS: The complete response (CR) rate was 72.7%, while the efficacy (CR + partial response) rate was 97.0%. The rate of good local control (i.e., CR without recurrence after PDT) achieved after the initial PDT (82.6%) was significantly higher than that achieved after the second or third PDT (10%); this rate remained at 62.1% without functional disturbance and disfigurement even after excluding four previously untreated patients. The final local control rate following PDT plus additional therapies was 73.8%. CONCLUSIONS: PDT is an effective therapy to treat HNSCC, and leads to an improved quality of life in patients with residual or recurrent disease. Lasers Surg. Med. 50:420-426, 2018. © 2018 Wiley Periodicals, Inc.

Risk and prognostic factors for multiple primary carcinomas in patients with head and neck cancer.

BACKGROUND: Unexpected multiple primary carcinomas (MPCs) that develop in patients with head and neck carcinomas complicate approaches to their management. We therefore investigated the clinical factors associated with survival outcomes after the treatment of MPCs. METHODS: We performed a retrospective review of records of 1104 patients who underwent treatment for primary head and neck carcinoma at Hamamatsu University Hospital. We evaluated clinical staging, age, sex, smoking, alcohol consumption, the primary tumor site (particularly the involvement of the mucosal epithelial lining of the aerodigestive tract), and overall survival (OS) as determined by Kaplan-Meier analysis. Information on patients' survival status was obtained after a mean follow-up period of 43.8 months (range, 1-144 months). RESULTS: Among 566 patients with mucosa-associated carcinoma arising in the epithelial lining, the 5- and 10-year OS rates (68.49% and 58.96%, respectively) were significantly shorter than those of patients with mucosa non-associated carcinoma (74.22%, and 66.76%, respectively) (log-rank P = 0.0219). Older age (P = 0.016) and male sex (P < 0.001) were likely independent risk factors for developing MPCs; smoking (P < 0.001) and alcohol consumption (P < 0.001) were also significant risk factors. CONCLUSION: Mucosa-associated carcinomas arising in the epithelial lining of the aerodigestive tract in the head and neck are a significant risk factor for developing MPC and are a poor prognostic factor. Careful follow-up and more frequent examinations of the aerodigestive tracts of these patients are recommended.