Practical guide for the diagnosis and management of primary ciliary dyskinesia.

OBJECTIVE: Primary ciliary dyskinesia (PCD) is a relatively rare genetic disorder that affects approximately 1 in 20,000 people. Approximately 50 genes are currently known to cause PCD. In light of differences in causative genes and the medical system in Japan compared with other countries, a practical guide was needed for the diagnosis and management of Japanese PCD patients. METHODS: An ad hoc academic committee was organized under the Japanese Rhinologic Society to produce a practical guide, with participation by committee members from several academic societies in Japan. The practical guide including diagnostic criteria for PCD was approved by the Japanese Rhinologic Society, Japanese Society of Otolaryngology-Head and Neck Surgery, Japanese Respiratory Society, and Japanese Society of Pediatric Pulmonology. RESULTS: The diagnostic criteria for PCD consist of six clinical features, six laboratory findings, differential diagnosis, and genetic testing. The diagnosis of PCD is categorized as definite, probable, or possible PCD based on a combination of the four items above. Diagnosis of definite PCD requires exclusion of cystic fibrosis and primary immunodeficiency, at least one of the six clinical features, and a positive result for at least one of the following: (1) Class 1 defect on electron microscopy of cilia, (2) pathogenic or likely pathogenic variants in a PCD-related gene, or (3) impairment of ciliary motility that can be repaired by correcting the causative gene variants in iPS cells established from the patient's peripheral blood cells. CONCLUSION: This practical guide provides clinicians with useful information for the diagnosis and management of PCD in Japan.

Executive summary: Japanese guidelines for allergic rhinitis 2020.

The Practical Guideline for the Management of Allergic Rhinitis, the fist guideline for allergic rhinitis in Japan, was prepared after a symposium held by the Japanese Society of Allergology in 1993. The current 9th edition was published in 2020 and is widely used today. The most recent collection of evidence from the literature was supplemented to the revised guideline to incorporate evidence-based medicine. The revised guideline includes updated epidemiology of allergic rhinitis in Japan, a figure representing the mechanisms of allergic rhinitis in both the onset and sensitization phases with the introduction of regulatory T cells and type 2 innate lymphoid cells, practical assessment for diagnosis, new pharmacotherapy agents such as anti-IgE mAb and a new drug delivery system for antihistamines, sublingual immunotherapy for children, dual sublingual immunotherapy for house dust mites and Japanese cedar pollen extract, new classification for surgery for allergic rhinitis, and treatment and prescriptions for older adults. An evidence-based step-by-step strategy for treatment is also described.

Effectiveness of Glecaprevir/Pibrentasvir for Hepatitis C: Real-World Experience and Clinical Features of Retreatment Cases.

Glecaprevir/pibrentasvir (G/P) are direct-acting antivirals (DAAs) that achieve a high sustained virological response (SVR) rate for hepatitis C virus (HCV) infection. We investigated G/P effectiveness for HCV patients based on real-world experience and the clinical features of retreatment cases. HCV patients (n = 182) were compared for clinical features and outcomes between first treatment (n = 159) and retreatment (n = 23) G/P groups. Overall, 77 patients (42.3%) were male, the median age was 68 years, and 86/66/1/4 cases had genotype 1/2/1+2/3, respectively. An SVR was achieved in 97.8% (178/182) of cases by intention-to-treat analysis and 99.4% (178/179) of cases by per-protocol analysis. There were no remarkable differences between the first treatment and retreatment groups for male (42.8% vs. 39.1%, p = 0.70), median age (68 vs. 68 years, p = 0.36), prior hepatocellular carcinoma (5.8% vs. 8.7%, p = 0.59), or the fibrosis markers AST-to-platelet ratio index (APRI) (0.5 vs. 0.5, p = 0.80) and fibrosis-4 (FIB-4) index (2.2 vs. 2.6, p = 0.59). The retreatment group had a significantly more frequent history of interferon treatment (12.3% vs. 52.2%, p < 0.01) and the Y93H mutation (25.0% vs. 64.7%, p = 0.02). The number of retreatment patients who had experienced 3, 2, and 1 DAA treatment failures was 1, 3, and 19, respectively, all of whom ultimately achieved an SVR by G/P treatment. In conclusion, G/P was effective and safe for both HCV first treatment and retreatment cases despite the retreatment group having specific resistance mutations for other prior DAAs. As G/P treatment failure has been reported for P32 deletions, clinicians should consider resistance mutations during DAA selection.

Past history of hepatocellular carcinoma is an independent risk factor of treatment failure in patients with chronic hepatitis C virus infection receiving direct-acting antivirals.

Direct-acting antiviral (DAA) treatment can achieve a high sustained virological response (SVR) rate in patients with hepatitis C virus (HCV) infection regardless of a history of hepatocellular carcinoma (HCC [+]). We examined 838 patients (370 men, median age: 69 years) who were treated with DAAs for comparisons of clinical findings between 79 HCC (+) (9.4%) and 759 HCC (-) (90.6%) patients and associations with treatment outcome. Male frequency was significantly higher in the HCC (+) group (60.8% vs 42.4%, P = 0.006). There were significant differences between the HCC (+) and HCC (-) groups for platelet count (115 vs 152 ×109 /L, P < 0.001), baseline alpha fetoprotein (AFP) (9.9 vs 4.5 ng/mL, P < 0.001) and the established fibrosis markers of FIB-4 index (4.7 vs 3.0, P < 0.001), AST-to-platelet ratio index (APRI) (1.1 vs 0.7, P = 0.009), M2BPGi (3.80 vs 1.78 COI, P < 0.001) and autotaxin (1.91 vs 1.50 mg/L, P < 0.001). The overall SVR rate was 94.7% and significantly lower in the HCC (+) group (87.3 vs 95.5%, P = 0.001). Multivariate analysis revealed that a history of HCC was independently associated with DAA treatment failure (odds ratio: 3.56, 95% confidence interval: 1.32-9.57, P = 0.01). In conclusion, patients with chronic HCV infection and prior HCC tended to exhibit more advanced disease progression at DAA commencement. HCC (+) status at the initiation of DAAs was significantly associated with adverse therapeutic outcomes. DAA treatment for HCV should therefore be started as early as possible, especially before complicating HCC.

A Very Rare Case of Hypereosinophilic Syndrome Secondary to Natural Killer/T-Cell Lymphoma.

Hypereosinophilic syndrome (HES) is a systemic disease characterized by an increased peripheral blood eosinophil count accompanied by systemic organ dysfunction. HES is classified into idiopathic HES, primary (neoplastic) HES (HESN), and secondary (reactive) HES (HESR). In this case report, a patient who developed peripheral blood eosinophilia and granulation tissue in the pharynx and paranasal sinus, which was initially diagnosed as chronic eosinophilic leukemia (CEL), categorized as HESN, but was eventually identified after the patient had died as natural killer/T-cell (NK/T) lymphoma, nasal type (ENKL), categorized as HESR, is presented. ENKL-induced HES is very rare but must be considered.

[ANALYSIS OF BACKGROUNDS AND LEVEL OF UNDERSTANDING OF TREATMENT OF POOR ADHERENCE AND DROPOUT CASES ON SUBLINGUAL IMMUNOTHERAPY FOR JAPANESE CEDAR POLLINOSIS IN THE FIRST FOLLOW-UP YEAR].

BACKGROUND: We considered the factors of poor adherence to and dropout from sublingual immunotherapy (SLIT) by verifying patient backgrounds 1 year after start of treatment. METHODS: We recruited 38 patients who began SLIT between November 2014 and September 2015. We analyzed their attributes and level of understanding of the treatment, and conducted a self-reported survey on factors behind dropout cases and poor adherence cases. RESULTS: Four patients dropped out 1 year after start of treatment. Three left for reasons related to anxiety about side effects. There were five cases of poor adherence. There was no significant difference between good adherence, poor adherence, and dropout regarding level of understanding of the treatment (p=0.59). In the comparison between good and poor adherence groups, except four dropout patients, the adherence tended to be poor in patients with short duration of disease, smoking patients, and young patients. Continuous rate of SLIT achieved about 90%, suggesting relatively high level of adherence. CONCLUSION: It appears possible that anxiety related to side effects could be a factor affecting dropout from SLIT. There was no significant difference regarding level of understanding of the treatment. The adherence tended to be poor in patients with short duration of disease, smoking patients, and young patients.

[Two cases of allergic fungal rhinosinusitis with bone destruction].

We report herein two cases of allergic fungal rhinosinusitis accompanied by bone destruction of the adjacent nasal sinuses. The first case involved a 21-year-old man who presented with left exophthalmos. Computed tomography (CT) showed soft tissue lesions in the left paranasal sinuses and destruction of the left lamina papyraceae, as well as infiltration of the lesion into the orbit. In the second case, a 39-year-old man, CT showed bone destruction of the skull base and medial wall of the left orbit. In both cases, total serum immunoglobulin (Ig)E level was >1000 IU/mL and fungus-specific IgEs were increased. Fungal hyphae were identified within the mucus on histopathological examination in both cases; however, no fungal invasion of the mucosa was apparent. Final diagnosis was allergic fungal rhinosinusitis (AFRS) in both cases. AFRS is a relatively new disease concept that was proposed in the early 1980s, with disease characteristics very similar to eosinophilic rhinosinusitis. Occasionally, AFRS must be differentiated from malignant disease or invasive fungal rhinosinusitis, so an understanding of the clinical features is important.

Lung functions of Japanese patients with chronic rhinosinusitis who underwent endoscopic sinus surgery.

BACKGROUND: Chronic rhinosinusitis (CRS), which is clinically classified into CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP), shows considerable geographic differences and heterogeneity. Eosinophilic (E) CRS with nasal polyps (ECRSwNP) has a higher degree of disease severity and higher frequency of comorbid asthma. Epidemiologic studies in different ethnic populations have improved understanding of the pathophysiology of the disease. Here we report the clinical characteristics of Japanese patients with medically refractory CRS undergoing endoscopic sinus surgery (ESS). METHODS: We recruited a total of 210 CRS patients and assessed them by nasal endoscopy, the Lund-Mackay score using computed tomography (CT), peripheral eosinophilia and smoking status. We also examined the comorbidity of asthma, effects of age and lung functions in the patients. RESULTS: In this study, 13% of CRSwNP patients and 20% of CRSwNP patients with peripheral blood eosinophilia exhibited obstructive lung dysfunction (FEV1/FVC <70%) despite the absence of an asthma diagnosis. Among elderly nonsmoker patients (≥ 60 years) who had never been diagnosed with asthma, 50% of CRSwNP patients with peripheral blood eosinophilia showed decreased FEV1/FVC <70%. CONCLUSIONS: Our findings suggest that asthma is under-diagnosed in CRS patients who undergo ESS, especially the elderly. Although the association between CRS and asthma has been recognized, increased attention to the comorbidity of obstructive airway diseases such as asthma is still needed for management of medically refractory CRS.

[Effect of posterior nasal neurectomy combined with the inferior turbinate surgery for Japanese cedar pollinosis].

INTRODUCTION: Up to 30% of the Japanese population suffers from Japanese cedar pollinosis, and some of these patients also have severe perennial allergies or other pollen allergies. Posterior nasal neurectomy has recently been reported as effective treatment for severe perennial allergic and intrinsic rhinitis. However, the efficacy of this surgery for seasonal allergic rhinitis has not been shown. In this study, the effectiveness of posterior nasal neurectomy combined with inferior turbinate surgery for patients with Japanese cedar pollinosis with concomitant intractable perennial allergies was evaluated with a questionnaire. SUBJECTS AND METHODS: Nine patients with Japanese cedar pollinosis, who also had perennial allergies, and undergone posterior nasal neurectomy combined with inferior turbinate surgery from April in 2005 to July in 2008, were enrolled. A numeric rating scale (NMR) was used to evaluate clinical symptoms in the pre- and post-surgery periods. The frequency of medication (oral administration and nasal spray) during the cedar pollinosis season was also evaluated. RESULTS: The NMR scores for all nasal and eye symptoms during cedar pollinosis season were significantly reduced after the surgery. The frequency of medication during the season was dramatically decreased after surgery. CONCLUSION: The present study demonstrates that posterior nasal neurectomy combined with inferior turbinate surgery is a highly effective treatment for Japanese cedar pollinosis. Since the Japanese cedar pollinosis season is limited to 2 to 3 months, such surgery is indicated for patients who suffer from severe perennial allergies and are also sensitized to some allergens such as Japanese cedar and ragweed pollen.

[Effect of posterior nasal neurectomy combined with the inferior turbinate surgery for the patients with perennial allergic rhinitis or vasomotor rhinitis].

INTRODUCTION: Until recently, Vidian neurectomy had been applied mainly in intractable vasomotor rhinitis and severe perennial allergic rhinitis. Although the results were excellent, the operation has not been applied recently because of the adverse events such as xerophthalmia and trigeminal neuralgia. To resolve these problems, a new surgical technique, posterior nasal neurectomy, was developed. In this report, we examined the effectiveness of posterior nasal neurectomy combined with the inferior turbinate surgery for severe perennial allergic rhinitis and intrinsic rhinitis by questionnaire. PATIENTS AND METHODS: Twenty patients who had undergone posterior nasal neurectomy combined with the inferior turbinate surgery between April in 2005 and March in 2009 were enrolled. Numeric Rating Scale was used to evaluate clinical symptoms and quality of life (QOL) of pre- and postsurgery. Frequency of medication (oral administration and nasal spray) was also evaluated. RESULTS: Questionnaires were collected from 17 patients. As for all patients but one, the surgery significantly reduced rhinorrhea, nasal obstruction, and sneezing. Furthermore, QOL for many symptoms such as sleep disorder and malaise/feebleness was also significantly improved after the surgery. Eighty-one percent of patients were satisfied with the surgery. CONCLUSION: Posterior nasal neurectomy combined with the inferior turbinate surgery is effective in alleviating clinical symptoms and improving QOL in the patients with severe perennial allergic rhinitis and intrinsic rhinitis, although a longer follow-up is needed.

Association of IL28B gene polymorphism with development of hepatocellular carcinoma in Japanese patients with chronic hepatitis C virus infection.

IL28B single nucleotide polymorphisms (SNPs) are associated with spontaneous and treatment-induced elimination of hepatitis C virus (HCV). To assess whether the IL28B rs8099917 SNP also affects the progression of chronic HCV infection, we genotyped 511 Japanese HCV patients, including 69 with hepatocellular carcinoma (HCC). The T/T genotype of rs8099917 was not associated with the development of HCC (p = 0.623), although stepwise logistic regression analysis showed that liver cirrhosis, age greater than 68 years, and serum albumin <4.2 mg/dl were associated with HCC onset. It appears that the IL28B SNP does not directly influence hepatocarcinogenesis in chronic HCV infection.

Association of serum cytokine levels with treatment response to pegylated interferon and ribavirin therapy in genotype 1 chronic hepatitis C patients.

BACKGROUND: We sought to clarify the associations among serum cytokines, amino acid substitutions in the interferon sensitivity-determining region (ISDR) and core region, and treatment outcome of pegylated interferon and ribavirin therapy in genotype 1 hepatitis C virus (HCV)-infected patients. METHODS: We quantified a total of 8 serum cytokines before, during, and after treatment in 79 genotype 1 chronic HCV patients. Viral ISDR and core region variants were determined by direct sequencing. RESULTS: High levels of interleukin (IL)-12 and IL-18 and more than 2 mutations in the ISDR were associated with a sustained virological response (SVR). Conversely, high baseline IL-10 levels and glutamine at amino acid 70 of the HCV core protein (Gln70) were significantly associated with a nonresponse to treatment, and patients with Gln70 had significantly higher IL-10 levels. In multivariate analysis, low IL-10, high IL-12, and high IL-18 levels were independently associated with an SVR. These 3 cytokine levels were decreased from baseline levels 4 weeks into treatment and remained low in patients with an SVR. CONCLUSION: Serum IL-10, IL-12, and IL-18 levels are predictive of the response to HCV treatment with pegylated interferon and ribavirin and are associated with amino acid substitutions in the ISDR and core region.

A patient with advanced hepatocellular carcinoma treated with sorafenib tosylate showed massive tumor lysis with avoidance of tumor lysis syndrome.

A 33-year-old man presented with pain and palsy of the leg in 2008 for treatment of hepatocellular carcinoma with huge distant metastases. The patient's tumors had slowly enlarged despite several treatments. Oral administration of sorafenib at 800 mg/day with careful observation was commenced in 2009. Laboratory investigations on day 7 showed massive tumor lysis. An abdominal CT showed multiple low density areas and tumor markers decreased, indicating extended tumor necrosis. In conclusion, clinicians should bear in mind not only the published adverse effects, but also massive tumor lysis, when treating patients with large tumor burden by sorafenib.

A case of granulocyte-colony stimulating factor-producing hepatocellular carcinoma confirmed by immunohistochemistry.

Granulocyte-colony stimulating factor (G-CSF) is a naturally occurring glycoprotein that stimulates the proliferation and maturation of precursor cells in the bone marrow into fully differentiated neutrophils. Several reports of G-CSF-producing malignant tumors have been published, but scarcely any in the hepatobiliary system, such as in hepatocellular carcinoma (HCC). Here, we encountered a 69-yr-old man with a hepatic tumor who had received right hepatic resection. He showed leukocytosis of 25,450/microL along with elevated serum G-CSF. Histological examination of surgical samples demonstrated immunohistochemical staining for G-CSF, but not for G-CSF receptor. The patient survived without recurrence for four years, but ultimately passed away with multiple bone metastases. In light of the above, clinicians may consider G-CSF-producing HCC when encountering patients with leukocytosis and a hepatic tumor. More cases are needed to clarify the clinical picture of G-CSF-producing HCC.

Primitive neuroectodermal tumor as a differential diagnosis of CD56-positive tumors in adults.

A 33-year-old Japanese man was referred to our hospital after a huge intrapelvic tumor with bilateral hydronephrosis was found following persistent lumbago. Natural killer/T-cell lymphoma was suspected due to positive immunostaining for CD56, but CHOP therapy was ineffective. Re-evaluation of the tumor cells showed that they were positive for CD99, neuron-specific enolase, and synaptophysin and had a t(11 ; 22) (q24 ; q12) translocation, leading to the revised diagnosis of primitive neuroectodermal tumor (PNET). Systemic chemotherapies and radiation therapy were added to surgical resection, and no recurrence has been detected for 3 years. Taken together, PNET may be considered in adult patients with CD56-positive tumors.

Granulocyte-colony stimulating factor-producing pancreatic adenosquamous carcinoma showing aggressive clinical course.

Herein, we encountered an 89-year-old woman with pancreatic cancer who presented with fever without infective focus, leukocytosis of 45,860 /microL, and elevation of serum granulocyte-colony stimulating factor (G-CSF). The patient could not receive any curative therapy due to an extremely aggressive clinical course. Specimens taken at necropsy revealed an adenosquamous carcinoma positive for G-CSF by immunohistochemistry; it was only the second reported case to date. She was finally diagnosed with G-CSF-producing pancreatic cancer. In light of the above, clinicians should consider the presence of G-CSF-producing tumors, including pancreatic cancer, when presented with patients showing leukocytosis of unknown origin and fever without infective focus.

A case of well-differentiated cholangiolocellular carcinoma visualized with contrast-enhanced ultrasonography using Sonazoid.

We here report the first case of cholangiolocellular carcinoma (CoCC) visualized with contrast-enhanced ultrasonography (CEUS) using a second-generation contrast agent, Sonazoid. A 76-year-old man was admitted to our hospital for evaluation of a hepatic tumor. The tumor was described as having hyper-enhancement in the early phase and persistent enhancement in the late phase by contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI), as well as hypervascularity by angiography. CEUS assessment of the nodule showed diffuse and homogeneous enhancement in the pure arterial phase, which became progressively hypoechoic relative to the adjacent liver parenchyma during the portal vein and late phases (mixed vascular phase), and showed a contrast defect with an unclear border in the Kupffer phase. Histologically we diagnosed this hepatic tumor as CoCC. In light of the above findings and the rarity of CoCC, it is helpful to incorporate the results of several imagings, such as CT, MRI, angiography and CEUS with a second-generation contrast agent when clinically diagnosing CoCC.

Expression of cysLT1 and cysLT2 receptor in chronic hyperplastic eosinophilic sinusitis.

Elevated production of cysteinyl leukotrienes (cysLTs) from sinus tissues and abundant sinus eosinophils are characteristic features of chronic hyperplastic eosinophilic sinusitis (CHS). CysLTs exert their action through G-protein-coupled receptors named cysLTs receptor type I (cysLT1R) and type II (cysLT2R). These expressions of cysLT receptors in the sinus mucosa have yet to be clarified and the relationship between eosinophilia and the expression of these receptors remains obscure. We compared the expressions of cysLT1R and cysLT2R in the sinus mucosa in patients with CHS, non-eosinophilic chronic sinusitis (NECS), and control sinus tissues; and analyzed the correlation between the expression of CysLTRs and the presence of sinus eosinophils by immunohistochemistry and real-time PCR. A significantly higher percentage of eosinophils expressing cysLT2R protein was observed in patients with CHS compared with NECS and controls. In addition, cysLT2R mRNA expression in CHS was significantly higher than in NECS and controls. Furthermore, a positive correlation was observed between cysLT2R mRNA expression and the number of infiltrated eosinophils. In contrast, the cysLT1R mRNA expression did not differ significantly among these groups. The effect of cysLTs on sinus eosinophils may be mediated through the cysLT2R in patients with CHS. These results may suggest the therapeutic benefit of cysLT2R antagonists in CHS.

Zygomycosis presenting as acute myocardial infarction during hematological malignancies.

Here we report two patients with hematological malignancies associated with complications of fatal cardiac zygomycosis. The first case, a 72-year-old man with myelodysplastic syndrome being treated with low-dose cytarabine, died of sudden cardiac arrest. An autopsy revealed disseminated zygomycosis accompanied with occlusion of the coronary artery by fungal thrombi. The second case, a 52-year-old woman with acute lymphoblastic leukemia, developed febrile neutropenia and skin eruptions with induration on the face and extremities during the first induction chemotherapy. She experienced sudden bradycardia with unstable hemodynamics and died of acute myocardial infarction. Histological examination of a skin biopsy demonstrated zygomycosis. In light of the above, it should be kept in mind that cardiac zygomycosis might occur in hematologically compromised patients presenting with acute myocardial infarction.