Effects of Body Mass Index on Hypertriglyceridemia Associated with Oral Bexarotene Therapy: A Post Hoc Analysis of an Open-Label Comparative Clinical Study of Combined Bexarotene and Phototherapy Versus Bexarotene Monotherapy for Japanese Patients with Cutaneous T-Cell Lymphoma.

BACKGROUND: Bexarotene, which has been approved for use in Japan since 2016, is an effective drug for cutaneous T-cell lymphoma; however, careful management is imperative because of its adverse events. We previously demonstrated the severity of bexarotene-associated hypertriglyceridemia and the need for bexarotene dose reduction for patients with cutaneous T-cell lymphoma and high body mass index (BMI); however, high BMI does not affect the efficacy of combined bexarotene and phototherapy treatment. OBJECTIVE: This study aimed to verify the effects of BMI on hypertriglyceridemia associated with oral bexarotene therapy. METHODS: We conducted a post hoc analysis of data from a previous randomized, open-label clinical study that compared combined bexarotene-phototherapy treatment with bexarotene monotherapy for cutaneous T-cell lymphoma by dividing patients into two groups based on BMI (<23 kg/m2 and ≥23 kg/m2). RESULTS: No statistically significant association was observed between patients with BMI ≥23 kg/m2 and severe hypertriglyceridemia; however, there was a significant association between BMI ≥23 kg/m2 and severe hypertriglyceridemia for patients who received bexarotene monotherapy, but not for those who received combined bexarotene-phototherapy treatment. The exact reasons for the discrepancies between the results of this thorough analysis and those of our past research are unclear. However, high BMI may be a risk factor for hypertriglyceridemia. Additional unidentified risk factors could also affect treatment outcomes. CONCLUSION: High BMI is the primary reason for hypertriglyceridemia-associated bexarotene dose reduction; however, unexplored risk factors other than high BMI could exist.

Relationships between lung function, allergy, and wheezing in urban children.

BACKGROUND: Allergic sensitization and low lung function in early childhood are risk factors for subsequent wheezing and asthma. However, it is unclear how allergic sensitization affects lung function over time. OBJECTIVE: We sought to test whether allergy influences lung function and whether these factors synergistically increase the risk of continued wheezing in childhood. METHODS: We analyzed longitudinal measurements of lung function (spirometry and impulse oscillometry) and allergic sensitization (aeroallergen skin tests and serum allergen-specific IgE) throughout early childhood in the Urban Environmental and Childhood Asthma study, which included high-risk urban children living in disadvantaged neighborhoods. Intraclass correlation coefficients were calculated to assess lung function stability. Cluster analysis identified low, medium, and high allergy trajectories, which were compared with lung function and wheezing episodes in linear regression models. A variable selection model assessed predictors at age 5 years for continued wheezing through age 12 years. RESULTS: Lung function adjusted for growth was stable (intraclass correlation coefficient, 0.5-0.7) from age 5 to 12 years and unrelated to allergy trajectory. Lung function and allergic sensitization were associated with wheezing episodes in an additive fashion. In children with asthma, measuring lung function at age 5 years added little to the medical history for predicting future wheezing episodes through age 12 years. CONCLUSIONS: In high-risk urban children, age-related trajectories of allergic sensitization were not associated with lung function development; however, both indicators were related to continued wheezing. These results underscore the importance of understanding early-life factors that negatively affect lung development and suggest that treating allergic sensitization may not alter lung function development in early to mid-childhood.

Cigarette smoking is an independent risk factor for developing vitiligo on the hands.

BACKGROUND: Vitiligo presents with varying clinical features based on the type and location. Treatment tends to be more effective on the face, neck, trunk, and mid-extremities, while the lips and distal extremities may be more resistant. Vitiligo in frequently exposed areas such as the face, arms, legs, and hands is typically associated with a lower Dermatology Life Quality Index. OBJECTIVES: We aimed to identify the characteristics and potential causes of vitiligo in challenging-to-treat regions, with particular focus on the hands. METHODS: We analyzed the clinical data of 337 patients with generalized vitiligo who visited our hospital between 2016 and 2022. For this study, we focused on patients with non-segmental vitiligo (NSV) specifically on their hands. Of the 337 patients, 248 had NSV and 89 had segmental vitiligo; 119 (47%) of those with NSV had vitiligo on their hands. Logistic regression models were applied to identify factors the factors linked to hand vitiligo, such as age, sex, duration of the condition, and smoking and alcohol history. RESULTS AND CONCLUSIONS: We developed a model to predict the risk of hand vitiligo using several factors. Among the factors analyzed, only smoking history was significantly associated with an increased risk (odds ratio: 3.13). In addition, we used clinical photography to evaluate color-graded frequency heat maps comprising 528 pixels. Vitiligo in nonsmokers widely distributed over the hand, predominantly the fingertips and joints, whereas vitiligo in smokers tended to be distributed mostly at the fingertips.

Case Reports of TFE3-Rearranged Renal Cell Carcinoma: FDG-PET Uptake Might Help Diagnosis.

Translocation and transcription factor E3 (TFE3)-rearranged renal cell carcinoma (RCC) is a rare subtype of RCCs characterised by the fusion of the TFE3 transcription factor genes on chromosome Xp11.2 with one of the multiple genes. TFE3-rearranged RCC occurs mainly in children and adolescents, although middle-aged cases are also observed. As computed tomography (CT)/magnetic resonance imaging (MRI) findings of TFE3-rearranged RCC overlap with those of other RCCs, differential diagnosis is often challenging. In the present case reports, we highlighted the features of the fluorine-18-labelled fluorodeoxyglucose positron emission tomography with CT (FDG PET-CT) in TFE3-rearranged RCCs. Due to the rarity of the disease, FDG PET-CT features of TFE3-rearranged RCC have not yet been reported. In our cases, FDG PET-CT showed high standardised uptake values (SUVmax) of 7.14 and 6.25 for primary tumours. This might imply that TFE3-rearranged RCC has high malignant potential. This is conceivable when the molecular background of the disease is considered in terms of glucose metabolism. Our cases suggest that a high SUVmax of the primary tumour is a clinical characteristic of TFE3-rearranged RCCs.

Impact of body mass index on the severity of bexarotene-associated hypertriglyceridemia: A post hoc analysis of an open-labeled clinical study of combined bexarotene and phototherapy in Japanese patients with cutaneous T-cell lymphoma.

Bexarotene is an effective oral drug for the treatment of cutaneous T-cell lymphoma, but careful management is required due to its various side effects. In particular, hypertriglyceridemia often requires a reduction or even suspension of bexarotene therapy. The risk factors of bexarotene-associated severe hypertriglyceridemia are not clear. Here, we conducted a post hoc analysis of the data from our previous clinical trial, which confirmed the efficacy and safety of combined bexarotene and phototherapy, to evaluate the effect of body mass index on bexarotene-associated hypertriglyceridemia. Twenty-five subjects were divided into two subgroups: normal and underweight (body mass index [BMI] <25 kg/m2 group) and overweight and obese (BMI ≥25 kg/m2 group) patients. The overall incidence of hypertriglyceridemia was 81.3% (13/16) in the BMI <25 kg/m2 group and 88.9% (8/9) in the BMI ≥25 kg/m2 group. The incidence of grade ≥3 hypertriglyceridemia (≥500 mg/dL) was 7.7% (1/13) in the BMI <25 kg/m2 group and 7/8 (87.5%) in the BMI ≥25 kg/m2 group (P < 0.001). Consequently, dose reduction in the BMI ≥25 kg/m2 group was larger than that in the BMI <25 kg/m2 group. The bexarotene-induced change in the serum triglyceride concentration was significantly increased in cutaneous T-cell lymphoma patients with a higher body mass index (ρ = 0.508, P = 0.009). The area under the curve was 0.886 (95% confidence interval 0.748-1.000, P = 0.002). With a body mass index cut-off of 24.85 kg/m2 , the sensitivity and specificity for identifying grade ≥3 hypertriglyceridemia were 0.875 and 0.882, respectively. The present findings suggest that BMI ≥25 kg/m2 is a risk factor for bexarotene-associated severe hypertriglyceridemia, therefore overweight and obese patients treated with bexarotene should receive lipid-lowering drugs prophylactically. Further studies for optimizing the initial bexarotene dose in such patients are required.

Influence of aldo-keto reductase 1C3 polymorphisms in early-onset female psoriasis patients.

The principal pathology of psoriasis is impaired skin barrier function, epidermal thickening, and granular layer loss. Exposure to extrinsic factors such as tobacco smoke and air pollutants is associated with the development of psoriasis. Aryl hydrocarbon receptors (AHRs) are activated by extrinsic factors associated with the development of psoriasis and act as transcriptional regulators. Expression of aldo-keto reductase (AKR) 1C3 in the epidermal spinous layer regulates epidermal keratinocyte differentiation via the AHR signaling pathway. We investigated whether single nucleotide polymorphisms (SNPs) in AKR1C3 are associated with the pathogenesis of psoriasis. The proportions of rs12529 G/C, C/C variants, and rs12387 A/A, A/G variants were twofold higher in Japanese psoriasis patients (n = 231) compared with a Japanese healthy cohort. The SNPs were significantly more common than the majority variants in female patients with disease onset ≤ 22 years of age. Patients with rs12529 G > C and rs12387 A > G SNPs exhibited significantly lower AKR1C3 expression and higher expression of late differentiation markers. In conclusion, AKR1C3 downregulation caused by rs12529 G > C and rs12387 A > G SNPs in the epidermis induces abnormal early differentiation of keratinocytes and skin barrier dysfunction, which may contribute to the genetic pathogenesis of psoriasis in young females.

Feasibility of Modified Endobronchial Ultrasound-Guided Intranodal Forceps Biopsy: A Retrospective Analysis.

BACKGROUND: Endobronchial ultrasound (EBUS)-guided intranodal forceps biopsy (IFB), a diagnostic bronchoscopic technique for intrathoracic lymphadenopathy, is performed following EBUS-guided transbronchial needle aspiration (TBNA). The current EBUS-IFB technique is complex and provides small sample volumes. We modified this technique to allow the use of standard-sized forceps. OBJECTIVES: The aim of this study was to assess the feasibility of the modified EBUS-IFB technique, which combines standard-sized forceps with standard EBUS-TBNA equipment. METHOD: This retrospective analysis included consecutive patients scheduled for EBUS-TBNA with attempted additional IFB between July 2020 and March 2021. The feasibility indices of IFB, technical success rate, diagnostic accuracy, and major complications were retrospectively investigated. We performed semi-quantitative evaluation of the histological specimens and univariable analyses to identify factors associated with IFB failure. RESULTS: During the study period, 295 patients underwent 307 EBUS-TBNAs; 195 cases were included in the analyses. Target lesions were mainly mediastinal lymph nodes (134 cases, 68.7%); the most frequent sites were #7 (61 cases) and #4R (50 cases). The median lesion size was 16.1 mm, the technical IFB success rate was 90.8%, and the diagnostic accuracy of the TBNA and IFB combination was 99.5%. One patient was lost to follow-up. Univariable analyses did not identify any factors involved in technical IFB failure. Major complications of pneumonia and pneumothorax occurred in 2 cases (1.0%). The median histological score was significantly higher in the IFB group than in the TBNA group (1.67 vs. 1.50, p = 0.032). CONCLUSIONS: Modified EBUS-IFB, combining standard-sized forceps with common EBUS-TBNA equipment, is feasible with few major complications.

Efficacy and safety of apremilast and phototherapy versus phototherapy only in psoriasis vulgaris.

Phototherapy and apremilast (oral phosphodiesterase-4 inhibitor) are well-known in the treatment of moderate to severe psoriasis vulgaris. However, current evidence on the efficacy and safety of their combination is not sufficient. This multicenter, randomized controlled study compared the efficacy and safety between phototherapy as monotherapy and phototherapy and apremilast as combination therapy in patients with psoriasis vulgaris. Patients with moderate to severe psoriasis vulgaris were assigned to combination (n = 29) and monotherapy (n = 13) groups. All patients underwent an 8-week phototherapy regimen comprising irradiation with narrowband UV-B. The patients in the combination group were also administered 10 mg to 60 mg of oral apremilast. We evaluated the improvement percentage based on the Psoriasis Area and Severity Index (PASI) score from baseline to week 8. Additionally, we evaluated the percentage of patients who achieved ≥75% improvement; changes in body surface area (BSA) and scores of EuroQol 5-dimensions 5-level, Dermatology Life Quality Index, and visual analog scale for pruritis from baseline to 4 and 8 weeks; and adverse events. Compared with the monotherapy group, the combination group had significantly lower PASI scores at 4 and 8 weeks and more patients who achieved a PASI score improvement of ≥75% at 8 weeks. Both groups exhibited a significant decrease in BSA; at 8 weeks, no significant difference was observed between the two groups, although the combination group tended toward a greater reduction in BSA. The intergroup differences in the changes at the three time points were not significant. Adverse events were more frequent in the combination group than in the monotherapy group. Our findings suggest that an 8-week combined apremilast and phototherapy regimen may not be adequate in patients for improvements in their subjective assessment of psoriasis, and longer treatment periods may be necessary.

Minor ST-T changes on electrocardiograms are associated with reduced constructive myocardial work in hypertensive patients with a preserved ejection fraction.

Minor ST-T changes on electrocardiograms are observed in patients with hypertensive heart disease with a preserved left ventricular ejection fraction (LVEF); however, the relationship between minor ST-T changes and global myocardial work on echocardiograms remains unclear. We evaluated the global longitudinal strain (GLS), global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE) in 186 hypertensive patients with preserved LVEF (>50%) using an offline analysis system (View Pal, GE). Minor ST-T changes as well as major ST-T changes (depression in ST in lead V5 > 1 mV) were also evaluated by electrocardiography. The mean age was 79.4 ± 8.2 years (men 37.6%). Patients with minor and major ST-changes had a smaller absolute GLS (-20.3 ± 3.1, -18.2 ± 3.7, and -15.2 ± 5.0%, P < 0.001) and a smaller constructive workload [GWI (2148 ± 486, 1938 ± 462, and 1685 ± 701 mmHg%, P = 0.002) and GCW (2419 ± 510, 2185 ± 466, and 1865 ± 702 mmHg%, P < 0.001)] than those with no ST-T changes. Additionally, patients with minor and major ST-T changes had increased wasted myocardial work [GWW (87 ± 61, 105 ± 56, and 127 ± 75 mmHg%, P = 0.045)], which resulted in reductions in the myocardial work efficiency [GWE (95 ± 4, 94 ± 3, and 89 ± 12%, P < 0.001)]. Even after adjustments for confounding factors, including EF, diastolic function parameters, LV hypertrophy, history of heart failure and atrial fibrillation, patients with minor ST-T changes had significantly smaller LV global constructive work in comparison to those without [GWI (2260 ± 33 vs. 2025 ± 76 mmHg%, P = 0.007) and GCW (2501 ± 45 vs. 2210 ± 105 mmHg%, P = 0.003)]. In conclusion, in hypertensive patients with preserved LVEF, minor ST-T changes on electrocardiograms were associated with reduced constructive work in the LV.

Diaphragmatic hernia during treatment of lung cancer harboring an EGFR mutation.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a first-line treatment for patients with nonsmall-cell lung cancer harboring EGFR mutations. We report a 65-year-old Japanese woman with nonsmall-cell lung cancer taking an EGFR-TKI who visited the emergency department with acute nausea and vomiting. Imaging studies demonstrated an incarcerated diaphragmatic hernia. Urgent diagnostic surgery revealed a gap in the diaphragm acting as a hernial orifice, where a metastatic tumor was detected. We consider that regression of the diaphragmatic metastasis by EGFR-TKI therapy resulted in perforation of the diaphragm, causing the diaphragmatic hernia. Gastrointestinal adverse events, e.g. nausea, vomiting and diarrhea, are common during EGFR-TKI treatment. However, this case suggests that in patients with diaphragmatic metastasis, we should consider the rare possibility of diaphragmatic perforation and a subsequent hernia.

Alectinib for Miliary Lung Metastasis in ALK-Positive Lung Adenocarcinoma.

BACKGROUND: Miliary pulmonary metastasis characterized by tiny nodules is a rare metastatic pattern in advanced non-small cell lung cancer (NSCLC) and is usually seen in patients harboring an EGFR mutation, and amylase-producing lung cancer is highly uncommon and rarely reported in NSCLC patients who have an EGFR mutation. CASE: A 32-year-old Japanese female was found to have miliary pulmonary nodules throughout both lung fields on a chest x-ray examination during an annual health check-up. Further examination by computed tomography (CT) revealed diffuse, bilateral, miliary nodules. Blood tests showed no increased tumor marker levels, but there was a significantly increased serum amylase level. A diagnosis of ALK-rearranged adenocarcinoma was made based on the results of a mediastinal lymph node biopsy obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). Treatment with alectinib resulted in rapid regression of the CT shadows and a reduction in the patient's serum amylase level. CONCLUSION: We have reported a case of ALK-rearranged NSCLC with a miliary pulmonary metastasis pattern that was sensitive to alectinib and in which the serum amylase level decreased in response to treatment with alectinib. Young patients with miliary pulmonary metastasis should be checked for all driver mutations.

Feasibility of intraoperative diagnosis of lung adenocarcinoma in situ to avoid excessive resection.

BACKGROUND: Limited lung resection is generally believed to be available for lung adenocarcinoma in situ (AIS). At our institute, intraoperative hematoxylin-eosin staining of frozen-section slides is routinely performed for evaluating tumor invasiveness after partial resection to avoid excessive lung resection. This study aimed to evaluate the feasibility and usefulness of intraoperative frozen-section diagnosis of AIS. METHODS: We retrospectively reviewed 143 patients with 151 AISs diagnosed by intraoperative frozen sections between 2012 and 2019 at our institute. All patients underwent limited resection because of the result of intraoperative frozen-section diagnosis. RESULTS: The total concordance rate between the diagnoses of AIS by intraoperative frozen sections and postoperative paraffin-embedded sections was 82.7% for 151 nodules. Although 21 minimally invasive adenocarcinomas (MIA) and 5 invasive adenocarcinomas were diagnosed as AIS intraoperatively, no patient had tumor recurrence after resection. Among 125 pathologically proven cases of AIS postoperatively, there were 67 (53.6%) radiologically invasive tumors including ground-glass nodules (GGNs) with part-solid component or pure-solid nodules. CONCLUSIONS: This intraoperative evaluation of frozen-section slides will help surgeons avoid excessive lung resection for AIS that was radiologically diagnosed as invasive adenocarcinoma. Intraoperative frozen-section diagnosis will provide to be clinically useful and lead to less invasive surgical treatment for lung nodules.

One-Stage Robotic Resection for Thoracic Dumbbell Tumor Without Repositioning.

A 67-year-old woman presented with a thoracic dumbbell-shaped tumor at the left T3-4 level. One-staged surgical resection using the spinal and robotic-assisted thoracic approach without repositioning was planned. The patient was placed in the prone position under general anesthesia. First the tumor was dissected from the dura after T3 left hemilaminectomy and T3/4 left facetectomy. Then posterior spinal fixation was performed. Second 3 ports were placed in her left thoracic cavity without repositioning, and the tumor was resected using a robotic-assisted thoracic approach. The tumor was a schwannoma without malignant potential. Convalescence was uneventful, and she was discharged 14 days postoperatively.

Migrated coil expectorated 12 years after embolization of pulmonary arteriovenous malformation, due probably to abscess formation around the coil.

Pulmonary arteriovenous malformations (PAVMs) are rare vascular structures providing direct capillary-free communications between pulmonary arteries and veins. Embolotherapy is indicated as a front-line therapy. We report an unusual long-term complication of coil embolization for a 44-year-old woman with hereditary hemorrhagic telangiectasia (HHT) who had repeatedly undergone the procedures for her PAVMs. She expectorated the coil which had been placed 12 years earlier and migrated to the bronchus according to the chest radiogram and bronchoscopy. Histology of the resected lung segment suggested the cavity communicating with the bronchus was the consequence of abscess formation around the coils. Even after technically successful embolization to PAVMs, long term follow-up should be necessary paying attention to the symptoms and imaging to avoid massive hemoptysis and subsequent emergency surgery.

[Efforts to Reduce the Risk of Febrile Neutropenia and to Increase the Response Rate to Docetaxel and Ramucirumab Therapy in Patients with Non-Small Cell Lung Cancer].

Docetaxel(DTX)plus ramucirumab(RAM)therapy is recommended as second-line or later treatment by the Japanese lung cancer guideline. However, febrile neutropenia(FN)is a frequent complication with this therapy. Efforts for reducing FN risk are essential. We administered pegfilgrastim, a durable granulocyte colony-stimulating factor, as primary prophylaxis for FN to all patients. We also reduced the dose of DTX according to its toxicity. Moreover, we used RAM monotherapy. Herein, we report the results of these efforts regarding DTX plus RAM therapy. We retrospectively reviewed the therapeutic results and occurrence of various adverse effects in 11 patients who started receiving DTX plus RAM therapy in our department between August 2016 and December 2017. Median number of DTX plus RAM cycles was 8(1-25). The following best effects were noted: 2(18%)patients, complete response: 5(45%), partial response: 2(18%), stable disease: and 2(18%), nonevaluable. No patient showed progressive disease. The overall response rate was 63.6%, and the disease control rate was 81.8%. Median progression-free survival was 127 days, and the 1-year progression-free survival rate was 27.3%. The median overall survival duration was not reached, and the 1-year overall survival rate was 53.0%. Adverse effects higher than Grade 3 occurred in 2 cases. FN was not observed. By using pegfilgrastim as primary prophylaxis, we could suppress FN onset in patients; furthermore, we observed better overall response and disease control rates than those observed in clinical trials.