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Objective: To evaluate the risk factors for motor seizures after Gamma Knife Radiosurgery (GKS) in patients with brain metastases and the effectiveness of anticonvulsant drugs. Methods: Between January 2009 and June 2012, 174 patients with new brain metastases were treated with single-session GKS without whole-brain radiation therapy. Seventy-five patients (43.1%) with brain metastases in the motor and adjacent areas were evaluated. Forty-six patients (61.3%) were male. The median age, number of brain metastases, and volume of the largest brain metastasis in the motor and adjacent areas were 71 years (range, 40-92 years), 4 (range, 1-20), and 2.6 mL (range, 0.006-24.5 mL), respectively. Extracranial disease was controlled in 9 patients (12%). Seven patients (9.3%) experienced motor seizures before GKS. The median prescription dose to the tumor margin and total skull integral dose were 21 Gy (range, 14-24 Gy) and 3.3 J (range, 0.4-11.2 J), respectively. Thirty- one patients (41.3%) were treated with anticonvulsant drugs after GKS (zonisamide, 10 patients; valproic acid, 8; phenytoin and phenobarbital, 5; carbamazepine and levetiracetam, 2; or gabapentin, 1). Results: Among the 51 patients with follow-up magnetic resonance images, local control failure and the appearance of new distant lesions occurred in 13 (25.5%) and 29 (56.9%), respectively. The median overall survival was 7.4 months (range, 0.7-34.8 months). Fifty- nine (78.7%) patients died. Motor seizures occurred in 7 patients (9.3%). The median motor seizure occurrence time was 1.8 months (range, 0.03-9.7 months). In 6 patients with post-GKS images, 5 (83.3%) experienced local control failure or enlargement of perifocal edema. In a monovariate analysis, more than 2 brain metastases in the motor and adjacent areas was a significant risk factor (p = 0.034). In a multivariate analysis, the number of brain metastases in the motor and adjacent areas was a significant risk factor (p = 0.044; hazard ratio = 1.725; 95% confidence interval = 1.014-2.935). Treatment with anticonvulsant drugs after GKS was not a significant prognostic factor (monovariate analysis, p = 0.825; multivariate analysis, p = 0.835). Conclusion: In our study, the number of brain metastases in the motor and adjacent areas was a significant risk factor for the development of motor seizures after GKS. The efficacy of treatments with anticonvulsant drugs could not been shown. Disclosure: No significant relationships. [ABSTRACT FROM AUTHOR]

We examined whether the administration of growth hormone (GH) improves insulin resistance in females of a non-obese hyperglycemic mouse model after birth with low birth weight (LBW), given that GH is known to increase muscle mass. The intrauterine Ischemia group underwent uterine artery occlusion for 15 min on day 16.5 of gestation. At 4 weeks of age, female mice in the Ischemia group were divided into the GH-treated (Ischemia-GH) and non-GH-treated (Ischemia) groups. At 8 weeks of age, the glucose metabolism, muscle pathology, and metabolome of liver were assessed. The insulin resistance index improved in the Ischemia-GH group compared with the Ischemia group ( p = 0.034). The percentage of type 1 muscle fibers was higher in the Ischemia-GH group than the Ischemia group ( p < 0.001); the muscle fiber type was altered by GH. In the liver, oxidative stress factors were reduced, and ATP production was increased in the Ischemia-GH group compared to the Ischemia group ( p = 0.014), indicating the improved mitochondrial function of liver. GH administration is effective in improving insulin resistance by increasing the content of type 1 muscle fibers and improving mitochondrial function of liver in our non-obese hyperglycemic mouse model after birth with LBW.

We report a case of a large vestibular schwannoma in an 80-year-old female patient that shrank after palliative Gamma Knife radiosurgery (GKS). Neurological symptoms included hearing deterioration and facial palsy. The tumor volume was 21.9 mL. Craniotomy was considered high-risk, and conventional GKS was risky, owing to the risk of transient enlargement. Therefore, GKS was performed on only a portion of the tumor. The marginal dose (12 Gy) volume was 3.8 mL (17.4%). The tumor began to shrink after transient enlargement. Sixty months later, the tumor volume was only 3.1 mL, and the patient was able to maintain independent activities of daily living without salvage treatment., Competing Interests: No potential conflict of interest relevant to this article was reported.

This study examined whey protein's impact on insulin resistance in a high-fat diet-induced pediatric obesity mouse model. Pregnant mice were fed high-fat diets, and male pups continued this diet until 8 weeks old, then were split into high-fat, whey, and casein diet groups. At 12 weeks old, their body weight, fasting blood glucose (FBG), blood insulin level (IRI), homeostatic model assessment for insulin resistance (HOMA-IR), liver lipid metabolism gene expression, and liver metabolites were compared. The whey group showed significantly lower body weight than the casein group at 12 weeks old ( p = 0.034). FBG was lower in the whey group compared to the high-fat diet group ( p < 0.01) and casein group ( p = 0.058); IRI and HOMA-IR were reduced in the whey group compared to the casein group ( p = 0.02, p < 0.01, p < 0.01, respectively). The levels of peroxisome proliferator-activated receptor α and hormone-sensitive lipase were upregulated in the whey group compared to the casein group ( p < 0.01, p = 0.03). Metabolomic analysis revealed that the levels of taurine and glycine, both known for their anti-inflammatory and antioxidant properties, were upregulated in the whey group in the liver tissue ( p < 0.01, p < 0.01). The intake of whey protein was found to improve insulin resistance in a high-fat diet-induced pediatric obesity mouse model.

We aimed to characterize the metabolomic profiles in preterm small-for-gestational age (SGA) infants using cord blood. We conducted a gestational age (GA)-matched case-control study that included 30 preterm infants who were categorized into two groups: SGA infants, with a birth weight (BW) < 10th percentile for GA (n = 15) and non-SGA infants, with BW ≥ 10th percentile for GA (n = 15). SGA infants with chromosomal or genetic abnormalities were excluded. At birth, the umbilicus was double-clamped, and the cord blood was sampled from the umbilical vein. Metabolomic analyses were performed using capillary electrophoresis time-of-flight mass spectrometry. The median GA at birth was not significantly different between the two groups [SGA, 32 (26-36) weeks; non-SGA, 32 (25-35) weeks; p = 0.661)]. Of the 255 metabolites analyzed, 19 (7.5%) showed significant differences between SGA and non-SGA infants. There were significant reductions in the carnosine, hypotaurine, and S-methylcysteine levels in SGA infants as compared to non-SGA infants (p < 0.05). Carnosine was correlated with gestational age, BMI before pregnancy, body weight gain during pregnancy (p = 0.002, p = 0.023, and p = 0.020, respectively). In conclusion, preterm SGA infants have low levels of cord blood antioxidative- and antiglycation-related metabolites, making them vulnerable to oxidative stress., (Copyright © 2024 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

Objective Compared to prospective trials, the early death rate of newly diagnosed acute promyelocytic leukemia (APL) in the real-world clinical setting is higher. However, the early death rate was heterogeneous according to the reported institutes. Thus, the therapeutic approach at each institute may be important for preventing early death. This study evaluated the management strategy for untreated APL in our institute to avoid early death. Methods We identified consecutive 21 patients with untreated APL who received induction therapy including all-trans retinoic acid (ATRA) between July 2007 and December 2021 at the University of Tokyo Hospital. Results As therapeutic approaches, 16 patients (76%) received ATRA administration on the day of admission, and the remaining 5 received ATRA within 4 days from admission. Notably, all patients received conventional chemotherapy added to ATRA at a median of 1 day from admission (range: 0-9 days). As clinical outcomes, no patient died during induction therapy for untreated APL, and all achieved complete molecular remission. Conclusion Compared to the previous nationwide survey, a higher proportion of patients at our institute received conventional chemotherapy in addition to ATRA, and it was initiated more promptly, which may have helped prevent early death.

Background: Angiosarcoma is a malignant mesenchymal tumor derived from vascular endothelial cells in which a primary intracranial origin is extremely rare. Most previous reports of primary central nervous system (CNS) angiosarcoma have been solitary cases., Observations: The authors report a case of primary CNS angiosarcoma that caused the development of multiple disseminated cerebral hemorrhagic lesions within a short period of time. This rapid progression of symptoms resulted in the death of the patient. During surgery, several nodules suggestive of a tumor were removed from just below the surface of the brain, mixed into the hematoma. A pathological examination revealed atypical cells mimicking blood vessels in the subarachnoid space that were positive for specific vascular endothelial markers., Lessons: In this case, multifocal angiosarcoma occurred on the brain surface and ventricles, suggesting cerebrospinal fluid dissemination. If multiple cerebral hemorrhages are found on the brain surface, multifocal angiosarcoma should also be considered.

Trypanosoma ( Megatrypanum ) spp. are isolated from domestic and wild ruminants, including deer, worldwide. The prevalence of trypanosomes in mammals is influenced by a number of factors such as host age and vector abundance. However, the seasonal variation of and factors affecting trypanosome infection in the wild deer population remain elusive. In this study, we analyzed the seasonal variation in trypanosome prevalence and the factors that affect Trypanosoma theileri Laveran, 1902, infection in wild sika deer (Ezo sika deer) Cervus nippon yesoensis (Heude, 1884) in Eastern Hokkaido through a two-year survey. Seasonal variation in the prevalence of trypanosome infection in the deer population ranged from 0 to 41% as per hematocrit concentration and 17 to 89% as per PCR results. In general, the prevalence of T. theileri by PCR in 2020 was higher than that in 2019. Moreover, the prevalence was significantly higher in the aged population than among the younger population. These findings may explain why individual conditions and sampling season were associated with trypanosome prevalence. This is the first study to investigate the seasonal variation in and risk factors affecting trypanosome infection in wild deer.

This study investigated the mechanism of reducing body fat via whey protein diet. Pregnant mice were fed whey or casein, and their offspring were fed by birth mothers. After weaning at 4 weeks, male pups received the diets administered to their birth mothers (n = 6 per group). At 12 weeks of age, body weight, fat mass, fasting blood glucose (FBG), insulin (IRI), homeostatic model assessment of insulin resistance (HOMA-IR), cholesterol (Cho), triglyceride (TG), the expression levels of lipid metabolism-related genes in liver tissues and metabolomic data of fat tissues were measured and compared between the groups. The birth weights of pups born were similar in the two groups. Compared to the pups in the casein group, at 12 weeks of age, pups in the whey group weighed less, had significantly lower fat mass, HOMA-IR and TG levels ( p < 0.01, p = 0.02, p = 0.01, respectively), and significantly higher levels of the antioxidant glutathione and the anti-inflammatory 1-methylnicotinamide in fat tissues ( p < 0.01, p = 0.04, respectively). No differences were observed in FBG, IRI, Cho levels ( p = 0.75, p = 0.07, p = 0.63, respectively) and expression levels of lipid metabolism-related genes. Whey protein has more antioxidant and anti-inflammatory properties than casein protein, which may be its mechanism for reducing body fat.

Objective: A retrospective comparative analysis of the outcomes of gamma knife radiosurgery (GKRS) for brain metastases from uterine cervical carcinoma (CC) and endometrial carcinoma (EC), investigated the efficacy and prognostic factors for survival and local tumor control. Histopathological analysis was also performed., Methods: The authors retrospectively reviewed 61 patients with 260 tumors of CC and 73 patients with 302 tumors of EC who had undergone GKRS., Results: The survival times after GKRS had no difference between CC and EC. Uncontrolled primary cancer was significant unfavorable factor. CC resulted in significantly higher neurological death and post-GKRS neurological deterioration. New lesions appeared intracranially after GKRS, with no significant difference between CC and EC. Local tumor control rates at 6, 12, and 24 months after GKRS were 90.0%, 86.6%, and 78.0% for CC and 92.2%, 87.9%, and 86.4% for EC. Primary cancer of CC, more than 7 cm 3 volume, and prescription dose less than 20 Gy were significantly correlated in control failure. Local tumor control rates were significantly lower for squamous cell carcinoma in CC. No significant differences were found between histopathological subtypes of EC., Conclusions: This study established a relationship between the efficacy of GKRS for CC and EC brain metastases and the histopathological. Though, survival time after GKRS has no difference between CC and EC, CC was significantly higher neurogenic death and neurological deterioration after GKRS. Squamous cell carcinoma had a significantly lower rate of local tumor control among all CC, thereby resulting in CC having lower local tumor control than EC., (Copyright © 2022 Elsevier Inc. All rights reserved.)

We herein report an 83-year-old woman with filgrastim-associated aortitis during chemotherapy for relapsed diffuse large B-cell lymphoma. She had been treated with filgrastim as a prophylaxis for neutropenia during the fourth cycle of chemotherapy from day 9 to 18. On day 21, she developed a fever. Contrast-enhanced computed tomography revealed aortitis of the descending aorta. The fever abated with non-steroidal anti-inflammatory drug treatment. A literature review identified a small number of aortitis cases all caused by prophylactic use of granulocyte colony-stimulating factors (G-CSFs), among which short-acting filgrastim was rarely encountered. The present and previous findings imply a possible relationship between aortitis and prophylactic G-CSF usage.

There have recently been a few case reports of cutaneous T-cell lymphomas following treatment of atopic dermatitis with dupilumab, which works binding to the interleukin (IL)-4 receptor and inhibiting the JAK/ STAT cascade located downstream of both IL-4 and IL-13. Here, we report the first case of Hodgkin lymphoma (HL) in a patient treated with dupilumab for one year. Based on multiple biopsies, this case was diagnosed as a rare combination of discordant lymphomas of HL and peripheral T-cell lymphoma. As both lymphomas are known to overexpress IL-13, future studies should carefully evaluate the effect of anti-IL-13 therapy. A literature review showed that dermatitis persisted or worsened in all reported lymphoma cases following dupilumab and cutaneous T-cell lymphoma was diagnosed within 2 years of the start of treatment with dupilumab. In these cases, with the addition of our own, the median interval was 12 months, and 31% needed multiple biopsies for diagnosis of lymphomas. Our results demonstrate a need to be alert to potential development of lymphomas associated with the IL-13 and IL-4 pathways in patients with poorly responsive atopic dermatitis receiving dupilumab, and to consider the possibility of composite or discordant lymphomas in diagnosis and treatment of lymphomas., (© 2022. Japanese Society of Hematology.)

Background: Actigraphy is a method used for determining sleep (S)/wakefulness (W) by actigraph, a device equipped with a built-in accelerometer and an algorithm validated for each device. The S/W determination algorithm for the waist-worn actigraph FS-760 has been formulated for adults. However, the algorithm for children has not been established. The purpose of this study was to formulate an algorithm for discriminating S/W in school-aged children using FS-760 and to evaluate its validity. We further tested the generalizability of existing algorithm for adults by applying it to the children's activity data and then examined factors associated with adult algorithm agreement rates by multiple regression analysis using combined adult and children data., Methods: Sixty-five, healthy, school-aged children (aged 6 to 15 years) were recruited and randomly assigned to two groups: A (n = 33) and B (n = 32). They underwent 8-h polysomnography (PSG) and wore FS-760 simultaneously to obtain activity data. To determine the central epoch of the sleep/wake states (𝑥), a five-order linear discriminant analysis was conducted using the activity intensity of group A for five epochs (𝑥 -2 , 𝑥 -1 , 𝑥, 𝑥 +1 , 𝑥 +2 ; 10 min) and evaluate its accuracy with the activity of group B. To reveal the factors associated with adult algorithm agreement rate, we integrated the activity, age, sleep efficiency of 15 adults (aged 20 to 39 years) and those of 65 children for multiple regression analysis., Results: The mean agreement rate of the developed algorithm was 91.0%, with a mean sensitivity (true sleep detection rate) of 93.0% and a mean specificity (true wakefulness detection rate) of 63.9%. The agreement rate of the adult algorithm applied to children's activity was significantly lower (81.8%) than that of the children algorithm. Multiple regression analysis showed that the agreement rates calculated by the adult algorithm were significantly related to mean activity of the 𝑥 epoch in NREM and REM sleep as well as age and sleep efficiency., Conclusions: The S/W states in school-aged children can be reliably assessed using the developed algorithm for waist-worn actigraph FS-760. Since the accuracy of the adult algorithms decreased when applied it to children which have different activity levels during sleep, the establishment and validation of population-specific S/W algorithms should be required., (© 2022. The Author(s).)

The number of low birthweight (LBW) infants weighing below 2500 g has not decreased in Japan. This study aimed to develop an adult non-obese hyperglycemic mouse model born with LBW to study the pathogenesis. At 16.5 days of gestation, transient intrauterine ischemia (blocked blood flow in both uterine arteries for 15 min) was performed in a subgroup of pregnant mice (group I). Non-occluded dams were used as sham controls (group C). After birth, female pups in each group were weaned at 4 weeks of age and reared on the normal diet until 8 weeks of age ( n = 7). Fasting blood glucose levels, serum immunoreactive insulin (IRI), and body composition were then measured. Metabolite analyses was performed on the liver tissues. Birthweight was significantly lower in group I compared with group C. Pups from group I remained underweight with low fat-free mass and showed hyperglycemia with high serum IRI and homeostasis model assessment of insulin resistance levels, indicating insulin resistance. Metabolite analyses showed significantly reduced adenosine triphosphate and nicotinamide adenine dinucleotide production and increased lactic acid in group I. The pathogenesis of our non-obese hyperglycemic mouse model may be due to increased myogenic insulin resistance based on mitochondrial dysfunction and reduced lean body mass.

Background and Purpose: To assess the long-term outcomes of intracranial dural arteriovenous fistula (DAVF) treated with stereotactic radiosurgery (SRS) alone or embolization and SRS (Emb-SRS) and to develop a grading system for predicting DAVF obliteration., Methods: This multi-institutional retrospective study included 200 patients with DAVF treated with SRS or Emb-SRS. We investigated the long-term obliteration rate and obliteration-associated factors. We developed a new grading system to estimate the obliteration rate. Additionally, we compared the outcomes of SRS and Emb-SRS by using propensity score matching., Results: The 3- and 4-year obliteration rates were 66.3% and 78.8%, respectively. The post-SRS hemorrhage rate was 2%. In the matched cohort, the SRS and Emb-SRS groups did not differ in the rates of obliteration (P=0.54) or post-SRS hemorrhage (P=0.50). In multivariable analysis, DAVF location and cortical venous reflux (CVR) were independently associated with obliteration. The new grading system assigned 2, 1, and 0 points to DAVFs in the anterior skull base or middle fossa, DAVFs with CVR or DAVFs in the superior sagittal sinus or tentorium, and DAVFs without these factors, respectively. Using the total points, patients were stratified into the highest (0 points), intermediate (1 point), or lowest (≥2 points) obliteration rate groups that exhibited 4-year obliteration rates of 94.4%, 71.3%, and 60.4%, respectively (P<0.01)., Conclusions: SRS-based therapy achieved DAVF obliteration in more than three-quarters of the patients at 4 years of age. Our grading system can stratify the obliteration rate and may guide physicians in treatment selection.

Objective: Brain metastasis is rare in ovarian cancer patients. The results of Gamma Knife radiosurgery (GKRS) for the treatment of patients with brain metastases from ovarian cancer were retrospectively analyzed to derive the efficacy and prognostic factors for survival and local tumor control. Further histopathological analysis was also performed., Methods: The authors retrospectively reviewed the medical records of 118 patients with 566 tumors who had undergone GKRS at the 10 GKRS institutions in Japan., Results: After the initial GKRS, the median overall survival time was 18.1 months. Multivariate analysis showed that uncontrolled primary cancer (p = 0.003) and multiple intracranial metastases (p = 0.034) were significant unfavorable factors. Ten patients died of uncontrolled brain metastases at a median of 17.1 months. The 6-, 12-, and 24-month neurological death rates were 3.2%, 4.6%, and 11.9%, respectively. The 6-, 12-, and 24-month neurological deterioration rates were 7.2%, 13.5%, and 31.4%, respectively. The 6-, 12-, and 24-month distant brain control failure rates were 20.6%, 40.2%, and 42.3%, respectively. Median tumor volume was 1.6 cm3 and marginal dose was 20 Gy. The 6-, 12-, and 24-month local tumor control rates were 97.6%, 95.2%, and 88.0%, respectively. Peritumoral edema (p = 0.043), more than 7-cm3 volume (p = 0.021), and prescription dose less than 18 Gy (p = 0.014) were factors that were significantly correlated in local tumor control failure. Eight patients had symptomatic radiation injury. The 6-, 12-, and 24-month GKRS-related complication rates were 3.3%, 7.8%, and 12.2%, respectively. Primary ovarian cancer was histopathologically diagnosed for 313 tumors in 69 patients. Serous adenocarcinoma was found in 37 patients and other types in 32 patients. Median survival times were 32.3 months for the serous type and 17.4 months for other types after initial GKRS. Patients with serous-type tumors survived significantly longer than patients with other types (p = 0.039). The 6-, 12-, and 24-month local tumor control rates were 100%, 98.8%, and 98.8%, respectively. Serous-type tumors were a significantly good prognosis factor for local tumor control after GKRS (p = 0.005)., Conclusions: This study established a relationship between the efficacy of GKRS treatment for brain metastases and the histological type of primary ovarian cancer. GKRS for ovarian cancer brain metastasis can provide satisfactory survival and local control, especially in cases of serous adenocarcinoma.

Background: Under the Coronavirus disease 2019 (COVID-19) pandemic, manifestations in children with Kawasaki disease (KD) are different between the Western and the Eastern countries. Particularly, there has not been a report comparing a series of KD in Japan, where KD was originally discovered and has a large number of registered cases., Methods: We compared patients with KD under the period of the COVID-19 pandemic in Japan with the report from Italy during its reported period by a retrospective, cohort, observational study in a Japanese single center., Results: Thirty-two patients with typical KD were treated during the study period, while the Italian study reported 10 patients with the signs of KD. Concerning the proof of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection, none (0%) of our KD cases showed a positive result and one and no patients developed the macrophage activation syndrome (MAS) and Kawasaki disease shock syndrome (KDSS), respectively; however, eight (80%) patients in the Italian series were confirmed with SARS-CoV-2 infection. MAS and KDSS developed in six and five patients, respectively., Conclusions: Cases reported as COVID-19 pandemic-related KD in Italy showed significantly different clinical characteristics from the typical KD symptoms known in Japan. Although they show KD-like manifestations, we cannot conclude that SARS-CoV-2 has the same etiology of our 'classic' KD at the present stage.

To prevent early death, management of coagulopathy is important in patients with untreated acute promyelocytic leukemia (APL). This study aimed to clarify factors associated with in-hospital death in patients with coagulopathy during induction therapy for APL. We retrospectively identified patients with newly diagnosed APL who received induction therapy including all-trans retinoic acid (ATRA) and developed coagulopathy, using a nationwide inpatient database in Japan. Of 1115 eligible patients, 175 (15%) died at a median of 13 days (interquartile range, 7-30) after admission. In the multivariable analysis, compared with younger patients (aged < 40 years), the occurrence of in-hospital death was significantly more common among older patients (aged ≥ 40 and < 60 years: odds ratio = 2.58 [95% confidence interval: 1.29-5.19]; aged ≥ 60 and < 80 years: 7.66 [3.89-15.10]; aged ≥ 80 years: 16.83 [7.41-38.21]). Delayed initiation of ATRA and no conventional chemotherapy were significantly associated with in-hospital death (1.79 [1.16-2.76] and 2.40 [1.47-3.92], respectively). A total of 699 patients (63%) received anticoagulant therapies, but none of these was significantly associated with lower mortality. Although the present study was constrained by a lack of laboratory findings because of database limitations, the results showed that untreated patients with APL, especially the elderly, had a poor prognosis. Immediate administration of ATRA may reduce in-hospital mortality., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Bendamusutine plus rituximab (BR) regimen is one of the standard regimens for indolent B-cell lymphomas, yet the possibility of reduction of cycles of BR therapy without compromising therapeutic effects is not still uncovered. We retrospectively surveyed 57 cases including 40 follicular lymphoma cases who underwent BR regimen in our institute. The overall response (OR) rate and complete response (CR) rate were 86.0% (95% confidential interval (CI), 74.2-93.7) and 54.4% (40.7-67.6), respectively. Five-year overall survival (OS) and 5-years progression-free survival (PFS) were 76.8% and 45.7%, respectively. We then grouped the patients by the number of administered cycles of BR regimen. PFS was significantly longer in 41 cases of the later cessation group (cycle 4-6) than in 16 cases of the earlier cessation group (cycle 1-3) (p = 0.012, 5-years PFS; 46.8% vs. 35.2%, respectively), and both of OR and CR rate of the former was better than the latter (OR rate; 95.1% vs. 62.5%, p < 0.01, CR rate; 61.4% vs. 31.3%, p = 0.04). Interestingly PFS of twenty-one (36.8%) cases receiving just 4 cycles was longer than that of 20 cases who received five or 6 cycles (p < 0.01, 5-years PFS; 71.8% vs. 23.2%, respectively). Focusing on the group of four cycles, the 12 case with CR revealed longer PFS than seven cases with partial response (PR), and median PFS was not reached in CR cases and 16.9 months in the PR cases (p < 0.01). These results suggest that four cycles at least should be administered if possible, and the outcome of the patients who discontinued BR after four cycles was not inferior to that of the cases who received five or six cycles. In conclusion, discontinuation after four cycles may be permissible in some cases with complete response to BR regimen., (© 2021 John Wiley & Sons Ltd.)

Introduction: There has been no comprehensive analysis of the age-specific efficacy of G-CSF to prevent febrile neutropenia (FN). We evaluated factors associated with FN occurrence according to patient age in rituximab-cyclophosphamide-doxorubicin-vincristine-prednisolone (R-CHOP) treatment., Methods: We retrospectively reviewed diffuse large B-cell lymphoma (DLBCL) patients aged ≥50 years, who underwent the first R-CHOP cycle between July 2010 and March 2017, using a Japanese inpatient database. Multivariable logistic regression analysis was performed to identify the factors associated with FN., Results: A total of 16,399 patients with untreated DLBCL were identified. Primary prophylaxis with pegfilgrastim was significantly associated with the lower occurrence of FN (odds ratio: 0.71 [95% confidence interval: 0.51-0.99]). Subgroup analysis according to age was then performed. Although there was no significance, primary prophylaxis with pegfilgrastim tended to have a lower odds ratio for the occurrence of FN in patients aged 50-60 years (0.86 [0.39-1.89]) and 61-70 years (0.64 [0.36-1.13]). In patients aged 71-80 years, primary prophylaxis with pegfilgrastim was significantly associated with reduced FN occurrence (0.46 [0.26-0.80]). Notably, in patients aged >80 years, the use of pegfilgrastim tended to be associated with a rather higher occurrence of FN (1.55 [0.84-2.87])., Conclusions: Preventing effect of G-CSF may be limited in patients aged >80 years., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Purpose: The thalamus, the region that forms the attentional network and transmits external sensory signals to the entire brain, is important for sleepiness. Herein, we examined the relationship between activity in the thalamus-seed brain network and subjective sleepiness., Materials and Methods: Fifteen healthy male participants underwent an experiment comprising a baseline evaluation and two successive interventions, a 9-day sleep extension followed by 1-night total sleep deprivation. Pre- and post-intervention tests included the Karolinska sleepiness scale and neuroimaging for arterial spin labeling and functional connectivity. We examined the association between subjective sleepiness and the functional magnetic resonance imaging indices., Results: The functional connectivity between the left or right thalamus and various brain regions displayed a significant negative association with subjective sleepiness, and the functional connectivity between the left and right thalamus displayed a significant positive association with subjective sleepiness. The graph theory analysis indicated that the number of positive functional connectivity related to the thalamus showed a strong negative association with subjective sleepiness, and conversely, the number of negative functional connectivity showed a positive association with subjective sleepiness. Arterial spin labeling analysis indicated that the blood flow in both the left and right thalami was significantly negatively associated with subjective sleepiness. Functional connectivity between the anterior cingulate cortex and salience network areas of the left insular cortex, and that between the anterior and posterior cingulate cortices showed a strong positive and negative association with subjective sleepiness, respectively., Conclusion: Subjective sleepiness and the thalamic-cortical network dynamics are strongly related, indicating the application of graph theory to study sleepiness and consciousness. These results also demonstrate that resting functional connectivity largely reflects the "state" of the subject, suggesting that the control of sleep and conscious states is essential when using functional magnetic resonance imaging indices as biomarkers., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Motomura et al.)

Secondary immune thrombocytopenic purpura (ITP) with non-Hodgkin lymphoma (NHL) is a rare disease. Although some treatment regimens are available for primary ITP, the treatment strategy for secondary ITP remains unconfirmed. We herein report a 79-year-old man who was diagnosed with secondary ITP with mantle cell lymphoma. Although intravenous immunoglobulin (IVIG) has been considered an effective option for secondary ITP, similar to the treatment of primary ITP, our patient did not benefit from IVIG. A literature review including the current report revealed that IVIG was ineffective in all treated patients. Secondary ITP with NHL should be treated differently from primary ITP.

Introduction: Brain metastasis (BM) is one of the most important issues in the management of breast cancer (BC), since BMs are associated with neurological deficits. However, the importance of BC subtypes remains unclear for BM treated with Gamma Knife radiosurgery (GKS). Thus, we conducted a multicenter retrospective study to compare clinical outcomes based on BC subtypes, with the aim of developing an optimal treatment strategy., Methods: We studied 439 patients with breast cancer and 1-10 BM from 16 GKS facilities in Japan. Overall survival (OS) was analyzed by the Kaplan-Meier method, and cumulative incidences of systemic death (SD), neurologic death (ND), and tumor progression were estimated by competing risk analysis., Results: OS differed among subtypes. The median OS time (months) after GKS was 10.4 in triple-negative (TN), 13.7 in Luminal, 31.4 in HER2, and 35.8 in Luminal-HER2 subtype BC (p < 0.0001). On multivariate analysis, poor control of the primary disease (hazard ratio [HR] = 1.84, p < 0.0001), active extracranial disease (HR = 2.76, p < 0.0001), neurological symptoms (HR 1.44, p = 0.01), and HER2 negativity (HR = 2.66, p < 0.0001) were significantly associated with worse OS. HER2 positivity was an independent risk factor for local recurrence (p = 0.03) but associated with lower rates of ND (p = 0.03). TN histology was associated with higher rates of distant brain failure (p = 0.03)., Conclusions: HER2 positivity is related to the longer OS after SRS; however, we should pay attention to preventing recurrence in Luminal-HER2 patients. Also, TN patients require meticulous follow-up observation to detect distant metastases and/or LMD.

The clinical impact of pegfilgrastim in day-to-day practice remains unclear. This study evaluated the effectiveness of pegfilgrastim compared with daily filgrastim in patients with DLBCL who received the first-cycle of R-CHOP treatment by using a Japanese national inpatient database. Patient characteristics were adjusted by using propensity-score matching and stabilized inverse probability of treatment weighting (IPTW). In 1295 propensity-score-matched pairs, the incidence of febrile neutropenia was significantly lower in the pegfilgrastim group (risk difference 6.1%, 95% CI 4.1%-8.1%) than in the filgrastim group. In the pegfilgrastim group, the length of hospital stay and the total costs were also significantly reduced (percent reduction 34% [95% CI: 31%-37%], percent reduction 12% [95% CI: 9%-15%], respectively). The stabilized IPTW showed comparable results. In day-to-day practice, the simple mode of pegfilgrastim administration may be advantageous.

Although several pedigrees of familial myelodysplastic syndromes/acute myeloid leukemia (fMDS/AML) have been reported, the epidemiology and clinical features has been poorly understood. To explore the epidemiology of this entity, we performed a retrospective nationwide epidemiological survey in Japan using questionnaire sheets. The questionnaire was sent to 561 institutions or hospitals certified by Japanese Society of Hematology, unearthing the existence of 41 pedigrees of fMDS/AML. Among them, we obtained the clinical information of 31 patients in 20 pedigrees. The median age of the initial diagnosis was 51 years (range 9-88 years) and the WHO classification 2008 ranged from refractory anemia (RA) to AML. Focusing on the familial MDS patients, refractory anemia with excess blasts (RAEB)-2 was the largest group (27.3%). The median overall survival (OS) of fMDS and fAML in this study were 71.6 and 12.4 months, and the five-year OS were 61.3 and 50%, respectively.

Vigilance deficits account for a substantial number of accidents and errors. Current techniques to detect vigilance impairment measure only the most severe level evident in eyelid closure and falling asleep, which is often too late to avoid an accident or error. The present study sought to identify ocular biometrics of intermediate impairment of vigilance and develop a new technique that could detect a range of deficits in vigilant attention (VA). Sixteen healthy adults performed well-validated Psychomotor Vigilance Test (PVT) for tracking vigilance attention while undergoing simultaneous recording of eye metrics every 2 hours during 38 hours of continuous wakefulness. A novel marker was found that measured VA when the eyes were open-the prevalence of microsaccades. Notably, the prevalence of microsaccades decreased in response to sleep deprivation and time-on-task. In addition, a novel algorithm for detecting multilevel VA was developed, which estimated performance on the PVT by integrating the novel marker with other eye-related indices. The novel algorithm also tracked changes in intermediate level of VA (specific reaction times in the PVT, i.e. 300-500 ms) during prolonged time-on-task and sleep deprivation, which had not been tracked previously by conventional techniques. The implication of the findings is that this novel algorithm, named "eye-metrical estimation version of the PVT: PVT-E," can be used to reduce human-error-related accidents caused by vigilance impairment even when its level is intermediate., (© Sleep Research Society 2020. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

The use of gamma knife radiosurgery (GKS) for meningiomas after cranial surgery has been extensively evaluated; however, studies on tumor progression, including recurrence out of the margin dose line, are scarce. Hence, we aimed to evaluate the meningioma recurrence after GKS within and out of the margin dose. We included 37 consecutive patients with World Health Organization (WHO) grade 1 meningiomas who were treated with GKS following cranial surgery. Radiologically indicated recurrences were classified into three patterns by their relationship to the margin dose and tumor. The median follow-up was 58.9 months; 2 (5.4%) patients died. Only 2 (5.4%) patients did not keep active daily lives because of tumor progression. Cumulative local control at 5 years was 85.2%. Local recurrence and recurrence out of the margin dose occurred in 5 (13.5%) and 13 (35.1%) patients, respectively. A larger preoperative maximum diameter was a risk factor for local recurrence (hazard ratio [HR]: 2.118; P = 0.033), adjacent progression (HR: 1.633; P = 0.015), and remote progression (HR: 2.016; P = 0.003). Symptomatic adverse radiation effects occurred in 1 patient. Salvage GKS and cranial surgery were performed in 9 (24.3%) and 8 (21.6%) patients, respectively. Progression to WHO grade 2-3 occurred in 5 (13.5%) patients. A larger preoperative maximum diameter was a risk factor for progression of WHO grade (HR: 2.016, P = 0.033). Progression out of the margin dose was associated with a larger preoperative tumor size., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Ltd.)

Purpose: To evaluate the efficacy of gamma knife radiosurgery (GKS) for brain metastases (BMs) from small-cell lung cancer after whole-brain radiotherapy (WBRT)., Methods: We retrospectively analyzed the usefulness and safety of GKS in 163 patients from 15 institutions with 1-10 active BMs after WBRT. The usefulness and safety of GKS were evaluated using statistical methods., Results: The median age was 66 years, and 79.1% of patients were men. The median number and largest diameter of BM were 2.0 and 1.4 cm, respectively. WBRT was administered prophylactically in 46.6% of patients. The median overall survival (OS) was 9.3 months, and the neurologic mortality was 20.0%. Crude incidences of local control failure and new lesion appearance were 36.6% and 64.9%, respectively. A BM diameter ≥ 1.0 cm was a significant risk factor for local progression (hazard ratio [HR] 2.556, P = 0.039) and neurologic death (HR 4.940, P = 0.031). Leukoencephalopathy at the final follow-up was more prevalent in the therapeutic WBRT group than in the prophylactic group (P = 0.019). The symptom improvement rate was 61.3%, and neurological function was preserved for a median of 7.6 months. Therapeutic WBRT was not a significant risk factor for OS, neurological death, local control, or functional deterioration (P = 0.273, 0.490, 0.779, and 0.560, respectively). Symptomatic radiation-related adverse effects occurred in 7.4% of patients., Conclusions: GKS can safely preserve neurological function and prevent neurologic death in patients with 1-10 small, active BMs after prophylactic and therapeutic WBRT.

Granulocyte colony-stimulating factor (G-CSF) is commonly administered to prevent serious complications caused by chemotherapy-induced neutropenia; however, several cases of arteritis following the administration of G-CSF have been reported. Here, we report three cases of patients with non-Hodgkin lymphomas (NHLs) who developed arteritis after the administration of G-CSF, estimate the probability of adverse drug reaction caused by G-CSF with two distinct algorithms, and review the literatures. Both algorithms indicated a causal relationship between G-CSF and arteritis. In a literature review of seven reported cases, including our three patients, the time from the administration of G-CSF to the onset of arteritis ranged from 9 days to 6 months, and five patients were treated with steroids. In one of our three cases, a 62-year-old female with NHL developed arteritis twice in different courses of chemotherapy. Hydrocortisone was administered in the second event, leading to prompt relief of the manifestation and abnormal laboratory data. This finding suggests steroids may be effective for arteritis. In conclusion, although the number of reported cases is limited, there appears to be an association between arteritis and the administration of G-CSF, and steroids are an effective therapeutic option.

Objective The therapeutic approach for transfusion-independent non-severe aplastic anemia (NSAA) is undetermined. This study aimed to investigate the efficacy of immunosuppressive therapy (IST) for NSAA. Methods We retrospectively reviewed 42 consecutive patients with transfusion-independent NSAA. NSAA was further divided into two stages according to the degree of cytopenia. Progression was defined as transition to a transfusion-dependent state. Results Twelve (29%) patients received IST with cyclosporine A (CsA). Eleven (26%) patients became transfusion-dependent. In all patients, a univariate analysis revealed that a low hemoglobin level (p=0.006) and low reticulocyte count (p=0.005) were associated with a high probability of progression. The estimated transfusion-free survival (TFS) was significantly prolonged by IST among patients with advanced-stage NSAA (p=0.002), while IST did not reduce the incidence of progression in the overall cohort (p=0.349). In the non-IST group, an advanced clinical stage was significantly associated with progression (p=0.003). In contrast, the clinical stage was not related to progression in the IST group (p=0.318). None of the patients had to discontinue treatment with CsA due to renal failure. Conclusion IST is expected to be effective in patients with advanced-stage NSAA.