Outcome of maintenance systemic chemotherapy with drug-free interval for metastatic urothelial carcinoma.

OBJECTIVE: Aiming to achieve long-term disease control, maintenance systemic chemotherapy (MSC) with a 1-3-month drug-free interval is continued in selected patients. We report our experience of MSC for metastatic urothelial carcinoma (UC). METHODS: Of 228 metastatic UC patients treated with systemic chemotherapy, 40 (17.5%, 40/228) had continuously undergone MSC. Data on the regimen, cycle number, and reason for the discontinuation of MSC were also collected. We analyzed OS from the initiation of MSC until death or the last follow-up, using the log-rank test to assess the significance of differences. RESULTS: The median number of cycles of chemotherapy was 6, and the responses were CR in 6, PR in 20, SD in 13, and PD in 1 before MSC. Gemcitabine plus CDDP or carboplatin was mainly performed as MSC (70%, 28/40). MSC was repeated quarterly in 30 (75%, 30/40), every two months in 8 (20%, 8/40), and with other intervals in 2 (5%, 2/40). Overall, a median of 3.5 cycles (range: 1-29) of MSC was performed. The reason for the discontinuation of MSC was PD in 24 (60%, 24/40), favorable disease control in 9 (22.5%, 9/40), and myelosuppression in 3 (7.5%, 3/40), and for other reasons in 2 (5%, 2/40). MSC was ongoing in 2 (5%, 2/40). The median OS was 27 months from the initiation of MSC. PS0 (P = 0.0169), the absence of lung metastasis (P = 0.0387), and resection of the primary site (P = 0.0495) were associated with long-term survival after MSC. CONCLUSIONS: In selected patients, long-term systemic chemotherapy could be performed with a drug-free interval. Our maintenance strategy with cytotoxic drugs may become one of the treatment options for long-term disease control.

Role of Multichance Fission in the Description of Fission-Fragment Mass Distributions at High Energies.

Fission-fragment mass distributions were measured for ^{237-240}U, ^{239-242}Np, and ^{241-244}Pu populated in the excitation-energy range from 10 to 60 MeV by multinucleon transfer channels in the reaction ^{18}O+^{238}U at the Japan Atomic Energy Agency tandem facility. Among them, the data for ^{240}U and ^{240,241,242}Np were observed for the first time. It was found that the mass distributions for all the studied nuclides maintain a double-humped shape up to the highest measured energy in contrast to expectations of predominantly symmetric fission due to the washing out of nuclear shell effects. From a comparison with the dynamical calculation based on the fluctuation-dissipation model, this behavior of the mass distributions was unambiguously attributed to the effect of multichance fission.

Therapeutic implication of genetic variants of IL13 and STAT4 in airway remodelling with bronchial asthma.

BACKGROUND: Several gene variants identified in bronchial asthmatic patients are associated with a decrease in pulmonary function. The effects of this intervention on pulmonary function have not been fully researched. OBJECTIVE: We determined the effects of high-dose inhaled corticosteroids (ICSs) on decreased pulmonary function in asthmatic Japanese patients with variants of IL13 and STAT4 during long-term treatments with low to mild doses of ICS. METHODS: In this study, 411 patients with bronchial asthma who were receiving ICSs and living in Japan were recruited, were genotyped, and underwent pulmonary function tests and fibreoptic examinations. The effects of 2 years of high-dose ICSs administered to asthmatic patients who were homozygous for IL13 AA of rs20541 or STAT4 TT of rs925847 and who progressed to airway remodelling were investigated. RESULTS: High-dose ICS treatment increased the pulmonary function of patients homozygous for IL13 AA of rs20541 but not of patients homozygous for STAT4 TT of rs925847. The increased concentrations of the mediators IL23, IL11, GMCSF, hyaluronic acid, IL24, and CCL8 in bronchial lavage fluid (BLF) were diminished after high-dose ICS treatment in patients homozygous for IL13 AA of rs20541. CONCLUSION AND CLINICAL RELEVANCE: IL13 AA of rs20541 and STAT4 TT of rs925847 are potential genomic biomarkers for predicting lower pulmonary function. The administration of high-dose ICSs to asthmatic patients with genetic variants of IL13 AA may inhibit the advancement of airway remodelling. The genetic variants of STAT4 TT did not respond to high-dose ICSs. Therefore, using medications other than ICSs must be considered even during the initial treatment of bronchial asthma. These genetic variants may aid in the realization of personalized and phenotype-specific therapies for bronchial asthma.

First-line treatment and outcome of elderly patients with primary central nervous system lymphoma (PCNSL)--a systematic review and individual patient data meta-analysis.

BACKGROUND: To investigate prognosis and effects of first-line therapy in elderly primary central nervous system lymphoma (PCNSL) patients. PATIENTS AND METHODS: A systematic review of studies about first-line therapy in immunocompetent patients ≥60 years with PCNSL until 2014 and a meta-analysis of individual patient data from eligible studies and international collaborators were carried out. RESULTS: We identified 20 eligible studies; from 13 studies, we obtained individual data of 405 patients, which were pooled with data of 378 additional patients (N = 783). Median age and Karnofsky Performance Score (KPS) was 68 years (range: 60-90 years) and 60% (range: 10%-100%), respectively. Treatments varied greatly, 573 (73%) patients received high-dose methotrexate (HD-MTX)-based therapy. A total of 276 patients received whole-brain radiotherapy (median 36 Gy, range 28.5-70 Gy). KPS ≥ 70% was the strongest prognostic factor for mortality [hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.41-0.62]. After a median follow-up of 40 months, HD-MTX-based therapy was associated with improved survival (HR 0.70, 95% CI 0.53-0.93). There was no difference between HD-MTX plus oral chemotherapy and more aggressive HD-MTX-based therapies (HR 1.39, 95% CI 0.90-2.15). Radiotherapy was associated with an improved survival, but correlated with an increased risk for neurological side-effects (odds ratio 5.23, 95% CI 2.33-11.74). CONCLUSIONS: Elderly PCNSL patients benefit from HD-MTX-based therapy, especially if combined with oral alkylating agents. More aggressive HD-MTX protocols do not seem to improve outcome. WBRT may improve outcome, but is associated with increased risk for neurological side-effects. Prospective trials for elderly PCNSL patients are warranted.

Intestinal amoebiasis in a patient with acute graft-versus-host disease after allogeneic bone marrow transplantation successfully treated by metronidazole.

Amoebiasis has rarely been reported in patients undergoing hematopoietic stem cell transplantation, although it is a world-wide infection and extremely common. We present a case of intestinal amoebiasis unexpectedly revealed by colonoscopy after allogeneic bone marrow transplantation from a human leukocyte antigen-mismatched unrelated donor for acute myeloid leukemia arising from chronic myelomonocytic leukemia and successfully treated by metronidazole.

Forensic identification using multiple lot numbers of an implanted device.

We report a case in which identification of a deceased individual was established using multiple lot numbers printed on a body implantable device. Autopsy of an unknown woman revealed an intramedullary nail inserted within her right femur. The device manufacturer was identified from the configuration of the intramedullary nail, and the "use history" was traced from lot numbers printed on the device's multiple parts. The deceased individual was thus identified as a woman who had attempted suicide by jumping from a height about a year previously and had been transported to a hospital and undergone surgery that included implantation of the intramedullary nail. The main factor contributing to the rapid identification was the manufacturer's and distributor's record of the use history (traceability) of the product, because of their accountability for purposes of quality control. A second contributing factor was multiple lot numbers, resulting in extremely low probability of the same combination of lot numbers being present in multiple individuals. This case confirmed the utility of multiple lot numbers of body implantable devices in forensic identification.

Quantitative genetic analysis of subspecific differences in body shape in the snail-feeding carabid beetle Damaster blaptoides.

A dimorphic pattern of macrocephalic (wide, short) and stenocephalic (narrow, long) body shapes is observed in snail-feeding carabid beetles globally. The former exhibits high performance in crushing snail shells with powerful jaws, whereas the latter specializes in eating snails' soft body directly by inserting the head into the shell. In the snail-feeding species Damaster blaptoides, the subspecies D. b. capito has a wide, short forebody, and D. b. fortunei has a narrow, long forebody. They exhibit distinct morphologies despite their geographic and phylogenetic proximity. To examine the genetic basis of the morphological differences between these two subspecies, we conducted quantitative genetic analyses by crossing these subspecies and producing F(1) and backcross hybrids. The hybrids had body shapes intermediate between the parental subspecies. The variation between wide, short and narrow, long forebodies was based on negative genetic correlations between width and length of the head and thorax. Between one and eight genetic factors were involved in the morphological differences between subspecies. We suggest that the morphological integration of forebody parts in a small number of loci has facilitated the marked morphological diversification between subspecies of D. blaptoides.

Inhibition of olanzapine-induced weight gain by the retinoid analog AM-80.

INTRODUCTION: Weight gain and metabolic abnormalities are common side effects of antipsychotic treatment. Retinoids have been suggested as promising substances to suppress obesity. This study has investigated the effects of a retinoid agonist AM-80 on olanzapine-induced weight gain and metabolic changes in rats. METHODS: Female Sprague-Dawley rats (7 weeks) were treated with AM-80 (1 mg/kg/day, subcutaneously) and/or olanzapine (4 mg/kg/day, intraperitoneally) for 21 days. Body weight and food/water intake were measured daily. The open field (OFT) and prepulse inhibition (PPI) tests were done on days 18 and 21, respectively. Animals were sacrificed on day 22 to measure weight of adipose tissues and serum levels of adiponectin and leptin levels. RESULTS: Olanzapine significantly increased body weight, food/water intake and the mass of inguinal adipose tissue (IAT) compared to vehicle-treated rats. AM-80 demonstrated significant inhibition of weight gain. No significant effect of olanzapine or AM-80 was found on behaviors or serum adiponectin/leptin levels. CONCLUSION: These findings suggests that AM-80 is a potential therapeutic agent to attenuate weight gain and metabolic side effects associated with olanzapine.

Relationship of Lesion Location to Postoperative Steroid Use in Eosinophilic Chronic Rhinosinusitis.

OBJECTIVES: Eosinophilic chronic rhinosinusitis (ECRS) is known to recur after surgery. The treatment choice for recurrent ECRS, such as oral steroids or biological agents, must be chosen carefully, and identifying the lesion location may be useful. This study aimed to evaluate the postoperative course of ECRS patients and assess the relationship between endoscopic lesion location and postoperative oral steroid use. METHODS: Patients with chronic rhinosinusitis who underwent bilateral endoscopic sinus surgery from April 2018 to March 2020 were divided into two groups based on the presence or absence of oral steroid use after surgery. The primary endpoint was the lesion location on endoscopic findings during surgery: middle turbinate, middle meatus, superior turbinate, superior meatus, nasal septum, and sphenoethmoidal recess. Subjective symptoms, blood tests, and computerized tomography (CT) findings (Lund-Mackay score) were evaluated as secondary endpoints. RESULTS: Among 264 patients, 88 were diagnosed histologically with ECRS (mean 48.98 ± 1.40 years, 67 males/21 females). Twenty-three patients were steroid-using, 65 were steroid-free, and six stopped attending their appointments. Patients with sphenoethmoidal recess lesions were significantly more likely to require steroids (p = 0.019). There was a significant association between steroid use and younger age (p = 0.041), olfactory dysfunction (p = 0.021), and all sinuses (Frontal sinus: p < 0.001, Anterior ethmoid sinus: p = 0.002, Posterior ethmoid sinus: p = 0.011, Maxillary sinus: p = 0.018, Sphenoid sinus: p = 0.034, Total score: p < 0.001). CONCLUSION: A sphenoethmoidal recess lesion was a risk factor for requiring postoperative steroids. Young age, olfactory dysfunction, and preoperative severe CT findings were also significant risk factors. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:2511-2516, 2023.

[Emphysema evaluation of the remaining lung post lobectomy].

The aim of this study was to confirm that the emphysematous changes had increased in the remaining lung on the operation side after lobectomy. Fourteen patients underwent quantitative analysis by computed tomography (CT) and respiratory function testing before and after the operation for upper or lower lobectomy of the lung between March 2005 and May 2007. The degree of emphysema was calculated by dividing the volume of the emphysematous region (CT values: -1,024 to -950 HU) by the volume of the entire lung (CT values: -1,024 to -600 HU) using a 1 mm thickness high resolution CT slice. Comparison by paired t-test showed significant differences between the emphysema rates pre and post operation in the operation side lung (15.3 +/- 7.9% and 21.7 +/- 10.0%, p = 0.02), but there were no significant differences in the contralateral lung (15.8 +/- 7.5% and 17.7 +/- 8.4%, p = 0.25). On the other hand, there was no significant change in the percent forced expiratory volume in one second (FEV1.0%) between pre and post operation (74.4 +/- 10.5% and 75.5 +/- 7.5%, p = 0.60). We consider that it is necessary to note that the emphysematous changes increased in the remaining lung on the operation side after lobectomy even though the FEV1.0% did not decrease at present.

Involvement of innate immunity in the pathogenesis of intestinal Behçet's disease.

The involvement of excessive T helper 1 (Th1) cell functions in the pathogenesis of Behçet's disease (BD) has been reported. We therefore studied Toll-like receptor (TLR)-expressing cells, which play important roles in innate immunity in patients with BD. Peripheral blood mononuclear cells (PBMC) of BD and healthy controls, and tissue specimens of intestinal BD and Crohn's disease (CD) were analysed for messenger RNA (mRNA) and protein expressions by reverse transcription-polymerase chain reaction and immunostaining respectively. PBMC of BD expressed TLR-2 and TLR-4 mRNA almost comparable with healthy controls. Intestinal lesions of BD expressed TLR-2 and TLR-4 mRNA consistently. In contrast, TLR-4 mRNA was expressed preferentially and TLR-2 mRNA was expressed less frequently in CD lesions. In intestinal samples of BD, TLR-2 and TLR-4 mRNA were detected in ileocaecal ulcer lesions, but not in unaffected sites of the same sample, indicating the association of the TLR expression with the disease manifestation of intestinal BD. TLR-2-expressing cells which were simultaneously cluster of distribution (CD)68-positive produced interleukin (IL)-12 in the lesions, indicating the participation of TLR-2-expressing cells in the Th1 skewed responses in vivo. As a possible ligand of TLR-2, in BD self-heat shock protein 60 was expressed in peripheral blood lymphocytes and intestinal tissues. Collectively, TLR-2-expressing cells as well as TLR-4-expressing cells accumulated in the intestinal lesions of BD. IL-12 produced by TLR-2-expressing cells may contribute to the induction of Th1-dominant immune responses in intestinal BD.

Unbalanced translocation der(1;7)(q10;p10) defines a unique clinicopathological subgroup of myeloid neoplasms.

The unbalanced translocation, der(1;7)(q10;p10), is one of the characteristic cytogenetic abnormalities found in myelodysplastic syndromes (MDS) and other myeloid neoplasms. Although described frequently with very poor clinical outcome and possible relationship with monosomy 7 or 7q- (-7/7q-), this recurrent cytogenetic abnormality has not been explored fully. Here we analyzed retrospectively 77 cases with der(1;7)(q10;p10) in terms of their clinical and cytogenetic features, comparing with other 46 adult -7/7q- cases without der(1;7)(q10;p10). In contrast with other -7/7q- cases, where the abnormality tends to be found in one or more partial karyotypes, der(1;7)(q10;p10) represents the abnormality common to all the abnormal clones and usually appears as a sole chromosomal abnormality during the entire clinical courses, or if not, is accompanied only by a limited number and variety of additional abnormalities, mostly trisomy 8 and/or loss of 20q. der(1;7)(q10;p10)-positive MDS cases showed lower blast counts (P<0.0001) and higher hemoglobin concentrations (P<0.0075) at diagnosis and slower progression to acute myeloid leukemia (P=0.0043) than other -7/7q- cases. der(1;7)(q10;p10) cases showed significantly better clinical outcome than other -7/7q cases (P<0.0001). In conclusion, der(1;7)(q10;p10) defines a discrete entity among myeloid neoplasms, showing unique clinical and cytogenetic characteristics.

Activation of RHOA-VAV1 signaling in angioimmunoblastic T-cell lymphoma.

Somatic G17V RHOA mutations were found in 50-70% of angioimmunoblastic T-cell lymphoma (AITL). The mutant RHOA lacks GTP binding capacity, suggesting defects in the classical RHOA signaling. Here, we discovered the novel function of the G17V RHOA: VAV1 was identified as a G17V RHOA-specific binding partner via high-throughput screening. We found that binding of G17V RHOA to VAV1 augmented its adaptor function through phosphorylation of 174Tyr, resulting in acceleration of T-cell receptor (TCR) signaling. Enrichment of cytokine and chemokine-related pathways was also evident by the expression of G17V RHOA. We further identified VAV1 mutations and a new translocation, VAV1-STAP2, in seven of the 85 RHOA mutation-negative samples (8.2%), whereas none of the 41 RHOA mutation-positive samples exhibited VAV1 mutations. Augmentation of 174Tyr phosphorylation was also demonstrated in VAV1-STAP2. Dasatinib, a multikinase inhibitor, efficiently blocked the accelerated VAV1 phosphorylation and the associating TCR signaling by both G17V RHOA and VAV1-STAP2 expression. Phospho-VAV1 staining was demonstrated in the clinical specimens harboring G17V RHOA and VAV1 mutations at a higher frequency than those without. Our findings indicate that the G17V RHOA-VAV1 axis may provide a new therapeutic target in AITL.

FDG-PET in T-cell and NK-cell neoplasms.

BACKGROUND: A growing number of studies demonstrate the utility of (18)fluoro-2-deoxyglucose positron emission tomography (FDG-PET) in the management of malignant lymphoma. The results of FDG-PET, however, have not been studied extensively for T-cell and natural killer (NK)-cell neoplasms. PATIENTS AND METHODS: We retrospectively evaluated pretreatment FDG-PET scans in 41 patients with T/NK-cell neoplasms diagnosed according to the World Health Organization (WHO) classification. Histological subtypes frequently included were peripheral T-cell lymphoma, unspecified (PTCLu, n = 11), extranodal NK/T-cell lymphoma, nasal type (ENKL, n = 8), primary cutaneous anaplastic large cell lymphoma (C-ALCL, n = 5), and angioimmunoblastic T-cell lymphoma (AILT, n = 4). RESULTS: FDG-PET detected a lymphoma lesion in at least one site in 36 out of 41 patients. The positive rate was equally high in most histological subtypes except for cutaneous lymphomas: PTCLu 91%, ENKL 100%, C-ALCL 60%, AILT 100%. All the patients without an FDG-avid lesion had lesions restricted to skin. Among patients who had cutaneous lesions, only 50% had FDG-avid cutaneous lesions, all of which were tumorous. The positive rate of FDG-PET for bone marrow involvement was only 20%. CONCLUSION: T/NK-cell neoplasms incorporated in this study were generally FDG-avid except for cutaneous lesions and bone marrow involvement.

Binding of Delta1, Jagged1, and Jagged2 to Notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of Notch2.

Delta1, Jagged1, and Jagged2, commonly designated Delta/Serrate/LAG-2 (DSL) proteins, are known to be ligands for Notch1. However, it has been less understood whether they are ligands for Notch receptors other than Notch1. Meanwhile, ligand-induced cleavage and nuclear translocation of the Notch protein are considered to be fundamental for Notch signaling, yet direct observation of the behavior of the Notch molecule after ligand binding, including cleavage and nuclear translocation, has been lacking. In this report, we investigated these issues for Notch2. All of the three DSL proteins bound to endogenous Notch2 on the surface of BaF3 cells, although characteristics of Jagged2 for binding to Notch2 apparently differed from that of Delta1 and Jagged1. After binding, the three DSL proteins induced cleavage of the membrane-spanning subunit of Notch2 (Notch2(TM)), which occurred within 15 min. In a simultaneous time course, the cleaved fragment of Notch2(TM) was translocated into the nucleus. Interestingly, the cleaved Notch2 fragment was hyperphosphorylated also in a time-dependent manner. Finally, binding of DSL proteins to Notch2 also activated the transcription of reporter genes driven by the RBP-Jkappa-responsive promoter. Together, these data indicate that all of these DSL proteins function as ligands for Notch2. Moreover, the findings of rapid cleavage, nuclear translocation, and phosphorylation of Notch2 after ligand binding facilitate the understanding of the Notch signaling.

A phase I/II trial of intrabone marrow cord blood transplantation and comparison of the hematological recovery with the Japanese nationwide database.

Intrabone marrow cord blood transplantation (IB-CBT) was proposed as a promising treatment modality to improve hematological recovery. However, clinical advantages of IB-CBT over conventional IV CBT have been unclear. We conducted a prospective single-center trial of IB-CBT to evaluate its safety and superiority in terms of hematological recovery. Fifteen adults with hematological malignancies were enrolled. A thawed and unwashed single cord blood unit was injected into the bilateral superior-posterior iliac crests under local anesthesia. Engraftments of neutrophils and platelets were achieved in 13 cases, with medians of 17 and 45 days, respectively. For the control, we extracted data from the Japanese nationwide database and compared the hematological recovery of contemporaneously transplanted 1135 CBT cases. Multivariate analysis revealed that IB-CBT enhanced platelet recovery (hazard ratio, 2.13; P=0.007), but neutrophil recovery did not differ significantly (hazard ratio, 1.70; P=0.19). Better donor chimerism was seen in the bone marrow of the ilium than of the sternum on day 14, suggesting that the local hematopoiesis at the injected site was established earlier than that at the remote bone marrow site. Collectively, IB-CBT was well tolerated and may enhance local engraftment, which promotes prompter platelet recovery than does IV-CBT.

Identification of cell-type-specific mutations in nodal T-cell lymphomas.

Recent genetic analysis has identified frequent mutations in ten-eleven translocation 2 (TET2), DNA methyltransferase 3A (DNMT3A), isocitrate dehydrogenase 2 (IDH2) and ras homolog family member A (RHOA) in nodal T-cell lymphomas, including angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified. We examined the distribution of mutations in these subtypes of mature T-/natural killer cell neoplasms to determine their clonal architecture. Targeted sequencing was performed for 71 genes in tumor-derived DNA of 87 cases. The mutations were then analyzed in a programmed death-1 (PD1)-positive population enriched with tumor cells and CD20-positive B cells purified by laser microdissection from 19 cases. TET2 and DNMT3A mutations were identified in both the PD1+ cells and the CD20+ cells in 15/16 and 4/7 cases, respectively. All the RHOA and IDH2 mutations were confined to the PD1+ cells, indicating that some, including RHOA and IDH2 mutations, being specific events in tumor cells. Notably, we found that all NOTCH1 mutations were detected only in the CD20+ cells. In conclusion, we identified both B- as well as T-cell-specific mutations, and mutations common to both T and B cells. These findings indicate the expansion of a clone after multistep and multilineal acquisition of gene mutations.

Preservation of ovarian function by ovarian shielding when undergoing total body irradiation for hematopoietic stem cell transplantation: a report of two successful cases.

The purpose of this study was to evaluate the possibility of preserving ovarian function by ovarian shielding to reduce the irradiation dose in total body irradiation (TBI). The subjects in the study were females aged less than 40 years, who were undergoing allogeneic hematopoietic stem cell transplantation using a TBI-based regimen and who desired to have children after transplantation. For ovarian shielding, abdominal computed tomography (CT) and skin marking were performed in both the supine and prone positions, prior to the TBI. A pair of columnar blocks was placed just above the patient's body. Thus far three patients have been treated. The serum estradiol level decreased to an undetectable level (<8.5 pg/ml) after transplantation and the follicle-stimulating hormone (FSH) level increased above 90 mIU/ml in all patients and they became amenorrheic. However, regular menstruation recovered in patients no. 1 and 2 about 800 and 370 days after transplantation, respectively, with a decrease in the serum FSH level. Menstruation did not recover in patient no. 3, and serum estradiol was transiently detected above 20 pg/ml. The preservation of ovarian function was made possible by ovarian shielding. However, a longer follow-up is needed to know if normal pregnancy and delivery can occur.