Stage IV renal cell carcinoma achieves pathologic complete response after two ipilimumab plus nivolumab courses despite severe immune-related adverse events: a case report.

BACKGROUND: Ipilimumab (Ipi) plus nivolumab (Nivo) is the recommended first-line treatment for renal cell carcinoma (RCC). This report describes a case where pancreatic metastases disappeared after only two courses of Ipi + Nivo therapy. The primary tumor was cured by surgery, and a pathological Complete Response (pCR) was observed despite multiple serious immune-related Adverse Events (irAEs). CASE PRESENTATION: A 54-year-old woman with RCC and pancreatic metastasis at stage IV, diagnosed with intermediate risk according to the International Metastatic RCC Database Consortium classification, underwent initiation of Ipi + Nivo therapy. On day 26, she developed hyperthyroidism accompanied by tachycardia, leading to the commencement of metoprolol tartrate treatment. Following the resolution of tachycardia, a second course of Ipi + Nivo therapy was administered on day 50. By day 70, the patient exhibited Grade 3 hepatic dysfunction, followed by the onset of hypothyroidism on day 75, necessitating treatment with steroids and levothyroxine. After positive treatment, a Grade 3 skin disorder emerged on day 87 while tapering steroids, prompting treatment with methylprednisolone (mPSL) pulse therapy. The skin disorder responded to steroids, allowing for tapering. However, on day 113, a recurrence of Grade 3 skin disorder occurred, necessitating another mPSL pulse. The patient responded well to treatment, exhibiting improvement in her condition. On day 131, she presented at the hospital with complaints of respiratory distress, prompting a Computed Tomography (CT) scan that revealed interstitial pneumonia. By day 272, subsequent CT imaging showed the disappearance of pancreatic metastasis and shrinkage of the primary tumor. On day 294, she underwent a laparoscopic left nephrectomy. Pathological analysis confirmed a pCR in the primary tumor, indicating successful eradication of RCC through surgical intervention. CONCLUSIONS: This case report presents a scenario where multiple severe irAEs appeared in a patient, yet metastases disappeared after only two courses of Ipi + Nivo therapy. The patient was ultimately cured by surgery and achieved a pCR. This case highlights that despite the occurrence of severe irAEs during RCC treatment with Ipi + Nivo therapy, they can be managed appropriately to maximize the therapeutic effects of checkpoint inhibitors.

Borane-Protecting Strategy for Hydrosilylation of Phosphorus-Containing Olefins.

Ir-catalyzed hydrosilylation of the alkenyl phosphine borane complex 1 was achieved to give the corresponding products 2. Because the phosphino group coordinates with metals and is unstable under aerobic conditions, the formation of the corresponding borane adduct was effective not only to promote the target hydrosilylation but also to keep 1 stable under aerobic conditions. The removal of coordinated borane from 2 was readily performed with the treatment by 1,4-diazabicyclo[2.2.2]octane to apply to further transformations. The immobilization and following deprotection of 2 on the surface of mesoporous silica were also examined.

Ift88 regulates enamel formation via involving Shh signaling.

OBJECTIVES: The ciliopathies are a wide spectrum of human diseases, which are caused by perturbations in the function of primary cilia. Tooth enamel anomalies are often seen in ciliopathy patients; however, the role of primary cilia in enamel formation remains unclear. MATERIALS AND METHODS: We examined mice with epithelial conditional deletion of the ciliary protein, Ift88, (Ift88fl / fl ;K14Cre). RESULTS: Ift88fl / fl ;K14Cre mice showed premature abrasion in molars. A pattern of enamel rods which is determined at secretory stage, was disorganized in Ift88 mutant molars. Many amelogenesis-related molecules expressing at the secretory stage, including amelogenin and ameloblastin, enamelin, showed significant downregulation in Ift88 mutant molar tooth germs. Shh signaling is essential for amelogenesis, which was found to be downregulated in Ift88 mutant molar at the secretory stage. Application of Shh signaling agonist at the secretory stage partially rescued enamel anomalies in Ift88 mutant mice. CONCLUSION: Findings in the present study indicate that the function of the primary cilia via Ift88 is critical for the secretory stage of amelogenesis through involving Shh signaling.

Successful treatment of BK virus-associated severe hemorrhagic cystitis with bilateral single-J ureteral stenting.

Introduction: BK virus-associated hemorrhagic cystitis is a significant complication of hematopoietic stem cell transplantation. Although severe BK virus-associated hemorrhagic cystitis is associated with treatment-related mortality, sufficient evidence regarding its management is lacking. Case presentation: A 14-year-old boy presented with BK virus-associated hemorrhagic cystitis and bladder clot retention after hematopoietic stem cell transplantation. Various urological interventions failed to improve cystitis. While bladder clot retention frequently recurred, surgical intervention was difficult because of the underlying hematological disorder. Hence, bilateral single-J ureteral stenting followed by Foley catheter placement was performed as a urinary diversion. The bladder clot completely disappeared 27 days after stenting. No additional procedure was required. BK virus-associated hemorrhagic cystitis did not recur after the blood clot disappeared. Conclusion: Bilateral single-J ureteral stenting followed by Foley catheter placement is a simple and effective treatment method and should be considered before surgical intervention for severe BK virus-associated hemorrhagic cystitis.

[The Method for Estimation of Radiation Dose of Eye Lens Covered by Radiation Protection Glasses Using Personal Dosimeter for Trunk of the Body and X-ray Shielding Material].

PURPOSE: Radiation protection glasses is a useful tool for dose reduction of eye lens. However, the method to evaluate the dose of eye lens, which is covered with radiation protection glasses in actual radiation management situation, has not been established. We invented the easy-to-use procedure to estimate the dose of eye lens inside of radiation protection glasses for occupationally exposed person using an X-ray shielding material and an additional personal dosimeter for trunk of the body. The objective of this study was to evaluate the feasibility of the new method. METHODS: The radiation field in interventional radiology (IR) was reconstructed. A personal dosimeter was set to the eye position and neck position of medical staff phantom. Each dosimeter was covered by radiation protection glasses or X-ray shielding material, and the 1 cm or 70 mm dose equivalent quantity in the neck position was compared to the 3 mm dose equivalent quantity in the eye position. RESULTS: The dose equivalent quantity measured inside of X-ray shielding material in the neck position was similar to that of inside radiation protection glasses. Thus, the X-ray attenuation by radiation protection glasses was able to be simulated using the X-ray shielding material. CONCLUSION: It was suggested that the dose of eye lens inside of radiation protection glasses could be easily estimated by covering the conventional personal dosimeter for trunk of the body with the X-ray shielding material.

Bacteremia Caused by Both Legionella pneumophila Serogroup 2 and Helicobacter cinaedi.

A 74-year-old woman with a history of pure red cell aplasia and hypogammaglobulinemia developed pneumonia. A urine antigen test and sputum subculture on buffered charcoal yeast extract (BCYE)α agar were positive for Legionella pneumophila. Serological testing identified L. pneumophila serogroup 2. An aerobic blood culture also became positive on day 5; its subculture on BCYEα agar revealed the same pathogen, but that on blood agar revealed Helicobacter cinaedi. We thus diagnosed her with bacteremia caused by both pathogens. Hence, in cases of H. cinaedi bacteremia along with pneumonia, the screening of other pathogens including L. pneumophila is needed.

Association Between Autistic Symptoms and Self-Stigma in Patients with Schizophrenia Spectrum Disorders.

PURPOSE: Self-stigma negatively influences self-esteem, quality of life, self-efficacy, treatment adherence, and recovery in psychiatric patients. By revealing personality traits that influence self-stigma, we can gain useful knowledge for the management of self-stigma. A previous meta-analysis indicated that patients with schizophrenia have higher scores on the Autism-Spectrum Quotient (AQ) than healthy controls. However, the relationship between autistic symptoms and self-stigma in patients with schizophrenia spectrum disorders remains unclear. Therefore, the present study aimed to reveal the association between autistic symptoms and self-stigma in patients with schizophrenia spectrum disorders. PATIENTS AND METHODS: We recruited 127 patients with schizophrenia spectrum disorders (schizophrenia, schizoaffective disorder, and delusional disorder). We assessed participants' self-stigma and autistic symptoms using the Internalized Stigma for Mental Illness (ISMI) scale and the Autism-Spectrum Quotient (AQ), respectively. The differences in the scores of ISMI and AQ according to patient characteristics were investigated. Multiple regression analysis controlling for age and gender was performed to determine the relationship between the total scores on the AQ and IMSI scale. RESULTS: Female patients showed a higher level of self-stigma than males. Unmarried patients showed a significantly higher score on the AQ than married patients. Multiple regression analysis adjusted for age and gender indicated that the total score on AQ might be a predictor of the overall rating on ISMI in patients with schizophrenia spectrum disorders. CONCLUSION: This study is the first to reveal the association between autistic symptoms and self-stigma in patients with schizophrenia spectrum disorders. Our results highlight the importance of considering autistic symptoms in the assessment and management of self-stigma in patients with schizophrenia spectrum disorders.

A case of pembrolizumab-induced hemophagocytic lymphohistiocytosis successfully treated with pulse glucocorticoid therapy.

Treatments using immune checkpoint inhibitors such as pembrolizumab lead to immune mediated adverse effects including hemophagocytic lymphohistiocytosis (HLH). Herein, we present a case where HLH developed after pembrolizumab administration, which was treated using high dose prednisolone. He developed high-grade fever complicated with liver dysfunction and diarrhea 7 days after pembrolizumab administration. Although treatment with oral prednisolone alleviated the symptoms, other adverse effects arose owing to a tapered prednisolone dose. Hyperferritinemia suggested the diagnosis of HLH and met the criteria for HLH diagnosis. He was thus administered intravenous pulses of methylprednisolone followed by high-dose oral prednisolone, which resolved these symptoms.

A comparison of the features of fluorine-18 fluorodeoxyglucose-positron emission tomography (FDG-PET) between IgG4-related disease with bilateral hilar lymphadenopathy and sarcoidosis.

We aimed to show the differentiation of the degree and distribution on Fluorine-18 fluorodeoxyglucose-positron emission tomography (FDG-PET) between patients with immunoglobulin G4-related disease (IgG4-RD) and sarcoidosis, though both diseases frequently show bilateral hilar lymphadenopathy (BHL). The clinical records were retrospectively reviewed in 25 patients with IgG4-RD with BHL and 15 patients with sarcoidosis (stage I-II) diagnosed at Shinshu University Hospital. All patients underwent FDG-PET at Aizawa Hospital from January 2004 to December 2015. The FDG accumulation pattern and maximum standardized uptake value (SUVmax) of the hilar lymph nodes were compared between the two groups. The IgG4-RD group (21 men; median age 69 years) showed a significant male predominance and older age compared with the sarcoidosis group (3 men, median age 55.4 years). The IgG4-RD group showed a significantly higher incidence of FDG accumulation in the lachrymal gland, submandibular gland, pancreas, prostate and periurethral and periarterial regions compared with the sarcoidosis group. In contrast, the sarcoidosis group showed a significantly higher incidence of FDG accumulation in the supraclavicular and abdominal lymph nodes, muscle and soft tissues compared with the IgG4-RD group. Furthermore, the SUVmax of the hilar lymph nodes was significantly higher in the sarcoidosis group (median 7.20) than in the IgG4-RD group (median 4.20, p=0.002). In conclusion, significant differences were observed in the FDG accumulation patterns and SUVmax values of the hilar lymph nodes between IgG4-RD with BHL and sarcoidosis, although both diseases develop through the lymphatic routes of the lungs and are frequently associated with BHL.

Total arch replacement for the treatment of a giant protruding thrombus in the thoracic aorta derived from an atherosclerotic lesion.

A thoracic aortic thrombus is rare. The causes of this condition and the feasible options for its treatment remain controversial. Preventing embolic complications are the most important for the management of thoracic aortic thrombi. Herein, we report a case of a giant protruding thrombus in the thoracic aorta. We suggest total arch replacement (TAR) using an open stent graft (OSG) as a favorable management technique for thoracic aortic thrombi. We also recommend bilateral axillary artery cannulation to prevent cerebral infarction.

Treatment-free remission after first-line dasatinib treatment in patients with chronic myeloid leukemia in the chronic phase: the D-NewS Study of the Kanto CML Study Group.

Treatment outcomes for chronic myeloid leukemia (CML) have dramatically improved with the development of tyrosine kinase inhibitors (TKI). However, due to the improved prognosis for CML, problems have arisen from long-term administration of TKI. The present study sought to verify whether more patients could achieve treatment-free remission (TFR) after stopping the administration of dasatinib using dasatinib as frontline treatment. Treatment-naïve chronic phase CML cases were treated with dasatinib as frontline treatment. Dasatinib treatment was stopped for 26 patients who achieved deep molecular response (DMR) within 24 months and were able to maintain DMR for an additional 2 years. Ten patients (38.5%) achieved DMR maintenance after 12 months. Recurrence was confirmed in 16 patients, and the median recurrence-free survival time was 5.1 months. The cumulative DMR rates at six and 12 months after restarting treatment were 84.6% and 100%, respectively. The results of this study demonstrated that the DMR maintenance rate after 12 months was 38.5%, which was not significantly different from previous TKI stop trials. The 2-year dasatinib administration period after reaching DMR did not contribute to improve TFR rates. These results suggest that the type of TKI is not associated with better TFR rates.

Impact of acute kidney injury on prognosis of chronic kidney disease after aortic arch surgery.

OBJECTIVES: Postoperative acute kidney injury (AKI) is a common complication associated with increased long-term mortality after cardiothoracic surgery. However, AKI after total aortic arch replacement (TAR) is not well studied. This study aimed to investigate the prognosis and impact of AKI on the long-term outcomes of chronic kidney disease (CKD) patients undergoing TAR. METHODS: We included 208 patients who underwent TAR between September 2003 and December 2014. Patients were divided into a CKD (n = 83, 40%) and non-CKD (n = 125, 60%) group. The definition of AKI followed the Risk, Injury, Failure, Loss of kidney function and End-stage kidney disease (RIFLE) criteria. Independent risk factors for all-cause death and AKI were identified with multivariable analysis. RESULTS: Postoperative AKI was observed in 24 patients (29%) and 39 patients (31%) of CKD and non-CKD groups, respectively. The survival rate of CKD patients was significantly lower than that of non-CKD patients (P = 0.02). Among CKD patients, the 5-year survival rate was 57% in those with AKI group and 92% in those without AKI; prognosis was significantly poorer in patients with AKI (P = 0.001). In the non-CKD group, there was no difference in prognosis between patients with or without AKI (P = 0.77). Multivariable logistic regression analysis revealed that intraoperative blood loss of ≥600 ml was the only predictor of AKI in the CKD group (odds ratio 4.32, P = 0.04). CONCLUSIONS: CKD is associated with reduced long-term survival after TAR. Postoperative AKI strongly influences long-term survival in CKD patients only.

Pralatrexate for Prolonged Treatment of Refractory Peripheral T-Cell Lymphoma, Not Otherwise Specified, with Prophylactic Leucovorin.

Peripheral T-cell lymphomas (PTCLs) are a rare and heterogenous group of hematological malignancies involving T or NK cells. PTCLs are generally associated with an aggressive course and poor prognosis. Pralatrexate (PDX) is the first FDA-approved agent for the treatment of refractory/recurrent PTCL. It has single-agent activity against PTCLs; however, oral mucositis represents dose-limiting toxicity in clinical practice. We report on the case of a patient administered with modified THP-COP therapy (pirarubicin [tetrahydropyranyl adriamycin], cyclophosphamide, and prednisone), who had bone or bone marrow as the primary lesion, which was treated successfully with PDX for an extended period of 1 year, with prophylactic use of leucovorin for oral mucositis. The maintenance dose of PDX was 30 mg/m2 IV, over 3 consecutive weeks dosing with a 1-week rest period due to bone marrow suppression. The patient also received leucovorin 5 mg PO 3 times daily from days 2 to 6 after each PDX administration. Disease activity was well controlled, stable, and no oral mucositis was observed over the course of treatment.

Hypoxic-conditioned cardiosphere-derived cell sheet transplantation for chronic myocardial infarction.

OBJECTIVES: Cell therapy provides a suitable environment for regeneration through paracrine effects such as secretion of growth factors. Cardiosphere-derived cells (CDCs) have a high capacity for growth factor secretion and are an attractive target for clinical applications. In particular, a cell sheet technique was reported to have clinical advantages by covering a specific region. Here, we examined the effect of the hypoxic-conditioned (HC) autologous CDC sheet therapy on a rabbit chronic myocardial infarction model. METHODS: CDC sheet function was assessed by the enzyme-linked immunosorbent assay and quantified by polymerase chain reaction in vitro (days 1-3 of conditioning). The rabbit chronic myocardial infarction model was established by left coronary ligation. Autologous CDCs were isolated from the left atrial specimen; CDC sheets with or without 2-day HC were transplanted onto the infarcted hearts at 4 weeks. The cardiac function was assessed by an echocardiography at 0, 4 and 8 weeks. A histological analysis of the host hearts was performed by tomato lectin staining at 8 weeks. RESULTS: The optimal HC duration was 48 h. HC significantly increased the mRNA expression levels of VEGF and ANG2 on day 2 compared to the normoxic-conditioned (NC) group. The HC group showed significant improvement in the left ventricular ejection fraction (64.4% vs 58.8% and 53.4% in the NC and control) and a greater lectin-positive area in the ischaemic region (HC:NC:control = 13:8:2). CONCLUSIONS: HC enhances the paracrine effect of a CDC sheet on angiogenesis to improve cardiac function in the chronic myocardial infarction model, which is essential for cardiomyocyte proliferation during cardiac regeneration.

Effect of Autotransfusion Using Intraoperative Predonated Autologous Blood on Coagulopathy during Thoracic Aortic Surgery: A Randomized Controlled Trial.

BACKGROUND: Intraoperative predonated autologous blood transfusion is thought to replenish platelets and coagulation factors and ameliorate coagulopathy. This study aimed to evaluate whether intraoperative predonated autotransfusion improves coagulopathy during thoracic aortic surgery. METHODS: Patients who underwent thoracic aortic surgery were randomized into two groups as follows: those who received intraoperative predonated blood (group A: n = 31) and those who did not receive (group N: n = 22). In group A, autologous blood was retransfused immediately after cessation of cardiopulmonary bypass (c-CPB). RESULTS: The mean intraoperative allogenic blood or blood product transfusion requirements were significantly lesser in group A than in group N (packed red blood cells [RBCs]: 6.3 ± 5.1 vs. 9.1 ± 4.3 units, p = 0.04; fresh frozen plasma [FFP]: 3.0 ± 4.1 vs. 6.1 ± 5.7 units, p = 0.03). After c-CPB, hemoglobin (Hb) level, platelet count, and coagulopathy became significantly worse than those at the start of surgery in both the groups. However, the values significantly improved 30 min after c-CPB only in group A. Renal function was significantly worse in group N. CONCLUSIONS: Intraoperative predonated autotransfusion significantly improved coagulopathy, with reduced allogeneic blood transfusion volume during thoracic aortic surgery. Furthermore, reduction of allogeneic blood transfusion may reduce the adverse effects on renal function.

Synthesis of neuraminidase-resistant sialoside-modified three-way junction DNA and its binding ability to various influenza viruses.

Natural sialic acid-modified compounds are capable of targeting influenza virus hemagglutinin (HA). However, these compounds have limited inhibitory effect because natural O-glycoside bond in these compounds are prone to be cleaved by neuraminidase (NA) on the surface of viruses. In this study, we synthesized NA-resistant sialoside that included unnatural S-glycoside bonds and modified this sialoside on a three-way junction (3WJ) DNA to display complementary distribution to its binding sites on a HA trimer. This S-glycoside-containing sialoside-modified 3WJ DNA showed certain NA resistance and maintained high binding affinity. Importantly, our observations showed that substituting natural O-glycoside with unnatural S-glycoside did not affect the binding affinity of the sialoside-modified 3WJ DNA for viruses. Thus, this study is an important step forward in the development of NA-resistant sialoside derivatives for more effective detection and inhibition of infection by a broad spectrum of viruses.

Rectal Lymphoid Follicle Aphthous Lesions Frequently Progress to Ulcerative Colitis with Proximal Extension.

Objective Rectal lymphoid follicular aphthous (LFA) lesions are related to ulcerative colitis (UC) and can be initial lesions of UC. We investigated the clinical course and prognosis of rectal LFA lesions. Methods This is a retrospective analysis of the clinical records at a single center. Patients Thirteen consecutive cases with LFA lesions treated at Hiroshima University Hospital between 1998 and 2015 were evaluated. Another 49 consecutive cases with ulcerative proctitis treated in the same period were enrolled as the control group. The clinical course and prognosis of both groups were evaluated. Results The group with LFA lesions included 9 women and 4 men with a median age of 39.9 years (range, 21-70 years). A total of 11 cases progressed to typical UC at 5-51 months. Proximal extension of these typical UC lesions was observed in 7 (53.8%) cases, which was significantly higher than in the control group (10 cases, 20.8%). Three cases (5-year accumulation incidence rate, 27.3%) progressed to steroid-intractable UC, a significantly higher incidence than that of the control group (3 cases; 5-year accumulation incidence rate, 6.9%). Conclusion Rectal LFA lesions frequently progress to typical UC with proximal extension, some of which become intractable to corticosteroid treatment.

Relief of vasospasm with fasudil after off-pump coronary artery bypass grafting: a case study.

BACKGROUND: Coronary vasospasm after coronary artery bypass grafting (CABG) is a rare but potentially lethal complication. It is often refractory to several vasodilators. We report a case of refractory coronary vasospasm relieved by fasudil injection. CASE PRESENTATION: A 74-year-old woman who had three instances of in-stent stenosis at the left anterior descending artery (LAD) was referred for CABG treatment. Preoperative coronary angiography showed 90% in-stent stenosis of the proximal LAD and 75% stenosis of the diagonal branch. We performed a left internal thoracic artery (LITA)-LAD bypass and a right internal thoracic artery (RITA) diagonal branch bypass. After anastomosis, transit time flow measurement revealed poor blood flow of LITA-LAD bypass even after re-anastomosis. We performed coronary angiography and detected a vasospasm in the native coronary arteries, which was not relieved using conventional vasodilators (calcium channel blockers, isosorbide dinitrate, and nicorandil) However, we were able to relieve the coronary vasospasm by administering fasudil (a Rho kinase inhibitor) injection without causing systemic hypotension. CONCLUSIONS: Fasudil may be an important vasodilator, especially in cases of coronary vasospasm after CABG.

Efficiency of the Lung Flute for sputum induction in patients with presumed pulmonary tuberculosis.

INTRODUCTION: High quality sputum helps increase the sensitivity of the diagnosis of pulmonary tuberculosis. OBJECTIVES: To evaluate the efficiency of the acoustic device (Lung Flute; LF) in sputum induction compared with the conventional method, hypertonic saline inhalation (HSI). METHODS: In this crossover study, patients with presumed pulmonary tuberculosis submitted 3 consecutive sputa: the first sputum without induction and the second and third ones using LF and HSI. We compared the efficiency of the 2 induction methods. RESULTS: Sixty-four participants were eligible. Thirty-five (54.6%) patients had negative smears on the first sputum without induction. Among those patients, 25.7% and 22.9% patients were smear-positive after using LF and HSI, respectively (P = .001). The positive conversion rate was not significantly different between the methods. The first samples without induction yielded 65.7% positive cultures, whereas 71.4% and 77.1% of the samples from LF and HSI were positive, respectively (P = .284). Similar results were observed in the nucleic acid amplification test [no induction (60.0%), LF (72.0%) and HSI (60.0%); P = .341]. In 29 smear-positive patients on the first sputum without induction, we observed no significant increase in smear grade, culture yield and nucleic acid amplification test positivity with either method. LF tended to induce fewer adverse events; desaturation (3.1% vs 11.1%; P = .082) and throat pain (1.5% vs 9.5%; P = .057). LF showed significantly fewer total adverse events (15.8% vs 34.9%; P = .023). CONCLUSIONS: Our study showed LF had similar sputum induction efficiency to HSI with relatively fewer complications.