The Simultaneous Onset of Pancreatitis and Colitis as Immune-related Adverse Events in a Patient Receiving Nivolumab Treatment for Renal Cell Carcinoma

Immune checkpoint inhibitors (ICIs), which have anti-tumor effects, are currently approved for treatment of several kinds of advanced malignancies. However, with their increasing use, a variety of immune-related adverse events (irAEs) in administered patients have been reported. We herein report a rare case of the simultaneous onset of acute pancreatitis and colitis as irAEs during nivolumab treatment given to a patient with renal cell carcinoma, who then shown marked improvement with corticosteroid therapy.     

The Impact of Purple-Flesh Potato (Solanum tuberosum L.) cv. “Shadow Queen” on Minor Health Complaints in Healthy Adults: A Randomized,Double-Blind,Placebo-Controlled Study

The purple-flesh potato (Solanum tuberosum L.) cultivar “Shadow Queen” (SQ) naturally contains anthocyanins. This randomized, double-blind, placebo-controlled study determines whether ingesting purple potatoes increases the number of mesenchymal stem cells (MSC) and improves stress response, a minor health complaint in healthy adults (registration number: UMIN000038876). A total of 15 healthy subjects (ages: 50–70 years) with minor health complaints were randomly assigned to one of two groups. For 8 weeks, the placebo group received placebo potatoes cv. “Haruka” and the test group received test potato cv. SQ containing 45 mg anthocyanin. The MSC count and several stress responses were analyzed at weeks 0 and 8 of the intake periods. The ingestion of a SQ potato did not affect the MSC count but markedly improved psychological stress response, irritability, and depression as minor health complaints compared with “Haruka”. No adverse effects were noted. Hence, an 8-week intake of SQ could improve stress responses.     

γ-secretase inhibitors augment efficacy of BCMA-targeting bispecific antibodies against multiple myeloma cells without impairing T-cell activation and differentiation

We here defined the impacts of γ-secretase inhibitors (GSIs) on T-cell-dependent BCMA-specific multiple myeloma (MM) cell lysis and immunomodulatory effects induced by bispecific antibodies (BisAbs). GSIs-induced membrane BCMA (mBCMA) accumulation reached near maximum within 4 h and sustained over 42h-study period on MM cell lines and patient MM cells. GSIs, i.e., 2 nM LY-411575 or 1 μM DAPT, robustly increased mBCMA densities on CD138⁺ but not CD3⁺ patient cells, concomitantly with minimum soluble/shed BCMA (sBCMA) in 1 day-culture supernatants. In ex vivo MM-T-cell co-cultures, GSIs overcame sBCMA-inhibited MM cell lysis and further enhanced autologous patient MM cell lysis induced by BCMAxCD3 BisAbs, accompanied by significantly enhanced cytolytic markers (CD107a, IFNγ, IL2, and TNFα) in patient T cells. In longer 7 day-co-cultures, LY-411575 minimally affected BCMAxCD3 BisAb (PL33)-induced transient expression of checkpoint (PD1, TIGIT, TIM3, LAG3) and co-stimulatory (41BB, CD28) proteins, as well as time-dependent increases in % effector memory/central memory subsets and CD8/CD4 ratios in patient T cells. Importantly, LY41157 rapidly cleared sBCMA from circulation of MM-bearing NSG mice reconstituted with human T cells and significantly enhanced anti-MM efficacy of PL33 with prolonged host survival. Taken together, these results further support ongoing combination BCMA-targeting immunotherapies with GSI clinical studies to improve patient outcome.Subject terms: Cancer immunotherapy, Immunotherapy     

Mxi1 mutations in human neurofibrosarcomas.

Mxi1 is thought to negatively regulate Myc function and may therefore be a potential tumor suppressor gene. Little effort has yet been made to find alterations involving this gene in human solid tumors. We screened 31 human gastric cancers, 7 esophageal cancers, 85 bone and soft tissue tumors of various types, including 4 neurofibrosarcomas. We also examined 29 human tumor cell lines consisting of 12 esophageal cancers, 7 glioma/glioblastomas and 10 others for Mxi1 mutations in exons 1, 2, 4 (HLH domain), 5 and 6. Polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and subsequent sequencing revealed three distinct polymorphisms in the intron-exon boundary upstream from exon 6. We discovered a missense mutation, GCA to GTA (Ala 54 Val), in exon 2 in a neurofibrosarcoma patient (case 1), two missense mutations, AAA to CAA (Lys 118 Gln) and GAA to GGA (Glu 154 Gly) in exon 5 of another neurofibrosarcoma patient (case 2), and 3 amino acid substitutions, GTG to GCG (Val 179 Ala), GTT to GCT (Val 181 Ala) and TTC to CTC (Phe 186 Leu), in a third neurofibrosarcoma patient (case 3). In case 3, loss of heterozygosity was also demonstrated by informative (TTC)3/(TTC)2 polymorphism. Our data demonstrate that mutations occur in the Mxi1 gene in neurofibrosarcoma. Missense mutations in the functional domain of Mxi1 in these cases may be involved in the pathogenesis of neurofibrosarcoma.     

Active Specific Chemoimmunotherapy of Lymph-node Metastasis from a Poorly Immunogenic Murine Fibrosarcoma

The fibrosarcoma MCA-SP, which was recently induced with methylcholanthrene (MCA) in C3H/ HeJ mice, displays poor immunogenicity in in vivo prophylaxis. A cell variant MCA-SPN1, which bears a tumor-specific transplantation antigen (TSTA) cross-reactive with the parental line MCA-SP, was selected because of its proclivity for axillary lymph-node metastases. Although these lymph-node metastases were resistant to sinecomitant (post-excisional) immunity, they were susceptible to combined active and passive specific Chemoimmunotherapy, using tumor-specific, 1-butanol-extracted, preparative isoelectric focusing-purified, TSTA (1 fig weekly sc injections), cyclophosphamide (CY, a single intraperitoneal 20 mg/kg dose), and adoptive transfer of immune splenic T lymphocytes, which had been re-stimulated in vitro with extracted TSTA and interleukin-2. This triple regimen both reduced the incidence of spontaneous lymph-node metastases, and prolonged the survival of tumor-bearing, as well as tumor-resected hosts. The results from local adoptive transfer assay using T-lymphocyte snbpopulations of spleen and lymph nodes in these treated hosts suggested that Lyt 2⁺ cytotoxic T-lymphocytes (CTL) mediated in vivo tumor-neutralization. Thus TSTA/CY/CTL therapy activates tumoricidal host responses effective against the poorly immunogenic MCA-SP tumor and its lymph-node metastases.     

Mixed type of total anomalous pulmonary venous return: a rare pattern of pulmonary venous drainage]

The occurrence of multiple drainage sites in total anomalous pulmonary venous return (TAPVR) has important implication in preoperative diagnosis and surgical treatment. We report a rare pattern of pulmonary venous drainage with the right upper pulmonary vein draining into the innominate vein and the other three pulmonary veins into the portal vein (Ib + III type). The preoperative diagnosis was made by echocardiography and confirmed by angiography. In operation, an anastomosis was made between the common pulmonary vein and the left atrium through posterior approach, but the right upper pulmonary vein was left uncorrected because the anomalously draining blood flow of a single pulmonary vein was about 20% of total pulmonary blood flow. The postoperative course was uneventful, however, the long-term follow-up is mandatory because of the right upper pulmonary vein being left uncorrected.     

The Wilms' tumor gene WT1-GFP knock-in mouse reveals the dynamic regulation of WT1 expression in normal and leukemic hematopoiesis.

The Wilms' tumor gene WT1 is overexpressed in most of human leukemias regardless of disease subtypes. To characterize the expression pattern of WT1 during normal and neoplastic hematopoiesis, we generated a knock-in reporter green fluorescent protein (GFP) mouse (WT1(GFP/+)) and assayed for WT1 expression in normal and leukemic hematopoietic cells. In normal hematopoietic cells, WT1 was expressed in none of the long-term (LT) hematopoietic stem cells (HSC) and very few (<1%) of the multipotent progenitor cells. In contrast, in murine leukemias induced by acute myeloid leukemia 1 (AML1)/ETO+TEL/PDGFbetaR or BCR/ABL, WT1 was expressed in 40.5 or 38.9% of immature c-kit(+)lin(-)Sca-1(+) (KLS) cells, which contained a subset, but not all, of transplantable leukemic stem cells (LSCs). WT1 expression was minimal in normal fetal liver HSCs and mobilized HSCs, both of which are stimulated for proliferation. In addition, overexpression of WT1 in HSCs did not result in proliferation or expansion of HSCs and their progeny in vivo. Thus, the mechanism by which expansion of WT1-expressing cells occurs in leukemia remains unclear. Nevertheless, our results demonstrate that the WT1(GFP/+) mouse is a powerful tool for analyzing WT1-expressing cells, and they highlight the potential of WT1, as a specific therapeutic target that is expressed in LSCs but not in normal HSCs.     

Comparison of lidocaine with and without bupivacaine for local dental anesthesia.

The purpose of this study was to investigate the effectiveness of a combination of bupivacaine and lidocaine and that of lidocaine alone for local dental anesthesia. First, on different days, healthy volunteers were given 2% lidocaine with 1/80,000 epinephrine or 2% lidocaine with 1/80,000 epinephrine + 0.5% bupivacaine, after which pain was produced with a pulp tester. No difference was found in the time until onset of anesthetic effect between the preparations. However, the duration of anesthetic effect was longer with both lidocaine and bupivacaine than with lidocaine alone. Next, patients undergoing dental surgery were given one of the anesthetic preparations, after which serum concentrations of the anesthetics and epinephrine were measured. The maximal serum concentration of lidocaine was higher and was reached sooner after injection in patients receiving lidocaine alone (1.74 microgram/ml after 5 min) than in patients receiving both anesthetics (0.85 microgram/ml after 3 min). The mean maximal serum concentration of lidocaine was higher in patients receiving lidocaine alone (1.77 +/- 0.03 microgram/ml) than in those receiving both anesthetics (0.99 +/- 0.45 microgram/ml). Furthermore, the mean plasma concentration of epinephrine 1 min after injection was significantly higher in patients receiving lidocaine alone (0.671 ng/ml) than in patients receiving both lidocaine and bupivacaine (0.323 ng/ml). The results of this study suggest that the combination of lidocaine with epinephrine and bupivacaine produces lower systemic levels of the anesthetic and epinephrine and a longer duration of activity than lidocaine with epinephrine alone for local dental anesthesia.     

Long-term follow-up of an individual with vitamin B6-dependent seizures

We report on a 31-year-old female with vitamin B6-dependent seizures whose seizure onset was in the neonatal period. Her elder brother had the same disorder and died in infancy. Administration of vitamin B6 was initiated in the postnatal period. At the age of 12 years 1 month, 2 months after withdrawal of vitamin B6, visual seizures began to occur frequently. Myoclonic seizures and occasional generalized convulsive seizures were also observed. At the same time, photoparoxysmal response and spontaneous diffuse spike-wave bursts were seen on her EEG. Myoclonic seizures were provoked by intermittent photic stimulation during the EEG. It is distinctive that visual seizures were one of the main seizure types in this patient, that her clinical course was relatively benign, and that she has normal intellectual outcome.