CD8⁺ tumor-infiltrating lymphocytes at primary sites as a possible prognostic factor of cutaneous angiosarcoma.

Tumor-infiltrating lymphocytes (TILs) have been reported as a prognostic factor in various cancers and are a promising target for immunotherapy. To investigate whether TILs have any impact on the prognosis of angiosarcoma patients, 55 non-treated patients (40 patients at stage 1 with cutaneous localized tumors, 4 patients at stage 2 with lymph node metastases and 11 patients at stage 3 with distant metastases) with angiosarcoma were evaluated retrospectively by immunohistochemistry stained CD4, CD8, FOXP3 and Ki67. The Kaplan-Meier method was used to estimate overall survival with patients at stage 1. Survival differences were analyzed by the log-rank test. Patients with higher numbers of CD8(+) TILs in their primary tumors survived significantly longer compared with patients with lower values. Moreover, the number of CD8 in TILs was positively correlated with a distant metastasis-free period. The total number of primary TILs (CD4 plus CD8) and CD8(+) primary TILs of stage 3 patients with distant metastases was positively correlated with their overall survival. To evaluate whether CD8(+) effector T cells are activated or differentiated, flow cytometric analysis of peripheral blood mononuclear cells (PBMC) was performed. The percentages of CD8(+) T cells producing IFN-γ in PBMC were significantly higher in patients with angiosarcoma (n = 10) compared not only with that of healthy controls (n = 20) but also patients with advanced melanoma (n = 11). These results suggest that anti-tumor immunity is clinically relevant in angiosarcoma.

Factors Associated With Postoperative Decisional Regret in Patients Undergoing Gastrointestinal Cancer Surgery: A Prospective Cohort Study.

BACKGROUND: Surgery is recommended as the first-line treatment option to cure resectable gastrointestinal (GI) cancer. However, patients occasionally feel postoperative regret after surgery. To date, it is not clear which factors are associated with patient regret after GI cancer surgery. The aim of this study was to investigate factors related to postoperative decision regret in patients undergoing surgery for GI cancer. METHODS: The present prospective study used questionnaires to analyze postoperative decision regret in patients undergoing GI cancer surgery in our institution between February and July 2020. Decision regret that patients felt after surgery was quantitatively measured using the decision regret scale (DRS). Multivariable linear regression models were used to examine factors related to postoperative decision regret. RESULTS: Among 70 patients analyzed, the median (interquartile range) DRS score was 10.0 (.0-25.0). Multivariable analysis showed that preoperative Trust in Physician Scale score (partial regression coefficient (B) = -.77; 95% confidence interval (CI) = -1.13 to -.41; P < .001) and postoperative complications (B = 9.17; 95% CI = 2.20 to 16.15; P = .0011) were significantly associated with DRS score. DISCUSSION: Preoperative trust in physician and postoperative complications were significantly associated with postoperative decision regret in patients undergoing surgery for GI cancer. Although patients may regret their choice of surgery when postoperative complications occur, trust in their physician may help reduce feelings of regret.

Identification of complications requiring interventions after gastrointestinal cancer surgery from real-world data: An external validation study.

Background: Recently, real-world data have been recognized to have a significant role for research and quality improvement worldwide. The decision on the existence or nonexistence of postoperative complications is complex in clinical practice. This multicenter validation study aimed to evaluate the accuracy of identification of patients who underwent gastrointestinal (GI) cancer surgery and extraction of postoperative complications from Japanese administrative claims data. Methods: We compared data extracted from both the Diagnosis Procedure Combination (DPC) and chart review of patients who underwent GI cancer surgery from April 2016 to March 2019. Using data of 658 patients at Kyoto University Hospital, we developed algorithms for the extraction of patients and postoperative complications requiring interventions, which included an invasive procedure, reoperation, mechanical ventilation, hemodialysis, intensive care unit management, and in-hospital mortality. The accuracy of the algorithms was externally validated using the data of 1708 patients at two other hospitals. Results: In the overall validation set, 1694 of 1708 eligible patients were correctly extracted by DPC (sensitivity 0.992 and positive predictive value 0.992). All postoperative complications requiring interventions had a sensitivity of >0.798 and a specificity of almost 1.000. The overall sensitivity and specificity of Clavien-Dindo ≥grade IIIb complications was 1.000 and 0.995, respectively. Conclusion: Patients undergoing GI cancer surgery and postoperative complications requiring interventions can be accurately identified using the real-world data. This multicenter external validation study may contribute to future research on hospital quality improvement or to a large-scale comparison study among nationwide hospitals using real-world data.

Refractory pyoderma gangrenosum associated with ulcerative colitis successfully treated with infliximab.

Pyoderma gangrenosum (PG) is a rare, immune-mediated ulcerating skin disease. In up to 50 percent of the cases, PG is associated with underlying systemic disorders, most commonly inflammatory bowel diseases, connective tissue diseases, or hematological disorders. Herein, we present a case of refractory PG associated with ulcerative colitis (UC), successfully treated with infliximab.

Letter: an adult case of hand-foot-mouth disease showing severe mucous involvement.

Hand-foot-mouth disease is a common childhood viral infection. Generally, small vesicles and erosions occur on the hands, feet and oral mucosa. We report an unusual case of this disease that occurred in an immunocompent adult and resulted in severe erosion on the lips and mucous membranes.

Risk Analysis of Eculizumab-Related Meningococcal Disease in Japan Using the Japanese Adverse Drug Event Report Database.

PURPOSE: Eculizumab, a drug that blocks activation of the terminal complement pathway, is useful in the treatment of several rare diseases. However, eculizumab-related meningococcal disease is a serious problem. Because of the difficulty diagnosing meningococcal disease, deaths from meningococcal disease may have been overlooked. The purpose of this study was to clarify the trend of meningococcal infection in patients on eculizumab and to evaluate the effectiveness of risk communication. METHODS: Pharmacovigilance analysis was conducted using the Japanese Adverse Drug Event Report database between the first quarter of 2010 and the second quarter of 2019. Of the reports of deaths, those with adverse event terms of fever, shock, altered state of consciousness, loss of consciousness, sepsis, organ failure, and disseminated intravascular coagulation were analyzed as deaths with suspected meningococcal infection. RESULTS: Of the 3559.2 person-years of eculizumab-exposed patients, 17 patients died with symptoms of meningococcal disease (including two confirmed cases). The mortality rate of meningococcal disease in patients exposed to eculizumab in Japan was estimated to be 0.56 (confirmed cases) to 4.8 (suspected cases) per 1000 person-years. Based on data from the National Epidemiological Surveillance of Infectious Disease, the mortality rate of meningococcal disease in the general population in Japan is 0.0042 per 100,000 person-years. Thus, the mortality rate from meningococcal disease in eculizumab-exposed patients is estimated to be 13,000 to 114,000 times the mortality rate from meningococcal disease in the general population of Japan. Academic societies warned of deaths from meningococcal disease in the first quarter of 2018, calling for appropriate action. Thereafter, only one death with symptoms of meningococcal disease has been reported. CONCLUSION: The analysis of the database showed that death from meningococcal disease in eculizumab-exposed individuals may occur more often than expected. This study also showed that appropriate risk communication reduced the fatality rate of meningococcal disease.

Necrotizing fasciitis caused by Haemophilus influenzae type b in an elderly patient.

Necrotizing fasciitis caused by Haemophilus influenzae type b is a rare infection of the skin and soft tissues. The only previously reported case involved a healthy infant. We report herein the case of an 81-year-old Japanese woman with diabetes mellitus who developed necrotizing fasciitis caused by H. influenzae type b.

Modification of the Dialysate Port of Plasma Separators for Safe Blood Purification in Japan.

A fatal mix-up of a hemofilter with a plasma separator occurred in 2011. The close resemblance between the two blood purification columns commonly used in Japan posed a fundamental risk for such mix-ups. Both the in-hospital case investigation committee and the relevant academic societies have independently proposed the modifications of the dialysate port (D port) of the plasma separator to avoid this type of misuse. To make these devices foolproof, medical professionals, including physicians and clinical engineers, and members of the Medical Technology Association of Japan discussed measures to prevent this type of recurrence. Since new standards were soon to be issued by the International Organization for Standardization (ISO), the modifications were temporarily postponed. In September 2016, the ISO released new standards for small-bore connectors. The shape changes of the D port from the current slip-in type (ISO8637) to the Luer lock type (ISO80369-7) had been already approved by the Ministry of Health, Labor and Welfare of Japan by the end of November 2018, including a temporal use of a converter to connect the current type of D port to the new type of blood circuit. We must address the next issue that the new standard and the older standard coexist in the clinical setting, which may create a new risk.

Large cell transformation mimicking regional lymphomatoid papulosis in a patient with mycosis fungoides.

A 57-year-old Japanese man with tumor-stage mycosis fungoides suddenly presented multiple small papules on the right chest. Histopathology of a biopsy specimen from the papules revealed medium-to-large pleomorphic lymphoid cells throughout the entire dermis but not in the epidermis, and the large cells expressed CD30 antigen. These newly-developed papules underwent spontaneous remission in the following 3 months. We reviewed the reported cases of mycosis fungoides, which showed CD30-positive large cell transformation and those of CD30-positive lymphoproliferative disorders associated with mycosis fungoides.

Development of a 2-h suicide prevention program for medical staff including nurses and medical residents: A two-center pilot trial.

BACKGROUND: Suicide is a crucial global health concern and effective suicide prevention has long been warranted. Mental illness, especially depression is the highest risk factor of suicide. Suicidal risk is increased in people not only with mental illness but also with physical illnesses, thus medical staff caring for physically-ill patients are also required to manage people with suicidal risk. In the present study, we evaluated our newly developed suicide intervention program among medical staff. METHODS: We developed a 2-h suicide intervention program for medical staff, based on the Mental Health First Aid (MHFA), which had originally been developed for the general population. We conducted this program for 74 medical staff members from 2 hospitals. Changes in knowledge, perceived skills, and confidence in early intervention of depression and suicide-prevention were evaluated using self-reported questionnaires at 3 points; pre-program, immediately after the program, and 1 month after program. RESULTS: This suicide prevention program had significant effects on improving perceived skills and confidence especially among nurses and medical residents. These significant effects lasted even 1 month after the program. LIMITATIONS: Design was a single-arm study with relatively small sample size and short-term follow up. CONCLUSIONS: The present study suggests that the major target of this effective program is nurses and medical residents. Future research is required to validate the effects of the program with control groups, and also to assess long-term effectiveness and actual reduction in suicide rates.

Expression of CCR5 in graft-versus-host disease (GVHD) of the skin: immunohistochemical staining of 38 cases.

To ascertain the involvement of CCR5 in prolongation of graft-versus-host disease (GVHD), we performed immunohistochemical staining of CCR5 in 38 GVHD samples (23 acute and 15 chronic). A total of seven out of 15 cases of chronic GVHD were positive for CCR5; however, only two out of 23 in acute GVHD were positive for CCR5. In three cases, expression of CCR5 in infiltrating lymphocytes was negative in the acute phase, but positive in the chronic phase of GVHD. These findings suggest that the immunopathological mechanism that differentiates between acute and chronic GVHD is a CCR5-mediated immunoreaction.

Investigation of the influence of cell density of human fibroblasts cryopreserved inside collagen sponges at various cooling rates.

The influence of cell density of cells cryopreserved inside a collagen matrix at various cooling rates was investigated. Human fibroblasts were three-dimensionally cultured for 2 days in a collagen sponge (20 mm in diameter and 1 mm in thickness) as an extracellular matrix to imitate biological tissue (artificial tissue). Different cell densities for the artificial tissue were used, from 10(5) to 10(7) cells/cm(3). Four artificial tissues were first stacked in a test chamber, frozen at a cooling rate of 0.3 to 50 degrees C/min in a solution of Dulbecco's Modified Eagle Medium, 20% fetal bovine serum and 10% dimethylsulfoxide, kept frozen below -185 degrees C for 2 hours, and then finally thawed. Membrane integrity of fibroblasts using a trypan blue exclusion assay was evaluated as an index for post-thaw cellular viability. Results show that with increasing cell density, the post-thaw membrane integrity decreased. Therefore, in the cryopreservation of biological tissue, it seems high cell density is one factor which causes a decline in viability.

[Angioedema].

Angioedema, deep mucocutaneous swelling, usually develops around the eyes and lips but may also affect the hands, feet, and throat. Allergic reactions to medications or foods can cause acute angioedema. Hereditary angioedema is a rare disorder, which is related to low levels or abnormal functioning of C1 inhibitors. Acquired C1 inhibitor deficiency is most frequently associated with B-cell lymphoproliferative disease. Some drugs including angiotensin-converting enzyme inhibitors can cause angioedema. Environmental elements such as pressure on the skin and exercise also can result in angioedema in some individuals. In addition, angioedema sometimes may occur in serum sickness, immune system disorders, or may be associated with eosinophilia.

[Effect of Water Intake on Allergy-like Events Associated with Non-ionic Iodine Contrast Agents].

The use of iodine contrast agents occasionally causes serious allergic symptoms including anaphylaxis. At Kyoto University Hospital to prevent nephropathy we began recommending water intake before and after administration of iodine contrast agents in September 2012. In the present study we investigated the effect of water intake on the incidence of allergy-like events after the use of non-ionic iodine contrast agents. We extracted the occurrence of allergy-like events from the incident report system in our hospital from January 2011 to September 2014, and classified these events into the following 3 grades: 1+ (follow-up); 2+ (medication treatment); and 3+ (hospitalization). The allergy-like incidence rate was calculated for subsequent evaluation according to season and water intake. Allergy-like events significantly decreased from 0.49% before the recommendation of water intake to 0.26% at 1 year and 0.20% at 2 years after implementing the recommendation. The incidence of allergy-like events was significantly higher in summer than in winter before water intake was recommended. After implementing the recommendation, the value for summer significantly decreased to an incidence similar to that of winter. Respiratory and gastrointestinal allergy-like symptoms were dramatically decreased after implementing the recommendation. Water intake may be useful for preventing allergy-like events associated with non-ionic iodine contrast agents, especially during the summer.

Signaling of gp34 (OX40 ligand) induces vascular endothelial cells to produce a CC chemokine RANTES/CCL5.

We previously showed that gp34 (OX40 ligand) expressed on vascular endothelial cells is not only involved in adhesion between activated T cells and endothelial cells but also by itself able to transmit intracellular signals leading to expression of c-fos and c-jun mRNA upon OX40 binding. In the present study, we searched for genes that were induced or upregulated by gp34 signaling in human umbilical vein endothelial cells (HUVECs) to define its downstream biological events. HUVECs expressing high levels of gp34 were stimulated with recombinant soluble OX40 or mock control and subjected to analysis using cDNA expression arrays. We found that a CC chemokine RANTES (regulated upon activation, normal T cell expressed and secreted)/CCL5 is one of such inducible genes. Reverse transcriptase-PCR analysis showed that expression of RANTES mRNA was induced after incubation with soluble OX40 and this induction was inhibited by anti-gp34 mAb. We could detect expression of intracellular RANTES protein by flow cytometry in HUVECs stimulated with soluble OX40 as well as fixed OX40 transfectant cells but not those stimulated with mock supernatants or mock transfectant cells. Again, this induction of RANTES protein was inhibited by anti-gp34 mAb. These results clearly indicate that gp34 signaling induces expression of RANTES at both mRNA and protein levels in HUVECs and suggest a possible link between the OX40/gp34 system and RANTES during the process of T cell adhesion to endothelial cells and subsequent extravasation.

Successful treatment of a patient with multicentric Castleman's disease who presented with thrombocytopenia, ascites, renal failure and myelofibrosis using tocilizumab, an anti-interleukin-6 receptor antibody.

We herein describe an unusual case of multicentric Castleman's disease accompanied by thrombocytopenia, ascites, renal failure and myelofibrosis in a Japanese woman. The patient was initially diagnosed as having myelodysplastic syndrome with myelofibrosis. The general condition of the patient deteriorated rapidly; however, treatment with tocilizumab, an anti-interleukin-6 receptor antibody, together with corticosteroids dramatically improved her symptoms. The clinical features of this case were similar to those of three cases previously reported by Takai et al. (Rinsho Ketsueki, 2010, 51:320-5), which were determined to be thrombocytopenia, anasarca, fever, reticulin myelofibrosis and organomegaly (TAFRO) syndrome, a possibly distinct clinical entity.