Peritoneal tuberculosis with elevated serum CA 125 levels: A case report

Laparotomy in a 62-year-old woman with elevated serum CA 125 antigen levels with the provisional diagnosis of ovarian carcinoma revealed peritoneal tuberculosis. After treatment with the bacteriocidal chemotherapeutic agents, the antigen level returned to the normal, and she has been well for 24 months postoperatively.     

Percutaneous Penetration Kinetics of Nitroglycerin and Its Dinitrate Metabolites Across Hairless Mouse Skin in Vitro

The percutaneous penetration kinetics of the antianginal, nitroglycerin (GTN), and its primary metabolites, 1,2- and 1,3-glyceryl dinitrate (1,2- and 1,3-GDN), were evaluated in vitro, using full-thickness hairless mouse skin. GTN and the 1,2- and 1,3-GDNs were applied (a) in aqueous solution as pH 7.4 phosphate-buffered saline (PBS) and (b) incorporated into lipophilic ointment formulations. The cutaneous transformation of GTN to its dinitrate metabolites was detected, but no interconversion between 1,2-GDN and 1,3-GDN was observed. Following application of the nitrates in PBS solution, all three compounds exhibited steady-state transport kinetics. The steady-state flux of GTN (8.9 ± 1.5 nmol cm^–2 hr^–1) was significantly greater (P < 0.05) than those of 1,2-GDN (0.81 ± 0.54 nmol cm^–2 hr^–1) and 1,3-GDN (0.72 ± 0.20 nmol cm^–2 hr^–1). The corresponding permeability coefficient () for GTN (20 ± 3 × 10^–3 cm hr^–1) was significantly larger than the corresponding values for 1,2-GDN (1.4 ± 0.9 × 10^–3 cm hr^–1) and 1,3-GDN (1.2 ± 0.4 × 10^–3 cm hr^–1), which were statistically indistinguishable (P > 0.05). Further analysis of the transport data showed that the differences between GTN and the GDNs could be explained by the relative stratum corneum/water partition coefficient (K _s) values of the compounds. The apparent partition parameters, defined as = K _s · h [where h is the diffusion path length through stratum corneum (SC)] were 19.8 ± 2.5 × 10^–2 cm for GTN and 1.91 ± 1.07 × 10^–2 and 1.81 ± 0.91 × 10^–2 cm for 1,2- and 1,3-GDN, respectively. However, when the nitrates were administered in an ointment base, the apparent partition parameter (') and permeability coefficient (') of GTN markedly decreased, to 2.51 ± 0.75 × 10^–2 cm and 1.6 ± 0.3 × 10^–3 cm hr^–1, respectively. In contrast, the ' and ' results for 1,2- and 1,3-GDN were not significantly different (P > 0.05) from the corresponding and values, which were measured following dosing as aqueous solutions. As a result, the steady-state fluxes of all three nitrates from the ointment formulation were comparable (GTN, 154 ± 28 nmol cm^–2 hr^–1; 1,2-GDN, 162 ± 22 nmol cm^–2 hr^–1; 1,3-GDN, 162 ± 34 nmol cm^–2 hr^–1). It follows that the dinitrates can be as efficiently delivered across the skin as GTN when a suitable formulation is employed. This finding may support transdermal therapy using 1,2- or 1,3-GDN if, indeed, they are found to be pharmacologically effective.     

A tumor metastasis‐associated molecule TWIST1 is a favorable target for cancer immunotherapy due to its immunogenicity

Although neoantigens are one of the most favorable targets in cancer immunotherapy, it is less versatile and costly to apply neoantigen‐derived cancer vaccines to patients due to individual variation. It is, therefore, important to find highly immunogenic antigens between tumor‐specific or associated antigens that are shared among patients. Considering the cancer immunoediting theory, immunogenic tumor cells cannot survive in the early phase of tumor progression including two processes: elimination and equilibrium. We hypothesized that highly immunogenic molecules are allowed to be expressed in tumor cells after an immune suppressive tumor microenvironment was established, if these molecules contribute to tumor survival. In the current study, we focused on TWIST1 as a candidate for highly immunogenic antigens because it is upregulated in tumor cells under hypoxia and promotes tumor metastasis, which is observed in the late phase of tumor progression. We demonstrated that TWIST1 had an immunogenic peptide sequence TWIST1_140–162, which effectively activated TWIST1‐specific CD4⁺ T‐cells. In a short‐term culture system, we detected more TWIST1‐specific responses in breast cancer patients compared with in healthy donors. Vaccination with the TWIST1 peptide also showed efficient expansion of TWIST1‐reactive HTLs in humanized mice. These findings indicate that TWIST1 is a highly immunogenic shared antigen and a favorable target for cancer immunotherapy.     

IFN‐α/β‐mediated NK2R expression is related to the malignancy of colon cancer cells

Neurokinin 2 receptor (NK2R), a G protein‐coupled receptor for neurokinin A (NKA), a tachykinin family member, regulates various physiological functions including pain response, relaxation of smooth muscle, dilation of blood vessels, and vascular permeability. However, the precise role and regulation of NK2R expression in cancer cells have not been fully elucidated. In this study, we found that high NK2R gene expression was correlated with the poor survival of colorectal cancer patients, and Interferon (IFN‐α/β) stimulation significantly enhanced NK2R gene expression level of colon cancer cells in a Janus kinas 1/2 (JAK 1/2)‐dependent manner. NKA stimulation augmented viability/proliferation and phosphorylation of Extracellular‐signal‐regulated kinase 1/2 (ERK1/2) levels of IFN‐α/β‐treated colon cancer cells and NK2R blockade by using a selective antagonist reduced the proliferation in vitro. Administration of an NK2R antagonist alone or combined with polyinosinic‐polycytidylic acid, a synthetic analog of double‐stranded RNA, to CT26‐bearing mice significantly suppressed tumorigenesis. NK2R‐overexpressing CT26 cells showed enhanced tumorigenesis and metastatic colonization in both lung and liver after the inoculation into mice. These findings indicate that IFN‐α/β‐mediated NK2R expression is related to the malignancy of colon cancer cells, suggesting that NK2R blockade may be a promising strategy for colon cancers.     

Successful allogeneic stem cell transplantation in two patients with acute myelogenous leukaemia and invasive aspergillosis by antifungal combination therapy

Invasive aspergillosis (IA) is an important cause of infectious morbidity and mortality in patients who undergo haematopoietic stem cell transplantation (HSCT). History of IA before allogeneic HSCT is still challenging because of the high risk of recurrence after HSCT. Recent advances in early‐stage diagnosis and new, more effective classes of antifungal agents have improved the management of IA in the HSCT recipients. We report two cases with acute myelogenous leukaemia after primary failure of induction chemotherapy with the patients developing pulmonary IA. They responded well to a combination of voriconazole (VCZ) and micafungin, resulting in a remarkable reduction of pulmonary IA lesions at short intervals. Thereafter, antifungal therapy was switched to liposomal amphotericin B (L‐AmB), followed by conditioning regimen for allogeneic HSCT, because of the possibility of VCZ altering the metabolism of chemotherapeutic agents and calcineurin inhibitors. Successful engraftment was achieved without severe adverse side‐effects or aggravation of IA after HSCT. Combining VCZ with micafungin followed by L‐AmB throughout HSCT could be advantageous in stabilising IA in HSCT patients.     

Antiplasmodial triterpenoids from Ekebergia capensis

From the stem bark of Ekebergia capensis, 10 new triterpenoid compounds, ekeberins A (1), B (2), C1 (3), C2 (4), C3 (5), D1 (6), D2 (7), D3 (8), D4 (9), and D5 (10), were isolated together with 17 known compounds. The structures of these new compounds were elucidated on the basis of the results of spectroscopic analysis, and the absolute configuration of compounds 6-10 were determined by partial synthesis from known compounds and using the Mosher ester method. Several of these compounds were screened in vitro against both chloroquine (CQ)-sensitive and -resistant Plasmodium falciparum isolates and were found to exhibit moderate antiplasmodial activity, with compounds 20 (7-deacetoxy-7-oxogedunin) and 27 (2-hydroxymethyl-2,3,22,23-tetrahydroxy-2,6,10,15,19,23-hexamethyl-6,10,14,18-tetracosatetraene) showing IC50 values of 6 and 7 microM, respectively. Compound 27 at a dose of 500 mg/kg showed moderate parasitemia suppression of 52.9% against P. berghei NK 65 in a mouse model.     

Precise anatomy of the vesico-uterine ligament for radical hysterectomy

OBJECTIVES: To clarify the anatomy of the vesico-uterine ligament (VUL), we meticulously separated the VUL under magnification (x2.5) during Okabayashi's radical hysterectomy. METHODS: Fifty-nine patients (TNM nomenclature: pTIb: 39, pT2a: 5, pT2b: 7, after trans-arterial anticancer-drug infusion treatment for the cervical cancer: 8) underwent this meticulous operation. Blood loss was recorded at two separate time points: during the separation of the VUL and after removal of the uterus. RESULTS: After complete separation of the uterine artery and superficial uterine vein from the ureter, we could identify the genuine connective tissue of the anterior leaf of the VUL in which we isolate and divide a distinct bundle of blood vessels: the cervicovesical vessels that cross over the ureter from the bladder to the cervix. The remaining tissues in the anterior leaf is only avascular connective tissue. The posterior leaf of the VUL is the tissue residing under the ureter connecting the posterior wall of the bladder and the lateral cervix/upper lateral vagina. In the connective tissues, we identified the middle and inferior vesical veins connecting with the deep uterine vein. The division of these veins could separate the urinary bladder with ureters completely from the lateral cervix and upper vagina. The mean blood loss during the separation of the VUL was 20+/-10 g (N=59) and after radical hysterectomy was 189+/-91.6 g (N=59). CONCLUSION: A precise network of blood vessels in the VUL is identified. The knowledge of this anatomy is important to perform radical hysterectomy.     

Development of the Japanese version of the Pediatric Quality of Life Inventory™ Brain Tumor Module

Background

The Pediatric Quality of Life Inventory? (PedsQL?) is a widely-used modular instrument for measuring health-related quality of life in children aged 2 to 18 years. The PedsQL? Brain Tumor Module is comprised of six scales: Cognitive Problems, Pain and Hurt, Movement and Balance, Procedural Anxiety, Nausea, and Worry. In the present study, we developed the Japanese version of the PedsQL? Brain Tumor Module and investigated its feasibility, reliability, and validity among Japanese children and their parents.

Methods

Translation equivalence and content validity were verified using the standard back-translation method and cognitive debriefing tests. Participants were recruited from 6 hospitals in Japan and the Children's Cancer Association of Japan, and questionnaires were completed by 137 children with brain tumors and 166 parents. Feasibility of the questionnaire was determined based on the amount of time required to complete the form and the percentage of missing values. Internal consistency was assessed using Cronbach's coefficient alpha. Test-retest reliability was assessed by retesting 22 children and 27 parents. Factorial validity was verified by exploratory factor analyses. Known-groups validity was described with regard to whole brain irradiation, developmental impairment, infratentorial tumors, paresis, and concurrent chemotherapy. Convergent and discriminant validity were determined using Generic Core Scales and State-Trait Anxiety Inventory for children.

Results

Internal consistency was relatively high for all scales (Cronbach's coefficient alpha > 0.70) except the Pain and Hurt scale for the child-report, and sufficient test-retest reliability was demonstrated for all scales (intraclass correlation coefficient = 0.45-0.95). Factorial validity was supported through exploratory factor analysis (factor-item correlation = 0.33-0.96 for children, 0.55-1.00 for parents). Evaluation of known-groups validity confirmed that the Cognitive Problems scale was sensitive for developmental impairment, the Movement and Balance scale for infratentorial tumors or paresis, and the Nausea scale for a patient currently undergoing chemotherapy. Convergent and discriminant validity with the PedsQL? Generic Core Scales and State-Trait Anxiety Inventory for children were acceptable.

Conclusions

The Japanese version of the PedsQL? Brain Tumor Module is suitable for assessing health-related quality of life in children with brain tumors in clinical trials and research studies.