pH-sensitive carbonate apatite nanoparticles as DNA vaccine carriers enhance humoral and cellular immunity

To demonstrate the potential of pH-sensitive carbonate apatite (CO₃Ap) nanoparticles as DNA vaccine carriers to enhance vaccination efficacy, we examined the humoral and cellular immune responses of C57BL/6 mice immunized with the plasmid expression vector pCI-neo encoding the full-length soluble ovalbumin (OVA) (pCI-neo-sOVA), pCI-neo-sOVA/CO₃Ap complexes, or pCI-neo/CO₃Ap complexes as a control. Mice immunized with a low dose of pCI-neo-sOVA-loaded CO₃Ap (10 μg) produced ex vivo splenocyte proliferation after stimulation with CD8 T-cell but not CD4 T-cell epitopes and a delayed-type-hypersensitivity reaction more efficiently than mice in the other groups. Furthermore, mice receiving this immunization generated the same levels of OVA-specific antibodies and interferon (IFN)-γ secretion after CD8 T-cell and CD4 T-cell epitope challenges as those in mice treated with 100 μg of free pCI-neo-sOVA, whereas mice injected with a high dose of pCI-neo-sOVA-loaded CO₃Ap (100 μg) or with control plasmids produced negligible levels of OVA-specific antibodies or IFN-γ. Therefore, our results showed that 10 μg of pCI-neo-sOVA delivered by CO₃Ap strongly elicited humoral and cellular immune responses. This study is the first to demonstrate the promising potential of CO₃Ap nanoparticles for DNA vaccine delivery.     

Association between magnetic resonance imaging characteristics and pathological findings in entire posterior cruciate ligament with mucoid degeneration

Magnetic resonance imaging (MRI) findings of a tram-track appearance and celery stalk appearance in mucoid degeneration of the cruciate ligament are valuable; however, their pathological basis is unclear. Because these appearances are generally seen throughout the entire ligament, the association between MRI findings and pathological findings must be verified in specimens of the whole degenerated ligament, including the ligamentous attachments to bone. We herein report two cases of mucoid degeneration of the posterior cruciate ligament with osteoarthritis of the knee requiring total knee arthroplasty. The entire degenerated ligament, including the ligamentous attachments to bone, was removed and pathologically evaluated. On pathological examination, the central portion of the lesion showed typical mucoid degeneration, whereas the marginal and adherent portions showed normal ligament tissue, consistent with a tram-track appearance on T2-weighted MRI. The fibrous normal ligament tissues in the longitudinal direction in regions of mucoid degeneration were consistent with a celery stalk appearance on T2-weighted MRI. No mucoid degeneration was found in the attachment area. The tram-track appearance and celery stalk appearance of mucoid degeneration on MRI can be explained by the pathological findings.     

Early onset of efficacy with fremanezumab in patients with episodic and chronic migraine: subanalysis of two phase 2b/3 trials in Japanese and Korean patients

BackgroundEarly onset of action has become recognized as an important efficacy feature of preventive migraine treatment, which can help overcome adherence issues commonly associated with older medications. Preventive treatments that target the calcitonin gene-related peptide (CGRP) or the CGRP receptor have been previously shown to provide early onset of action.MethodsThis subanalysis of primary endpoints of two separate phase 2b/3 studies sought to determine the onset of action of fremanezumab in Japanese and Korean patients with episodic migraine (EM) and chronic migraine (CM).ResultsIn EM patients (n = 357), both fremanezumab quarterly and fremanezumab monthly led to greater reductions in weekly migraine days (days/week) than placebo from the first week after the initial injection and thereafter during the remainder of the study period. Similarly, CM patients (n = 571) had a greater reduction in headache days of at least moderate severity (days/week) with fremanezumab (total) than placebo. The percentage of patients with a migraine day (EM) or headache day at least moderate severity (CM) was lower in those treated with fremanezumab than placebo and this effect was apparent from as early as Day 2 (1 day after first injection).ConclusionsThese results suggest that fremanezumab has an early onset of action, as noted in previous post hoc analyses of anti-CGRP monoclonal antibodies.Trial registrationClinicalTrials.gov. {"type":"clinical-trial","attrs":{"text":"NCT03303092","term_id":"NCT03303092"}}NCT03303092, Registered 5 October 2017, {"type":"clinical-trial","attrs":{"text":"NCT03303079","term_id":"NCT03303079"}}NCT03303079, Registered 5 October 2017.     

Association of gBRCA1/2 mutation locations with ovarian cancer risk in Japanese patients from the CHARLOTTE study

Whether germline (g) breast cancer susceptibility gene (BRCA) mutations are located within or outside the ovarian cancer cluster region (OCCR) (1380‐4062 bp for gBRCA1, and between 3249‐5681 bp and 6645‐7471 bp for gBRCA2) may influence risk variations for ovarian cancers. This ad hoc analysis of the CHARLOTTE epidemiological study in Japan assessed the distribution of gBRCA1/2 mutations in patients with newly diagnosed ovarian cancer, and investigated an association between gBRCA1/2 mutation locations and ovarian cancer risk. Differences in patient background and clinical characteristics in subgroups stratified by gBRCA1/2 mutation locations were also evaluated. We analyzed the data of 93 patients (14.7%) from the CHARLOTTE study who were positive for gBRCA1/2 mutations. After excluding 16 cases with L63X founder mutation, 28 (65.1%) of gBRCA1 mutations were within the OCCR. Of 30 gBRCA2 mutations, 15 (50.0%) were within the OCCR. Of 27 patients (one patient excluded for unknown family history) with gBRCA1 mutations located in the OCCR, 11 (40.7%) had a family history of ovarian cancer; the proportion of patients with a family history of ovarian cancer and gBRCA1 mutations outside the OCCR was lower (13.3%). Sixty percent of patients with gBRCA1 mutations outside the OCCR had a family history of breast cancer; the proportion of patients with a family history of breast cancer and gBRCA1 mutations within the OCCR was relatively lower (33.3%). Understanding the mutation locations may contribute to more accurate risk assessments of susceptible individuals and early detection of ovarian cancer among gBRCA mutation carriers.     

Prognostic Factors in the Surgical Treatment of Ruptured Abdominal Aortic Aneurysms

Although the operative mortality following elective aneurysmectomy has achieved satisfactory results, that following surgery for ruptured abdominal aortic aneurysms (AAAs) remains high. The purpose of this study was to identify the factors affecting the mortality rate associated with the treatment of ruptured AAAs. Between 1978 and 1999, 33 patients underwent emergency surgery for a ruptured AAA. The operative mortality was 33.3% and in-hospital mortality was 6.0%. Hypotension, defined as a systolic blood pressure <80 mmHg, was seen in 19 patients at the time of presentation, 9 of whom underwent surgery in this state. In the remaining 10 patients, it was possible to increase the systolic blood pressure to ≥80 mmHg preoperatively. Of the 11 patients who died within 30 days of surgery, 9 had hypotension at the time of induction of anesthesia and only 2 had a systolic blood pressure of ≥80 mmHg. A satisfactory outcome was achieved in patients whose condition met the following criteria: a systolic blood pressure ≥80 mmHg at the time of operation, minimal aortic cross-clamping time, less blood loss and blood transfusions, and a shorter operation time to repair the ruptured AAA. Concomitant heart disease was also found to be an important prognostic factor. Received: June 16, 1999 / Accepted: March 24, 2000     

Predictive factors for long-term survival in patients with intrahepatic cholangiocarcinoma

BACKGROUND: In order to elucidate the predictive factors for long-term survival in patients with intrahepatic cholangiocarcinoma (ICC), we evaluated 7 patients who survived for more than 5 years (5-year survivors). METHODS: We examined the clinicopathologic and biologic factors of the 5-year survivors, and these findings were then compared with those in 20 patients who died within 5 years after surgery (control group). RESULTS: In the 5-year survivors, the gross appearance of the tumors included a mass-forming (MF) type in 5 cases, an intraductal growth (IG) type in 1, and another type (microcarcinoma with hepatolithiasis) in 1. No case demonstrated a periductal infiltrating (PI) type. Except for 1 case with an IG type tumor, no lymph node metastasis was seen in any patients. All of the 5-year survivors were classified from stage I to III, and all also underwent a curative resection. The clinicopathologic factors demonstrating significant differences between the 5-year survivors and the control group included the gross type of the tumor, lymph node involvement, the surgical margin, curability, and pTNM stage. CONCLUSION: The predictive factors for long-term survival in patients with ICC are thus suggested to include not only tumor staging and curability, but also lymph node metastasis and the gross type of the tumors.     

Combined Assay of Serum Levels of CA125 and CA19-9 in Endometrial Carcinoma

Serum levels of CA125 and CA19-9 were examined in 225 cases with endometrial carcinoma before treatment and 32 cases with recurrent endometrial carcinoma. The positive rates in the 225 cases were 27.1% for CA125, 24.0% for CA19-9, and 38.7% for the combined assay. The serum levels of both CA125 and CA19-9 significantly increased with surgical staging. The presence of lymph node metastasis and extrauterine spread exhibited a marked influence on the serum levels of both CA125 and CA19-9. Myometrial invasion and vessel permeation also increased serum levels of CA125, whereas peritoneal cytology and adnexal metastasis exhibited no influence on CA125 levels or CA19-9 levels. Twenty-five of 33 cases who showed either more than 100 U/ml of CA125 level or more than 100 U/ml of CA19-9 level were classified as surgical stage III or IV. The combined assay demonstrated a 71.9% positive rate at the time of detection of the recurrence (65.6% for CA125, 43.7% for CA19-9). In 34.4% of the 32 recurrent cases, elevated levels of the tumor markers were the first sign of recurrence. These data indicate that the use of CA19-9 in combination with CA125 is noteworthy in the management of patients with endometrial carcinoma.     

The mechanism of growth-regulation of glioma cells by trapidil

Summary Trapidil is a PDGF antagonist that can inhibit the proliferation of the PDGF-producing glioma cells, U251MG. As the mechanism of growth-regulation by trapidil remains unclear, we studied its effect on the growth of U251MG cells. We performed a cell cycle analysis and examined the intracellular transduction pathway and oncogene expression in serum-stimulated glioma cells with or without trapidil.After the serum starvation for 3 days, glioma cell proliferation was stimulated by the addition of serum. Cell cycle analysis showed that cell cycle perturbations induced by trapidil included a decreased transition rate from G₀-G₁ to S phase, suggesting that some metabolic event is required for progress through the G₀-G₁ phase and that this event is sensitive to trapidil. Internal signal transduction mechanisms are central in the molecular control of cell growth. One such regulator is the protein kinase C(PKC) system and the c-fos gene is likely to be a direct target of intracellular signal transduction pathways. Therefore, we hypothesize that the intracellular PKC activity and c-fos expression of the trapidil-treated cells are suppressed. We posit that trapidil affects the intracellular signal transduction pathway PKC activity and c-fos expression in cells stimulated with serum containing growth factors.     

Prognostic factors in patients who survived more than 10 years after undergoing surgery for metastatic brain tumors: report of 5 cases and review of the literature

BACKGROUND: Although the overall prognosis of patients with metastatic brain tumors is dismal, a small number survive longer than 10 years after craniotomy. We report 5 patients who survived for more than 10 years after undergoing treatment for metastatic brain tumor. METHODS: The 5 patients who survived for more than 10 years after undergoing craniotomy were among 56 consecutively treated patients with solitary metastatic brain tumors. We retrospectively examined their clinical course, treatment, and variables associated with their longer survival and compared these 5 patients with other reported cases of metastatic brain tumor. RESULTS: The histologic tumor types and the sites of origin of the primary tumor varied: two were from lung cancer and one each was from colon cancer, renal cell, and cervical carcinoma of the uterus. Common features among the long-term survivors were: systemic disease was absent, the metastatic tumor was located in the non-eloquent area of the non-dominant hemisphere, they were in good neurologic condition before surgery, there was a long interval between the diagnosis and treatment of the primary lesion and the diagnosis of the brain metastasis, and the patients received postoperative irradiation/chemotherapy. CONCLUSION: Aggressive surgical treatment may be justified in young patients with a solitary metastatic brain tumor, as long as they are free of active systemic metastases.     

Saphenous vein grafting for Peyronie's disease: a case report

We present a case of Peyronie's disease in a 50-year-old male with a progressive, painful induration (3 x 2 x 0.5 cm) in the dorsal region of the penis. In order to correct the high degree of penile curvature, we made a venous patch graft from the saphenous vein under general anesthesia and straightened the penis. Six months after the operation, a recurrent induration was observed in the proximal region of the penis, and the penis became slightly shortened.