Immunological evaluation of personalized peptide vaccination in refractory small cell lung cancer

Since the prognosis of small cell lung cancer (SCLC) remains poor, development of new therapeutic approaches, including immunotherapies, would be desirable. In the current study, to evaluate immunological responses in refractory SCLC patients, we conducted a small scale phase II clinical trial of personalized peptide vaccination (PPV), in which vaccine antigens are selected based on pre-existing host immunity. Ten refractory SCLC patients, who had failed to respond to chemo- and/or chemoradiotherapies (median number of regimens, 2.5; median duration, 20.5 months), were enrolled. A maximum of four human leukocyte antigen (HLA)-matched peptides showing higher antigen-specific humoral responses were subcutaneously administered (weekly for six consecutive weeks and then bi-weekly thereafter). PPV was terminated before the 3rd administration in four patients because of rapid disease progression, whereas the remaining six patients completed at least one cycle (six times) of vaccinations. Peptide-specific immunological boosting was observed in all of the six patients at the end of the first cycle of vaccinations, with their survival time of 25, 24.5 (alive), 10 (alive), 9.5, 6.5, and 6 months. Number of previous chemotherapy regimens and frequency of CD3(+) CD26(+) cells in peripheral blood were potentially prognostic in the vaccinated patients (hazard ratio [HR] = 2.540, 95% confidence interval [CI] = 1.188-5.431, P = 0.016; HR = 0.941, 95% CI = 0.878-1.008, P = 0.084; respectively). Based on the feasible immune responses in refractory SCLC patients who received at least one cycle (six times) of vaccinations, PPV could be recommended for a next stage of larger-scale, prospective clinical trials.     

p53 mutations in tumor and non-tumor tissues of thorotrast recipients: a model for cellular selection during radiation carcinogenesis in the liver.

Concerns over cancer development from exposure to environmental sources of densely ionizing, high linear energy transfer (LET) radiation, such as alpha-particles from radon, is a current public health issue. The study of tumors attributable to high LET irradiation would greatly augment our insights into the biological mechanisms of carcinogenesis. Chronic low-dose-rate internal exposure to alpha-radiation from thorium dioxide deposits following intravascular administration of the radiographic contrast agent Thorotrast is known to markedly increase the risk of cancer development, especially that of hepatic angiosarcomas and cholangiocarcinomas. Although the mechanism is hypothesized to be via cellular damage, DNA being a major target, wrought by the high LET alpha-particles, the specific genes and the actual sequence of events involved in the process of transforming a normal cell into a malignant one are largely unknown. To shed some light on the molecular mechanisms of cancer development during a lifetime exposure to alpha-radiation, we analyzed the most commonly affected tumor suppressor gene in humans, p53, in 20 Thorotrast recipients who developed cancer, mostly of hepatic bile duct and blood vessel origin. Of the 20 cases, 19 were found to harbor p53 point mutations. Moreover, the accompanying non-tumor tissues from these patients also had p53 mutations, albeit at lower frequency. The distribution pattern of the point mutations was significantly different between the non-tumor and tumor tissues, with most mutations in malignant tissues located in the highly conserved domains of the p53 gene. Our results support the idea that p53 mutations are important in the genesis of Thorotrast-induced tumors but that these point mutations are a secondary outcome of genomic instability induced by the irradiation. Additionally, non-tumor cells harboring p53 mutations may gain some survival advantage in situ but mutations in the domains responsible for the formation of structural elements critical in binding DNA may be necessary for a cell to reach full malignancy.     

The Kesennuma Study in Miyagi,Japan: Study Design and Baseline Profiles of Participants

BackgroundTo clarify the association between psychosocial problems and frailty in the areas affected by the Great East Japan Earthquake, and to develop strategies for preventive long-term care in the community, we launched the Kesennuma Study in 2019. This report describes the study design and the participants’ profiles at baseline.MethodsThe prospective study comprised 9,754 people (4,548 men and 5,206 women) randomly selected from community-dwelling independent adults aged 65 to 84 who were living in Kesennuma City, Miyagi. The baseline survey was conducted in October 2019. It included information on general health, socio-economic status, frailty, lifestyle, psychological factors (eg, personality, depressive moods), and social factors (eg, social isolation, social capital). A follow-up questionnaire survey is planned. Mortality, incident disability, and long-term care insurance certifications will also be collected.ResultsA total of 8,150 questionnaires were returned (83.6% response rate), and 7,845 were included in the analysis (80.4%; mean age 73.6 [standard deviation, 5.5] years; 44.7% male). About 23.5% were considered frail. Regarding psychological and social functions, 42.7% had depressive moods, 29.1% were socially isolated, and only 37.0% participated in social activities at least once a month. However, 82.5% trusted their neighbors.ConclusionWhile local ties were strong, low social activity and poor mental health were revealed as issues in the affected area. Focusing on the association between psychological and social factors and frailty, we aim to delay the need for long-term care for as long as possible, through exercise, nutrition, social participation, and improvement of mental health.Key words: frailty, community-dwelling older adults, population approach, Kesennuma Study, psychological and social functions     

Argon laser trabeculoplasty in black and white patients with primary open-angle glaucoma

The effect of argon laser trabeculoplasty (ALT) on lowering intraocular pressure (IOP) was studied retrospectively in 68 black patients and 42 white patients with uncontrolled primary open-angle glaucoma on maximally tolerated medical therapy. Patients with the diagnosis of pigmentary or pseudoexfoliation glaucoma and those having previous intraocular or laser surgery were excluded. While the mean age of the black patients (66.9 years) was lower than the white patients (72.2 years), the prelaser IOP was similar between the two groups: 26.2 mmHg for the black patients and 25.5 mmHg for the white patients. The mean IOP one year (18.4 mmHg for black patients and 18.4 mmHg for white patients) and two years (19.5 mmHg and 20.3 mmHg, respectively) after ALT was the same between the two groups of patients. A similar percentage of black (85%) and white (83%) patients showed more than a 15% decrease in IOP from their prelaser values one year after treatment. The IOP lowering effect of ALT decreased during the second post-operative year; but the diminished response was identical in patients of both races, with 71% of patients of both groups still showing greater than 15% reduction from their pre-laser IOP. We conclude that ALT is equally effective in lowering IOP for black and white patients with medically uncontrolled primary open-angle glaucoma.     

Clinical risk factors for poor neonatal outcomes in umbilical cord prolapse

Objectives: To clarify the clinical risk factors associated with poor neonatal outcomes due to umbilical cord prolapse (UCP).

Methods: A postal questionnaire survey was attempted in Japan. The clinical risk factors and managements associated with poor neonatal outcomes were analyzed in cases of UCP treated in Japan.

Results: A total of 267 cases of UCP (out of 2?037?460 total deliveries) were analyzed. The rates of intrauterine death, neonatal death and survival with disability were 3.4%, 5.6% and 7.1%, respectively. The multivariate regression analysis for these poor neonatal outcomes revealed that the significant risk factors included a prolapsed amniotic sac (adjusted odds ratio (aOR), 4.49), preterm labor (aOR, 2.99) and replacement of the prolapsed umbilical cord into the uterus (aOR, 2.87). However, UCP that occurred during labor (aOR, 0.28) and emergency cesarean section (aOR, 0.11) were associated with a reduction in the rates of poor outcomes. The interval between the diagnosis of UCP and delivery was significantly longer in the infants with a poor outcome than intact survival (median 30 versus 24?min, p?=?0.048).

Conclusion: An emergency cesarean section should be carried out immediately to ensure a better outcome for the infant.     

Clinical features of polyhydramnios associated with fetal anomalies

The purpose of this study was to examine the clinical features of pregnancy complicated by polyhydramnios associated with fetal anomalies. Sixty-nine patients with a singleton pregnancy complicated by polyhydramnios were retrospectively analyzed. Based on prenatal ultrasonographic findings, 13 cases were considered to have idiopathic polyhydramnios and the remaining 56 cases were associated with fetal anomalies. Between these two groups, no significant difference was found in the gestational weeks when polyhydramnios developed. However, significant difference was noted in the maximum amniotic fluid index (AFI) values during the pregnancy period; 25.4 +/- 2.7 cm in the former, and 30.6 +/- 8.9 cm in the latter (P = 0.0004). In all of 13 cases with idiopathic polyhydramnios, AFI values remained less than 30 cm until delivery. Twenty-two patients (39%) with fetal anomalies required a prenatal treatment such as amnioreduction and tocolysis, whereas only one patient (7.7%) with idiopathic polyhydramnios needed tocolysis therapy (P = 0.03). There was a significant risk of premature delivery with fetal anomalies (35.6 +/- 3.9 weeks' gestation vs. 38.8 +/- 1.5 weeks' gestation, P = 0.004) because of refractory polyhydramnios, rupture of membranes, non-reassuring fetal status, and intrauterine fetal death, and although most infants with idiopathic polyhydramnios were appropriate-for-dates, many of the infants with congenital anomalies were small-for-dates. Significant risk of fetal anomalies should be considered in pregnant women with severe polyhydramnios (AFI > or = 30 cm), an increased trend of amniotic fluid during the pregnancy period, polyhydramnios requiring a prenatal treatment, or fetal growth restriction. On the other hand, based on our experience, a fetus without these conditions seems to have a low risk of congenital anomalies even if polyhydramnios is noted.     

Colorectal Cancer Screening Program in Songjiang district,Shanghai between 2015 and 2017: Evaluation of participation rate and the associated factor

Little is known about the participation rate of newly implemented colorectal cancer (CRC) screening programs in China. Our goals were to identify factors associated with nonparticipation for CRC screening in Songjiang District, Shanghai.We analyzed individuals included in an observational cohort study from 4 towns (Xin Qiao, She Shan, Mao Gang, and Zhong Shan) in Songjiang District. The participation rate was calculated for the CRC screening program based on a fecal immunochemical test and a risk assessment questionnaire between 2015 and 2017 inclusive.Of the 27,130 individuals eligible for inclusion in this study, 20,863 (76.9%) participated in CRC screening at least once during 2015 and 2017. The factors linked with nonparticipation were; being male (odds ratio [OR] 0.87, 95% confidence interval [CI] 0.82–0.93, P < .01), unmarried (OR 0.71, 95% CI 0.64–0.80, P < .01), having a high education level (middle school, OR 0.82, 95% CI 0.74–0.90, P < .01, high school or above, OR 0.64, 95% CI 0.57–0.73, P < .01), absence of chronic disease (OR 0.90, 95% CI 0.85–0.96, P < .01), and living in 2 out of the 4 towns covered (Xin Qiao, OR 0.72, 95% CI 0.66–0.78, P < .01, Zhong Shan, OR 0.29, 95% CI 0.26–0.31, P < .01).The current study revealed several associated factors with nonparticipation for the CRC screening in Songjiang district. These findings will help identify target populations that require an individualized approach to increase the participation rate.     

Massive cystic lymphangiomas of a fetus

We present a fetus with progressive massive subcutaneous lymphangiomas leading to intrauterine death. A 28-year-old woman was referred to our hospital because of a precordial cystic mass of the fetus. An ultrasound revealed lymphangiomas extending from bilateral axillae to the anterior chest wall. At 18 weeks' gestation, amniocentesis was performed and the karyotype of the fetus was found to be normal 46, XY. Thereafter the lesions increased in size gradually and spread over the body. Amniotic fluid decreased, pericardial, and pleural effusion appeared, and cardiomegaly became evident. The fetus died in utero at 25 weeks' gestation. Postmortem examination revealed a male fetus surrounded with multicystic soft masses spreading over the body, and syndactyly (left third and fourth fingers) was present. Histologically, a number of irregularly dilated lymphatics extended through subcutaneous tissues to the skeletal muscles. No communications between the cysts and the thoracic or abdominal cavity existed, and no lymphatic dilations in the viscera were confirmed. As far as we know, such conditions have rarely been reported. Considering that in previous literature, a favorable prognosis of a fetus with an atypically located (lateral cervical or non-cervical) lymphangioma with a normal karyotype has been reported, our case may be included in a distinct pathological entity. When we find a lymphangioma in a fetus, careful follow-up by ultrasound is mandatory.     

Conotoxin GIIIA: selective inhibition of 22Na influx via voltage-dependent Na channels in adrenal medullary cells

Summary Conotoxin GIIIA and GIIIB from the marine snail Conus geographus have been reported to inhibit voltage-dependent Na channels in skeletal muscle and postganglionic sympathetic neuron, but have no effect on Na channels in brain, giant axon and heart. In eel electroplax, conotoxins were also shown to share the common binding sites with saxitoxin (see review Gray et al. 1988).In bovine adrenal medullary cells, conotoxin GIIIA inhibited veratridine-induced influx of ²²Na, ⁴⁵Ca and secretion of catecholamines with an IC₅₀ of 6 mol/l, while saxitoxin suppressed veratridine-induced responses with an IC₅₀ of 6.3 nmol/l. [³H]Saxitoxin binding to the cells was inhibited by unlabeled saxitoxin with an IC₅₀ of 5.1 nmol/l, but was slightly reduced by 10 mol/l conotoxin GIIIA. Conotoxin GIIIA, at 10 mol/l, did not alter carbachol-induced influx of ²²Na, ⁴⁵Ca and secretion of catecholamines as well as high K-induced ⁴⁵Ca influx and catecholamine secretion.These results indicate that conotoxin GIIIA, at concentrations 950 fold higher than saxitoxin, inhibits Na influx via voltage-dependent Na channels, but has no effect on the nicotinic receptor-ion channel complex or the voltage-dependent Ca channels. Conotoxin GIIIA seems to bind at the sites which are distinct from saxitoxin, but are functionally linked to the voltage-dependent Na channels. Conotoxins may be useful for the classification of Na channels in excitable cell membranes. Send offprint requests to A. Wada at the above address     

Bowel Obstruction due to Shiitake Mushrooms: Diagnostic Features on Computed Tomography

Shiitake mushrooms are edible mushrooms popular in East Asian cuisine. We herein report a 69-year-old man with abdominal distension and vomiting after ingesting several pieces of sautéed Shiitake mushrooms. Abdominal computed tomography (CT) revealed ring-shaped and crescent-shaped low-density objects (-100 to -300 Hounsfield units) in the ileum. Based on the specific shapes and CT numbers of the foreign bodies, he was diagnosed with small bowel obstruction due to Shiitake mushrooms. After conservative treatment, he passed four pieces of Shiitake mushrooms. Despite the rarity, the condition can be diagnosed before exploratory surgery by careful and detailed interpretation of CT findings.