Tumor-related leukocytosis is associated with poor radiation response and clinical outcome in uterine cervical cancer patients.

BACKGROUND: To evaluate response to radiation and clinical outcome of uterine cervical cancer patients with tumor-related leukocytosis (TRL) at initial diagnosis and during definitive radiotherapy. PATIENTS AND METHODS: We retrospectively analyzed 2456 patients with stage IA-IVA uterine cervical cancer who received definitive radiotherapy with (37.4%) or without (62.6%) platinum-based chemotherapy between 1986 and 2012. TRL was defined as two or more occurrences of leukocytosis over 9000/µl at the time of diagnosis and during the course of treatment. Locoregional failure-free survival (LFFS) and overall survival (OS) were compared between patients with or without TRL. RESULTS: The median age of all patients was 55 years, and the median follow-up time was 65.1 months. TRL was observed in 398 patients (16%) at initial diagnosis; TRL (+) patients were younger and had larger tumors, advanced stage, and more frequent lymph node metastases (all P < 0.05). TRL (+) patients showed a significantly lower rate of complete remission than TRL (-) patients (89.9% versus 96.3%, respectively, P = 0.042). Ten-year LFFS and OS for all patients were 84% and 78%, respectively. LFFS and OS were significantly lower in TRL (+) patients than TRL (-) patients (10-year LFFS: 69% versus 87% respectively, P < 0.001; 10-year OS: 63% versus 81% respectively P < 0.001). After propensity score matching, LFFS and OS rates in TRL (+) patients remained significantly lower than for TRL (-) patients; this significant difference was also observed on multivariate analysis. Twenty-six percent of patients with locoregional failure (n = 345) were TRL (+) and had significantly poorer median OS (6 versus 12 months, P = 0.001). CONCLUSION: This study reveals the aggressive nature of cervical cancer with TRL and its poor response to radiation therapy. Given the unfavorable prognosis and higher probability of treatment failure, optimal diagnostic and therapeutic approaches and careful monitoring for early detection of recurrence should be considered for these patients.

Dopaminergic manipulations and its effects on neurogenesis and motor function in a transgenic mouse model of Huntington's disease.

Huntington's disease (HD) is an inherited neurodegenerative disorder that is classically defined by a triad of movement and cognitive and psychiatric abnormalities with a well-established pathology that affects the dopaminergic systems of the brain. This has classically been described in terms of an early loss of dopamine D2 receptors (D2R), although interestingly the treatments most effectively used to treat patients with HD block these same receptors. We therefore sought to examine the dopaminergic system in HD not only in terms of striatal function but also at extrastriatal sites especially the hippocampus, given that transgenic (Tg) mice also exhibit deficits in hippocampal-dependent cognitive tests and a reduction in adult hippocampal neurogenesis. We showed that there was an early reduction of D2R in both the striatum and dentate gyrus (DG) of the hippocampus in the R6/1 transgenic HD mouse ahead of any overt motor signs and before striatal neuronal loss. Despite downregulation of D2Rs in these sites, further reduction of the dopaminergic input to these sites by either medial forebrain bundle lesions or receptor blockade using sulpiride was able to improve both deficits in motor performance and adult hippocampal neurogenesis. In contrast, a reduction in dopaminergic innervation of the neurogenic niches resulted in impaired neurogenesis in healthy WT mice. This study therefore provides evidence that D2R blockade improves hippocampal and striatal deficits in HD mice although the underlying mechanism for this is unclear, and suggests that agents working within this network may have greater effects than previously thought.

Is elective nodal irradiation beneficial in patients with pathologically negative lymph nodes after neoadjuvant chemotherapy and breast-conserving surgery for clinical stage II-III breast cancer? A multicentre retrospective study (KROG 12-05).

BACKGROUND: To evaluate the effects of elective nodal irradiation (ENI) in clinical stage II-III breast cancer patients with pathologically negative lymph nodes (LNs) (ypN0) after neoadjuvant chemotherapy (NAC) followed by breast-conserving surgery (BCS) and radiotherapy (RT). METHODS: We retrospectively analysed 260 patients with ypN0 who received NAC followed by BCS and RT. Elective nodal irradiation was delivered to 136 (52.3%) patients. The effects of ENI on survival outcomes were evaluated. RESULTS: After a median follow-up period of 66.2 months (range, 15.6-127.4 months), 26 patients (10.0%) developed disease recurrence. The 5-year locoregional recurrence-free survival and disease-free survival (DFS) for all patients were 95.5% and 90.5%, respectively. Pathologic T classification (0-is vs 1 vs 2-4) and the number of LNs sampled (<13 vs ≥13) were associated with DFS (P=0.0086 and 0.0012, respectively). There was no significant difference in survival outcomes according to ENI. Elective nodal irradiation also did not affect survival outcomes in any of the subgroups according to pathologic T classification or the number of LNs sampled. CONCLUSIONS: ENI may be omitted in patients with ypN0 breast cancer after NAC and BCS. But until the results of the randomised trials are available, patients should be put on these trials.

Intermediate-risk grouping of cervical cancer patients treated with radical hysterectomy: a Korean Gynecologic Oncology Group study.

BACKGROUND: In this study, we sought to identify a criterion for the intermediate-risk grouping of patients with cervical cancer who exhibit any intermediate-risk factor after radical hysterectomy. METHODS: In total, 2158 patients with pathologically proven stage IB-IIA cervical cancer with any intermediate-risk factor after radical hysterectomy were randomly assigned to two groups, a development group and a validation group, at a ratio of 3 : 1 (1620 patients:538 patients). To predict recurrence, multivariate models were developed using the development group. The ability of the models to discriminate between groups was validated using the log-rank test and receiver operating characteristic (ROC) analysis. RESULTS: Four factors (histology, tumour size, deep stromal invasion (DSI), and lymphovascular space involvement (LVSI)) were significantly associated with disease recurrence and included in the models. Among the nine possible combinations of the four variables, models consisting of any two of the four intermediate-risk factors (tumour size ≥3 cm, DSI of the outer third of the cervix, LVSI, and adenocarcinoma or adenosquamous carcinoma histology) demonstrated the best performance for predicting recurrence. CONCLUSION: This study identified a 'four-factor model' in which the presence of any two factors may be useful for predicting recurrence in patients with cervical cancer treated with radical hysterectomy.

Short communication: antiviral activity of subcritical water extract of Brassica juncea against influenza virus A/H1N1 in nonfat milk.

Subcritical water extract (SWE) of Brassica juncea was studied for antiviral effects against influenza virus A/H1N1 and for the possibility of application as a nonfat milk supplement for use as an "antiviral food." At maximum nontoxic concentrations, SWE had higher antiviral activity against influenza virus A/H1N1 than n-hexane, ethanol, or hot water (80°C) extracts. Addition of 0.5mg/mL of B. juncea SWE to culture medium led to 50.35% cell viability (% antiviral activity) for Madin-Darby canine kidney cells infected with influenza virus A/H1N1. Nonfat milk supplemented with 0.28mg/mL of B. juncea SWE showed 39.62% antiviral activity against influenza virus A/H1N1. Thus, the use of B. juncea SWE as a food supplement might aid in protection from influenza viral infection.

Increased risk for post-operative corneal injuries in patients who undergo laparoscopic gynecologic surgery.

BACKGROUND: The objective of this study was to verify whether or not the incidence of post-operative corneal injuries (PCIs) in patients who undergo laparoscopic gynecologic surgery is higher than patients who undergo non-laparoscopic gynecologic surgery. METHODS: The peri-operative variables were extracted from the medical records of patients who underwent gynecologic surgery under general anesthesia at our institute between January 2004 and June 2010. The extracted variables were age, day of week of surgery, type of surgery (laparoscopy vs. non-laparoscopy), surgical scheduling (elective vs. emergent), pre-operative hemoglobin, surgery time, peri-operative transfusions, and PCIs. The association of peri-operative variables with PCIs was examined using univariate and multivariate analyses. RESULTS: A total of 6992 consecutive patients were included in this study. PCIs occurred in 23 patients (0.3%). Based on univariate analysis, the type of surgery and surgery times were associated with PCIs. Based on multivariate analysis, laparoscopy and lengthy surgery times significantly increased the risk for PCIs. The median duration of PCI symptoms was 3 days (range, 1-11 days); no patient had long-term sequalae. CONCLUSION: Laparoscopic gynecologic surgery increases the incidence of PCI compared with non-laparoscopic gynecologic surgery.

Systematic analysis of swine leukocyte antigen-DRB1 nucleotide polymorphisms using genomic DNA-based high-resolution genotyping and identification of new alleles.

In an attempt to enable comprehensive high-resolution genotyping of the swine leukocyte antigen (SLA) gene, we performed a systemic analysis of nucleotide polymorphisms at introns 1 and 2 and exon 2 from diverse alleles of SLA-DRB1 and DRB1 pseudogenes. We amplified and cloned 16 partial sequences of SLA-DRB1 and DRB2 introns 1 and 2 from different alleles, and analyzed them together with sequences of four reported SLA-DRB pseudogenes, DRB2, 3, 4, and 5. The results showed the presence of extreme nucleotide variations within introns 1 and 2 of SLA-DRB-related genes including substitutions and deletions. On the basis of these results, we developed a comprehensive genotyping method for SLA-DRB1 by genomic polymerase chain reaction (PCR) and subsequent direct sequencing. A total of 415 animals were genotyped and 67 allelic combinations from 18 DRB1 alleles were identified. Among them, two alleles, SLA-DRB1*kn04 and *kn05, were previously unreported. SLA-DRB1 genotyping results from this study combined with those of SLA-DQB1 from our previous study presented 10 SLA class II haplotypes, three of which were previously unreported. Population analysis using seven different pig breeds showed differences in the allele frequency of SLA-DRB1 among breeds. Our results should benefit biological experiments requiring sequence-level genotyping results of SLA-DRB1 and further study of the complete genetic diversity of SLA-DRB1 using field samples.

Safety and Efficacy of Stent-Assisted Coiling of Unruptured Intracranial Aneurysms Using Low-Profile Stents in Small Parent Arteries.

BACKGROUND AND PURPOSE: Stent-assisted coiling of intracranial aneurysms arising from small vessels (≤ 2.0 mm) is a common procedure. However, data regarding its treatment outcomes are scarce. This study evaluated the clinical and radiologic outcomes of stent-assisted coiling using low-profile stents for aneurysms of small parent arteries. MATERIALS AND METHODS: From November 2015 to October 2020, sixty-four patients with 66 aneurysms arising from parent arteries of ≤2.0 mm were treated with stent-assisted coiling using a Low-Profile Visualized Intraluminal Support Junior (LVIS Jr) or the Neuroform Atlas stent in a single institution. The clinical and radiologic data were retrospectively reviewed, and the risk factors for procedure-related complications were evaluated. RESULTS: The LVIS Jr and Neuroform Atlas stents were used in 22 (33.3%) and 44 (66.7%) cases, respectively. Technical success was achieved in 66 cases (100%). Immediate postprocedural aneurysm occlusion grades assessed by the Raymond-Roy occlusion classification were I (57.6%), II (19.7%), and III (22.7%), respectively. Procedure-related complications occurred in 10 cases (15.2%), with 8 thromboembolic complications (12.1%) and 2 hemorrhagic complications (3.0%). Procedure-related morbidity was 4.5% without mortality. On multivariate analysis, current smoking (odds ratio = 7.1, P = .021) had a statistically significant effect on procedure-related complications. CONCLUSIONS: Stent-assisted coiling of intracranial aneurysms with low-profile stents in small vessels (≤ 2.0 mm) had a 100% success rate and a 15.2% overall complication rate with 4.5% morbidity. Current smoking was a significant risk factor associated with procedure-related complications.

A purified group A streptococcal pyrogenic exotoxin. Physiochemical and biological properties including the enhancement of susceptibility to endotoxin lethal shock.

Purified pyrogenic exotoxin from Group A streptococcal filtrates (Streptococcus pyogenes, type 10, strain NY-5) has been characterized primarily as a protein complexed with hyaluronic acid. Amino acid composition and analysis revealed a typical acidic protein with an average molecular weight of 29,000. The purified exotoxin was free of streptolysins O and S, nicotinamide adenine dinucleotidases (NADases), deoxyribonucleases (DNases), mucopeptide, and endotoxins. The biological activity was destroyed when the exotoxin was heated at 65 degrees C for 30 min or boiled for 2 min. The biological activities investigated were pyrogenicity in rabbits (minimal pyrogenic dose-3 hr, 0.07 microg/kg), lethality in rabbits (LD(50), 3500 microg/kg), skin test dose in human skin (> 10(9) skin test doses, per mg toxin), cytotoxicity of rabbit spleen macrophage (Cytotoxic Index 0.5-10 microg/ml), enhancement of susceptibility to endotoxin shock (in rabbits > 100,000-fold), and antigenic analysis (A-type toxin). The exotoxin was immunogenic and it was possible, therefore, to immunize animals against the various toxic activities. The immunity was specific for the A-type toxin. The clinical implications of the highly significant enhancement effect of these exotoxins are discussed. It is suggested that clinical or subclinical infection with Group A streptococci could prepare the host for fatal shock from Gram-negative infections or the inadvertent injection of small amounts of Gram-negative bacterial endotoxins.

Simple and comprehensive SLA-DQB1 genotyping using genomic PCR and direct sequencing.

To enable the efficient analysis of a highly polymorphic swine major histocompatibility complex (MHC) class II gene, swine leukocyte antigen (SLA)-DQB1, we developed a simple and comprehensive high-resolution genotyping protocol. To obtain sufficient sequence information to design a set of common genotyping primers for SLA-DQB1, we cloned SLA-DQB1 introns 1 and 2 from 11 alleles with official four-digit allelic designations and sequenced the regions directly surrounding the SLA-DQB1 exon 2. Significant intronic nucleotide variations, including several deletions, were identified. Based on 733-bp assembled genomic sequences including introns 1 and 2 and exon 2 from 11 different alleles, a primer set was identified that allowed the ubiquitous amplification and analysis of the complete SLA-DQB1 exon 2 sequence. We then developed a method to directly sequence the amplified polymerase chain reaction (PCR) products without further experimental steps. We especially focused on avoiding superimposed peaks, which arose from the presence of allelic deletions, in the sequencing electropherogram of SLA-DQB1 heterozygous animals. The genotyping accuracy was evaluated by comparing the results of genomic sequence-based typing (GSBT) with those of other available methods, including cDNA sequence-based typing (SBT), low-resolution PCR typing with sequence-specific primers, allelic segregation analysis, and heterozygote simulation typing. In all cases, the results were consistent between SLA-DQB1 GSBT and previously reported methods or expected results. We applied it to genotype 350 animals from seven pig breeds. The observed level of heterozygosity from our genotyping was ∼51%, reflecting that a large portion of the animals were inbred miniature pigs. Among the seven pig breeds tested, the allelic diversity of SLA-DQB1 was highest in Berkshire pigs. In conclusion, we have developed a simple and effective SLA-DQB1 GSBT method by combining simple genomic DNA PCR and direct sequencing. Our new method may aid in the study of SLA diversity and disease resistance and susceptibility.

Acid-base alterations during laparoscopic abdominal surgery: a comparison with laparotomy.

BACKGROUND: Carbon dioxide insufflation during laparoscopic surgery results in an acid-base imbalance. The purpose of this study was to investigate the effect of pneumoperitoneum on the acid-base status using Stewart's approach. METHODS: Thirty patients undergoing abdominal surgery were allocated to the laparotomy group (n=15) or the laparoscopy group (n=15). The acid-base parameters were measured 10 min after the induction (T1), 40 min after opening the peritoneum or pneumoperitoneum according to the group (T2), at the end of the surgery (T3), and 1 h after the surgery (T4). RESULTS: There were no significant differences in the standard base excess (SBE), strong ion gap, or anion gap between the two groups. In both groups, the SBE decreased at T2, T3, and T4 compared with baseline value. At T3 and T4 in the laparotomy group, the apparent strong ion difference (SIDa) and pH were decreased whereas the lactate and chloride were increased compared with their baseline values. At T2 in the laparoscopy group, the pH was decreased whereas Pa(CO(2)) was increased compared with their baseline values. CONCLUSIONS: The decrease in the pH during the pneumoperitoneum was affected by the increase in Pa(CO(2)), which promptly returned to a normal value after the desufflation. On the other hand, the decrease in the pH after laparotomy was affected by the metabolic factors, which persisted an hour after the surgery.

Prevalence of hepatic parasites in Korean wild rats (Rattus norvegicus) and their association with pulmonary arteriolar medial hypertrophy.

C hepatica, an important zoonotic parasite, and C fasciolaris are common parasites in rodents. In rodent livers, C hepatica causes sequential morphologic changes that are designated as early, intermediate, or late phase, and C fasciolaris forms cysts surrounded by fibroplasia and granulomatous inflammation. The present study describes the prevalence of these parasites and associated liver and lung lesions in wild rats (Rattus norvegicus) living around pig farms in South Korea. Selected parenchymal organs, including liver and lung, of 89 wild rats were examined. Of 89 rats, 28 (31.5%) were infected with either C hepatica or C fasciolaris or with both parasites. Severe medial hypertrophy of small arterioles was observed in the lungs of 11 of the 28 parasite-infected rats (P < .01). The pulmonary arteriolar hypertrophy in the rats infected with C hepatica was strongly associated with early and/or intermediate phases (88.8%) of morphologic change in the livers (P < .01). As such, this report is the first to suggest a significant association between parasite-induced hepatitis and pulmonary arteriolar hypertrophy in rodents. Further studies are warranted for the use of C hepatica-infected rats as an animal model to explore the underlying mechanisms of portopulmonary hypertension in humans.

Toxicity study of a new camptothecin anti-cancer agent CKD-602 in dogs: 4-week continuous intravenous dose by infusion pump and 4-week repeated intravenous dose.

In evaluating toxicity, one of the most important factors is the administration method, because it can affect the exposure and absorbance level of the test article, and, consequently, influence the interpretation of toxicity test results. Continuous intravenous (IV) administration is a widely used administration method for anti-cancer drugs in clinical settings. Previous studies have reported the toxic effects of the test article following repeated IV dosing of CKD-602, a novel camptothecin-derivative anti-tumor agent that was developed by Chong Kun Dang Pharmaceutical Corporation in Seoul, Korea. However, CKD-602-related toxicities induced by IV infusion administration have not yet been evaluated, although the drug is more widely used in clinical settings. In the present study, CKD-602 was administered using a continuous IV infusion pump and using repeated IV administration at doses of 0, 0.003, or 0.01 mg/kg/day for 4 weeks to compare and evaluate the drug-induced toxicities using the two different administration methods. Higher mortality, more severe clinical symptoms, increased complete blood count, serum biochemistry, and histopathology were demonstrated when CKD-602 was administered using the 4-week continuous IV infusion pump method compared with the repeated IV administration method. Based on these results, we conclude that the administration of CKD-602 using the 4-week continuous IV infusion pump method can elicit more severe toxicity than that using 4-week repeated IV dosing method. Thus, more attention should be paid to the administration of CKD-602 using continuous IV infusion in the clinical setting.

Efficacy and Safety of Flow-Diverter Therapy for Recurrent Aneurysms after Stent-Assisted Coiling.

BACKGROUND AND PURPOSE: Flow-diverter treatment for previously stented aneurysms has been reported to be less effective and prone to complications. In this study, we evaluated the effectiveness and safety of flow diverters for recurrent aneurysms after stent-assisted coiling. MATERIALS AND METHODS: Patients who underwent flow-diverter placement for recurrent aneurysms after stent-assisted coiling between March 2015 and March 2019 were recruited. Clinical and radiographic characteristics and clinical and angiographic outcomes were retrospectively evaluated. RESULTS: Among 133 patients who underwent flow-diverter insertion, 17 (male/female ratio = 5:12; mean age, 53.8 years) were treated for recurrent aneurysms after stent placement with (n = 16) or without (n = 1) coiling. Eight patients initially presented with subarachnoid hemorrhage; 7, with headache; and 2, with visual field defects. Angiographic morphology included large/giant saccular in 12 patients, dissecting in 2, fusiform in 1, traumatic pseudoaneurysm in 1, and ruptured blood blister-like aneurysm in 1. The duration between the first treatment and flow-diverter placement ranged from 2 weeks to 15 months (median, 6 months). Flow-diverter placement was successful in all cases without any complications. All patients had favorable outcomes (mRS, 0-2), without any newly appearing symptoms. Aneurysms were followed up with conventional angiography at least once in 6-18 months. Sixteen aneurysms showed complete occlusion, and 1 aneurysm was enlarged. CONCLUSIONS: Results from this case series investigating flow-diverter placement for recurrent aneurysms after stent-assisted coiling suggested that the procedure is safe and effective. Further study in a larger population may be warranted.

Developmental toxic potential of 1,3-dichloro-2-propanol in Sprague-Dawley rats.

This study investigated the potential adverse effects of 1,3-dichloro-2-propanol (1,3-DCP) on pregnant dams and the embryo-fetal development after maternal exposure on gestational days (GD) 6 through 19 in Sprague-Dawley rats. The test chemical was administered to pregnant rats by gavage at dose levels of 0, 10, 30, and 90mg/kg per day (n=10 for each group). All dams underwent Caesarean sections on GD 20, and their fetuses were examined for morphological abnormalities. Maternal toxicity was noted at 90mg/kg/day. Manifestations of toxicity included clinical signs of illness, lower body weight gain, decreased food intake, and increases in the weight of the adrenal glands and the liver. Developmental toxic effects including decreases in fetal body weight and increases in visceral and skeletal variations also occurred at the highest dose. At 30mg/kg, only a minimal maternal toxicity, including a decrease in maternal food intake and an increase in the liver weight, was observed. No adverse maternal or developmental effects were observed at 10mg/kg/day. These results revealed that a 14-day repeated oral dose of 1,3-DCP was minimally embryotoxic but not teratogenic at a maternal toxic dose (90mg/kg/day), and was not embryotoxic at a minimally maternal toxic dose (30mg/kg/day) in rats. Because the developmental toxicity of 1,3-DCP was observed only in the presence of maternal toxicity, it is concluded that the developmental findings observed in the present study are secondary effects to maternal toxicity. Under these experimental conditions, the no-observed-adverse-effect level of 1,3-DCP is considered to be 10mg/kg/day for dams and 30mg/kg/day for embryo-fetal development.

Dynamics of population code for working memory in the prefrontal cortex.

Some neurons (delay cells) in the prefrontal cortex elevate their activities throughout the time period during which the animal is required to remember past events and prepare future behavior, suggesting that working memory is mediated by continuous neural activity. It is unknown, however, how working memory is represented within a population of prefrontal cortical neurons. We recorded from neuronal ensembles in the prefrontal cortex as rats learned a new delayed alternation task. Ensemble activities changed in parallel with behavioral learning so that they increasingly allowed correct decoding of previous and future goal choices. In well-trained rats, considerable decoding was possible based on only a few neurons and after removing continuously active delay cells. These results show that neural activity in the prefrontal cortex changes dynamically during new task learning so that working memory is robustly represented and that working memory can be mediated by sequential activation of different neural populations.

Solid pseudopapillary carcinoma of the pancreas: differentiation from benign solid pseudopapillary tumour using CT and MRI.

AIM: To describe the computed tomography (CT) and magnetic resonance imaging (MRI) findings that differentiate solid pseudopapillary carcinomas (SPC) from benign solid pseudopapillary tumours (SPT) of the pancreas. MATERIALS AND METHODS: Preoperative CT or MRI images for 26 patients (eight patients with SPC and 18 patients with SPT) were retrospectively reviewed. In addition to the general morphological features, the presence of pancreatic duct dilation, vascular invasion, and extrapancreatic metastases were comparatively assessed. RESULTS: There were no significant differences between pancreatic SPC and benign SPT with respect to tumour size, location, capsule thickness, internal composition, and pattern of calcification, nor was there any correlation with the age and gender of the patients. Pancreatic duct dilation was present in four of the eight (50%) SPC patients, and was absent in all benign SPT patients (p=0.005). Vascular encasement by the tumour (n=2) and hepatic metastases (n=2) were also exclusively demonstrated in SPC patients. Multivariate logistic regression analysis showed that pancreatic duct dilation (p=0.001), vessel encasement (p=0.027), and metastasis (p=0.027) were the variables that can be used to differentiate SPC from benign SPT. CONCLUSION: SPC of the pancreas may help to differentiate from benign SPT using the imaging features of aggressive behaviour of pancreatic duct dilation and vessel encasement with or without extrapancreatic metastases.