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Background: Phenytoin is the most commonly reported aromatic Anti-Epileptic Drug (AED) to cause Cutaneous Adverse Drug Reactions (CADRs). Cutaneous adverse drug reactions may be immune or non-immune mediated. It has been observed that predisposition is multifactorial and that gene mutations alone cannot be the cause. Objectives: In this study, we investigated the patient, disease, and drug-related risk factors associated with phenytoin-induced cutaneous adverse drug reactions in South Indian epileptic patients. Methods: This study was conducted as a single-center prospective case-control study over a period of 13 months. The Fisher’s exact test and multivariate binary logistic regression analysis were used to test the association of single and multiple variables, respectively. Results: This study comprised 26 patients with phenytoin-induced cutaneous adverse drug reactions (PHT-CARDs) and 32 phenytoin-tolerant controls with a mean age of 40.60±18.15 and 36.21±14.71 years, respectively. Among 26 phenytoin-induced cutaneous adverse drug reactions, 76.92% cases were mild-moderate reactions and 23.07% were severe. The onset latency period of these reactions ranged from 7-42 days. The multivariate analysis showed that multiple AEDs (OR =18.62, 95% CI 4.28-80.87, p=< .001) and comorbidities (OR= 5.98, 95% CI 1.33-26.78, p=.01) are risk factors for PHT-CADRs. PHT-SCARs were shown to be associated with previous allergy history (OR= 31, % CI 2.40-398.8, p=.008). Conclusion: The risk factors found to be associated with CARDs in South Indian Epileptic patients are multiple AEDs, comorbidities, and past allergic history. Therefore, physicians and other associated health care professionals should closely monitor the patients when phenytoin is employed.

Objectives/hypothesis Radiation-associated sarcomas of the head and neck (RASHN) are known but rare sequelae after radiation for squamous cell carcinoma. The purpose of this study was to characterize RASHN, estimate the risk of RASHN in head and neck squamous cell patients after therapeutic radiation, and compare their survival to that of patients with de novo sarcomas of the head and neck (dnSHN). Study design Retrospective database analysis. Methods RASHN and dnSHN cases were collected from the Surveillance, Epidemiology, and End Results Database to identify risk factors and calculate incidence and latency. Survival was compared between RASHN and dnSHN. Results The risk of RASHN was 20.0 per 100,000 person-years. The average latency period was 124.2 months (range 38-329). The cumulative incidence of RASHN at 20 years was 0.13%. Oral cavity and oropharynx primaries demonstrate increased risk. Five-year overall survival of RASHN was 22.4% compared to 64.5% for dnSHN. Conclusions RASHN are confirmed to be rare. RASHN have poor overall survival and worse survival compared to dnSHN. The impact of intensity-modulated radiation therapy protocols on this risk is unknown. Modifiable risk factors of smoking and alcohol consumption continue to dwarf radiation therapy as risk factors of second primary head and neck cancers. Level of evidence 3 Laryngoscope, 2021.

This study evaluated the time trends in mobile phone subscriber number by mobile network generation (G) and brain cancer incidence by type in Korea. We obtained data from the Information Technology Statistics of Korea (1984-2017) and Korea Central Cancer Registry (1999-2017). The average annual percent change was estimated using Joinpoint regression analysis. We evaluated 29,721 brain cancer cases with an age-standardized incidence rate (ASR) of 2.89/100,000 persons. The glioma and glioblastoma annual ASR significantly increased in 2.6% and 3.9% of males and 3.0% and 3.8% of females, respectively. The ASR for frontal lobe involvement was the highest. The ASR of gliomas of unspecified grade annually increased by 7.8%; those for unspecified topology and histology decreased. The incidence of glioma, glioblastoma, frontal, temporal, and high-grade glioma increased among those aged ≥60 years. No association was observed between the mobile phone subscriber number and brain cancer incidence in Korea. Furthermore, long-term research is warranted because of the latency period of brain cancer. © 2021 Bioelectromagnetics Society.

Importance Owing to improved survival among US patients with prostate cancer (PC), patients tend to live long enough after a PC diagnosis for non–cancer-related comorbidities to be associated with their overall survival. Although studies have investigated causes of death among patients with localized PC, data are lacking regarding causes of death among patients with metastatic PC. Objective To assess causes of death among US patients with metastatic PC from 2000 to 2016. Design, Setting, and Participants This retrospective cohort study used data from the Surveillance, Epidemiology, and End Results Program database to analyze a sample of 26 168 US men who received a diagnosis of metastatic PC from January 1, 2000, to December 31, 2016. Data were analyzed from February 2 to July 28, 2020. Exposure Diagnosis of metastatic PC. Main Outcomes and Measures Standardized mortality ratios (SMRs) for different causes of death were calculated by dividing the observed number of deaths from each cause of death by the expected number of deaths in the age-matched US male population for the same period, adjusting for age and race/ethnicity. Results Of 26 168 patients with metastatic PC included in the analysis, 48.9% were aged 50 to 70 years (mean age at diagnosis, 70.83 years); 74.5% were White individuals, and 72.7% received a diagnosis of stage M1b metastatic PC. A total of 16 732 patients (63.9%) died during the follow-up period. The mean age at death was 74.13 years. Most deaths (59.0%) occurred within the latency period of 2 years after diagnosis of metastatic PC, whereas 31.6% occurred 2 to 5 years after diagnosis and 9.4% occurred more than 5 years after diagnosis. Of the total deaths, 13 011 (77.8%) were from PC, 924 (5.5%) were from other cancers, and 2797 (16.7%) were from noncancer causes. During all latency periods, the most common noncancer causes of death were cardiovascular diseases (SMR, 1.34; 95% CI, 1.26-1.42), chronic obstructive pulmonary disease (SMR, 1.19; 95% CI, 1.03-1.36), and cerebrovascular diseases (SMR, 1.31; 95% CI, 1.13-1.50). Conclusions and Relevance In this cohort study, deaths from noncancer causes, including cardiovascular disease, constituted a substantial number of deaths among men with metastatic PC. Therapy and follow-up should be tailored to the needs of each patient with metastatic PC, and counseling regarding future health risks should be provided.

Background: Patient-derived xenograft (PDX) models have been a focus of attention because they closely resemble the tumor features of patients and retain the molecular and histological features of diseases. They are promising tools for translational research. In the current systematic review, we identify publications on PDX models of cervical cancer (CC-PDX) with descriptions of main methodological characteristics and outcomes to identify the most suitable method for CC-PDX. Methods: We searched on PubMed to identify articles reporting CC-PDX. Briefly, the main inclusion criterion for papers was description of PDX created with fragments obtained from human cervical cancer specimens, and the exclusion criterion was the creation of xenograft with established cell lines. Results: After the search process, 10 studies were found and included in the systematic review. Among 98 donor patients, 61 CC-PDX were established, and the overall success rate was 62.2%. The success rate in each article ranged from 0% to 75% and was higher when using severe immunodeficient mice such as severe combined immunodeficient (SCID), nonobese diabetic (NOD) SCID, and NOD SCID gamma (NSG) mice than nude mice. Subrenal capsule implantation led to a higher engraftment rate than orthotopic and subcutaneous implantation. Fragments with a size of 1–3 mm3 were suitable for CC-PDX. No relationship was found between the engraftment rate and characteristics of the tumor and donor patient, including histology, staging, and metastasis. The latency period varied from 10 days to 12 months. Most studies showed a strong similarity in pathological and immunohistochemical features between the original tumor and the PDX model. Conclusion: Severe immunodeficient mice and subrenal capsule implantation led to a higher engraftment rate; however, orthotopic and subcutaneous implantation were alternatives. When using nude mice, subrenal implantation may be better. Fragments with a size of 1–3 mm3 were suitable for CC-PDX. Few reports have been published about CC-PDX; the results were not confirmed because of the small sample size.

Objective Pituitary carcinoma is a rare tumor, defined as a tumor of adenohypophyseal cells with systemic or craniospinal metastasis. We present a case of a growth hormone (GH)-secreting pituitary carcinoma with a review of literature to better characterize this disease. Design Case report and literature review of 25 cases of GH-secreting pituitary carcinomas Results The age of diagnosis of GH-secreting carcinomas ranged 24–69 years old with a mean age of 44.4 with 52% of cases present in females. Mean latency period between diagnosis of acromegaly and transition to pituitary carcinoma was 11.4 years with mean survival being 3.4 years. Conclusion Growth hormone (GH)-secreting pituitary carcinomas are rare and hard to distinguish from aggressive pituitary adenomas. From review of literature, treatment options include debulking surgery, radiotherapy, or chemotherapy with dismal outcomes. There are no diagnostic markers or features which can predict metastatic progression of these tumors. Future studies with genomic landscapes and relevant tumor markers are needed to identify pituitary tumors most likely to metastasize.

Sir,We have reviewed the letters submitted by Finkelstein (2019) and Madigan et al. (2019) regarding our updated pooled analysis of mesothelioma risk following occupational exposures to cosmetic ta...

Overlay of diseases of the biliary system to diabetes mellitus type 2 can contribute to the enhancement of disorders of protein, lipid and carbohydrate metabolism and affect the mechanisms of regulation at the cellular molecular level. Therefore, the need for early diagnosis and study of the features of the course of chronic cholecystitis against the background of diabetes mellitus type 2 is a pressing issue of internal medicine. The motor-evacuation and cholecretory functions of the biliary system and the features of the course of chronic cholecystitis on the background of diabetes mellitus type 2 were studied. 93 patients were examined, of which 62 were patients with combined diabetes mellitus type 2 and chronic cholecystitis and 31 patients with isolated chronic cholecystitis. The control group was represented by 20 apparantly healthy individuals, who were representative of the age and number of male and female probands. The course of chronic cholecystitis was found to be accompanied by impaired gallbladder motor (evacuation) function, which was manifested by an increase in the latency period, the volume of the cavity of the gallbladder, the emptying coefficients in the dynamics and a decrease in the index of contraction of the gallbladder. In the presence of diabetes mellitus type 2, an atypical course of chronic cholecystitis may be formed, characterized by motor-evacuation disorders of the biliary tract and physico-chemical changes in bile, the severity of which exceeds those of isolated chronic cholecystitis. The peculiarities of the course of chronic cholecystitis in patients with diabetes mellitus type 2 are manifested by insignificant clinical symptoms and distinct changes at both stages of cholecystosonography, which may be the result of the development of autonomic neuropathy. In diabetes mellitus type 2, it is advisable to determine the status of the gallbladder (cholecystosonography) in order to prevent the risk of complications (cholelithiasis) and timely administration of antimicrobial therapy in the presence of an additional inflammation.

Background We aimed to investigate the risk and survival of chronic myeloid leukemia (CML) after breast cancer (BC) diagnosis. Methods We used the Surveillance, Epidemiology, and End Results ‘SEER’ database. Females, diagnosed with BC between 1992 and 2014, were selected and followed for the development of CML after a 6-month latency period from BC diagnosis. We used the Multiple Primary Standardized Incidence Ratios session of the SEER*Stat software (version 8.3.4) to calculate the Observed/Expected (O/E) ratios with 95% confidence intervals (CI). To calculate the overall survival, we performed an unadjusted Kaplan-Meier analysis using the SPSS software. Results We included 474,866 females with BC, of which 178 were later diagnosed with CML. We found the risk of CML to increase significantly after BC diagnosis (O/E = 1.26, 95% CI: 1.08-1.45) and the risk was specifically higher within the first 5 years of diagnosis (O/E = 1.45, 95% CI: 1.16-1.8). When the risk was stratified by cancer stage, localized BC was associated with a significant increase in CML risk within 5 years of diagnosis (O/E = 1.4, 95% CI: 1.06-1.82), while regional BC was associated with a significant increase in CML risk after more than 5 years of diagnosis (O/E = 1.59, 95% CI: 1.09-2.25). Moreover, radiotherapy, chemotherapy, and presence of hormonal receptors were associated with a significant increase in CML risk in BC patients. The median overall survival of CML after BC was 28 months. Conclusion Breast cancer patients have an increased risk of developing CML and further investigation is required to establish the causes of this finding.

More than 7000 incident cancers diagnosed in Canada in 2015 were attributable to infections. The future infection-associated cancer burden can be lowered by reducing the prevalence of major cancer-causing infections; hepatitis B virus (HBV), hepatitis C virus (HCV), Helicobacter pylori (H. pylori) and human papillomavirus (HPV). We modeled the future impact of (1) 10%, 25%, and 50% relative reductions in the prevalence of HBV, HCV and H. pylori and (2) different school-based HPV vaccination coverage levels (lower, current, higher) on Canadian cancer incidence by the year 2042. We modeled counterfactual reductions in HBV, HCV and H. pylori prevalence in 2018, assuming a latency period of 15-years, to estimate the impact on cancer incidence starting in 2033. The number of HPV-attributable cancers among vaccinated cohorts was a function of pre-2018 vaccine coverage levels and the 2018 counterfactuals. A 50% counterfactual reduction in the prevalence of HBV, HCV and H. pylori could prevent an estimated 10,585 cancers from 2018 to 2042; a 25% reduction could prevent 5293 cancers and a 10% reduction could prevent 2117 cancers. Assuming continuity of current estimated country-wide HPV vaccine coverage, 3977 anogenital and 1073 head and neck cancers could be prevented from 2018 to 2042, whereas vaccine coverage of 80% in girls and boys could prevent an additional 311 cancers. Almost 16,000 cancers could be prevented in Canada from 2018 to 2042 with a 50% relative reduction in HBV, HCV and H. pylori prevalence and 80% HPV vaccine coverage of girls and boys.

Hereditary amyloidosis associated with mutations in the transthyretin gene (hATTR) is a progressive devastating disease, with a fatal outcome occurring within 10years after onset. In recent years, TTR gene silencing therapy appeared as a promising therapeutic strategy, showing evidence that disease progression can be slowed and perhaps reversed. We report here 18 subjects affected by hATTR amyloidosis treated with patisiran, a small interfering RNA acting as TTR silencer, and evaluated with a PND score, the NIS and NIS-LL scale, and a Norfolk QOL-DN questionnaire at baseline and then every 6 months. A global clinical stabilizationwas observed for the majority of the patients, with mild-moderate improvements in some cases, even in advanced disease stage (PND score &gt, 2). Analysis of NIS, NIS-LL and Norfolk QOL-DN results, and PND score variation suggest the possible presence of a 6-month latency period prior to benefit of treatment.

Background. This study aimed to evaluate the risk factors of developing second primary malignancies (SPMs) among patients with pancreatic neuroendocrine neoplasms (pNENs) and the prognosis of pNENs patients with SPMs (pSPMs) using data from the Surveillance, Epidemiology, and End Results (SEER) database. Methods. Data from patients diagnosed with pNENs between 1988 and 2016 were extracted. A case-control study was conducted to investigate the risk factors of developing SPMs among patients with pNENs. Meanwhile, cox regression analysis was also conducted to obtain the independent prognostic factors in pSPMs. Results. Of 7,630 patients with pNENs, 326 developed SPMs. Patients with pNENs who had not undergone surgery and had been diagnosed in recent periods had a higher risk of developing SPMs. The following independent prognostic predictors for pSPMs were identified: age, latency period, SEER stage, radiotherapy, and surgery. Conclusions. These findings may improve the surveillance of risk factors for developing SPMs in patients with pNENs and the prognostic risk factors in pSPMs.

Infantile spasms (IS) is a serious epileptic syndrome that frequently occurs in infancy. Adrenocorticotropic hormone (ACTH) is generally the first-line treatment for IS; however, side effects limit its application. Melatonin (MT) has been used in clinical treatment for sleep disorders with only minor side effects. Further, MT was shown to be a powerful anticonvulsant in an animal model of epilepsy. In this research, we aimed to compare the anticonvulsant efficacy of ACTH and/or MT for treatment of IS and explore the mechanisms underlying the anticonvulsant activity of MT, using an N-methyl-d-aspartate (NMDA)-induced IS model in neonatal rats following exposure to prenatal stress. Latency to the onset of spasms and the total number of spasms were recorded to assess spasm severity. Treatment with ACTH and/or MT significantly reduced the number of spasms and prolonged the latency period. Additionally, expression of GR-α, HDAC2, BNDF, TrkB, and C-Cbl were significantly increased by induction with NMDA, and this effect was reversed by ACTH and/or MT treatment. Hence, our data suggest that combined ACTH and MT treatment is effective for reducing the number of spasms and increasing the latency period in NMDA rats, by restoring dysregulation of the HPA axis. These findings have the potential to provide a new strategy for the treatment of IS.

Background Traumatic spinal cord injury (SCI) is also a combat-related injury that is increasing in modern warfare. The aim of this work is to inform medical experts regarding the different course of bladder cancer in able-bodied patients compared with SCI patients based on the latest medical scientific knowledge, and to present decision-making aids for the assessment of bladder cancer as a late sequela of traumatic SCI. Methods A study conducted between January 1998 and December 2019 in the BG Trauma Hospital Hamburg formed the basis for the decision-making aids. Urinary bladder cancer was diagnosed in 40 out of 7396 treated outpatient and inpatient SCI patients. General patient information, latency period, age at initial diagnosis, type of bladder management and survival of SCI patients with bladder cancer were collected and analysed. T category, grading and tumour entity in these patients were compared with those in the general population. Relevant bladder cancer risk factors in SCI patients were analysed. Furthermore, relevant published literature was taken into consideration. Results Initial diagnosis of urinary bladder cancer in SCI patients occurs at a mean age of 56.4 years (SD ± 10.7 years), i.e., approximately 20 years earlier as compared with the general population. These bladder cancers are significantly more frequently muscle invasive (i.e., T category ≥ T2) and present a higher grade at initial diagnosis. Furthermore, SCI patients show a significantly higher proportion of the more aggressive squamous cell carcinoma than that of the general population in areas not endemic for the tropical disease schistosomiasis. Consequently, the survival time is extremely unfavourable. A very important finding, for practical reasons is that, in the Hamburg study as well as in the literature, urinary bladder cancer is more frequently observed after 10 years or more of SCI. Based on these findings, a matrix was compiled where the various influencing factors, either for or against the recognition of an association between SCI and urinary bladder cancer, were weighted according to their relevance. Conclusions The results showed that urinary bladder cancer in SCI patients differs considerably from that in able-bodied patients. The presented algorithm is an important aid in everyday clinical practice for assessing the correlation between SCI and bladder cancer.

Malignant mesothelioma is an aggressive tumor resistant to current therapies with a latency period ranging between 20 and 60 years, caused by inhalation of asbestos fibers, that continues to represent a social and healthcare issue. The high percentage of people exposed to asbestos for professional or environmental reasons is associated with the high biopersistence of its fibers and with its widespread use in the last century. Approximately 20-40% of men report an occupational history that might have caused the workplace exposure (criteria Helsinki, 1997). Some authors are evaluating the possible use of bioindicators as a screening and early diagnosis tool. In this regard, the use of microRNAs has been proposed as powerful diagnostic and prognostic biomarkers for many tumors and human diseases. This review focuses on the current state of knowledge on the key role of microRNAs expression as new malignant mesothelioma biomarkers, in early clinical diagnostic applications.

The Korean Radiation Worker Study investigated the health effects of protracted low-dose radiation among nuclear-related occupations in the Nuclear Safety and Security Commission in Korea. From 2016&ndash, 2017, 20,608 workers were enrolled (86.5% men and 30.7% nuclear power plant workers). The mean cumulative dose &plusmn, standard deviation between 1984 and 2017 (1st quarter) was 11.8 &plusmn, 28.8 (range 0&ndash, 417) mSv. Doses below recording level (&le, 0.1 mSv) were reported in 7901 (38.3%) cases, 431 (2%) had cumulative doses &ge, 100 mSv. From 1999&ndash, 2016, 212 cancers (189 men, 23 women) occurred, thyroid cancer predominated (39.2%, 72 men, 11 women). In men, the standardized incidence ratio (SIR) for all cancers was significantly decreased (SIR = 0.76, 95% CI 0.66&ndash, 0.88), however, that for thyroid cancer was significantly increased (SIR = 1.94, 95% CI 1.54&ndash, 2.44). Compared to the non-exposed group (&le, 0.1 mSv), the relative risk (RR) in the exposed group (&gt, 0.1 mSv) after adjusting for sex, attained age, smoking status, and duration of employment was 0.82 (95% CI 0.60&ndash, 1.12) for all cancers and 0.83 (95% CI 0.49&ndash, 1.83) for thyroid cancer. The preliminary findings from this baseline study with a shorter follow-up than the latency period for solid cancer cannot exclude possible associations between radiation doses and cancer risk.

Background: drug-induced pancreatitis is an unexplored entity. Methods: a retrospective cohort study was performed at a referral center. Patients with drug-induced acute pancreatitis between 2008 and 2018 were included. Baseline patient characteristics, involved drugs, clinical course and recurrence were analyzed. Results: drug-induced pancreatitis represented 2.8 % of acute pancreatitis (47/1,665) and 18 different drugs were involved (thiopurines 61.8 %). The latency period was less than one month in 87.2 % of cases. Pancreatitis was mild in 89.3 % and recurrence risk was 2.3 %. Conclusion: drugs are a rare cause of pancreatitis, which mostly occurs within the first month of treatment, is usually mild and is associated with a low risk of recurrence.

Objective This study was to investigate the clinical characteristics and prognosis of autoimmune encephalitis (AE) associated with anti-Glutamic Acid Decarboxylase 65 (GAD65). Patients and methods From Jan 2016 to Aug 2018, three patients diagnosed as anti-GAD65 AE in our hospital were retrospectively analyzed for their general demographic characteristics, clinical presentation, cerebrospinal fluid (CSF) cytology, brain imaging, EEG, treatment and prognosis. Results We found that Anti-GAD65 AE may be more common in young and middle-aged women, with initial presentations of refractory status epilepticus or cognitive decline following the disease progresses, but with less psychiatric symptoms than other types of AEs. The abnormal signals of MRI may be obvious in bilateral frontal, temporal lobe and hippocampus. Conclusion The production of anti-GAD65 may have a certain latency period, and it is usually negative at the onset stage. More studies need to be performed on larger populations and further understand the potential mechanisms underlying the above clinical features of anti-GAD65 AE.

Introduction Childhood acute leukemias (AL) and lymphomas achieve good survival rates. However, second neoplasms (SN) are a devastating event. Methods From August 1987 to December 2016, 34 of 3321 (1%) patients with diagnosis of AL or lymphoma developed SN. SN were AL (n=16), CNS tumors (n=5), endocrinal tumors (n=3), lymphomas (n=2), schwannoma (n=2) assorted sarcomas (n=4), retinal melanoma (n=1), and Vanek tumor (n=1). Median latency was 51 (range, 10 to 110) months for hematological malignancies and 119 (range, 25 to 236) months for solid tumors (P=0.001). Results A total of 33 patients with SN were treated taking into account cumulative doses of anthracyclines and radiotherapy. Twenty-three (67.6%) patients achieved complete remission (CR), 5 died early during therapy and 5 were refractory or partial responders. Six patients presented relapses of the SN and 1 died in CR. Seventeen patients remain alive in CR, with a median follow-up of 110 (range, 4 to 276) months. Conclusions (1) The latency period was significantly longer for patients developing solid tumors than for those developing AL. (2) AL was the most frequent SN. (3) Our results strongly encourage giving standard therapy to SN, considering cumulative doses of previous treatment, since similar probabilities of surviving as "de novo" counterparts can be achieved.

Introduction Osteosarcomas are potentially lethal malignant bone tumours, more commonly found in the long bones than in the maxillofacial region. Sarcomas are known for their difficult diagnosis, rapid progression and poor prognosis. Observation We present a case of osteosarcoma of the maxilla in a young subject who was treated and followed for 2 years. The diagnosis and the start of treatment were made 12 months after the first symptoms. The definitive diagnosis was made by pathological examination of the resection specimen. The treatment required several therapeutic means combining surgery, chemotherapy and radiotherapy. Discussion The treatment of osteosarcoma most often combines surgery, chemotherapy and radiotherapy; however, surgery remains the treatment of choice. Chemotherapy has significantly improved the prognosis of long bone osteosarcomas, however its role in the treatment of maxillary osteosarcomas remains controversial. It is currently accepted that protocols combining neo-adjuvant chemotherapy with adjuvant chemotherapy provide better results than adjuvant chemotherapy alone. Analysis of the surgical specimen provides an early assessment of the response to chemotherapy and determines the adjuvant therapy. The prognosis of osteosarcoma depends on several parameters, including the latency period between the first symptoms and therapeutic management; the size of the tumour; its location, with maxillary locations having a poorer prognosis than mandibular locations; the quality of tumour removal; whether or not there is a response to neo-adjuvant chemotherapy; whether or not there are metastases and the degree of differentiation.

Aims To compare bladder cancer incidence between patients initiating pioglitazone treatment and patients initiating treatment with dipeptidyl-peptidase-4 inhibitors [DPP-4s] or sulfonylureas. Methods We identified Medicare beneficiaries aged >65 years who initiated treatment with pioglitazone (N = 38 700), DPP-4s (N = 82 552) or sulfonylureas (N = 126 104) between 2007 and 2014 after at least 6 months without prescriptions for these drug classes. Patients were followed from second prescription until bladder cancer outcome (2 claims within 60 days) using a 6-month induction/latency period, censoring for treatment change, death or end of 2014. We used propensity score-weighted Cox proportional-hazards models to obtain adjusted hazard ratios (aHR) and their 95% confidence intervals. Results Overall mean age of participants was 75 years and 41% were men. Over a median of 1.2 treatment years, 727 beneficiaries developed bladder cancer. Pioglitazone initiators had an increased incidence of bladder cancer (308 vs 204 [DPP-4s] or 231 [sulfonylureas] per 100 000 person-years; aHR, 1.57 [1.23-2.00] vs DPP-4s and 1.32 [1.02-1.70] vs sulfonylureas). The increased risk emerged within the first 2 years of treatment (aHR, 1.63 [1.22-2.17] vs DPP-4s and 1.32 [0.98-1.78] vs sulfonylureas). If treatment was discontinued within the first 2 years, the risk after 2 years post initiation was attenuated (aHR, 0.89 [0.61-1.28]) compared with patients treated for more than 2 years (aHR, 1.45 [0.93-2.26]) both vs DPP-4s. Findings were consistent across secondary and sensitivity analyses. Conclusions Pioglitazone was associated with an elevated risk of bladder cancer compared with DPP-4s and sulfonylureas. The elevated risk emerged within the first 2 years of treatment and was attenuated after discontinuing. Pioglitazone's relative effectiveness should be weighed against a small absolute increase in risk of bladder cancer.

OnabotulinumtoxinA was approved for treatment of chronic migraine (CM) after publication of Phase 3 Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) trials. However, the PREEMPT trials lasted only up to 1 year. The main aim of our retrospective study was to evaluate whether a prolonged treatment of onabotulinumtoxinA (18 months, six quarterly cycles) will sustain or further improve the efficacy results and the quality of life achieved at 6 and 12 months. Patients were adults with CM with or without overuse of drugs, with at least six regularly repeat onabotulinumtoxinA treatments, administered according to the PREEMPT protocol. The outcomes were investigated after 6, 12, and 18 months of treatment with respect to baseline and with respect to each previous study time point. Headache days and hours, and dosage of headache medication taken with latency period, were collected from the patients daily. Quality of life was evaluated by means of the Migraine Disability Assessment (MIDAS) questionnaire. At each study time point, the proportion of responder patients with respect to baseline was evaluated. For all measures, the baseline data were referred to the previous month before starting. Forty-seven patients were evaluated. Our data show a decrease in the monthly headache days and hours, at each study evaluation, with respect to the previous one. They showed that beyond the first year, a statistically significant difference in the monthly days of headache compared at 18 vs. 12 months is observed. A significantly higher proportion of patients (with a response greater than 75% decrease from baseline in the frequency of headache days and hours) was observed at month 18 compared to month 12. The proportion of patients in MIDAS grade I increased over time, and a statistically significant improvement in MIDAS I score was obtained from month 12 to month 18. A positive modification in the consumption of analgesics over time was observed (p for trend

Objectives: To identify the factors that predict the progression of radiological radiation pneumonitis (RP) to symptomatic RP, and to evaluate the usefulness of the neutrophil-lymphocyte ratio (NLR) as a marker of RP severity and prognosis in stage III non-small cell lung cancer (NSCLC) patients treated with definitive concurrent chemoradiotherapy (CCRT). Materials and Methods: We retrospectively reviewed 61 patients treated between January 2010 and December 2015. Patients' demographic characteristics, clinical data, laboratory findings, and treatment parameters were analyzed to determine the predictive factors associated with progression from radiological RP to symptomatic RP. Results: Forty-seven patients (77%) exhibited radiological RP at a median of 78 days after radiation therapy (RT) completion, and 15 (32%) of these patients developed symptomatic RP. The interval between RT completion and radiological RP presentation was shorter in patients who progressed to symptomatic RP (p=0.001); progression was highly probable if this latency period was ≤2 months (p=0.002). Stage and RT technique correlated with symptomatic RP development (p=0.046 and p=0.046, respectively). Among dosimetric factors, a V20 (defined as the lung volume receiving ≥20 Gy) of >30% was the most significant predictor of symptomatic RP (p=0.001). The NLR and C-reactive protein level at radiological RP were higher in patients who developed symptomatic RP (p=0.067 and p=0.012, respectively). On multivariate analysis, a V20 >30% and an NLR at radiological RP >6 were associated with symptomatic RP development. Conclusion: The NLR at radiological RP is a useful biomarker for predicting symptomatic RP development after CCRT in stage III NSCLC patients. This article is protected by copyright. All rights reserved.

Background: Patients with chronic obstructive pulmonary disease (COPD) have an elevated risk of Parkinson’s disease (PD) whereas β2-adrenoreceptor agonists, the cornerstone of COPD therapy, are associated with lower risk of PD. Objective: To examine the association between β2-agonist use and PD risk in patients with COPD. Methods: We performed a nested case-control study based on the health administrative data of British Columbia, Canada (1997–2015). Individuals with ≥40 years of age were included if they satisfied a validated case definition of COPD. Within the COPD cohort, we identified a PD sub-cohort in which patients have incurred ≥1 PD-related healthcare encounter and then filled ≥1 anti-PD medication within 90 days after the initial PD diagnosis. Each PD patient was then matched to five COPD patients without PD based on the latency period between the first COPD diagnosis and the first dispensation of anti-PD medication (≥4 years), as well as age, sex, calendar year and COPD severity. We used conditional logistic regression to estimate rate ratios to β2-agonists adjusting for potential confounder. Results: From 242,641 COPD patients, the final analysis included 662 patients in the PD sub-cohort and 3310 in the non-PD sub-cohorts (a 1:5 ratio). Therapeutic use of β2-agonists did not significantly affect the subsequent two-year risk of PD (versus no use, hazard ratios: regular use, 0.93 [95% CI: 0.76-1.16, p=0.53], irregular use, 0.96 [95% CI: 0.75–1.22, p=0.72]). Conclusion: In a population-based sample of surviving COPD patients β2-agonists users had a similar risk of developing PD as compared to the non-users.

According to national guidelines, conventional management of preterm premature rupture of membranes (PPROM) is hospitalization until induction. Outpatient management could be another option. Our objective was to compare latency period between patients managed in hospital versus outpatients. A retrospective before/after monocentric study that occured from 2002 to 2015. Were included all patients with PPROM prior to 35 weeks with homecare inclusion criteria. The primary outcome measure was to study length of latency period (delay between PPROM and delivery). Second outcome measures were maternal and perinatal morbidities and mortalities. Among the 395 women included after PPROM, 191 were managed as outpatients and 204 in hospital. In the outpatient group, the length of latency period was longer than in the inpatient group [39 (IQR 20 to 66) versus 21 (IQR 13 to 42) days; p

International audience; Although medical ionizing radiation (IR) has clear clinical benefits, it is an established carcinogen. Our study estimates the number of new cancer cases in France in 2015 attributable to IR exposure from medical procedures. Exposures from external (X-rays, CT scans, interventional radiology) and internal (nuclear medicine) sources were considered. We used 2007 national frequencies of diagnostic examinations by sex and age to estimate the lifetime organ dose exposure adjusted for changes in the use of such procedures over time. The Biological Effects of Ionizing Radiation VII risk models were used to estimate the corresponding excess cancer risk, assuming an average latency period of 10 years. Additionally, we used cancer incidence data from the French Cancer Registries Network. Of the 346,000 estimated new cancer cases in adults in France in 2015, 2300 cases (940 among men and 1360 among women) were attributable to diagnostic IR, representing 0.7% of all new cancer cases (0.5% for men and 0.9% for women). The leading cancers attributable to medical IR were female breast (n = 560 cases), lung (n = 500 cases) and colon (n = 290 cases) cancers. Compared to other risk factors, the contribution of medical IR to the cancer burden is small, and the benefits largely outweigh its harms. However, some of these IR-associated cancer cases may be preventable through dose optimization of and enhanced justification for diagnostic examinations. © 2019 UICC

Studies on children exposed to ionizing radiation by computed tomography (CT) indicate an increased risk of leukemia and central nervous system (CNS) tumors. Evidence of the risks associated with diagnostic X-ray examinations, the most frequent examination in pediatric radiology, in which the radiation dose is up to 750 times lower compared to CT examinations, is less clear.a#13; This study presents results of the second follow-up for the risk of childhood cancer in a cohort of children (alt;15 years) with diagnostic X-ray exposure at a large German hospital during 1976-2003 followed for additional 10 years until 2016.a#13; With a latency period of six months, 92,998 children contributed 794,549 person-years. The median effective dose was 7 μSv. 100 incident cancer cases were identified: 35 leukemia, 13 lymphomas, 12 CNS tumors, 15 blastomas, 15 sarkomas and 10 other solid tumors, consisting of six germ cells tumors, three thyroid cancers and one adrenocortical carcinoma. For all cancer cases combined the standardized incidence ratio (SIR) was 1.14 (95% confidence interval (CI) 0.93-1.39), for leukemia 1.15 (95% CI 0.63-1.61), for lymphomas 1.03 (95% CI 0.55-1.76), for CNS tumors 0.65 (95% CI 0.34-1.14), for blastomas 1.77 (95% CI 0.91-2.91), for sarkomas 1.28 (95% CI 0.71-2.11) and for other solid tumors 2.38 (95% CI 1.14-4.38). Dose-response analysis using Poisson regression revealed no trend for dose groups. Results did not differ substantially with a latency period of two years for all cancer entities and five years for solid tumors in sensitivity analyses.a#13; Overall, the null results of the first follow-up were confirmed. Although an association between radiation exposure and a risk for certain solid tumors like thyroid cancer is known, the significantly increased SIR in the group of other solid tumors must be critically interpreted in the context of the small number of cases and the very low doses of radiation exposure in this group.a#13; a#13

Background Patient-derived xenograft (PDX) involve the direct surgical transfer of fresh human tumor samples to immunodeficient mice. This systematic review aimed to identify publications of head and neck cancer PDX (HNC-PDX) models, describing the main methodological characteristics and outcomes. Methods An electronic search was undertaken in four databases, including publications having used HNC-PDX. Data were analyzed descriptively. Results 63 articles were yielded. The nude mouse was one most commonly animal model used (38.8 %), and squamous cell carcinoma accounted for the majority of HNC-PDX (80.6 %). Tumors were mostly implanted in the flank (86.3 %), and the latency period ranged from 30 to 401 days. The successful rate ranged from 17 % to 100 %. Different drugs and pathways were identified. Conclusion HNC-PDX appears to significantly recapitulate the morphology of the original HNC and represents a valuable method in translational research for the assessment of the in vivo effect of novel therapies for HNC.

To identify factors associated with shortened latency in expectantly managed women diagnosed with preeclampsia without severe features between 23 0/7 and 35 6/7weeks' gestation.This was a retrospective cohort study performed at a large community-based hospital between 2009 and 2014, evaluating all mothers between 23 0/7 and 35 6/7weeks' gestation with a diagnosis of preeclampsia without severe features. We collected maternal demographics, symptoms, vital signs and laboratory values within six hours of admission. Maternal and neonatal outcomes were stratified by latency period of less than or greater than/equal to seven days (7d or ⩾7d).Overall mean latency was 7.6±12.1days. When stratifying subjects to7d or ⩾7d latency, neither maternal demographics nor gestational age at diagnosis differed between groups. For subjects with ⩾7d latency, pregnancy was prolonged by a mean of 24days compared to the7d latency group (34 1/7 vs 30 4/7weeks GA, P=0.001). Systolic blood pressure greater than 160mmHg within the first six hours of hospital presentation correlated with a more than 3-fold risk for requiring delivery within seven days of diagnosis (OR 3.26 95% CI 1.40-7.58).Within our cohort of preterm women admitted with preeclampsia without severe features, elevated systolic blood pressure on admission conveyed significant risk for delivery within seven days.

Profound deafness (PD) is unlikely to be the only cause of endolymphatic hydrops (EH) in patients with delayed endolymphatic hydrops (DEH). Further studies in large patient cohorts are required to determine the etiologic co-factors involved in the development of EH in patients with PD and DEH.DEH usually occurs in patients with sustained unilateral PD who then develop episodic vertigo or fluctuating hearing loss. The latency can vary markedly between PD and development of DEH, but the factors affecting inner ear homeostasis and causing EH during this latency period remain unclear. The study aimed to assess the differences in EH and functional status of the inner ear between patients with PD only and those with DEH.Two PD and 10 DEH patients who had developed PD in early childhood were enrolled. Gadolinium-enhanced magnetic resonance imaging of the inner ear was performed in all patients to assess the degree of EH in the vestibule and cochlea.There was no evidence of EH in the affected ears of patients with PD alone. DEH patients, however, showed significant EH in either the cochlea or vestibule, suggesting that EH development and DEH onset were strongly correlated.

This study was conducted to evaluate cognitive enhancing effect and ameliorative effects of black seed oil in scopolamine induced rat model of cognitive impairment. These effects were investigated on scopolamine-induced dementia model in Morris water maze test (MWM) and Y maze test. The hippocampal histoarchitectural responses to scopolamine and Nigella sativa oil were also examined. Scopolamine (1 mg/kg ip) was given to induce dementia, followed by oral administration of BSO (1 ml/kg) for 14 consecutive days. MWM and Y-maze paradigms were used to assess hippocampal and frontal dependent memory respectively, thereafter the rats were sacrificed and brains were removed for histopathologic studies. Scopolamine resulted in memory impairment, by delayed latency in the MWM, reduced percentage alternation in the Y maze that was coupled by alterations in the cortico-hippocampal neurons. Posttreatment of rats with BSO mitigated scopolamine-induced amnesia, by reducing latency period and increasing percentage alternation and histological changes. The observed anti-amnestic effect of BSO makes it a promising anti-amnesic agent for clinical trials in patients with cognitive impairment.

We conducted a comprehensive review of the literature to characterize the etiology of secondary glioma following acute lymphocytic leukemia (ALL) patients. The analysis included 98 cases with an average age of onset of ALL of 5.9 years (range 1.5 to 26). The average latency period was 7.8 years until diagnosis of secondary glioma. Radiation therapy was administered in 92 cases for the primary malignancy at an average dose of 20.7 Gy. The median survival time of patients treated with multimodality treatment for secondary glioma was 23 months (95 % confidence interval 12-27 months), and multimodality therapy improved survival time significantly (p = 0.0029). The exact cause for the development of glioma following ALL is not clear. The risk of a secondary glioma in childhood cancer survivors may be influenced by genetic and other predisposing factors as well as by treatment type. In patients diagnosed with ALL, the risk of secondary glioma warrants a longer follow-up period that continues long after the risk of relapse of the primary malignancy has passed. Moreover, multimodality therapy should be considered in cases of secondary glioma following ALL.

Background: The association of the mobile phone use and risk of brain tumor remains controversial among radiation epidemiologists. Methods: We hypothesized if an association between brain tumor and mobile phone use exists, this association will be manifested as a cohort effect (as a proxy of association be­tween mobile phone use and brain tumor) in the incidence rates of brain tumor during the period of 1990 to 2009. We used age-period-cohort methodology (generalized log-linear model) and compared the distribution of cohort effects in the observed rates of brain tu­mor from 1990 to 2009 to the cohort effects from rates driven based on epidemiological study results that reported a positive association between brain tumor and mobile phone use in the Nordic population. Three latency period of 1-4 years with odds ratio (OR) of 1.2, latency period of 5-9 years with OR of 1.3, and latency period of more than 10 years with OR of 2.7 were used to estimate expected rates. Results: The distribution of cohort effects between observed and expected rates were more similar among the males compared with females. A shorter latency was more con­sistent to observed rates. Conclusion: Our study supports a possible a weak association between mobile phone use and brain tumor; further fueling the controversies in association.

Purpose The effects of recombinant human bone morphogenetic protein-2 (rhBMP-2) and osteogenically differentiated adipose tissue-derived stem cells (ADSC) on new bone formation in high-speed distraction osteogenesis of adult rabbit cranium were investigated. Materials and Methods A total of 41 adult rabbits were used in the study. Distraction began after a 5-day latency period at a rate of 1.5 mm twice a day until 10-mm length gain was obtained both in the control group, where a bone defect was induced, and in the experimental group, in which ADSC (group A), rhBMP-2 (group B), or both (group C) were injected in the distraction gap after distraction. At 4, 8, and 12 weeks after distraction, computed tomography analysis was done to determine the bone defect dimension and bone mineral density (BMD), while histologic examination was also done to calculate bone formation ratio. Results Bone defect dimension significantly decreased in groups B and C, compared with the control group, at 4 and 12 weeks after distraction. BMD was significantly increased in groups B and C at 4 weeks. On histologic examination, bone formation ratio was significantly increased in group C only at 12 weeks. Conclusion This study suggests that the use of rhBMP-2 in combination with or without ADSC is helpful to promote bone regeneration in high-speed distraction osteogenesi s of adult rabbit cranium.

Compared to secondary acute myeloid leukemia, secondary acute lymphoblastic leukemia (sALL) is poorly characterized. We utilized data from the Surveillance, Epidemiology, and End Results (SEER) 13 database to further elucidate patient characteristics and prognostic factors in sALL. Cases of adult de novo acute lymphoblastic leukemia (ALL) and sALL in patients with primary breast, rectum, cervix, or ovarian cancers or lymphoma with a latency period of at least 12 months were identified within the SEER 13 database. Survival in sALL and de novo ALL were compared after propensity matching based on age, gender, race, ALL subtype, and year of diagnosis. 4124 cases of de novo ALL and 79 cases of sALL were identified. sALL patients were older at diagnosis (median 62 years vs. 44 years; p

Bullous pemphigoid (BP) is an autoimmune blistering skin disorder. Recently, BP induced by dipeptidyl peptidase‐4 (DPP‐4) inhibitors has been a concern. Although DPP‐4 inhibitors are commonly used in the Asian population because of their safety and efficacy, BP associated with DPP‐4 inhibitors is sometimes seen in clinical settings. Here, we report five Japanese cases of BP associated with the agents. In the present cases, BP occurred in older adults using four different DPP‐4 inhibitors, which showed various clinical manifestations in terms of latency period for BP, sex, glycemic control and diabetes duration. Withdrawal of DPP‐4 inhibitors was effective in improving BP, and achieved remission even in cases requiring oral steroid administration and intravenous immunoglobulin therapy. Clinicians should note the importance of early diagnosis of this clinical condition and initiate prompt withdrawal of DPP‐4 inhibitors.

Background The increasing occurrence of radiation-induced second primary squamous cell carcinoma of the oral cavity (RISCCO) after radiotherapy for nasopharyngeal carcinoma (NPC) has become a noteworthy complication that can influence long-term survival. This study aimed to analyze the associations of clinicopathologic characteristics with prognostic factors among patients who developed RISCCO after radiotherapy for NPC. Methods A total of 41,446 NPC patients admitted to Sun Yat-sen University Cancer Center (SYSUCC) between August 1989 and January 2019 were reviewed. Among these patients, 88 RISCCO patients who satisfied the inclusion criteria were included in the study. Results During our study, the incidence of RISCCO after radiotherapy was 0.21% (88/41,446) among NPC patients at SYSUCC. The latency period ranged from 1.0 to 34.0 years (median, 9.0 years), and the latency of RISCCO was notably shorter for patients who received intensity-modulated radiation therapy than that for patients who received conventional radiotherapy using cobalt-60 or 6-MV X-rays (median, 4.0 years vs. 11.0 years, P = 0.013). The 1-, 3-, and 5-year overall survival (OS) rates for the entire cohort of 88 patients were 79.0%, 46.6%, and 35.2%, respectively. The 5-year OS rate for the 79 patients who received treatment was 45.7%, and the 5-year OS rate for the 9 patients who refused treatment was 0%. T classification and surgery were identified as independent prognostic factors associated with a high OS rate. Conclusions Surgery as the first-choice treatment may improve survival and prognosis. A long-term follow-up is needed for early detection of RISCCO in NPC patients.

Background and purpose Over 1 million metal-on-metal hip replacements were implanted. Even well-functioning implants produce wear debris that can cause tissue damage, disseminate and cause DNA damage. We aimed to establish if there was an association between metal-on-metal hip replacement and the risk of subsequently developing cancer compared with alternative hip replacements. Methods We performed a population based prospective longitudinal cohort study using data from the National Joint Registry linked to Hospital Episode Statistics (n = 403,881 patients). We examined the incidence of a new diagnosis of cancer in patients who received a metal-onmetal bearing in comparison with those who received a non metal-on-metal bearing. Kaplan-Meier estimates of time to first cancer diagnosis were used with Cox proportional hazards regression models to assess the effect on the time to cancer diagnosis for all cancer types, haematological, malignant melanoma, urinary tract cancers or prostate cancer in men. Results The maximum follow up available was 11.8 years with 25% of patients followed up for more than 6.8 years (mean follow up 4.6 years; median 4.3; IQR 2.1–6.8; range 0.01–11.8). Analyses by gender that adjusted for age at primary and presence or absence of linked Welsh (PEDW) records showed no increase in the risk of developing cancer according to the bearing surface implanted for all cancers, haematological cancers, malignant melanoma, urinary tract cancers or prostate cancer in men. For patients receiving a second hip replacement, there was also no difference. Conclusion We have demonstrated that there is currently no evidence of an increase in the risk of cancer following primary hip replacement according to the type of bearing material used. Although the risk of revision in metal-on-metal bearing hip replacements is higher, it is reassuring that the risk of a new diagnosis of cancer is not currently increased. Despite the long term follow up available in this study, the latency period for some cancers is very long and therefore continued monitoring is required to ensure no new patterns emerge that may indicate need for universal screening.

The temporal course and severity of metastasis to distant organs is a complex process depending on multiple features varying in different cancers and individuals. In patients previously treated for a localized tumor, the latency period before clinical evidence of metastatic relapse is made up of a sequence of events with unpredictable temporal kinetics (1).

Although prostate cancer (PCa) screening is conducted before testosterone replacement therapy (TRT), clinically occult PCa cases may exist. To evaluate whether the possible inclusion of occult PCa cases distorts the effect of TRT on risk of PCa, we followed 776 hypogonadal males (TRT = 400, non-TRT = 376) from a urology center in Germany from 2004 to 2016, with a mean follow-up period of 7 years. We assumed occult cases might take 1–2 years (latency period) to become clinically detectable after receiving TRT. We selected several latency periods (12/18/24 months) and compared the risk of PCa in the TRT and non-TRT group over the latency period, from the end of latency period till the end of follow-up, and over the whole follow-up time. Overall, 26 PCa cases occurred in the non-TRT group vs 9 cases in the TRT group. Within 18 months of follow-up, 9 cases occurred in the TRT group vs 0 cases in the non-TRT group; from the end of 18 months till the end of follow-up, 26 cases occurred in the non-TRT group vs 0 cases in the TRT group. The adjusted table showed seemingly adverse effects of TRT on PCa development within 18 months (p = 0.0301) and beneficial effects from the end of 18 months till the end of follow-up (p = 0.0069). Similar patterns were observed for 12 or 24 months as the latency period. TRT may make occult PCa cases detectable within early phase of treatment and present a beneficial effect in the long run. Future longitudinal studies are needed to confirm findings from our exploratory analyses.

To determine the effects of diet, rats were placed on a standard diet (4% fat) or on a modified Western (high-fat diet, HFD) diet (21% fat) at 43 days of age (DOA) and administered methylnitrosourea (MNU) at 50 DOA. Rats were administered effective (tamoxifen, vorozole, and Targretin) or ineffective (metformin and Lipitor) chemopreventive agents either by daily gavage or in the diet beginning at 57 DOA and continuing until sacrifice (190 DOA). Latency period of the tumors was determined by palpation, and multiplicity and cancer weights per rat were determined at final sacrifice. Rats on the HFD versus standard diet had: (i) a 6% increase in final body weights; (ii) significant decreases in tumor latency; and (iii) significant increases in final tumor multiplicity and average tumor weight. Tamoxifen, vorozole, and Targretin were highly effective preventive agents, whereas Lipitor and metformin were ineffective in rats on either diet. Serum was collected at 78 DOA and at sacrifice (190 DOA), and metabolomics were determined to identify the metabolite changes due to diets and effective agents. Rats given the HFD had increased levels of saturated free fatty acids (including myristate) and decreased levels of 2-aminooctanoate. Furthermore, rats on the HFD diet had increased levels of 2-aminobutyrate and decreases in glycine markers previously identified as indicators of prediabetes. Targretin increased long-chain glycophospholipids (e.g., oleyl-linoleoyl-glycerophosphocholine) and decreased primary bile acids (e.g., taurocholate). Tamoxifen increased palmitoyl-linoleoyl-glycophosphocholine and decreased stearoyl-arachidonyl glycophosphocholine. Finally, increased levels of methylated nucleotides (5-methylcytidine) and decreased levels of urea cycle metabolites (N-acetylcitrulline) were associated with the presence of mammary cancers.

Stereotactic radiosurgery (SRS) using the Gamma Knife (GK) is now being increasingly utilized for the treatment of brain metastases. However, there are a few reported cases of SRS-induced brain neoplasms. We herein report the case of a Japanese woman with metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor (EGFR)-mutations who was treated four times with a GK for brain metastases. She developed glioblastoma 5.7 years after the initial GK surgery. Radiation-induced secondary neoplasms generally appear after a latency period of several years. Advances in cancer therapy have improved the survival of patients with NSCLC, providing enough time for secondary neoplasms to appear after SRS.

The lithium-pilocarpine model of epilepsy reproduces several features of temporal lobe epilepsy in humans, including the chronological timeline of an initial latency period followed by the development of spontaneous seizures. Epilepsy therapies in humans are implemented, as a rule, after the onset of the spontaneous seizures. We here studied the potential effect on epileptogenesis of starting an early treatment during the latency period, in order to prevent the development of spontaneous seizures. Adult male Wistar rats were treated with 3 mEq/kg LiCl, and 20 h later 30 mg/kg pilocarpine. Once status epilepticus (SE) was achieved, it was allowed to last for 20 min, and then motor seizures were controlled with the administration of 20 mg/kg diazepam. At 1DPSE (DPSE, days post-status epilepticus), animals started to receive 400 mg/kg/day gabapentin or saline for 4 days. At 5DPSE, we observed that SE induced an early profuse microglial and astroglial reactivity, increased synaptogenic trombospondin-1 expression and reduced AQP4 expression in astroglial ending feet. Blood brain barrier (BBB) integrity seemed to be compromised, as infiltrating NG2+ macrophages and facilitated access to the CNS was observed by transplanting eGFP+ blood cells and bone marrow-derived progenitors in the SE animals. The early 4-day gabapentin treatment successfully reduced microglial cell reactivity and blood-borne cell infiltration, without significantly altering the mRNA of proinflammatory cytokines IL-1β and TNFα immediately after the treatment. After 21DSPE, another group of animals that developed SE and received 4 days of gabapentin treatment, were re-exposed to subconvulsive accumulative doses of pilocarpine (10 mg/kg/30 min) and were followed by recording the Racine scale reached. Early 4-day gabapentin treatment reduced the Racine scale reached by the animals, reduced animal mortality, and reduced the number of animals that achieved SE (34% vs. 72%). We conclude that early gabapentin treatment following SE, during the latency period, is able to reduce neuroinflammation and produces a persistent effect that limits seizures and increases convulsive threshold, probably by restricting microglial reactivity and spurious synaptogenesis. Fil: Rossi, Alicia Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; Argentina Fil: Murta, Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; Argentina Fil: Auzmendi, Jerónimo Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; Argentina Fil: Ramos, Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; Argentina

Purpose: To investigate the effect of 2-[(4-hydroxy-phenylamino)-methylene]-5,5-dimethyl-cyclohex (HPDH) on mammary carcinogenesis induced by 7,12-dimethylbenz(a)anthracene in female Sprague Dawley rats.Methods: Among three groups of rats (50 each) used in the study, the control group was fed standard diet alone, ibuprofen group received standard diet containing 1200 mg/kg ibuprofen while HPDH group was administered standard diet containing 1200 mg/kg HPDH. The treatment was for 10 days for all the groups. All the animals received 20 mg of DMBA intragastrically by gavage. Clinical parameters for the rats were recorded weekly. Micrometer caliper was used to measure the diameter of all the tumors at the end of the experiment and tumor volume calculated. Histological evaluation was performed using hematoxylin and eosin (H&E) staining. High performance liquid chromatography (HPLC) was used to determine the level of HPDH and ibuprofen in the serum of the animals.Results: The data revealed a significant decrease in the number of rats with mammary tumor, number of tumors/rat and tumor volume by 54, 72 and 75 %, respectively, in HPDH group compared to control group. The ibuprofen- treated rats also showed significant decrease in the number of rats with tumor, number of tumors/rat and tumor volume by 43, 55, and 59 %, respectively. Treatment of rats with HPDH increased the latency period of tumor induction significantly (p < 0.005). Median detection period (50 % of tumors) was 92, 83 and 56 days, respectively, in HPDH, ibuprofen and control groups, respectively, after DMBA induction.Conclusion: These results demonstrate that HPDH possesses strong chemopreventive activity against mammary carcinogenesis.Keywords: Carcinogenesis, Mammary tumor, Median detection period, Tumor, Latency period, Chemopreventive activity, Ibuprofen

The efficacy of the synthetic reproductive hormone WOVA-FH was evaluated for the ovulatory performance and egg quality of Clarias batrachus at three different doses, viz. 0.5, 1.0 and 1.5 ml/kg of body weight of brooder fish. After a 16-h latency period, both males and females of Clarias batrachus were simultaneously taken in a ratio 1:1 for milt collection and stripping. Ovulatory performance parameters such as stripped egg quantity, spawning fecundity and fertilisation rate were the highest (p

The incidence of brain metastasis (BM) among women with metastatic breast cancer (MBC) is currently on the rise, and it is estimated that between 10-30% of patients diagnosed with breast cancer may also develop BM (Weil 2005). BM is considered a late complication in the clinical setting and is an infrequent occurrence even in mice studies that readily metastasise to other organs (Valiente 2014). While pre-menopausal status and negative estrogen receptor (ER) status are seen as main risk factors (Gil-Gil 2013), it is now recognised that BM is emerging as an increasing clinical problem across the various MBC subtypes. BM patients have very poor overall survival and as a result it is crucial to identify the factors that promote the survival and adaptation of breast cancer cells to allow them to colonise distant sites such as the brain. The ability to predict the BM potential could be of great clinical importance and in this study we decided to investigate the mechanisms underlying BM across the various MBC subtypes. To our surprise, in a cohort of breast cancer patients we found a comparable number of ER positive and ER negative BM. We established that ER positive patients (n=10) had a substantially longer disease latency period (median disease free survival (DFS) 36 months, range 8-85 months) in comparison to ER negative patients (n=8, HER2 positive, n=2, triple negative, n=6), (median DFS 24 months, range 9-60 months). To understand and elucidate the gene alterations required for successful colonisation of the brain we undertook RNAseq of sequential primary and brain metastatic tumours from ER positive (n=4) and ER negative (n=3) breast cancer patients. Significant elevations in gene expression were observed in the brain metastatic tumours in comparison to the matched primary. Though a large degree of patient heterogeneity was observed, common ER-specific metastatic pathways were identified. This study highlights the requirement of unique gene sets for the colonisation to the brain and that functional characterisation of the differentially expressed genes will enable the identification of novel molecular targets for prevention and treatment of breast cancer BM. Citation Format: Damir Vareslija, Ailis Fagan, Jean McBryan, Patrick Buckley, Michael Farrell, Arnold DK Hill, Leonie Young. Global analysis of the transcriptome in matched primary and metastatic tumours defines ER specific gene alterations [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-07-26.

Background Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare disease which can cause severe morbidity and mortality. The aim of this study is to evaluate the clinical manifestation and course of DRESS syndrome. Methods We conducted a retrospective analysis of prospectively collected data in 45 patients with DRESS syndrome diagnosed between September 2009 and August 2011. Results The most common causative drug group was antibiotics (n = 13, 28.9%), followed by anticonvulsants (n = 12, 26.7%), antituberculosis drugs (n = 6, 13.3%), non-steroidal anti-inflammatory drugs (n = 4, 8.9%), undetermined agents (n = 4, 8.9%), allopurinol (n = 3, 6.7%), and others (n = 3, 6.7%). The latency period ranged from 2 to 120 days, with a mean of 20.2 ± 24.3 days. The longest latency period was noted for the antituberculosis drug group, at 46.5 ± 29.9 days. Eosinophilia in peripheral blood examination was noted in 35 subjects (77.8%). Atypical lymphocytosis was noted in 16 patients (35.6%), and thrombocytopenia in seven patients (15.6%). Hepatic involvement was noted in 39 (86.7%) study patients, kidney in eight (17.8%), lung in four (8.9%), and central nervous system in one (2.3%). Systemic corticosteroids were administered to 10 patients (22.2%). Forty-three patients (95.6%) showed complete recovery, while two patients had poor outcomes. Conclusions DRESS syndrome was not more uncommon than generally recognised. Antibiotics were the most frequently implicated drug group, followed by anticonvulsants. Most patients with this disease showed a better clinical outcome than that which had been generally expected.

Complications can occur following a prolonged latency period after radiation therapy for cancer, and this is a growing concern because secondary tumors are potentially fatal. Few studies have examined secondary tumors in patients who received radiation therapy as children.This retrospective study examined 1697 pediatric patients with central nervous system tumors who received treatment at Taipei Veterans General Hospital from January 1, 1975, to December 31, 2013. Secondary tumors developed in 27 of 681 patients who received cranial irradiation. Overall survival was estimated using the Kaplan-Meier method, and the significance of differences was determined by the log-rank test.The overall cumulative incidence of secondary tumors at 25 years was 3.96%, and there were similar numbers of male patients (n = 16) and female patients (n = 11). The mean age at diagnosis was 8.8 years (range, 3-16.5 years), the median dose of cranial irradiation was 52.5 Gy (mean, 53.4 Gy), the mean latency period was 14.6 years (range, 2-33 years), and the mean age at diagnosis of a secondary tumor was 23.1 years. The secondary tumors were mainly meningiomas (n = 13), sarcomas (n = 7), and high-grade gliomas (n = 6), and the mean latency periods were 19.66, 8.00, and 10.83 years, respectively. The overall survival rate from these secondary tumors was significantly different (P .05). Age at irradiation of7 years and craniospinal irradiation significantly increased the risk of a secondary tumor (P .05). Secondary tumors developed in 11 of 128 patients (8.6%) with primary medulloblastomas, which was higher than the overall cumulative incidence.Clinicians should consider the increased risk of secondary tumors in long-term cancer survivors who received craniospinal irradiation as children. Using a selective dose de-escalation strategy or deferring radiation therapy for young patients at highest risk of secondary cancers should be studied.