Longer Latency Period Research Articles

Clinical Features of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Induced by Immune Checkpoint Inhibitor versus Non-Immune Checkpoint Inhibitor Drugs in China: A Cross-Sectional Study and Literature Review.

Immune checkpoint inhibitors (ICIs) can cause life-threatening Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Large-scale original research on ICI-induced SJS/TEN is limited. This study aimed to explore the unique clinical characteristics and potential pathophysiological mechanisms of SJS/TEN induced by ICIs. This cross-sectional study compared the clinical features of SJS/TEN induced by ICIs and non-ICIs, and reviewed the case characteristics of ICI-induced SJS/TEN. Clinical features were analyzed using independent t-tests, Mann-Whitney U-tests, and multivariable regression models. This study enrolled 41 cases of ICI-induced SJS/TEN and 107 non-ICI-induced cases from January 22, 2015, to May 28, 2024. ICI-induced SJS/TEN patients exhibited a trend towards a longer latency period (β: 17, 95% CI: -1.49 to 35.48), a smaller affected body surface area (BSA) (β: -40.68, 95% CI: -71.59 to -9.77), and milder oral and ocular mucositis than non-ICI-induced cases. A literature review identified PD-1 inhibitors as the primary ICIs involved and systemic corticosteroids as the most frequent intervention. No statistically significant difference in mortality rate was observed between patients treated with systemic corticosteroids alone and those receiving combination therapies (P= 0.85). The mortality rate for ICI-induced SJS/TEN was 24.5%. This study offered the largest comparative analysis to date, highlighting the unique clinical features of ICI-induced SJS/TEN, including a smaller affected BSA, a prolonged latency period trend, and milder oral and ocular mucositis. We described the epidemiology, clinical presentation, and therapeutic strategies for ICI-induced SJS/TEN. These findings not only contribute to a deeper understanding of the complex immune-inflammatory pathways in severe immune-related cutaneous adverse events (ircAEs) but also may inform the development of more targeted and effective treatments.

Formulation of adult food-protein–induced enterocolitis syndrome diagnostic scoring system differentiating from immediate-type food allergy

BackgroundAdult food-protein–induced enterocolitis syndrome (FPIES) has recently been recognized, and there are no international diagnostic criteria for this disease. Differentiating adult FPIES from immediate-type food allergy reactions and providing specific treatment for each in an emergency are important, but methods have not been developed. ObjectiveTo develop a diagnostic scoring system for adult FPIES by comparing it with an immediate-type food allergy (IgE-mediated food allergy [IgE-FA]). MethodsThis retrospective cohort study of food-avoidant adults based on the diagnostic criteria for adult FPIES reported by Gonzalez et al was conducted through telephone interviews. We compared the clinical profiles of the patients with FPIES and IgE-FA. Adult FPIES-associated factors were extracted using multivariate analysis, and a diagnostic scoring system was developed based on odds ratios. ResultsA total of 48 (16.7%) of 288 adults with food allergies were diagnosed with FPIES; of these, 240 (83.3%) had IgE-FA. Seafood was the most common cause of FPIES in adults (68.8%). Multivariate analysis identified an age of onset older than 26 years, more than 10 episodes, a longer latency period, cold sweat, abdominal distention, and vomiting as adult FPIES-associated factors. An adult FPIES diagnostic scoring system was developed using odds ratios with a high area under the curve (0.978), 100% sensitivity, and 87.0% specificity. ConclusionClinical profiles and an adult FPIES diagnostic scoring system were developed for the first time. This scoring system can be useful in differentiating adult FPIES and IgE-FA when treating food-related acute reactions.

Data Linkages for Wildfire Exposures and Human Health Studies: A Scoping Review.

Wildfires are increasing in frequency and intensity, with significant consequences that impact human health. A scoping review was conducted to: (a) understand wildfire-related health effects, (b) identify and describe environmental exposure and health outcome data sources used to research the impacts of wildfire exposures on health, and (c) identify gaps and opportunities to leverage exposure and health data to advance research. A literature search was conducted in PubMed and a sample of 83 articles met inclusion criteria. A majority of studies focused on respiratory and cardiovascular outcomes. Hospital administrative data was the most common health data source, followed by government data sources and health surveys. Wildfire smoke, specifically fine particulate matter (PM2.5), was the most common exposure measure and was predominantly estimated from monitoring networks and satellite data. Health data were not available in real-time, and they lacked spatial and temporal coverage to study health outcomes with longer latency periods. Exposure data were often available in real-time and provided better temporal and spatial coverage but did not capture the complex mixture of hazardous wildfire smoke pollutants nor exposures associated with non-air pathways such as soil, household dust, food, and water. This scoping review of the specific health and exposure data sources used to underpin these studies provides a framework for the research community to understand: (a) the use and value of various environmental and health data sources, and (b) the opportunities for improving data collection, integration, and accessibility to help inform our understanding of wildfires and other environmental exposures.

Evolution of intermediate latency strategies in seasonal parasites.

Traditional mechanistic trade-offs between transmission and parasite latency period length are foundational for nearly all theories on the evolution of parasite life-history strategies. Prior theoretical studies demonstrate that seasonal host activity can generate a trade-off for obligate-host killer parasites that selects for intermediate latency periods in the absence of a mechanistic trade-off between transmission and latency period lengths. Extensions of these studies predict that host seasonal patterns can lead to evolutionary bistability for obligate-host killer parasites in which two evolutionarily stable strategies, a shorter and longer latency period, are possible. Here we demonstrate that these conclusions from previously published studies hold for non-obligate host killer parasites. That is, seasonal host activity can select for intermediate parasite latency periods for non-obligate killer parasites in the absence of a trade-off between transmission and latency period length and can maintain multiple evolutionarily stable parasite life-history strategies. These results reinforce the hypothesis that host seasonal activity can act as a major selective force on parasite life-history evolution by extending the narrower prior theory to encompass a greater range of disease systems.

Predictive Factors Associated With Radiation Myelopathy in Pediatric Patients With Cancer: A PENTEC Comprehensive Review

Radiation myelitis (RM) is a rare complication of radiation therapy (RT). The Pediatric Normal Tissue Effects in the Clinic spinal cord task force aimed to identify RT dose effects and assess risk factors for RM in children. Through systematic review, we analyzed RT dose, fraction size, latency between completion of RT and toxicity, chemotherapy use, age when irradiated, and sex. We conducted literature searches of peer-reviewed manuscripts published from 1964 to June 2017 evaluating RM among children. Normality of variables was assessed with Kolmogorov-Smirnov or Shapiro-Wilk tests. Spearman's rank correlation coefficients were used to test correlations between RT dose/fraction size and latency between RT and development of toxicity. Of 1329 identified and screened reports, 144 reports were fully reviewed and determined to have adequate data for analysis; 16 of these reports had a total of 33 cases of RM with a median age of 13 years (range, 0.2-18) at the time of RT. The most common primary tumor histologies were rhabdomyosarcoma (n = 9), medulloblastoma (n = 5), and Hodgkin lymphoma (n = 2); the most common chemotherapy agents given were vincristine (n = 15), intrathecal methotrexate (n = 12), and intrathecal cytarabine (n = 10). The median RT dose and fraction size were 40 Gy (range, 24-57.4 Gy) and 1.8 Gy (range, 1.3-2.6 Gy), respectively. RT dose resulting in RM in patients who also received chemotherapy was lower than in those not receiving chemotherapy (mean 39.6 vs 49.7 Gy; P = .04). There was no association of age with RT dose. The median latency period was 7 months (range, 1-29). Higher RT dose was correlated with longer latency periods (P = .03) to RM whereas sex, age, fraction size, and chemotherapy use were not. Two of 17 patients with adequate follow-up recovered from RM; unfortunately, it was fatal in 6 of 15 evaluable patients. Complication probability modeling was not possible because of the rarity of events. This report demonstrates a relatively short latency from RT (with or without chemotherapy) to RM and a wide range of doses (including fraction sizes) associated with RM. No apparent association with age at the time of RT could be discerned. Chemotherapy appears to reduce spinal cord tolerance. Recovery from RM is rare, and it is often fatal.

Multi‐institutional retrospective review of acute generalized exanthematous pustulosis (AGEP) induced by hydroxychloroquine

AbstractBackgroundAcute generalized exanthematous pustulosis (AGEP) is a rare and severe cutaneous drug eruption. Hydroxychloroquine (HCQ) is one of the known culprit drugs with less than 60 cases reported in the literature, and may have a more severe clinical presentation compared to AGEP induced by other drugs. There are no standardized management strategies for HCQ‐induced AGEP outside of drug discontinuation.ObjectivesCharacterize the clinical presentation of HCQ‐induced AGEP and management strategies.MethodsRetrospective chart review of nine patients clinically diagnosed with HCQ‐induced AGEP using the EuroSCAR score from 2017 to 2022 at four academic medical centres in the United States.ResultsAll patients in our series were female and the median age was 52. Four patients initially presented with fever, and eight patients had neutrophilia. Median time to rash was 15 days. Biopsies obtained in six patients showed typical characteristics of AGEP. In most patients, rash morphology consisted of generalized pinpoint pustules atop atypical targetoid lesions and annular plaques. Five patients were hospitalized for AGEP. All patients were treated with methylprednisolone and/or prednisone, and the average days treated with systemic corticosteroids was 35.ConclusionsOur case series is the largest to date describing HCQ‐induced AGEP. Clinicians should be wary that HCQ‐induced AGEP may present with a longer latency period after drug initiation and with atypical targetoid and annular lesions. Early initiation of systemic corticosteroids should be considered due to the severity of this drug reaction with addition of cyclosporine in refractory cases.

Acquired Immune Deficiency Syndrome correlation with SARS-CoV-2 N genotypes

BackgroundEpigenetics and clinical observations referring to Betacoronavirus lead to the conjecture that Sarbecovirus may have the ability to infect lymphocytes using a different way than the spike protein. In addition to inducing the death of lymphocytes, thus drastically reducing their population and causing a serious immune deficiency, allows it to remain hidden for long periods of latency using them as a viral reservoir in what is named Long-Covid Disease. Exploring possibilities, the hypothesis is focused on that N protein may be the key of infecting lymphocytes. MethodThe present article exhibits a computational assay for the latest complete sequences reported to GISAID, correlating N genotypes with an enhancement in the affinity of the complex that causes immune deficiency in order to determine a good docking with the N protein and some receptors in lymphocytes. ResultsA novel high-interaction coupling of N-RBD and CD147 is presented as the main way of infecting lymphocytes, allowing to define those genotypes involved in their affinity enhancement. ConclusionThe hypothesis is consistent with the mutagenic deriving observed on the in-silico assay, which reveals that genotypes N/120 and N/152 are determinant to reduce the Immune Response of the host infecting lymphocytes, allowing the virus persists indefinitely and causing an Acquire Immune Deficiency Syndrome.

Effects of thymoquinone and memantine alone and in combination on memory and hippocampal morphology in rats with streptozotocin-induced Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease. Thymoquinone (TQ) has broad biological functions, including antiinflammatory, antioxidant, neuroprotective properties. Memantine (MEM) is indicated for the symptomatic treatment of moderate to severe AD. We aimed to evaluate the effect of TQ alone or in combination with MEM on memory and hippocampal morphology in an STZ-induced rat AD model. Thirty male rats were included in this study. The AD model was created by giving ICV STZ. The rats were divided into 5 groups (n = 6 each). Group 1 (control group): The rats received only ICV-STZ 3 mg/kg for 2 weeks. Group 2 (sham group): In addition to ICV STZ, 9% NaCl, 1 mL/day i.p. for 2 weeks of injection, was applied. Group 3 (TQ group): In addition to ICV STZ, rats received TQ 10 mg/kg i.p. for 2 weeks. Group 4 (MEM group): In addition to ICV STZ, rats were given MEM at a dose of 5 mg/kg for two weeks. Group 5 (TQ+MEM group): In addition to ICV STZ, this group was given TQ (10 mg/kg/day, i.p.) and MEM (5 mg/kg/day, i.p.) for 2 weeks. On the 15th day, passive avoidance learning (PAL) was applied to all groups. Then, rats were sacrificed, neurons in the hippocampal CA1, CA2, CA3 regions were evaluated. Groups 3, 4, 5 had longer latency periods than groups 1 and 2. The neuron density in the CA1, CA2, CA3 regions had decreased in groups 1 and 2 compared to groups 3, 4, 5. There were significantly more neurons in groups 3, 4, 5 than in groups 1 and 2. We found that TQ alone and in combination with MEM showed ameliorative effects on memory and hippocampal morphology. TQ may offer a promising treatment strategy for AD.

Tachyarrhythmias after extracardiac conduit Fontan procedure in the long-term follow-up: may native anatomy of single ventricle predict their occurrence?

Abstract Funding Acknowledgements Type of funding sources: None. Background Arrhythmic complications, especially tachycardias, represent a common and important comorbidity during long-term follow up (FU) in patients with Fontan palliation for complexes congenital heart diseases (CHDs) with univentricular hearts. Surgical Fontan technique has evolved from direct atrio-pulmonary connection via the intracardiac lateral tunnel to the latest extracardiac conduit (ECC) procedure. Despite its shorter FU compared to previous techniques, the ECC variation is nowadays the main approach for many improvements, including lower incidence of arrhythmic complications (especially atrial arrhythmias). Purpose The aim of this study was to evaluate, during a long-term FU, the incidence of tachyarrhythmias and their correlation with the morphology of CHDs’ single ventricle native anatomy in a large cohort of patients with previous ECC Fontan procedure. Methods In this single centre observational cohort study, we retrospectively evaluated 351 patients treated with ECC Fontan palliation in our Institution between January 1987 and October 2017. Exclusion criteria were ECC Fontan take-down and a FU less than 5 years. CHD diagnosis, single ventricle native anatomy and surgical history were reviewed. Patients had cardiac examination once a year. We divided the overall study population in 2 groups based on unique ventricle's morphology: left-type (LV group) or right-type (RV group). Results A total of 303 patients [56% males; mean age at last FU 20 (IQR 15-28) years; 64.7% LV group] with ECC Fontan were enrolled. The mean FU was 16 (IQR 11-20, the longest 33) years. No sudden arrhythmic cardiac death occurred. Ten patients (6 of the LV group) underwent cardiac transplantation for Fontan failure. During FU, 34 patients of the LV (17.3%) and 22 of the RV group (20.2%) showed at least one tachyarrhythmia after a mean time of 12.1 and 12.9 years from ECC procedure, respectively. One patient (LV group) had one tachyarrhythmia in the early time period, <30 days from procedure. LV group showed a higher incidence of supraventricular tachyarrhythmias (SVTs) than RV group (68% vs 41% of total arrhythmias, p=0.08); in contrast, in RV group we found a higher number of ventricular tachyarrhythmias (VTs) compared to the other group (73% vs 41%, p=0.04). We observed both types of tachyarrhythmias (SVT and VT) in 3 patients of LV and 2 of RV group. Conclusions This study, with one of the largest cohort and longest FU after ECC Fontan, shows that ECC is associated with higher arrhythmic complications than previously reported, even though with longer latency period than other Fontan procedures. Moreover, our results suggest that patients with right-type single ventricle native anatomy are significantly more prone to develop VTs compared to those with left-type ventricle. This may reflect the drawbacks of the right ventricle physiology within Fontan circulation where the right ventricle acts for long time as the main pump of the circulatory system.

The mechanisms and diagnostic potential of lncRNAs, miRNAs, and their related signaling pathways in cervical cancer.

Cervical cancer (CC), the fourth most prevalent type of cancer among women worldwide, is associated with high rates of morbidity and mortality. Due to the long period of latency in CC, most patients are already in the middle to late stages when initially diagnosed, which greatly reduces the clinical cure rate and quality of survival, thus resulting in poor outcomes. In recent years, with continuous exploration in the fields of bioinformatics and molecules, it has been found that ncRNAs, including miRNAs and lncRNAs, without the ability to translate proteins are capable of activating or inhibiting certain signaling pathways by targeting and modulating the level of expression of proteins involved in these signaling pathways. ncRNAs play important roles in assisting with diagnosis, drug administration, and prediction of prognosis during CC progression. As an entry point, the mechanisms of interaction between miRNAs, lncRNAs, and signaling pathways have long been a focus in basic research relating to CC, and numerous experimental studies have confirmed the close relationship of miRNAs, lncRNAs, and signaling pathways with CC development. Against this background, we summarize the latest advances in the involvement of lncRNA- and miRNA-related signaling pathways in the development of CC to provide guidance for CC treatment.

Causes of death among patients with hepatocellular carcinoma in United States from 2000 to 2018.

The gains in survival outcomes of US patients with hepatocellular carcinoma (HCC) have come at the expense of developing non-cancer-related morbidities, such as cardiovascular diseases (CVDs) and infections. However, population-based data on causes of death (CODs) in patients with HCC are scarce. A cancer registry database in the United States was used to analyze the CODs among patients with HCC. Death cause distribution and standardized mortality ratios were calculated to quantify the disease-specific death burden. A total of 40,094 patients with a histological diagnosis of HCC were identified from the SEER-18 database between 2000 and 2018, of which 30,796 (76.8%) died during the follow-up period. The majority of these deaths (25,153, 81.7%) occurred within 2 years after diagnosis, 13.2% (4075) occurred within 2-5 years, and 5.1% (1568) occurred after 5 years. All age groups had a lower burden of female deaths than of male deaths during the study period. With respect to CODs, 23,824 (77.4%), 2289 (7.4%), and 4683 (15.2%) were due to HCC, other cancers, and non-cancer causes, respectively. Non-cancer-related deaths were more common among older patients and those with longer latency periods since diagnosis. The major causes of non-cancer-related deaths are other infectious and parasitic diseases, including HIV and CVDs. CODs during HCC survivorship varied, and a growing number of survivors tended to die from causes other than HCC, with an increasing latency period since diagnosis. Comprehensive analyses of mortality patterns and temporal trends could underpin strategies to reduce these risks.

Clinical features of acute generalized exanthematous pustulosis caused by hydroxychloroquine in rheumatology patients and exploration of CARD14 gene mutations.

Acute generalized exanthematous pustulosis (AGEP) is a rare condition characterized by superficial pustules following drug ingestion or infection. Currently, there is no clear link between rheumatism and AGEP. It has been described that hydroxychloroquine (HCQ) is a rare cause of acute generalized epidermal necrolysis (AGEP). Presently, there are limited studies on HCQ-induced AGEP. We aimed to explore the clinical features and associated gene expression of AGEP induced after HCQ treatment exposure in rheumatology patients. We assessed patients with HCQ-induced AGEP diagnosed at the Second Affiliated Hospital of Guizhou University of Chinese Medicine between January 1, 2017, and May 1, 2022. We also reviewed similar cases reported in specific databases. The study included five females (mean age, 40.2 years), and the mean time from initiation of HCQ treatment to symptom onset was 12.2 d. All patients received steroids and allergy medications after HCQ discontinuation, and the rash completely resolved within an average of 25.2 d. We performed whole exome sequencing and Sanger validation in our patient sample. CARD14 gene mutations were detected in three patients. Additionally, seven mutation sites were detected. HCQ-induced AGEP may have a longer latency period and regression time than AGEP induced by other drugs. Our patients all experienced CARD14 gene mutations. AGEP often resolves with topical therapy and drug discontinuation, although some cases require systemic steroid therapy. In the future, patients with rheumatism should pay attention to the effectiveness of HCQ during treatment and be aware of the associated skin toxicity.

Comparison of transvaginal cervical cerclage versus laparoscopic abdominal cervical cerclage in cervical insufficiency: a retrospective study from a single centre

BackgroundCervical cerclage has been proposed as an effective treatment for cervical insufficiency, but there has been controversy regarding the surgical options of cervical cerclage in singleton and twin pregnancies. This study aimed to compare the pregnancy outcomes between transvaginal cervical cerclage (TVC) and laparoscopic abdominal cervical cerclage (LAC) in patients with cervical insufficiency. We also aimed to evaluate the efficacy and safety, and provide more evidence to support the application of cervical cerclage in twin pregnancies.MethodsA retrospective study was carried out from January 2015 to December 2021. The primary outcomes were the incidence of spontaneous preterm birth (sPTB) < 24 weeks, < 28, < 32, < 34 weeks, and < 37weeks, gestational age at delivery, and the incidence of admission for threatened abortion or preterm birth after cervical cerclage. The secondary outcomes included admission to the Neonatal Intensive Care Unit, adverse neonatal outcomes and neonatal death. We also analysed the pregnancy outcomes of twin pregnancies after cervical cerclage.ResultsA total of 289 patients were identified as eligible for inclusion. The LAC group (n = 56) had a very low incidence of sPTB ˂ 34 weeks, and it was associated with a significant decrease in sPTB < 28 weeks, ˂32 weeks, ˂34 and < 37 weeks, and admission to the hospital during pregnancy for threatened abortion or preterm birth after cervical cerclage (0 vs.27%; 1.8% vs. 40.3%; 7.1% vs. 46.8%; 14% vs. 63.5%, 8.9% vs. 62.2%, respectively; P < 0.001), and high in gestational age at delivery compared with the TVC group (n = 233) (38.3 weeks vs.34.4 weeks,P < 0.001). Neonatal outcomes in the LAC group were significantly better than those in the TVC group. The mean gestational age at delivery was 34.3 ± 1.8 weeks, with a total foetal survival rate of 100% without serious neonatal complications in twin pregnancies with LAC.ConclusionIn patients with cervical insufficiency, LAC appears to have better pregnancy outcomes than TVC. For some patients, LAC is a recommended option and may be selected as the first choice. Even in twin pregnancies, cervical cerclage can improve pregnancy outcomes with a longer latency period, especially in the LAC group.

Local recurrence of mammary Paget’s disease after nipple-sparing mastectomy and implant breast reconstruction: a case report and literature review

ObjectiveTo provide a rare case of local recurrent Paget’s disease after nipple-sparing mastectomy (NSM) with immediate breast reconstruction with 10 years of disease-free survival and to analyze the clinical and pathological characteristics.BackgroundMammary Paget’s disease can be considered a rare type of local recurrence after breast cancer treatment, both in cases of conservative surgery and NSM with immediate breast reconstruction (Lohsiriwat et al, Ann Surg Oncol 19:1850-1855, 2012). Recurrent patients who present with nipple-areolar Paget’s disease usually have unfavorable primary pathological characteristics and different latency periods. However, the recurrent status in patients with favorable primary pathological characteristics and the latency periods after NSM with immediate breast reconstruction are unclear.MethodsFirst, we present a case of local recurrent Paget’s disease in a young patient diagnosed with invasive breast carcinoma at age 30 who underwent NSM with primary silicone reconstruction. Then, the keywords “Paget’s disease” and “nipple-sparing mastectomy” were selected. Articles including the local recurrence of Paget’s disease after NSM were collected from the PubMed, Springer, and OVID databases, and the acquired relevant data were analyzed. We did not restrict our search by study design or publication date.ResultsFive studies describing 31 cases of local recurrent Paget’s disease after NSM with implant breast reconstruction were included. The mean patient age reported was 45 years, and the average latency period from NSM to the local recurrence of Paget’s disease was 40.2 months. Recurrent tumor histological features were Paget’s disease with ductal carcinoma in situ (DCIS) in 16 patients (50%), Paget’s disease without DCIS in 13 patients (40.6%), and Paget’s disease with ductal intraepithelial neoplasia (DIN) in 3 patients (9.4%). The primary tumor histological feature was estrogen receptor (ER)(−)/progesterone receptor (PR)(−)/human epidermal growth factor receptor (HER-2)(+) in 21 patients (77.8%). Neither locoregional relapse nor metastatic events were found in these recurrent patients who accepted NAC excision after 4–5 years of follow-up. Our reported case showed that the patient experienced pregnancy and lactation after primary adjuvant chemotherapy and endocrine therapy. However, she developed an eczematoid lesion in the NAC 120 months after breast surgery. The histopathological examination was consistent with Paget’s disease of the breast. Complete NAC and breast silicone prosthesis removal were performed. The patient accepted no systematic or local therapy and is currently alive. It is noteworthy that the biological features of the primary tumor were ER(+), PR(+), and HER-2(−); however, the recurrent tumor changed to ER(−), PR(−), and HER-2(+).ConclusionsThe local recurrence of Paget’s disease after NSM is uncommon; it may develop at a very early age and have a very long time to recurrence, as in our patient, who presented with recurrence 10 years after primary surgery. Surgeons should be wary of local recurrence of the nipple-areola complex after NSM in patients with ER-negative and HER-2-positive primary tumors. However, patients with ER/PR-positive and HER-2-negative tumors should not be neglected; we reported a case of an ER/PR-positive and HER-2-negative primary tumor, and ER-positive recurrent cases have the longest latency period. The local recurrence rate of Paget’s disease after NSM is low, and the prognosis is good in recurrent patients who accept further extensive NAC excision. Further systematic treatment was not considered for this patient.

AASLD practice guidance on drug, herbal, and dietary supplement-induced liver injury.

AASLD practice guidance on drug, herbal, and dietary supplement-induced liver injury.

Management of Psychiatric Disorders in Patients with Hepatic and Gastrointestinal Diseases.

Management of Psychiatric Disorders in Patients with Hepatic and Gastrointestinal Diseases.

A Framework for Cumulative Risk Assessment: Exploring the Carcinogenic Effects of Chemical Mixtures.

Open in a separate window Humans are commonly exposed to mixtures of chemicals in their environments, rather than to one compound at a time. Accordingly, researchers have long been interested in the complex task of studying how mixtures affect disease end points.1 Cynthia Rider and colleagues recently proposed in Environmental Health Perspectives2 a research program on mixtures and cancer based on the key characteristics of carcinogenic chemicals.3 “We wanted to apply what we have learned from studying outcomes with shorter exposure periods to a more complex scenario,” says Rider, a toxicologist at the National Institute of Environmental Health Sciences and first author of the new paper. “Because cancer results from the cumulative impact of multiple low-dose hits in several pathways during a long period of latency, the analysis of mixture effects is especially challenging.” Open in a separate window Although people are exposed to many chemicals over their lifetimes—in food, water, personal care products, air, and other media—toxicology has historically studied agents individually. The authors of a new commentary recommend strategies for studying exposures to chemical mixtures. Image: © iStock/NoSystem Images.

Effects of GnRHa and hCG with or without dopamine receptor antagonists on the spawning efficiency of African catfish (Clarias gariepinus) reared in hatchery conditions

Optimization of artificial reproduction is essential for minimizing genetic diversity, especially when fish are captured from their natural habitats and spawned in controlled conditions. In the present study, there was evaluation of the effects of gonadotropin-releasing hormone analogue (GnRHa) and human chorionic gonadotropin (hCG) with or without dopamine receptor antagonists such as domperidone (DOM) and metoclopramide (MET) on the spawning efficiency of African catfish (Clarias gariepinus) reared in captivity. The control group was intramuscularly (IM) injected with 1 mL of sterile saline solution. The fish specimens of the other six groups were injected IM with GnRHa or hCG, or in combination with either DOM or MET. None of the specimens had ovulations in the control group. There was the longest latency period in specimens treated with only GnRHa or hCG. There were the largest egg mass weight, fecundity, and hatchability (%) in specimens of the GnRHa + MET group. These findings indicate that GnRHa or hCG combined with dopamine receptor antagonists such as DOM and MET resulted in a marked enhancement of ovulation rate and increased the egg mass, fecundity, and hatchability of the treated C. gariepinus, and the values when there was inclusion of the MET treatment exceeded those when there was treatment with DOM.

Therapy-Related Myeloid Neoplasms Are Not Always Dismal If They Have Better Cytogenetic Profile and Longer Latency Period from Preceding Anti-Cancer Treatment

Currently, any myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) developed after previous exposure to chemotherapy and/or radiation (CT/RT) are defined as therapy-related myeloid neoplasms (t-MNs). However, this medical history-oriented definition has an inherent uncertainty considering possibilities of pathogenetically only minimally related or even irrelevant to previous exposure to CT/RT in a part of patients. We investigated whether there were any specific factors that could separate ‘by definition tMNs’ into better vs. poorer prognosis, thereby necessitate different therapeutic strategies.From July 2006 to May 2017, 82 adult patients were diagnosed as MDS or AML in Seoul National University Hospital, Seoul, Korea, with clear medical records of prior exposure to ≥ 1 of followings; alkylating agents, topoisomerase 2 inhibitors (Topo2I), and radiotherapy. After excluding 8 patients with acute promyelocytic leukemia, 74 patients (43 t-AML and 31 t-MDS) were analyzed (median age 58, range 19-82). The patients were treated by conventional therapeutic modalities for MDS/AML including intensive chemotherapy (IC; n = 30), hypomethylating agents (HMAs; n = 26), upfront allogeneic stem cell transplantation (allo-SCT; n = 2), low-dose cytarabine (n = 1), and best supportive care (BSC; n = 15). Lymphoid malignancies (31.1%) and breast cancer (21.7%) were the most common preceding cancers. More than half of the patients (54.1%; 40 patients) had received both alkylators and Topo2Is and previously known differences of characteristics between alkylator/radiation vs. Topo2I groups including median time of latency and initial presentation of t-MNs (either t-MDS or t-AML) were not observed. Median time from the last exposure of CT/RT to diagnosis of t-MN was 21.8 months (range, 0.8-134).During median follow-up period of 20.6 months (95% CI 5.7-35.5 months) from diagnosis of tMNs, median overall survival (OS) was 11.6 months (95% CI 7.8-15.3 months). There was no difference of OS between t-MDS and t-AML (p = 0.136) or treatment with IC vs. HMAs (p = 0.143). Patients who had ≥ 3 abnormalities and/or complete or partial deletion of chromosome 5 or 7 (n = 35) showed inferior OS compared to those without the abnormalities (median OS 6.9 vs. 19.5 months; p = 0.048). By contrast, patients who had normal karyotype (NK) or core-binding factor (CBF) cytogenetics [t(8;21), inv(16), or t(16;16)] (n = 24; 16 for NK and 8 for CBF) showed significantly superior OS compared to their counterpart (median OS 38.8 vs. 6.2 months and 3-year OS 56.4% vs. 10.6%; p < 0.001; Figure). In addition to the absence of NK/CBF cytogenetics, age ≥ 70 years at diagnosis of t-MN, development of t-MN < 12 months from the last exposure to CT/RT, and metastatic or active status of preceding cancer at the time of t-MN diagnosis, were associated with inferior OS in univariate analysis. Multivariate analysis showed that absence of NK/CBF cytogenetics in addition to development of t-MN < 12 months from the last exposure to CT/RT, a parameter indicative of more recent damage of body by exposure to CT/RT, were independent factors of poor prognosis (Table).Among 59 patients after excluding 15 patients who received BSC only for palliative aim, poor prognosis of lacking NK/CBF cytogenetics was overcome by allo-SCT (hazard ratio 0.44, 95% CI 0.20-0.95, p = 0.036). When analysis was limited to patients with t-AML who received either IC or HMAs, patients with NK/CBF cytogenetics had higher rate of achieving a complete remission (CR) compared to those without NK/CBF cytogenetics (75% vs. 25%). patients who achieved CR showed higher 3-year OS compared to those who had persistent disease (64.3% vs. 16.2%, p = 0.030).Those results show that t-MN patients who have NK/CBF cytogenetics and fit to intensive treatment including allo-SCT can achieve comparable outcomes to de novo MDS/AML and suggest that those patients may have a different pathogenesis from that of genetically heavily damaged t-MNs. Future studies serially comparing genetic pathways and mutations within the heterogeneous tMNs would contribute to establish more fine-tuned, a genetics-oriented definition of tMNs. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Selected Articles from This Issue

Ductal carcinoma in situ (DCIS) breast cancers are non-invasive but can progress to invasive ductal carcinoma (IDC) through tumor intrinsic and -extrinsic factors that are poorly understood. In this study, Trinh and colleagues model interactions between DCIS/IDC tumors and their respective immune cell infiltrates using integrated molecular analyses. The authors find that IDC tumors are often genetically related to their DCIS precursors despite long periods of latency between the two stages, and that features of the tumor immune microenvironment are established early in tumor development and could shap. the progression to IDC. In particular, recurrent TP53 and PIK3CA mutations were associated with sustained inflammatory immune cell activity across the DCIS-IDC transition. The authors argue that, despite their status as neoantigens, these mutations and others could be retained through immune editing of the tumor. While in-depth study in a diverse cohort is needed, these data suggest a key role for the immune system in shaping the progression of certain DCIS tumors to IDC based on their constellation of genomic alterations.Patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) face a dismal prognosis, and clinical management of PDAC is limited to cytotoxic regimens. 5-fluorouracil is a key component of these regimens, but its use is hampered by systemic toxicity due to the off-target effects of its metabolites and inefficient conversion to the active metabolite, FdUMP. Here, Haber and colleagues report a novel fluoropyrimidine agent, CF10. Consisting of a capped polymeric chain of FdUMP molecules, CF10 displayed enhanced efficacy, increased stability, and reduced toxicity in preclinical models compared to precursor compounds such as 5-fluorouracil. While CF10 was shown to be effective as a single agent in preclinical models of PDAC, combination with an experimental Poly (ADP-ribose) Glycohydrolase (PARG) inhibitor or PARG ablation resulted in synergistic induction of DNA damage and PDAC cell death. Taken together, the data nominate CF10 as a promising candidate that could significantly improve the efficacy of standard-of-care regimens for PDAC.Mutations in the PI3K/AKT pathway are common in cancer and have significant implications for cell metabolism, proliferation, and survival. Despite its central role in cell biology, pharmacological agents targeting this pathway have met with limited success in the clinic. Now, using CRISp. to model specific genetic lesions, Gao and colleagues have uncovered differential functions of mutations in AKT isoforms: E17K mutations in AKT1 and AKT2 both conferred survival and proliferation advantages, but AKT1 E17K had the additional effect of suppressing invasion. Specifically, AKT1 mutation prevented nuclear localization of β-catenin, thereby repressing ZEB1 expression and impeding migratory capacity. This effect on cell migration was not observed in the context of AKT2 activation nor in the context PIK3CA or PTEN mutations, which activate both AKT1 and AKT2. The authors therefore suggest that the use of pharmacological inhibitors of the AKT pathway may paradoxically drive disease progression in certain genetic backgrounds by releasing an AKT1-mediated brake on cell migration and epithelial-mesenchymal transition.BH3-mimetic compounds such as venetoclax have potent pro-apoptotic effects in leukemic B cells, but tumors frequently amplify their expression of anti-apoptotic BH2 domain-containing proteins, such as MCL-1, to circumvent pro-apoptotic therapeutics. In this study, Smith and colleagues employ a genome-wide CRISPR screen to identify pathways involved in regulating MCL-1 expression, and thereby identify the heme-regulated inhibitor (HRI) as a key target. The authors show that, in the absence of heme or when the interaction between heme and HRI are pharmacologically disrupted, HRI initiates the cellular stress response and suppresses MCL-1 expression. These effects were not observed when HRI expression was genetically ablated, suggesting that HRI represents a control node for the modulation of MCL-1 expression in leukemic cells. These data nominate HRI and the heme-sensing pathway as a potential candidate for development of combinatorial regimens to enhance the efficacy of BH3-mimetics in certain subsets of leukemia patients.