PGC-1α drives small cell neuroendocrine cancer progression towards an ASCL1-expressing subtype with increased mitochondrial capacity.

Adenocarcinomas from multiple tissues can converge to treatment-resistant small cell neuroendocrine (SCN) cancers comprised of ASCL1, POU2F3, NEUROD1, and YAP1 subtypes. We investigated how mitochondrial metabolism influences SCN cancer (SCNC) progression. Extensive bioinformatics analyses encompassing thousands of patient tumors and human cancer cell lines uncovered enhanced expression of PGC-1α, a potent regulator of mitochondrial oxidative phosphorylation (OXPHOS), across several SCNC types. PGC-1α correlated tightly with increased expression of the lineage marker ASCL1 through a positive feedback mechanism. Analyses using a human prostate tissue-based SCN transformation system showed that the ASCL1 subtype has heightened PGC-1α expression and OXPHOS activity. PGC-1α inhibition diminished OXPHOS, reduced SCNC cell proliferation, and blocked SCN prostate tumor formation. PGC-1α overexpression enhanced OXPHOS, tripled the SCN prostate tumor formation rate, and promoted commitment to the ASCL1 lineage. These findings reveal the metabolic heterogeneity among SCNC subtypes and identify PGC-1α-induced OXPHOS as a regulator of SCNC lineage plasticity.

Temporal evolution reveals bifurcated lineages in aggressive neuroendocrine small cell prostate cancer trans-differentiation.

Trans-differentiation from an adenocarcinoma to a small cell neuroendocrine state is associated with therapy resistance in multiple cancer types. To gain insight into the underlying molecular events of the trans-differentiation, we perform a multi-omics time course analysis of a pan-small cell neuroendocrine cancer model (termed PARCB), a forward genetic transformation using human prostate basal cells and identify a shared developmental, arc-like, and entropy-high trajectory among all transformation model replicates. Further mapping with single cell resolution reveals two distinct lineages defined by mutually exclusive expression of ASCL1 or ASCL2. Temporal regulation by groups of transcription factors across developmental stages reveals that cellular reprogramming precedes the induction of neuronal programs. TFAP4 and ASCL1/2 feedback are identified as potential regulators of ASCL1 and ASCL2 expression. Our study provides temporal transcriptional patterns and uncovers pan-tissue parallels between prostate and lung cancers, as well as connections to normal neuroendocrine cell states.

Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial.

There is an urgent need for first-line treatment options for patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. Claudin-18 isoform 2 (CLDN18.2) is expressed in normal gastric cells and maintained in malignant G/GEJ adenocarcinoma cells. GLOW (closed enrollment), a global, double-blind, phase 3 study, examined zolbetuximab, a monoclonal antibody that targets CLDN18.2, plus capecitabine and oxaliplatin (CAPOX) as first-line treatment for CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma. Patients (n = 507) were randomized 1:1 (block sizes of two) to zolbetuximab plus CAPOX or placebo plus CAPOX. GLOW met the primary endpoint of progression-free survival (median, 8.21 months versus 6.80 months with zolbetuximab versus placebo; hazard ratio (HR) = 0.687; 95% confidence interval (CI), 0.544-0.866; P = 0.0007) and key secondary endpoint of overall survival (median, 14.39 months versus 12.16 months; HR = 0.771; 95% CI, 0.615-0.965; P = 0.0118). Grade ≥3 treatment-emergent adverse events were similar with zolbetuximab (72.8%) and placebo (69.9%). Zolbetuximab plus CAPOX represents a potential new first-line therapy for patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma. ClinicalTrials.gov identifier: NCT03653507 .

ILUSTRO: Phase II Multicohort Trial of Zolbetuximab in Patients with Advanced or Metastatic Claudin 18.2-Positive Gastric or Gastroesophageal Junction Adenocarcinoma.

PURPOSE: Zolbetuximab, an IgG1 monoclonal antibody, binds to claudin 18.2 (CLDN18.2) and mediates tumor cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. We sought to examine zolbetuximab combinations in CLDN18.2-positive HER2-negative gastric/gastroesophageal junction (G/GEJ) adenocarcinoma. PATIENTS AND METHODS: This phase II study assessed efficacy and safety of zolbetuximab, alone or with modified FOLFOX6 (mFOLFOX6) or pembrolizumab, in CLDN18.2-positive advanced/metastatic G/GEJ adenocarcinoma. Patients received zolbetuximab as monotherapy in third/later-line (Cohort 1A, n = 30), with mFOLFOX6 in first-line (Cohort 2, n = 21), or with pembrolizumab in third/later-line (Cohort 3A, n = 3) treatment. The primary endpoint for Cohort 1A was objective response rate (ORR). Key secondary endpoints were ORR (Cohorts 2 and 3A), overall survival (OS; Cohort 1A), and progression-free survival (PFS) and safety (all cohorts). RESULTS: ORR was 0% in Cohorts 1A and 3A, and 71.4% [95% confidence interval (CI), 47.82-88.72] in Cohort 2. Median PFS was 1.54 months (95% CI, 1.31-2.56) in Cohort 1A, 2.96 months (95% CI, 1.48-4.44) in Cohort 3A, and 17.8 months (95% CI, 8.05-25.69) in Cohort 2. Median OS in Cohort 1A was 5.62 months (95% CI, 2.27-11.53). Gastrointestinal adverse events occurred across cohorts [nausea, 63%-90% (grade ≥ 3, 4.8%-6.7%) and vomiting, 33%-67% (grade ≥ 3, 6.7%-9.5%)]. CONCLUSIONS: Zolbetuximab plus mFOLFOX6 demonstrated promising efficacy in previously untreated patients with CLDN18.2-positive G/GEJ adenocarcinoma. These data support the first-line development of zolbetuximab in patients whose tumors are CLDN18.2-positive. Across cohorts, zolbetuximab treatment was tolerable with no new safety signals.

Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial.

BACKGROUND: Zolbetuximab, a monoclonal antibody targeting claudin-18 isoform 2 (CLDN18.2), has shown efficacy in patients with CLDN18.2-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma. We report the results of the SPOTLIGHT trial, which investigated the efficacy and safety of first-line zolbetuximab plus mFOLFOX6 (modified folinic acid [or levofolinate], fluorouracil, and oxaliplatin regimen) versus placebo plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma. METHODS: SPOTLIGHT is a global, randomised, placebo-controlled, double-blind, phase 3 trial that enrolled patients from 215 centres in 20 countries. Eligible patients were aged 18 years or older with CLDN18.2-positive (defined as ≥75% of tumour cells showing moderate-to-strong membranous CLDN18 staining), HER2-negative (based on local or central evaluation), previously untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma, with radiologically evaluable disease (measurable or non-measurable) according to Response Evaluation Criteria in Solid Tumors version 1.1; an Eastern Cooperative Oncology Group performance status score of 0 or 1; and adequate organ function. Patients were randomly assigned (1:1) via interactive response technology and stratified according to region, number of organs with metastases, and previous gastrectomy. Patients received zolbetuximab (800 mg/m2 loading dose followed by 600 mg/m2 every 3 weeks) plus mFOLFOX6 (every 2 weeks) or placebo plus mFOLFOX6. The primary endpoint was progression-free survival assessed by independent review committee in all randomly assigned patients. Safety was assessed in all treated patients. The study is registered with ClinicalTrials.gov, NCT03504397, and is closed to new participants. FINDINGS: Between June 21, 2018, and April 1, 2022, 565 patients were randomly assigned to receive either zolbetuximab plus mFOLFOX6 (283 patients; the zolbetuximab group) or placebo plus mFOLFOX6 (282 patients; the placebo group). At least one dose of treatment was administered to 279 (99%) of 283 patients in the zolbetuximab group and 278 (99%) of 282 patients in the placebo group. In the zolbetuximab group, 176 (62%) patients were male and 107 (38%) were female. In the placebo group, 175 (62%) patients were male and 107 (38%) were female. The median follow-up duration for progression-free survival was 12·94 months in the zolbetuximab group versus 12·65 months in the placebo group. Zolbetuximab treatment showed a significant reduction in the risk of disease progression or death compared with placebo (hazard ratio [HR] 0·75, 95% CI 0·60-0·94; p=0·0066). The median progression-free survival was 10·61 months (95% CI 8·90-12·48) in the zolbetuximab group versus 8·67 months (8·21-10·28) in the placebo group. Zolbetuximab treatment also showed a significant reduction in the risk of death versus placebo (HR 0·75, 95% CI 0·60-0·94; p=0·0053). Treatment-emergent grade 3 or worse adverse events occurred in 242 (87%) of 279 patients in the zolbetuximab group versus 216 (78%) of 278 patients in the placebo group. The most common grade 3 or worse adverse events were nausea, vomiting, and decreased appetite. Treatment-related deaths occurred in five (2%) patients in the zolbetuximab group versus four (1%) patients in the placebo group. No new safety signals were identified. INTERPRETATION: Targeting CLDN18.2 with zolbetuximab significantly prolonged progression-free survival and overall survival when combined with mFOLFOX6 versus placebo plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Zolbetuximab plus mFOLFOX6 might represent a new first-line treatment in these patients. FUNDING: Astellas Pharma, Inc.

Viral detection from negative mumps cases with respiratory symptoms in Gwangju, South Korea in 2021.

Mumps is the second-most reported infectious disease in South Korea; however, due to the low pathogen confirmation rate in laboratory diagnoses, we proposed a method for reevaluating the high incidence rate via the laboratory verification of other viral diseases. In 2021, 63 cases of pharyngeal or cheek mucosal swabs of suspected mumps cases in Gwangju, South Korea, were assessed for causative pathogens using massive simultaneous pathogen testing. More than one respiratory virus was detected in 60 cases (95.2%), 44 (73.3%) of which were codetected. Human rhinovirus was detected in 47 cases, followed by human herpesvirus (HHV)6 in 30; HHV4 (17), human bocavirus (17), HHV5 (10), and human parainfluenza virus 3 (6) were also detected. Our findings suggest the need for further investigations on the pathogenesis of diseases mimicking mumps, which are considered to aid with appropriate public health responses, treatment, and the prevention of infectious disease outbreaks.

Emerging hantavirus infection in wild rodents captured in suburbs of Gwangju Metropolitan City, South Korea.

BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) caused by hantaviruses is a frequently reported acute hemorrhagic fever in South Korea. These viruses are transmitted by various rodent species such as Apodemus agrarius. METHODOLOGY/PRINCIPAL FINDINGS: To investigate hantavirus infection and seroprevalence in rodents, wild rodents were captured from two districts in the suburbs of Gwangju Metropolitan City from January 2016 to December 2018. Nested reverse-transcription polymerase chain reaction (RT-PCR) targeting the hantavirus-specific L segment and indirect immunofluorescence antibody (IFA) assay using Hantaan virus antigen slides were performed. A total of 585 wild rodents were captured-512 A. agrarius, 49 Crocidura lasiura, and 24 Myodes regulus. Nested RT-PCR was performed to examine the rate of hantavirus infection in wild rodents, and 1.88% (11/585) of all rodents, 1.17% (6/512) of A. agrarius, 6.12% (3/49) of C. lasiura, and 8.33% (2/24) of M. regulus tested positive. The nucleotide sequence analysis of the eleven PCR-positive products revealed that six PCR products showed over 85% sequence similarity with the Jeju virus, four showed over 99.7% similarity with the Hantaan virus, and one showed over 95.3% homology with the Imjin virus. Moreover, IgG antibodies against the Hantaan virus were detected in 6.15% (36/585) of all rodents, 6.8% (35/512) of A. agrarius, and 4.17% (1/24) of M. regulus. IgG antibodies were not detected in C. lasiura. CONCLUSIONS/SIGNIFICANCE: Hantaviruses were detected in all three wild rodent species of A. agrarius, C. lasiura, and M. regulus captured in the suburbs of Gwangju Metropolitan City, South Korea, and it was demonstrated that they were various strains of hantaviruses such as the Hantaan, Jeju, and Imjin viruses.

First report of Borrelia burgdorferi sensu stricto detection in a commune genospecies in Apodemus agrarius in Gwangju, South Korea.

Lyme disease is a tick-borne infectious disease caused by the Borrelia burgdorferi sensu lato complex. However, the distribution of Borrelia genospecies and the tissue detection rate of Borrelia in wild rodents have rarely been investigated. Here, we studied 27 wild rodents (Apodemus agrarius) captured in October and November 2016 in Gwangju, South Korea, and performed nested polymerase chain reaction targeting pyrG and ospA to confirm Borrelia infection. Eight rodents (29.6%) tested positive for Borrelia infection. The heart showed the highest infection rate (7/27; 25.9%), followed by the spleen (4/27; 14.8%), kidney (2/27; 7.4%), and lungs (1/27; 3.7%). The B. afzelii infection rate was 25.9%, with the highest rate observed in the heart (7/27; 25.9%), followed by that in the kidney and spleen (both 2/27; 7.4%). B. garinii and B. burgdorferi sensu stricto were detected only in the spleen (1/27; 3.7%). This is the first report of B. burgdorferi sensu stricto infection in wild rodents in South Korea. The rodent hearts showed a high B. afzelii infection rate, whereas the rodent spleens showed high B. garinii and B. burgdorferi sensu stricto infection rates. Besides B. garinii and B. afzelii, B. burgdorferi sensu stricto may cause Lyme disease in South Korea.

Epidemiological Characteristics of Rodents and Chiggers with Orientia Tsutsugamushi in the Republic of Korea.

A survey of rodents and chiggers associated with Orientia tsutsugamushi was conducted in a rural region of the Republic of Korea (Korea) between 2014 and 2018. Overall Apodemus agrarius 15.2% had the highest seropisitive for O. tsutsugamushi, followed by Myodes regulus 11.4%. Monthly risk factors using logistic regression analysis were not associated with O. tsutsugamushi infections in rodents. The overall prevalence rate of O. tsutsugamushi among chiggers was 0.3%. The chigger (Leptotrombidium scutellare) and monthly (October) risk factors were associated with O. tsutsugamushi human infections (P<0.05). Orientia tsutsugamushi infections are endemic in rodents in Korea and people, for example, soldiers who are active outdoors, must employ preventive measures, especially during October (P<0.05). When there are many reports of O. tsutsugamushi infections in Korea. The Boryong strain 85.7% (2/14) was the most common strain detected in chiggers, followed by the Shimokoshi 7.1% (1/14) and Karp 7.1% strains.

Epidemiological Characteristics of Field Tick-Borne Pathogens in Gwang-ju Metropolitan Area, South Korea, from 2014 to 2018.

OBJECTIVES: The importance of tick-borne diseases is increasing because of climate change, with a lack of long-term studies on tick-borne pathogens in South Korea. To understand the epidemiological characteristics of tick-borne diseases, the monthly distribution of field ticks throughout the year was studied in South Korea between May 2014 and April 2018 in a cross sectional study. METHODS: The presence of various tick-borne pathogens (Rickettsia species, Borrelia species, Anaplasma phagocytophilum) was confirmed by using polymerase chain reaction, to provide information for a prevention strategy against tick-borne pathogenic infections, through increased understanding of the relationship between seasonal variation and risk of infection with Rickettsia species. This was performed using logistic regression analysis (SPSS 20, IBM, USA) of the data obtained from the study. RESULTS: During the study period there were 11,717 ticks collected and 4 species identified. Haemapysalis longicornis was the most common species (n = 10,904, 93.1%), followed by Haemapysalis flava (n = 656, 5.6%), Ixodes nipponensis (n = 151, 1.3%), and Amblyomma testudinarium (n = 6, 0.05%) The results of this cross-sectional study showed that Haemapysalis flava carried a higher risk of transmission of Rickettsia species than other tick species (p < 0.05). CONCLUSION: In conclusion, due attention should be paid to preventing tick-borne infections in humans whilst engaged in outdoor activities in Spring and Autumn, particularly in places where there is a high prevalence of ticks.

Targeting RET Kinase in Neuroendocrine Prostate Cancer.

The increased treatment of metastatic castration-resistant prostate cancer (mCRPC) with second-generation antiandrogen therapies (ADT) has coincided with a greater incidence of lethal, aggressive variant prostate cancer (AVPC) tumors that have lost dependence on androgen receptor (AR) signaling. These AR-independent tumors may also transdifferentiate to express neuroendocrine lineage markers and are termed neuroendocrine prostate cancer (NEPC). Recent evidence suggests kinase signaling may be an important driver of NEPC. To identify targetable kinases in NEPC, we performed global phosphoproteomics comparing several AR-independent to AR-dependent prostate cancer cell lines and identified multiple altered signaling pathways, including enrichment of RET kinase activity in the AR-independent cell lines. Clinical NEPC patient samples and NEPC patient-derived xenografts displayed upregulated RET transcript and RET pathway activity. Genetic knockdown or pharmacologic inhibition of RET kinase in multiple mouse and human models of NEPC dramatically reduced tumor growth and decreased cell viability. Our results suggest that targeting RET in NEPC tumors with high RET expression could be an effective treatment option. Currently, there are limited treatment options for patients with aggressive neuroendocrine prostate cancer and none are curative. IMPLICATIONS: Identification of aberrantly expressed RET kinase as a driver of tumor growth in multiple models of NEPC provides a significant rationale for testing the clinical application of RET inhibitors in patients with AVPC.

Severe Fever with Thrombocytopenia Syndrome Associated with Manual De-Ticking of Domestic Dogs.

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease. SFTS is caused by the SFTS virus, a novel phlebovirus, and is spread by ticks. Methods: A 50-year-old man was admitted to our hospital with the chief complaint of fever and was diagnosed with confirmed SFTS. An epidemiological investigation was conducted, and immunofluorescent antibody assays (IFAs) were performed to determine the role of the patient's three dogs in the transmission. PCR assays were performed using ticks that were collected with the dragging and flagging method from the patient's dogs and home. Results: PCR results were positive, and IFA confirmed an increased antibody titer. Although the reverse transcription PCR results of the three dogs were negative for SFTS virus, one dog had an elevated SFTS IFA immunoglobulin G (IgG) titer of 1:1,024. Moreover, a number of ticks were observed in the area surrounding the dog cages. Based on the findings of the patient interview, the patient was likely to have acquired SFTS by blood splash because he removed or burst ticks from the dogs with his bare hands. Although no tick bites were reported, tick transmission could not be ruled out. Studies have shown that only one in three individuals with a diagnosis of SFTS recalls a tick bite; thus, a definite exclusion of tick transmission in this case was not possible. Conclusions: The epidemiological findings of our case suggest a possible relationship between tick infestation in domestic dogs and SFTS virus transmission to humans. However, there is no direct evidence supporting this viral transmission route. Future studies are needed to further investigate a potential route of SFTS transmission by exposure to engorged tick blood or pet dogs.

A genetically defined disease model reveals that urothelial cells can initiate divergent bladder cancer phenotypes.

Small cell carcinoma of the bladder (SCCB) is a rare and lethal phenotype of bladder cancer. The pathogenesis and molecular features are unknown. Here, we established a genetically engineered SCCB model and a cohort of patient SCCB and urothelial carcinoma samples to characterize molecular similarities and differences between bladder cancer phenotypes. We demonstrate that SCCB shares a urothelial origin with other bladder cancer phenotypes by showing that urothelial cells driven by a set of defined oncogenic factors give rise to a mixture of tumor phenotypes, including small cell carcinoma, urothelial carcinoma, and squamous cell carcinoma. Tumor-derived single-cell clones also give rise to both SCCB and urothelial carcinoma in xenografts. Despite this shared urothelial origin, clinical SCCB samples have a distinct transcriptional profile and a unique transcriptional regulatory network. Using the transcriptional profile from our cohort, we identified cell surface proteins (CSPs) associated with the SCCB phenotype. We found that the majority of SCCB samples have PD-L1 expression in both tumor cells and tumor-infiltrating lymphocytes, suggesting that immune checkpoint inhibitors could be a treatment option for SCCB. We further demonstrate that our genetically engineered tumor model is a representative tool for investigating CSPs in SCCB by showing that it shares a similar a CSP profile with clinical samples and expresses SCCB-up-regulated CSPs at both the mRNA and protein levels. Our findings reveal distinct molecular features of SCCB and provide a transcriptional dataset and a preclinical model for further investigating SCCB biology.

Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer.

Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, consisting of AR+ luminal tumor cells and AR- neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purification of NE cells from primary fresh human prostate adenocarcinoma based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies revealed CXCR2 to be a driver of the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells were critical for the tumor microenvironment by providing a survival niche for the AR+ luminal cells. We demonstrate that the combination of CXCR2 inhibition and AR targeting is an effective treatment strategy in mouse xenograft models. Such a strategy has the potential to overcome therapy resistance caused by tumor cell heterogeneity.

Prevalence of Orientia tsutsugamushi, Anaplasma phagocytophilum and Leptospira interrogans in striped field mice in Gwangju, Republic of Korea.

This study investigated the prevalence of Orientia tsutsugamushi, Anaplasma phagocytophilum, and Leptospira interrogans in wild rodents through molecular detection using organ samples and through serological assay using blood samples of mice collected from two distinct sites in Gwangju Metropolitan City, Republic of Korea (ROK). A total of 47 wild rodents, identified as Apodemus agrarius (A. agrarius), were captured from June to August 2016. The seroprevalence of antibodies against bacterial pathogens in A. agrarius sera was analyzed; 17.4% (8/46) were identified as O. tsutsugamushi through indirect immunofluorescence assay and 2.2% (1/46) were identified as Leptospira species through passive hemagglutination assay. Using polymerase chain reaction, the spleen, kidney and blood samples were investigated for the presence of O. tsutsugamushi, A. phagocytophilum, and L. interrogans. Out of the 47 A. agrarius, 19.1% (9/47) were positive for A. phagocytophilum and 6.4% (3/47) were positive for L. interrogans, while none were positive for O. tsutsugamushi. Four out of 46 (8.7%) blood samples, six out of 45 (13.3%) spleen samples, and one out of 47 (2.1%) kidney samples were positive for A. phagocytophilum. Three out of 47 (6.4%) kidney samples were positive for L. interrogans. The sequencing results of PCR positive samples demonstrated > 99% similarity with A. phagocytophilum and L. interrogans sequences. A. phagocytophilum was mostly detected in the spleen, whereas L. interrogans was mostly detected in the kidneys. Notably, A. phagocytophilum and L. interrogans were detected in A. agrarius living in close proximity to humans in the metropolitan suburban areas. The results of this study indicate that rodent-borne bacteria may be present in wild rodents in the metropolitan suburban areas of ROK.

Differences in Characteristics and Comorbidity of Cluster Headache According to the Presence of Migraine.

BACKGROUND AND PURPOSE: Cluster headache (CH) can present with migrainous symptoms such as nausea, photophobia, and phonophobia. In addition, an overlap between CH and migraine has been reported. This study aimed to determine the differences in the characteristics of CH according to the presence of comorbid migraine. METHODS: This study was performed using data from a prospective multicenter registry study of CH involving 16 headache clinics. CH and migraine were diagnosed by headache specialists at each hospital based on third edition of the International Classification of Headache Disorders (ICHD-3). We interviewed patients with comorbid migraine to obtain detailed information about migraine. The characteristics and psychological comorbidities of CH were compared between patients with and without comorbid migraine. RESULTS: Thirty (15.6%) of 192 patients with CH had comorbid migraine, comprising 18 with migraine without aura, 1 with migraine with aura, 3 with chronic migraine, and 8 with probable migraine. Compared to patients with CH without migraine, patients with CH with comorbid migraine had a shorter duration of CH after the first episode [5.4±7.4 vs. 9.0±8.2 years (mean±standard deviation), p=0.008], a lower frequency of episodic CH (50.0% vs. 73.5%, p=0.010), and a higher frequency of chronic CH (13.3% vs. 3.7%, p=0.033). Psychiatric comorbidities did not differ between patients with and without comorbid migraine. The headaches experienced by patients could be distinguished based on their trigeminal autonomic symptoms, pulsating character, severity, and pain location. CONCLUSIONS: Distinct characteristics of CH remained unchanged in patients with comorbid migraine with the exception of an increased frequency of chronic CH. The most appropriate management of CH requires clinicians to check the history of preceding migraine, particularly in cases of chronic CH.

Pan-cancer Convergence to a Small-Cell Neuroendocrine Phenotype that Shares Susceptibilities with Hematological Malignancies.

Small-cell neuroendocrine cancers (SCNCs) are an aggressive cancer subtype. Transdifferentiation toward an SCN phenotype has been reported as a resistance route in response to targeted therapies. Here, we identified a convergence to an SCN state that is widespread across epithelial cancers and is associated with poor prognosis. More broadly, non-SCN metastases have higher expression of SCN-associated transcription factors than non-SCN primary tumors. Drug sensitivity and gene dependency screens demonstrate that these convergent SCNCs have shared vulnerabilities. These common vulnerabilities are found across unannotated SCN-like epithelial cases, small-round-blue cell tumors, and unexpectedly in hematological malignancies. The SCN convergent phenotype and common sensitivity profiles with hematological cancers can guide treatment options beyond tissue-specific targeted therapies.

Detection of Borrelia miyamotoi in Ixodes nipponensis in Korea.

BACKGROUND: This study investigated Borrelia species prevalence in ticks from vegetation, through a molecular method, in Gwangju Metropolitan City, South Korea. METHODOLOGY/PRINCIPAL FINDINGS: A total of 484 ticks were collected through flagging and dragging in a suburban area of Gwangju Metropolitan City, South Korea, in 2014. These ticks were morphologically identified and subjected to nested PCR, targeting Borrelia-specific CTP synthase (pyrG), outer surface protein A (ospA) and flagellin (flaB) genes. Molecular biological species identification of Borrelia-positive ticks was conducted via 16S rRNA PCR assays. Of the 484 ticks collected, 417 (86.2%) were identified as Haemaphysalis longicornis, 42 (8.7%) as H. flava, and 25 (5.2%) as Ixodes nipponensis. All the ixodid ticks containing Borrelia species bacteria were confirmed to be I. nipponensis adults, by both morphological and molecular methods. Of the 25 I. nipponensis ticks collected, four (16%) were positive for Borrelia species, three of which were B. afzelii and one B. miyamotoi. CONCLUSIONS/SIGNIFICANCE: Our study has shown the harboring of B. miyamotoi by I. nipponensis in South Korea. Morphological and molecular genetic analyses revealed that, in South Korea, I. nipponensis could potentially transmit B. miyamotoi to humans.

Comparison of tube feeding in stroke patients: Nasogastric tube feeding versus oroesophageal tube feeding-A pilot study.

BACKGROUNDS: Patients with central nervous system injuries present with dysphagia and may require non-oral feeding methods, like percutaneous endoscopic gastrostomy, nasogastric (NG) tube, or oroesophageal (OE) tube. The prevalence of pneumonia in patients with gastroesophageal reflux (GER) is significantly higher than that in patients without GER. We aimed to determine the most appropriate tube feeding with low risk of GER by comparing the results of 24-hour pH monitoring studies in patients who were administered 2 types of feeding: NG tube and OE tube. METHODS: In this pilot study, 6 stroke patients underwent 24-hour esophageal pH monitoring during NG tube feeding and OE tube feeding, sequentially. Parameters collected included acid exposure time, mean esophageal pH, number of reflux episode, time of bolus reflux for both total 24-hour pH study data and postprandial data, and deMeester composite score. RESULTS: Total acid reflux time (minutes) decreased more with OE tube feeding than that with NG tube feeding in the total 24-hour pH study. The number of reflux episodes decreased in both total and postprandial data with OE tube feeding versus NG tube feeding (P < .05). There were no significant differences in mean esophageal pH and total time of bolus reflux between the 2 groups. CONCLUSIONS: Although we could not definitively conclude that OE tube feeding decreased the severity of GER compared with NG tube feeding, there were significant differences in 4 out of 9 parameters. OE tube can be a substitute for NG tube in patients with dysphagia after stroke leading to GER disease.

Molecular detection of viruses causing hemorrhagic fevers in rodents in the south-west of Korea.

Many pathogens causing hemorrhagic fevers of medical and veterinary importance have been identified and isolated from rodents in the Republic of Korea (ROK). We investigated the occurrence of emerging viruses causing hemorrhagic fevers, such as hemorrhagic fever with renal syndrome (HFRS), severe fever with thrombocytopenia syndrome (SFTS), and flaviviruses, from wild rodents. Striped field mice, Apodemus agrarius (n = 39), were captured during 2014-2015 in the south-west of ROK. Using molecular methods, lung samples were evaluated for SFTS virus, hantavirus, and flavivirus, and seropositivity was evaluated in the blood. A high positive rate of hantavirus (46.2%) was detected in A. agrarius lungs by reverse transcription-nested polymerase chain reaction (RT-N-PCR). The monthly occurrence of hantavirus was 16.7% in October, 86.7% in November, and 25% in August of the following year (p < 0.001). Moreover, 17.9% of blood samples were serologically positive for hantavirus antibodies. The most prevalent strain in A. agrarius was Hantaan virus. All samples were positive for neither SFTS virus nor flavivirus. Hantaan virus was detected in 86.7% of A. agrarius in November (autumn), and thus, virus shedding from A. agrarius can increase the risk of humans contracting HFRS. These findings may help to predict and prevent disease outbreaks in ROK.