Translational insights and overall survival in the U31402-A-U102 study of patritumab deruxtecan (HER3-DXd) in EGFR-mutated NSCLC.

BACKGROUND: Human epidermal growth factor receptor 3 (HER3) is broadly expressed in non-small-cell lung cancer (NSCLC) and is the target of patritumab deruxtecan (HER3-DXd), an antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. U31402-A-U102 is an ongoing phase I study of HER3-DXd in patients with advanced NSCLC. Patients with epidermal growth factor receptor (EGFR)-mutated NSCLC that progressed after EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy (PBC) who received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks had a confirmed objective response rate (cORR) of 39%. We present median overall survival (OS) with extended follow-up in a larger population of patients with EGFR-mutated NSCLC and an exploratory analysis in those with acquired genomic alterations potentially associated with resistance to HER3-DXd. PATIENTS AND METHODS: Safety was assessed in patients with EGFR-mutated NSCLC previously treated with EGFR TKI who received HER3-DXd 5.6 mg/kg; efficacy was assessed in those who also had prior PBC. RESULTS: In the safety population (N = 102), median treatment duration was 5.5 (range 0.7-27.5) months. Grade ≥3 adverse events occurred in 76.5% of patients; the overall safety profile was consistent with previous reports. In 78/102 patients who had prior third-generation EGFR TKI and PBC, cORR by blinded independent central review (as per RECIST v1.1) was 41.0% [95% confidence interval (CI) 30.0% to 52.7%], median progression-free survival was 6.4 (95% CI 4.4-10.8) months, and median OS was 16.2 (95% CI 11.2-21.9) months. Patients had diverse mechanisms of EGFR TKI resistance at baseline. At tumor progression, acquired mutations in ERBB3 and TOP1 that might confer resistance to HER3-DXd were identified. CONCLUSIONS: In patients with EGFR-mutated NSCLC after EGFR TKI and PBC, HER3-DXd treatment was associated with a clinically meaningful OS. The tumor biomarker characterization comprised the first description of potential mechanisms of resistance to HER3-DXd therapy.

Chronic rhinitis and stress: the possible culprits of midfacial segment pain.

BACKGROUND: Bilateral symmetrical pain in the midfacial region without evidence of sinonasal disease is termed midfacial segment pain (MSP), about which little is known. The present study explored the prevalence of facial pain and the risk factors for MSP. METHODS: We analysed cross-sectional data from the Korea National Health and Nutrition Examination Survey (KNHANES). Those who reported facial pain or pressure lasting at least three months with no evidence of a sinonasal disease on nasal endoscopy were considered to have MSP. The participants were categorised according to the presence of facial pain and chronic rhinosinusitis. Basic demographic data and medical conditions, including hypertension, diabetes mellitus, and dyslipidemia, were compared between subject groups. We also evaluated psychological stress, depressive episodes, and suicidal thoughts, as well as physician-diagnosed nasal diseases, including chronic rhinitis and symptomatic nasal septal deviation. Univariate and multivariate logistic regression analyses were performed to determine risk factors for MSP. RESULTS: Of 31,999 participants, the prevalence of facial pain was 0.59%. A total of 58 (0.18%) respondents had MSP, of whom 40 (73.5%) were female. On univariate analysis, female sex, chronic rhinitis, and psychological stress were more prevalent in the subjects with MSP than the control subjects. However, in the multivariate analysis, only chronic rhinitis and psychological stress remained significant, while the female sex exhibited only marginal significance. CONCLUSION: Chronic rhinitis and psychological stress may be significant risk factors for MSP.

First Report of Pseudomonas cichorii Causing Bacterial vein necrosis on Perilla plants [Perilla frutescens (L.) Britton.] in South Korea.

Perilla (Perilla frutescens L.) is the second most important upland crop and the third largest edible oil crop in Korea (Shin and Kim 1994). During a disease survey in Busan, Korea in September 2021, symptoms of vein necrosis were observed in perilla plants, with incidences of approximately 30% and 50% in two fields. Symptoms of spots on the perilla appeared as leaf dryness and spots with water-soaked blotches largely concentrated on the mid-veins of leaves. The lesions were initiated with water-soaked spots on the leaf or stem and gradually turned black or brown. Necrosis was also observed in the stems. A bacterium was isolated on Luria-Bertani (LB) agar from diseased leaf tissues that were surface-disinfected with 70% ethyl alcohol for 3-5 min and then washed with sterile water three times. Three pieces of sterilized leaf tissue (size: 0.5 × 0.5 cm) were mixed with 500 µL sterile water for 30 min, and then the suspension was serially diluted and spread on LB agar. Subsequently, isolates were cultivated on LB agar and King's Medium B agar (KMB) (Schaad et al. 2001), and they were predominantly cream-colored and circular bacterial colonies with undulated margins. The bacterial colonies on KMB displayed fluorescence under 365 nm UV light. The isolates were analyzed with the GEN III MicroPlate (Biolog, Hayward, CA, USA), and all isolates were identified as Pseudomonas cichorii, a devastating plant bacterium that damages a wide range of host plants worldwide, including in South Korea (Hikichi et al. 2013; Ramkumar et al. 2015). To identify the species of the bacterial pathogen, genomic DNA of four isolates (BS4922, BS4167, BS4345, and BS4560) was extracted, and the 16S rRNA gene and hrcRST gene were amplified with universal primers, 27F/1492R and Hcr1/Hcr2, and sequencing was then done (Patel et al. 2019). In the BLAST analysis, the 16S rRNA sequences (GenBank OM060656, OM275434, OM275435, OM275436) showed a 100% and 99% similarity to P. cichorii strains MAFF 302698 (AB724286) and P. cichorii strain Pc-Gd-4 (KU923373), respectively. Further, hrcRST gene sequences (GenBank OM143596, OM268864, OM268865, and OM268866) showed high similarity (>99%) with P. cichorii strain P16-51 (MG518230). A pathogenicity test of the four isolates was performed on 3 - 4 weeks old perilla plants by creating wounds with a needle on the lower leaves and stems, and then the plants were inoculated by spraying inoculum (108 CFU/ml). The plants that served as the negative control were wounded and sprayed with unsterilized water. The inoculated perilla plants were placed in a greenhouse at 28 ± 2oC , 80-85% relative humidity, and a natural photoperiod. The inoculation site began to show symptoms of water-soaked brown lesions. Disease symptoms such as leaf dryness, water-soaked blotches on the mid-vein of leaves, and necrosis on plant stems were observed in the inoculated plants 7-10 days after inoculation, whereas the plants of the negative control group did not show any symptoms. The bacteria were re-isolated from the diseased tissues of the plants, and DNA sequence analysis identified them as P. cichorii. Additionally, all isolates induced hypersensitivity reactions in tobacco and tomato leaves within 24 h after inoculation. To our knowledge, this is the first report of P. cichorii infecting perilla in South Korea. The findings in this study will provide the basic information for the development of diagnostic tools and management measures against P. cichorii in perilla.

Analysis of predisposing factors in unilateral maxillary sinus fungal ball: the predictive role of odontogenic and anatomical factors.

BACKGROUND: The pathogenesis of maxillary sinus fungal ball (MSFB) is explained by aerogenic and odontogenic factors. We evaluated the predisposing factors, including intranasal anatomical and dental factors for increased diagnostic accuracy. METHODOLOGY: In this study, 117 patients who underwent endoscopic sinus surgery for unilateral MSFB were included. Preoperative computed tomography (CT) scans were used to analyze the presence of anatomical variations (anterior and posterior nasal septal deviation (NSD), concha bullosa (CB), infraorbital cell (haller cell), paradoxical middle turbinate, everted uncinate process and MS size). Dental factors including history of dental procedures and findings on CT scans were reviewed. RESULTS: Anterior and posterior NSD toward non-affected side were significantly associated with the presence of FB. The presence of CB and infraorbital cell was higher in the non-affected side rather than in the lesion side. Compared to non-affected MS, FB-presence MS was shallower and had a larger height to depth ratio. The presence of dental history was significantly higher on FB-presence MS than non-affected MS. In multivariable analysis, posterior NSD toward non-affected side, dental history increased the aOR of MSFB, while the presence of CB and infraorbital cell decreased the aOR of MSFB. CONCLUSIONS: The occurrence of MSFB seems to be associated with ipsilateral odontogenic factors, followed by anatomic variations including posterior NSD toward non-affected side and absence of CB and infraorbital cell.

Increased risk of cardiovascular diseases in patients with chronic rhinosinusitis: a longitudinal follow-up study using a national health screening cohort.

BACKGROUND: Chronic rhinosinusitis (CRS) is one of the most common chronic inflammatory diseases and is characterized by sinonasal inflammation that lasts longer than 12 weeks. Whether the effect of chronic inflammation caused by CRS on cardiovascular diseases (CVDs) is similar to its effect on other inflammatory disorders has not been thoroughly evaluated. We aimed to demonstrate whether CRS patients have a higher prevalence of CVDs, including stroke and ischemic heart disease (IHD). METHODOLOGY: We compared the prevalence of various comorbidities between CRS and control participants through a case-control cohort study from 2002 to 2015 that included 514,866 participants. CRS (n=6,552) and control (n=26,208) participants who were over 40 years old were selected by matching age, sex, income, and area of residence at a 1:4 ratio. RESULTS: A stratified Cox proportional hazards model was utilized to assess the hazard ratio (HR) of CRS for stroke and IHD. The HRs for stroke and IHD were significantly increased in CRS patients compared to controls after adjusting for obesity, alcohol consumption, smoking, systolic and diastolic blood pressure, fasting blood glucose, total cholesterol, hemoglobin, and Charlson Comorbidity Index (CCI) scores. The HR of stroke was significantly higher in the absence of nasal polyps than in the presence of nasal polyps. The HR of IHD was significantly increased in the CRS group regardless of the presence of nasal polyps. CONCLUSIONS: This study showed that CRS participants had a significantly higher prevalence of stroke and IHD.

Integrase strand transfer inhibitor treatment does not increase the incidence of immune reconstitution inflammatory syndrome in HIV-infected Koreans.

OBJECTIVES: Immune reconstitution inflammatory syndrome (IRIS) is a major concern when starting antiretroviral therapy (ART) in patients with advanced HIV infection. The aim of this study was to determine the incidence and risk factors of IRIS in HIV-infected Koreans initiating ART, and whether integrase strand transfer inhibitor (INSTI) treatment increases the risk of IRIS. METHODS: This retrospective analysis included adults living with HIV, seen at four university-affiliated hospitals in South Korea, who were naïve to ART and had a CD4 T-cell count < 200 cells/µL between January 2004 and May 2019. IRIS was determined through a medical record review within 6 months of ART initiation. Propensity score-matched case-control study between the non-INSTI and INSTI groups was performed. RESULTS: The study included 501 patients; 192 were assigned to the INSTI group, who started ART based on INSTIs as the initial treatment. There were opportunistic infections (OIs) in 253 (50.5%) cases before ART initiation. The three most common OIs were Pneumocystis jirovecii pneumonia, candidiasis and tuberculosis (TB). We identified 47 cases of IRIS; TB-IRIS was the most common type. The incidence of IRIS within 6 months of ART initiation was 9.4%, and there were no significant differences in baseline characteristics and incidence of IRIS between the matched groups. The risk factors for IRIS were pre-ART CD4 T-cell count (< 30 cells/µL), higher pre-ART viral load (≥ 75 000 copies/mL), and TB-OI. CONCLUSIONS: The incidence of IRIS was 9.4% in Korean HIV patients. The INSTI regimen was not related to IRIS occurrence.

TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer.

BACKGROUND: Osimertinib is a potent, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). The multi-arm phase Ib TATTON study (NCT02143466) was designed to assess the safety and tolerability of osimertinib in combination with other targeted therapies: selumetinib (MEK1/2 inhibitor), savolitinib (MET-TKI), or durvalumab [anti-programmed cell death ligand 1 (anti-PD-L1) monoclonal antibody]. PATIENTS AND METHODS: Patients with advanced EGFR-mutant non-small-cell lung cancer and disease progression on a prior EGFR-TKI were enrolled and allocated to dose-escalating cohorts combining osimertinib 80 mg orally (p.o.) once a day with selumetinib (25-75 mg p.o. twice a day; continuous or intermittent), savolitinib (600-800 mg p.o. once a day), or durvalumab (3-10 mg/kg intravenous every 2 weeks). RESULTS: At data cut-off (28 February 2018), 77 patients were enrolled and received osimertinib plus selumetinib (n = 36), savolitinib (n = 18), or durvalumab (n = 23). Most common adverse events (any grade), occurring in ≥20% of patients across dose groups, were: selumetinib arm-diarrhea (75%), rash (58%), nausea (47%); savolitinib arm-nausea (67%), rash (56%), vomiting (50%); durvalumab arm-rash (48%), vomiting (43%), diarrhea (39%). Dose-limiting toxicities were reported in the selumetinib 25 mg (n = 1), 50 mg (n = 1), and 75 mg (n = 4) continuous-dose groups, savolitinib 600 mg (n = 1) and 800 mg dose groups (n = 2), and durvalumab 10 mg/kg (n = 1) dose group. The objective response rate was 42% (95% confidence interval 26% to 59%), 44% (22% to 69%), and 43% (23% to 66%) in the selumetinib, savolitinib, and durvalumab arms, respectively. CONCLUSION: Our results demonstrate the feasibility of combining osimertinib 80 mg with selumetinib or savolitinib at identified tolerable, active doses. A combination of osimertinib with durvalumab was not feasible due to increased reporting of interstitial lung disease. Osimertinib-based combination therapies represent a compelling approach now being further investigated. CLINICAL TRIALS NUMBER: NCT02143466.

Osimertinib versus platinum-pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis.

BACKGROUND: In AURA3 (NCT02151981), osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), significantly prolonged progression-free survival and improved response in patients with EGFR T790M advanced non-small-cell lung cancer (NSCLC) and progression on prior EGFR-TKI treatment. We report the final AURA3 overall survival (OS) analysis. PATIENTS AND METHODS: Adult patients were randomized 2 : 1 to osimertinib (80 mg orally, once daily) or pemetrexed plus carboplatin/cisplatin (platinum-pemetrexed) intravenously, every 3 weeks (≤6 cycles). Patients could crossover to osimertinib on progression confirmed by blinded independent central review. OS and safety were secondary end points. RESULTS: A total of 279 patients were randomly assigned to receive osimertinib and 140 to platinum-pemetrexed (136 received treatment). At data cut-off (DCO; 15 March 2019), 188 patients (67%) receiving osimertinib versus 93 (66%) receiving platinum-pemetrexed had died. The hazard ratio (HR) for OS was 0.87 [95% confidence interval (CI) 0.67-1.12; P = 0.277]; the median OS was 26.8 months (95% CI 23.5-31.5) versus 22.5 months (95% CI 20.2-28.8) for osimertinib and platinum-pemetrexed, respectively. The estimated 24- and 36-month survival was 55% versus 43% and 37% versus 30%, respectively. After crossover adjustment, there was an HR of 0.54 (95% CI 0.18-1.6). Time to first subsequent therapy or death showed a clinically meaningful advantage toward osimertinib (HR 0.21, 95% CI 0.16-0.28; P < 0.001). At DCO, 99/136 (73%) patients in the platinum-pemetrexed arm had crossed over to osimertinib, 66/99 (67%) of whom had died. The most common adverse events possibly related to study treatment were diarrhea (32%; grade ≥3, 1%) and rash (grouped term; 32%; grade ≥3, <1%) in the osimertinib arm, versus nausea (47%; grade ≥3, 3%) in the platinum-pemetrexed arm. CONCLUSIONS: In patients with T790M advanced NSCLC, no statistically significant benefit in OS was observed for osimertinib versus platinum-pemetrexed, which possibly reflects the high crossover rate of patients from platinum-pemetrexed to osimertinib. CLINICAL TRIALS NUMBER: ClinicalTrials.gov NCT02151981; https://clinicaltrials.gov/ct2/show/NCT02151981.

Role of tumour location and surgical extent on prognosis in T2 gallbladder cancer: an international multicentre study.

BACKGROUND: In gallbladder cancer, stage T2 is subdivided by tumour location into lesions on the peritoneal side (T2a) or hepatic side (T2b). For tumours on the peritoneal side (T2a), it has been suggested that liver resection may be omitted without compromising the prognosis. However, data to validate this argument are lacking. This study aimed to investigate the prognostic value of tumour location in T2 gallbladder cancer, and to clarify the adequate extent of surgical resection. METHODS: Clinical data from patients who underwent surgery for gallbladder cancer were collected from 14 hospitals in Korea, Japan, Chile and the USA. Survival and risk factor analyses were conducted. RESULTS: Data from 937 patients were available for evaluation. The overall 5-year disease-free survival rate was 70·6 per cent, 74·5 per cent for those with T2a and 65·5 per cent among those with T2b tumours (P = 0·028). Regarding liver resection, extended cholecystectomy was associated with a better 5-year disease-free survival rate than simple cholecystectomy (73·0 versus 61·5 per cent; P = 0·012). The 5-year disease-free survival rate was marginally better for extended than simple cholecystectomy in both T2a (76·5 versus 66·1 per cent; P = 0·094) and T2b (68·2 versus 56·2 per cent; P = 0·084) disease. Five-year disease-free survival rates were similar for extended cholecystectomies including liver wedge resection versus segment IVb/V segmentectomy (74·1 versus 71·5 per cent; P = 0·720). In multivariable analysis, independent risk factors for recurrence were presence of symptoms (hazard ratio (HR) 1·52; P = 0·002), R1 resection (HR 1·96; P = 0·004) and N1/N2 status (N1: HR 3·40, P < 0·001; N2: HR 9·56, P < 0·001). Among recurrences, 70·8 per cent were metastatic. CONCLUSION: Tumour location was not an independent prognostic factor in T2 gallbladder cancer. Extended cholecystectomy was marginally superior to simple cholecystectomy. A radical operation should include liver resection and adequate node dissection.

ANTECEDENTES: En el cáncer de vesícula biliar, la ubicación del tumor subdivide el estadio T2 en tumores con invasión del lado peritoneal y del lado del hígado (T2a y T2b). Para los tumores que invaden el lado peritoneal (T2a) se sugiere que se puede obviar la resección hepática sin que ello comprometa el pronóstico. Sin embargo, este argumento no ha sido validado. El estudio tuvo como objetivo investigar el valor pronóstico de la localización del tumor en el cáncer de vesícula biliar T2 y establecer la extensión adecuada de la resección quirúrgica. MÉTODOS: Se recogieron los datos clínicos de pacientes que se sometieron a cirugía por cáncer de vesícula biliar en 14 hospitales de Corea, Japón, Chile y Estados Unidos. Se realizaron análisis de la supervivencia y de los factores de riesgo. RESULTADOS: Se dispuso de datos de 937 pacientes para ser evaluados. La tasa de supervivencia global libre de enfermedad a los 5 años fue del 70,6%, y las de T2a y T2b del 74,5% y 65,5% (P = 0,028). Con respecto a la resección hepática, la colecistectomía extendida presentó una tasa mejor de supervivencia libre de enfermedad a los 5 años que la colecistectomía simple (73,0% versus 61,5%, P = 0,012). La tasa de supervivencia libre de enfermedad a los 5 años fue marginalmente mejor para la colecistectomía extendida que para la colecistectomía simple tanto en T2a (76,5% versus 66,1%, P = 0,094) como en T2b (68,2% versus 56,2%, P = 0,084). Las tasas de supervivencia libre de enfermedad a los 5 años no fueron diferentes entre la resección hepática en cuña y la segmentectomía S4b+S5 (74,1% versus 71,5%, P = 0,720). En el análisis multivariable, los factores de riesgo independientes para la recidiva fueron la presencia de síntomas (cociente de riesgos instantáneos, hazard ratio, HR 1,52, P = 0,002), la resección R1 (HR 1,96, P = 0,004) y el estadio N1/N2 (N1 HR 3,40, P < 0,001; N2 HR 9,56, P < 0,001). El 70,8% de las recidivas eran metastásicas. CONCLUSIÓN: La localización del tumor no fue un factor pronóstico independiente en el cáncer de vesícula biliar T2. La colecistectomía extendida fue marginalmente superior que la colecistectomía simple. La cirugía radical debe incluir una resección hepática y una linfadenectomía adecuada.

Validation of a nomogram to predict the risk of cancer in patients with intraductal papillary mucinous neoplasm and main duct dilatation of 10 mm or less.

BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN) is premalignant pancreatic lesion. International guidelines offer limited predictors of individual risk. A nomogram to predict individual IPMN malignancy risk was released, with good diagnostic performance based on a large cohort of Asian patients with IPMN. The present study validated a nomogram to predict malignancy risk and invasiveness of IPMN using both Eastern and Western cohorts. METHODS: Clinicopathological and radiological data from patients who underwent pancreatic resection for IPMN at four centres each in Eastern and Western countries were collected. After excluding patients with missing data for at least one malignancy predictor in the nomogram (main pancreatic duct diameter, cyst size, presence of mural nodule, serum carcinoembryonic antigen and carbohydrate antigen (CA) 19-9 levels, and age). RESULTS: In total, data from 393 patients who fit the criteria were analysed, of whom 265 were from Eastern and 128 from Western institutions. Although mean age, sex, log value of serum CA19-9 level, tumour location, main duct diameter, cyst size and presence of mural nodule differed between the Korean/Japanese, Eastern and Western cohorts, rates of malignancy and invasive cancer did not differ significantly. Areas under the receiver operating characteristic (ROC) curve values for the nomogram predicting malignancy were 0·745 for Eastern, 0·856 for Western and 0·776 for combined cohorts; respective values for the nomogram predicting invasiveness were 0·736, 0·891 and 0·788. CONCLUSIONS: External validation of the nomogram showed good performance in predicting cancer in both Eastern and Western patients with IPMN lesions.

ANTECEDENTES: La neoplasia mucinosa papilar intraductal (intraductal papillary mucinous neoplasm, IPMN) es una lesión pancreática premaligna. Las guías internacionales incluyen un número limitado de factores predictivos de riesgo individual. Para predecir el riesgo individual de malignidad del IPMN se ha propuesto un nomograma con un buen rendimiento diagnóstico, basado en una gran cohorte de pacientes asiáticos con IPMN. Este estudio validó el nomograma para predecir el riesgo de cáncer y de invasión de la IPMN utilizando cohortes tanto orientales como occidentales. MÉTODOS: Se recogieron datos clínico-patológicos y radiológicos de pacientes en los que se realizó una resección de páncreas por IPMN en 4 centros en países orientales y en 4 centros de países occidentales. Se excluyeron los pacientes en los que en el nomograma faltaba ≥ 1 factor(es) predictivo(s) de malignidad (diámetro del conducto pancreático principal, tamaño del quiste, presencia de nódulo mural, niveles séricos de CEA y CA19-9, y edad). RESULTADOS: En total, se analizaron datos de 393 pacientes que cumplían con los criterios de inclusión, de los cuales 265 eran de centros orientales y 128 de centros occidentales. Aunque la edad media, el sexo, el valor logarítmico del nivel sérico de CA19-9, la localización del tumor, el diámetro del conducto principal, el tamaño del quiste y la presencia de un nódulo mural difirieron entre las cohortes de Corea/Japón y las cohortes oriental y occidental, las tasas de malignidad y de cáncer invasivo no fueron significativamente diferentes. Las áreas bajo la curva operativa del receptor (area under the receiver operating curve, AUC) que mostró el nomograma para predecir la malignidad fueron: cohorte oriental: 0,745; cohorte occidental: 0,856 y cohortes combinadas: 0,776; y para predecir la invasión tumoral fueron: cohorte oriental: 0,736; cohorte occidental: 0,891, y cohortes combinadas: 0,788. CONCLUSIÓN: La validación externa del nomograma mostró un buen rendimiento en la predicción de cáncer, tanto en pacientes orientales como occidentales con lesiones IPMN.

Association of genetic ancestry with striatal dopamine D2/D3 receptor availability.

Despite ethnic differences in allele frequencies of variants in dopaminergic genes associated with dopamine D2/D3 receptor availability (D2R), no study to date has investigated the relationship between genetic ancestry and striatal D2R. Here, we show that ancestry-informative markers significantly predict dorsal striatal D2R in 117 healthy ethnically diverse residents of the New York metropolitan area using Positron Emission Tomography (PET) with [11C]raclopride (P<0.0001), while correcting for age, sex, BMI, education, smoking status, and estimated socioeconomic status (ZIP codes). Effects of ethnicity on D2R were not driven by variation in dopaminergic candidate genes. Instead, candidate gene associations with striatal D2R were diminished when correcting for ancestry. These findings imply that future studies investigating D2 receptor genes should covary for genetic ancestry or study homogeneous populations. Moreover, ancestry studies on human neurobiology should control for socioeconomic differences between ethnic groups.

Systemic lupus erythematosus is a risk factor for cancer: a nationwide population-based study in Korea.

OBJECTIVE: Specific differences in cancer risk have been observed between systemic lupus erythematosus patients and the general population. Although meta-analyses have estimated cancer incidence in systemic lupus erythematosus patients, results have been inconclusive. Hence, we aimed to assess malignancy risk in systemic lupus erythematosus patients, compared to the risk in the general population. METHODS: Systemic lupus erythematosus patients ( n = 21,016; mean age 41.67 ± 13.14 years; female 90.22%) were selected from the Korean National Health Insurance Service database between 2008 and 2014. Age- and sex-matched controls were randomly sampled in a 5:1 ratio ( n = 105,080). RESULTS: During the 7 years of follow up, malignancy was detected in 763 (3.63%) systemic lupus erythematosus patients and 2667 (2.54%) controls. Systemic lupus erythematosus patients had a higher risk of malignancy than controls (odds ratio 1.44; 95% confidence interval 1.327-1.559), after multivariate adjustment. Systemic lupus erythematosus patients had a higher odds ratio for developing cervical, thyroid, ovarian, and oral cancer, as well as lymphoma, leukemia, and multiple myeloma than controls. Based on subgroup analysis, male systemic lupus erythematosus patients and patients younger than 40 years showed the highest lymphoma risk. CONCLUSIONS: Systemic lupus erythematosus might be an independent risk factor for cancer. Therefore, the importance of cancer screening programs should be emphasized in systemic lupus erythematosus patients. Our study is the first large nationwide cohort study for evaluating the risk of cancer in systemic lupus erythematosus patients.

Rapid tool for identification of bacterial strains using Fourier transform infrared spectroscopy on genomic DNA.

AIMS: We developed a new rapid and reliable method for identifying bacteria using a combination of Fourier transform infrared (FT-IR) spectroscopy of bacterial genomic DNA and multivariate analysis. METHODS AND RESULTS: FT-IR spectra of genomic DNA from four type strains of Pseudomonas spp., three type strains of Escherichia spp. and two type strains of Bacillus spp. were analysed in the 4000-400 cm-1 region. Spectral differences were found in the frequency regions of N-H stretching (amide I), C=O stretching vibrations (amide II) and PO2 - ionized asymmetric and symmetric stretching. Partial least squares discriminant analysis of the FT-IR spectra showed that the microbial strains could be discriminated by hierarchical clustering analysis. CONCLUSIONS: FT-IR spectral analysis of bacterial genomic DNA has potential for the rapid identification of bacteria at the genus and species levels. SIGNIFICANCE AND IMPACT OF THE STUDY: This study reports a new bacterial identification method using multivariate analysis of FT-IR spectra of bacterial genomic DNA.

Production of Handmade Open Pulled Straw (OPS) Using Digital Heating Gun for the Vitrification Process.

BACKGROUND: Vitrification is the most popular technique for the cryopreservation of oocytes and embryos, replacing slow freezing methods. MATERIALS AND METHODS: This study evaluated the efficient manufacturing methods of handmade open pulled straw (OPS) with a digital heating gun that could be proposed for vitrification. RESULTS: Production efficiency of OPS using 0.5 mL straw was detected at 0, 66.1, 90.5 and 85.7% for 1~2 s and 9.5, 33.3, 47.6 and 23.8% for 2~3 s of heating time at 250, 350, 400 and 450°C respectively. The production rate of OPS using 0.25 mL straw was perceived at 33.3, 76.2, 83.3, 95.2 and 57.6 % for 1.5~2.5 s time with the optimized heat setting at 330, 340, 350, 360 and 370°C respectively. The desired inner diameter (200~300 µm) of OPS could be varied according to the gamete size, embryo developmental stages or cell lines of different species. Based on our data, the production efficiency of OPS using 0.25-mL straw were increased beyond using a 0.5-mL straw. CONCLUSION: Handmade OPSs could be efficiently produced with a digital heating gun to generate a vitrification device for freezing gametes, embryos and cell lines.

Surgeon volume and prognosis of patients with advanced papillary thyroid cancer and lateral nodal metastasis.

BACKGROUND: Surgery is the most important treatment modality for papillary thyroid cancer (PTC). However, the relationship between surgeon volume and long-term oncological outcomes has not been explored. METHODS: Patients diagnosed with N1b PTC after initial thyroid surgery between 1 July 1994 and 31 December 2011 were eligible for inclusion in the study. Surgeons were categorized into high (at least 100 operations per year) and low (fewer than 100 operations per year) volume groups. Kaplan-Meier survival analysis according to surgeon volume was performed, and Cox proportional hazard modelling was used to estimate hazard ratios (HRs) with 95 per cent confidence intervals according to patient, tumour and surgeon factors. RESULTS: A total of 1103 patients with a median follow-up of 81 (i.q.r. 62-108) months were included in the study. During follow-up, 200 patients (18·1 per cent) developed structural recurrence. A high surgeon volume was associated with low structural recurrence (P = 0·006). After adjustment for age, sex and conventional risk factors for recurrence (histology, tumour size, gross extrathyroidal extension, margin status, more than 5 positive lymph nodes, radioactive iodine therapy), the adjusted HR for structural recurrence for low-volume surgeons was 1·46 (95 per cent c.i. 1·08 to 1·96), compared with high-volume surgeons. Distant metastasis (P = 0·242) and disease-specific mortality (P = 0·288) were not affected by surgeon volume. CONCLUSION: Surgeon volume is associated with structural recurrence, but not distant metastasis or cancer-specific death in patients with N1b PTC. Surgeon volume is important in initial surgery for advanced PTC with extensive nodal metastasis in order to ensure curative outcome and reduce treatment-related morbidity.

Prognostic significance of gross extrathyroidal extension invading only strap muscles in differentiated thyroid carcinoma.

BACKGROUND: In the eighth edition of the AJCC staging system for differentiated thyroid carcinoma (DTC), minimal extrathyroidal extension (ETE) is no longer a determinant of T3 category. Instead, gross ETE invading only strap muscles has been designated as a new T3b category. The long-term prognosis of patients with DTC and gross ETE invading only strap muscles was investigated. METHODS: This was a retrospective analysis of patients who underwent thyroidectomy between 1996 and 2005. Differences in cancer-specific and recurrence-free survival according to extent of ETE were assessed. RESULTS: A total of 3174 patients with DTC were included. No significant differences were observed in 10-year cancer-specific survival among patients with no ETE (98·6 per cent), microscopic ETE (98·3 per cent) and gross ETE invading only strap muscles (98·9 per cent) (P = 0·375). The 10-year recurrence-free survival rate for patients with gross ETE invading only strap muscles (89·2 per cent) was shorter than that for patients with no ETE (93·7 per cent; P = 0·016), but similar to that of patients with microscopic ETE (90·3 per cent). In univariable analysis, patients with gross ETE invading only strap muscles had a significantly higher risk of recurrence than those with no ETE (hazard ratio (HR) 1·67, 95 per cent c.i. 1·10 to 2·55; P = 0·017). In multivariable analysis, gross ETE invading only strap muscles was not an independent predictor of recurrence (HR 1·09, 0·71 to 1·69; P = 0·685). CONCLUSION: Although gross ETE invading only strap muscles may provide prognostic information about long-term recurrence, it does not affect mortality. The actual impact of gross ETE invading only strap muscles will be important in revising the staging system in the future.

Bone mineral density in osteoporotic patients with pyogenic vertebral osteomyelitis: effect of early versus late treatment for osteoporosis.

Patients with pyogenic vertebral osteomyelitis (PVO) are at greater risk of bone loss. However, treatment guidelines for bone loss have been lacking. Early bisphosphonate treatment within 6 weeks after PVO diagnosis was significantly associated with superior outcome in femoral BMD at 2-year follow-up, compared to that with late treatment. INTRODUCTION: Due to absence of concern and proper guidelines, management of bone loss or osteoporosis in PVO is often neglected or delayed. A retrospective cohort study was planned to investigate differences in bone mineral density (BMD) in PVO patients with osteoporosis according to the timing of osteoporosis treatment. METHODS: The PVO cohort consisted of 192 patients with osteoporosis who visited our institution between January 2003 and March 2015 and received bisphosphonate treatment for osteoporosis. According to the interval between PVO diagnosis and initiation of bisphosphonate, the patients were divided into three groups: group A (within 6 weeks after PVO diagnosis), group B (between 6 weeks and 3 months after diagnosis), and group C (more than 3 months after PVO diagnosis). RESULTS: The percent increase in total femoral BMD in group A was significantly larger than that in group B at 2-year follow-up (p = 0.036). Similarly, the percent increase in trochanteric (p = 0.008) and total femoral (p = 0009) BMD in group A was significantly larger than that in group C at 2-year follow-up. Even after multivariate adjustment, total femoral BMD changes were significantly associated with the treatment group. Group B (odds ratio = 2.824, p = 0.013) and group C (odds ratio = 3.591, p = 0.001) were more significantly associated with total femoral BMD decreases at 2-year follow-up compared with group A. CONCLUSIONS: Early bisphosphonate treatment within 6 weeks after PVO diagnosis (group A) was significantly associated with superior outcome in femoral BMD at 2-year follow-up, compared to that with late treatment (groups B and C).

Clinical and laboratory features of patients with osteomalacia initially presenting with neurological manifestations.

Patients with osteomalacia often visit the neurology department with conditions mimicking other myopathies. We analyzed clinical features of osteomalacia patients who visited the neurology department. These patients frequently presented with hypocalcemia, hypovitaminosis D, and pain with less severe weakness. Osteomalacia should be considered when patients present with pain and weakness. INTRODUCTION: Osteomalacia is a disease of bone metabolism; however, some patients with osteomalacia initially visit the neurology department. As these patients often complain of weakness and gait disturbance, osteomalacia can be confused with other myopathies. We analyzed the clinical features of patients with osteomalacia who visited the neurology department. METHODS: We retrospectively reviewed the medical records. Osteomalacia was diagnosed based on symptoms, laboratory features, and imaging results. We compared the characteristics of patients with osteomalacia who visited the neurology department with (1) those who did not visit the neurology department and (2) patients with idiopathic inflammatory myopathy. RESULTS: Eighteen patients with osteomalacia visited the neurology department (NR group). The common etiologies in the NR group included tumors or antiepileptic medication, whereas antiviral medication was the most common in patients who did not visit the neurology department (non-NR group). The NR group showed lower serum calcium (p = 0.004) and 25-hydroxyvitamin D (p = 0.006) levels than the non-NR group. When compared with patients with inflammatory myopathy, both groups showed proximal dominant weakness. However, pain was more common in osteomalacia than in myopathy (p = 0.008), and patients with osteomalacia showed brisk deep tendon reflex more often (p = 0.017). Serum calcium (p = 0.003) and phosphate (p < 0.001) levels were lower in osteomalacia than in myopathy. CONCLUSIONS: It was not uncommon for patients with osteomalacia to visit the neurology department. The clinical presentation of these patients can be more complex owing the superimposed neurological disease and accompanying hypocalcemia. Osteomalacia should be considered when patients present with pain and weakness.

Systemic lupus erythematosus is a risk factor for cardiovascular disease: a nationwide, population-based study in Korea.

OBJECTIVE: To investigate the incidence and clinical significance of cardiovascular disease in systemic lupus erythematosus patients. METHODS: We included systemic lupus erythematosus patients ( n = 18,575) without previous cardiovascular disease and age- and sex-matched individuals without systemic lupus erythematosus (controls; n = 92,875) from the Korean National Health Insurance Service database (2008-2014). Both cohorts were followed up for incident cardiovascular disease and death until 2015. RESULTS: During follow up, myocardial infarction occurred in 203 systemic lupus erythematosus patients and 325 controls (incidence rate: 1.76 and 0.56 per 1000 person-years, respectively), stroke occurred in 289 patients and 403 controls (incidence rate: 2.51 and 0.70 per 1000 person-years, respectively), heart failure occurred in 358 patients and 354 controls (incidence rate 3.11 and 0.61 per 1000 person-years, respectively), and death occurred in 744 patients and 948 controls (incidence rate 6.54 and 1.64 per 1000 person-years, respectively). Patients with systemic lupus erythematosus had higher risks for myocardial infarction (hazard ratio: 2.74, 95% confidence interval: 2.28-3.37), stroke (hazard ratio: 3.31, 95% confidence interval: 2.84-3.86), heart failure (hazard ratio: 4.60, 95% confidence interval: 3.96-5.35), and cardiac death (hazard ratio: 3.98, 95% confidence interval: 3.61-4.39). CONCLUSIONS: Here, systemic lupus erythematosus was an independent risk factor for cardiovascular disease, thus cardiac assessment and management are critical in systemic lupus erythematosus patients.

Differential protein stability and clinical responses of EML4-ALK fusion variants to various ALK inhibitors in advanced ALK-rearranged non-small cell lung cancer.

Background: Anaplastic lymphoma kinase (ALK) inhibition using crizotinib has become the standard of care in advanced ALK-rearranged non-small cell lung cancer (NSCLC), but the treatment outcomes and duration of response vary widely. Echinoderm microtubule-associated protein-like 4 (EML4)-ALK is the most common translocation, and the fusion variants show different sensitivity to crizotinib in vitro. However, there are only limited data on the specific EML4-ALK variants and clinical responses of patients to various ALK inhibitors. Patients and methods: By multiplex reverse-transcriptase PCR, which detects 12 variants of known EML4-ALK rearrangements, we retrospectively determined ALK fusion variants in 54 advanced ALK rearrangement-positive NSCLCs. We subdivided the patients into two groups (variants 1/2/others and variants 3a/b) by protein stability and evaluated correlations of the variant status with clinical responses to crizotinib, alectinib, or ceritinib. Moreover, we established the EML4-ALK variant-expressing system and analyzed patterns of sensitivity of the variants to ALK inhibitors. Results: Of the 54 tumors analyzed, EML4-ALK variants 3a/b (44.4%) was the most common type, followed by variants 1 (33.3%) and 2 (11.1%). The 2-year progression-free survival (PFS) rate was 76.0% [95% confidence interval (CI) 56.8-100] in group EML4-ALK variants 1/2/others versus 26.4% (95% CI 10.5-66.6) in group variants 3a/b (P = 0.034) among crizotinib-treated patients. Meanwhile, the 2-year PFS rate was 69.0% (95% CI 49.9-95.4) in group variants 1/2/others versus 32.7% (95% CI 15.6-68.4) in group variants 3a/b (P = 0.108) among all crizotinib-, alectinib-, and ceritinib-treated patients. Variant 3a- or 5a-harboring cells were resistant to ALK inhibitors with >10-fold higher half maximal inhibitory concentration in vitro. Conclusion: Our findings show that group EML4-ALK variants 3a/b may be a major source of ALK inhibitor resistance in the clinic. The variant-specific genotype of the EML4-ALK fusion allows for more precise stratification of patients with advanced NSCLC.