Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA.

BACKGROUND: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups. PATIENTS AND METHODS: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR). RESULTS: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]. CONCLUSIONS: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.

Gender differences in osteoporotic hip fractures in Sarawak General Hospital.

INTRODUCTION: Osteoporosis and osteoporotic fracture pose a major public health problem in our ageing population, and particularly concerning is the increased morbidity and mortality associated with osteoporotic hip fractures. While overall diagnosis and treatment for osteoporosis have improved, osteoporosis in men remains underdiagnosed and undertreated. We aim to describe the difference in clinical characteristics between elderly men and women with osteoporotic hip fractures in Sarawak General Hospital. MATERIALS AND METHODS: All patients diagnosed with osteoporotic hip fracture admitted to Sarawak General Hospital from June 2019 to March 2021 were recruited, and demographic data and clinical features were obtained. RESULTS: There were 140 patients with osteoporotic hip fracture, and 40 were men (28.6%). The mean age for males was 74.1 ± 9.5 years, while the mean age for females was 77.4 ± 9.1 years (p=0.06). The types of fracture consisted of neck of femur=78, intertrochanteric=61 and subtrochanteric=1. More men were active smokers (15% vs 1%, p<0.001). There were 20 men with secondary osteoporosis (50%), while 13 women (13%) had secondary osteoporosis (p<0.001). The causes of secondary osteoporosis among the men were hypogonadism, COPD, glucocorticoid-induced osteoporosis, renal disease, androgen deprivation therapy, thyroid disorder, prostate cancer and previous gastrectomy. There were two deaths among the men and four deaths among the women during the inpatient and 3 months follow-up period. There was no statistical significance between the mortality rates between male patients (5%) and female patients (4%) (p=0.55). CONCLUSION: There were more females with osteoporotic hip fractures, and there were significantly more males with secondary osteoporotic hip fractures.

Rapid antigen test during a COVID-19 outbreak in a private hospital in Hong Kong.

INTRODUCTION: In response to two nosocomial clusters of coronavirus disease 2019 (COVID-19) in our hospital, we adopted a series of strict infection control measures, including regular rapid antigen test (RAT) screening for high-risk patients, visitors, and healthcare workers. We evaluated the diagnostic performance of a locally developed RAT, the INDICAID COVID-19 Rapid Antigen Test (Phase Scientific, Hong Kong), using respiratory samples from both symptomatic and asymptomatic individuals. METHODS: Real-time reverse-transcription polymerase chain reaction (rRT-PCR)-confirmed deep throat saliva (DTS) and pooled nasopharyngeal swab and throat swab (NPS/TS) samples collected from 1 November to 30 November 2020 were tested by INDICAID. Screening RATs were performed on asymptomatic healthcare workers during a 16-week period (1 December 2020 to 22 March 2021). RESULTS: In total, 20 rRT-PCR-confirmed samples (16 DTS, four pooled NPS/TS) were available for RAT. Using the original sample, RAT results were positive in 17/20 samples, indicating 85% sensitivity (95% confidence interval [CI]=62.11%-96.79%). Negative RAT results were associated with higher cycle threshold (Ct) values. For samples with Ct values <25, the sensitivity was 100%. Of the 49 801 RATs collected from healthcare workers, 33 false positives and one rRT-PCR-confirmed case were detected. The overall specificity was 99.93% (95% CI=99.91%-99.95%). The positive and negative predictive values were 2.94% (95% CI=2.11%-4.09%) and 100%, respectively. CONCLUSION: The INDICAID COVID-19 RAT demonstrated good sensitivity for specimens with high viral loads and satisfactory specificity for low-risk, asymptomatic healthcare workers.

Nivolumab with carboplatin, paclitaxel, and bevacizumab for first-line treatment of advanced nonsquamous non-small-cell lung cancer.

BACKGROUND: This international, randomized, double-blind phase III study (ONO-4538-52/TASUKI-52) evaluated nivolumab with bevacizumab and cytotoxic chemotherapy as first-line treatment for nonsquamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Between June 2017 and July 2019, this study enrolled treatment-naïve patients with stage IIIB/IV or recurrent nonsquamous NSCLC without sensitizing EGFR, ALK, or ROS1 alterations. They were randomly assigned in a 1 : 1 ratio to receive nivolumab or placebo in combination with carboplatin, paclitaxel, and bevacizumab every 3 weeks for up to six cycles, followed by nivolumab/placebo with bevacizumab until progressive disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by an independent radiology review committee (IRRC). RESULTS: Overall, 550 patients from Japan, Korea, and Taiwan were randomized; of these patients, 273 and 275 received the nivolumab and placebo combinations, respectively. In the present preplanned interim analysis with a median follow up of 13.7 months, the IRRC-assessed median PFS was significantly longer in the nivolumab arm than in the placebo arm (12.1 versus 8.1 months; hazard ratio 0.56; 96.4% confidence interval 0.43-0.71; P < 0.0001). The PFS benefit was observed across all patients with any programmed death-ligand 1 (PD-L1) expression levels including PD-L1-negative patients. The IRRC-assessed objective response rates were 61.5% and 50.5% in the nivolumab and placebo arms, respectively. The incidence of treatment-related adverse events of grade 3 or 4 was comparable between the two arms; treatment-related adverse events leading to death were observed in five and four patients in the nivolumab and placebo arms, respectively. CONCLUSION: The TASUKI-52 regimen should be considered a viable new treatment strategy for treatment-naïve patients with advanced nonsquamous NSCLC.

Sacral tumours and their mimics: pictorial review and diagnostic strategy.

Sacral tumours encompass an extensive range of differential diagnosis. The clinical presentation is often non-specific, including neurological deficits and low back pain. Accurate diagnosis of sacral lesions is challenging and requires a comprehensive imaging strategy and robust knowledge on the imaging characteristics of different pathological processes. This review will provide an updated overview of the computed tomography (CT), magnetic resonance imaging (MRI), and integrated positron-emission tomography (PET)-CT features of some common and rare sacral tumours and their mimics. Several clinical scenarios with specific diagnostic considerations and treatment implications will be described.

Prognostic significance of bone marrow 2-[18F]-fluoro-2-deoxy-d-glucose uptake in diffuse large B-cell lymphoma: relation to iliac crest biopsy results.

AIM: To investigate the prognostic significance of bone marrow (BM) 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) uptake in relation to posterior iliac crest BM biopsy (BMB) results in diffuse large B-cell lymphoma (DLBCL). MATERIALS AND METHODS: Pretreatment integrated positron-emission tomography(PET)/computed tomography (CT) images of 512 DLBCL patients who underwent BMB and received rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy were analysed retrospectively. BM uptake was assessed visually and by maximum standard uptake value (SUVmax). Associations with lymphoma-specific survival (LSS) were assessed using Kaplan-Meier and Cox regression analyses. RESULTS: FDG(+) BM was observed in 64 cases (41 focal, 12 heterogeneous, 11 diffuse). This finding distinguished iliac crest involvement (positive in 59 and negative in 453) with 89.6% accuracy (459/512) and 93.6% specificity (424/453). In BMB(+) patients, BM-to-liver SUVmax ratio >1.8 concurred perfectly with FDG(+) BM. During 52 months of follow-up, there were 156 lymphoma-related deaths. In the entire population, multivariate analysis revealed high International Prognostic Index (IPI; p<0.001), old age (p=0.003), bulky disease (p=0.011), BMB(+) (p=0.028), and FDG(+) BM (p=0.019) as independent predictors of worse LSS. In the BMB(+) subgroup, high National Comprehensive Cancer Network-revised IPI (NCCN-IPI; p=0.029) and FDG(+) BM (p=0.008) were significant independent predictors. Among BMB(+) patients with low to low-intermediate NCCN-IPI, FDG(+) BM was associated with significantly worse 2-year LSS (33.3% versus 100%; p=0.017). The same was true among those with high-intermediate NCCN-IPI (34.7% versus 76.9%.; p=0.026). CONCLUSION: Increased BM FDG in DLBCL is a predictor of worse LSS independent of BMB results and other prognostic variables including IPI/NCCN-IPI.

Shear-wave velocity for colorectal cancer liver metastases as a potential prognostic factor after chemotherapy: a preliminary study.

AIM: To evaluate whether shear-wave velocity (SWV) can be used for predicting the prognoses of patients with colorectal cancer liver metastases (CRLMs) after chemotherapy. MATERIALS AND METHODS: Our institutional review board approved this prospective study, and written informed consent was obtained. SWV of CRLMs were obtained using point shear-wave elastography using acoustic radiation force impulse from 25 patients prior to and 2, 7, and 14 days after chemotherapy. Progression-free survival (PFS) after chemotherapy was estimated using the Kaplan-Meier method. The Cox proportional hazard regression model was used to determine significant predictive factors for PFS. For measurement reproducibility, an additional 37 patients with CRLMs were enrolled and assessed using intraclass correlation coefficients (ICCs). RESULTS: After chemotherapy, 10 and 15 patients were classified into responder and non-responder groups, respectively. The estimated 1- and 3-year PFS values in the whole cohort were 36% and 8%, respectively. A decrease in the SWV value on day 2 relative to the initial value was a significant predictive factor for better PFS outcome (hazard ratio = 0.20, 95% confidence interval = 0.07-0.57, p=0.003). The estimated 1 and 3-year PFS rates were 66.7% and 22.2%, respectively, in nine patients with decreased SWV values on day 2 and significantly higher than 18.8% and 0% of 16 patients with increased SWV values on day 2. The ICC value of SWV of CRLMs in the additional 37 patients was 0.823 (95% CI = 0.685-0.905), indicating good agreement. CONCLUSION: SWV values of CRLMs could provide prognostic information in patients with CRLMs treated with chemotherapy, as decreased SWV values on day 2 after chemotherapy was a significant predictive factor for better PFS.

Low-dose CT angiography of the lower extremities: a comparison study of image quality and radiation dose.

AIM: To investigate the image quality and radiation dose of ultralow-dose (ULD) and low-dose (LD) lower-extremity computed tomography (CT) angiography (LE-CTA) using the advanced modelled iterative reconstruction (ADMIRE) algorithm to detect peripheral arterial disease (PAD) in comparison with standard-dose (SD) CT. MATERIALS AND METHODS: One hundred and seven consecutive patients were examined using LE-CTA at 70 kVp and a dual-source scanner to achieve three image sets using 30% (ULD), 70% (LD), and 100% (SD) tube loads. Qualitative analysis was conducted by examining the three image sets for overall quality. The image quality of arterial segments was analysed by two independent readers. In addition, the CT dose index (CTDIvol) was measured in the three image sets. RESULTS: The mean overall quality scores were 3.4±0.6 for ULD CT, 3.9±0.3 for LD CT, and 3.9±0.2 for SD CT. Both readers scored the arterial segments as 2-4 (adequate-excellent) in the three image sets. In addition, 89.4% (93/104) and 54.8% (57/104) segments of PAD with calcified plaques were scored 4 between SD and LD CT and between SD and ULD CT, respectively, and 45.2% (47/104) segments had a lower score by one point in ULD CT compared with SD CT. The mean CTDIvol was 4.1±1.1 mGy for SD CT, 2.9±0.8 mGy for LD CT, and 1.2±0.3 mGy for ULD CT. CONCLUSIONS: LD/ULD CT at 70 kVp using ADMIRE reconstruction enables a reduction in the radiation dose while enabling adequate evaluation or follow-up of PAD based on LE-CTA.

Talazoparib versus chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer: final overall survival results from the EMBRACA trial.

BACKGROUND: In EMBRACA, talazoparib prolonged progression-free survival versus chemotherapy (hazard ratio [HR] 0.542 [95% confidence interval (CI) 0.413-0.711]; P < 0.0001) and improved patient-reported outcomes (PRO) in germline BRCA1/2 (gBRCA1/2)-mutated advanced breast cancer (ABC). We report final overall survival (OS). PATIENTS AND METHODS: This randomized phase III trial enrolled patients with gBRCA1/2-mutated HER2-negative ABC. Patients received talazoparib or physician's choice of chemotherapy. OS was analyzed using stratified HR and log-rank test and prespecified rank-preserving structural failure time model to account for subsequent treatments. RESULTS: A total of 431 patients were entered in a randomized study (287 talazoparib/144 chemotherapy) with 412 patients treated (286 talazoparib/126 chemotherapy). By 30 September 2019, 216 deaths (75.3%) occurred for talazoparib and 108 (75.0%) chemotherapy; median follow-up was 44.9 and 36.8 months, respectively. HR for OS with talazoparib versus chemotherapy was 0.848 (95% CI 0.670-1.073; P = 0.17); median (95% CI) 19.3 months (16.6-22.5 months) versus 19.5 months (17.4-22.4 months). Kaplan-Meier survival percentages (95% CI) for talazoparib versus chemotherapy: month 12, 71% (66% to 76%)/74% (66% to 81%); month 24, 42% (36% to 47%)/38% (30% to 47%); month 36, 27% (22% to 33%)/21% (14% to 29%). Most patients received subsequent treatments: for talazoparib and chemotherapy, 46.3%/41.7% received platinum and 4.5%/32.6% received a poly(ADP-ribose) polymerase (PARP) inhibitor, respectively. Adjusting for subsequent PARP and/or platinum use, HR for OS was 0.756 (95% bootstrap CI 0.503-1.029). Grade 3-4 adverse events occurred in 69.6% (talazoparib) and 64.3% (chemotherapy) patients, consistent with previous reports. Extended follow-up showed significant overall improvement and delay in time to definitive clinically meaningful deterioration in global health status/quality of life and breast symptoms favoring talazoparib versus chemotherapy (P < 0.01 for all), consistent with initial analyses. CONCLUSIONS: In gBRCA1/2-mutated HER2-negative ABC, talazoparib did not significantly improve OS over chemotherapy; subsequent treatments may have impacted analysis. Safety was consistent with previous observations. PRO continued to favor talazoparib.

A phase II, multicenter, two cohort study of 160 mg osimertinib in EGFR T790M-positive non-small-cell lung cancer patients with brain metastases or leptomeningeal disease who progressed on prior EGFR TKI therapy.

BACKGROUND: Up to 40% of patients with non-small-cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) mutations treated with EGFR tyrosine kinase inhibitors (TKIs) present with disease progression in the central nervous system (CNS), either as brain metastases (BM) or leptomeningeal metastases (LM). Osimertinib (80 mg), a third-generation, irreversible, oral EGFR TKI, has shown efficacy in active CNS metastases. However, efficacy of osimertinib 160 mg in BM or LM is unclear. PATIENTS AND METHODS: This prospective, single-arm, two cohort study evaluated the efficacy of osimertinib 160 mg in T790M-positive BM or LM NSCLC patients who progressed on prior EGFR TKI (NCT03257124) treatment. The primary end points were objective response rate (ORR) (H1 = 30%) for the BM cohort and overall survival (OS) (H1 = 5 months) for the LM cohort. RESULTS: The median follow-up duration was 10.1 months and 9.6 months for the BM and LM cohorts, respectively. In the BM cohort, intracranial ORR and disease control rate were 55.0% and 77.5%, respectively. The median progression-free survival (PFS) was 7.6 months [95% confidence interval (CI) 5.0-16.6]; the median OS was 16.9 months [95% CI 7.9-not reached (NR)]. In the LM cohort, intracranial disease control rate was 92.5% and complete response rate was 12.5%. The median OS was 13.3 months (95% CI 9.1-NR); the median PFS was 8.0 months (95% CI 7.2-NR). Subgroup analyses based on previous exposure to T790M-targeting agents, including osimertinib 80 mg or other third-generation EGFR TKIs, showed no difference in PFS in both the BM (n = 18, P = 0.39) and LM (n = 17, P = 0.85) cohorts. Previous radiotherapy favored PFS in the BM cohort (hazard ratio 0.42, P = 0.04). The most common adverse events were decreased appetite, diarrhea, and skin rash; however, most were grade 1-2. CONCLUSION: Thus, osimertinib 160 mg demonstrated promising ORR and survival benefit with a tolerable safety profile in EGFR T790M-positive NSCLC patients with CNS metastasis who progressed on prior EGFR TKIs.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with locally-advanced unresectable non-small-cell lung cancer: a KSMO-ESMO initiative endorsed by CSCO, ISMPO, JSMO, MOS, SSO and TOS.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of early and locally-advanced non-small-cell lung cancer (NSCLC) was published in 2017, and covered the diagnosis, staging, management and treatment of both early stage I and II disease and locally-advanced stage III disease. At the ESMO Asia Meeting in November 2018, it was decided by both the ESMO and the Korean Society of Medical Oncology (KSMO) to convene a special face-to-face guidelines meeting in 2019 in Seoul. The aim was to adapt the ESMO 2017 guidelines to take into account potential differences related to ethnicity, cancer biology and standard practices associated with the treatment of locally-advanced, unresectable NSCLC in Asian patients. These guidelines represent the consensus opinions reached by those experts in the treatment of patients with lung cancer who represented the oncology societies of Korea (KSMO), China (CSCO), India (ISMPO), Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and it was independent of both local current treatment practices and the treatment availability and reimbursement situations in the individual participating Asian countries.

Mechanisms of ischaemic neural progenitor proliferation: a regulatory role of the HIF-1α-CBX7 pathway.

AIMS: Investigations of the molecular mechanisms of hypoxia- and ischaemia-induced endogenous neural progenitor cell (NPC) proliferation have mainly focused on factors secreted in response to environmental cues. However, little is known about the intrinsic regulatory machinery underlying the self-renewing division of NPCs in the brain after stroke. METHODS AND RESULTS: Polycomb repressor complex 1-chromobox7 (CBX7) has emerged as a key regulator in several cellular processes including stem cell self-renewal and cancer cell proliferation. The hypoxic environment triggering NPC self-renewal after CBX7 activation remains unknown. In this study, we found that the upregulation of CBX7 during hypoxia and ischaemia appeared to be from hypoxia-inducible factor-1α (HIF-1α) activation. During hypoxia, the HIF-1α-CBX7 cascade modulated NPC proliferation in vitro. NPC numbers significantly decreased in CBX7 knockout mice generated using CRISPR/Cas9 genome editing. CONCLUSIONS: We provided the novel insight that CBX7 expression is regulated through HIF-1α activation, which plays an intrinsically modulating role in NPC proliferation.

Blood utilization and clinical outcomes in pancreatic surgery before and after implementation of patient blood management.

BACKGROUND: Over the past decade, patient blood management (PBM) programs have been developed to reduce allogeneic blood utilization. This is particularly important in pancreatic surgery, which has historically been associated with high transfusion requirements and morbid event rates. This study investigated blood utilization and clinical outcomes in pancreatic surgery before, during, and after the implementation of PBM. STUDY DESIGN AND METHODS: A total of 3482 pancreatic surgery patients were assessed in a 10-year retrospective cohort study (2009-2019) at a single academic center. Baseline patient characteristics, transfusion practices, postoperative morbidity (infectious, thrombotic, ischemic, respiratory, and renal complications), mortality, and length of stay were compared between patients in the pre-PBM (2009-2013), early-PBM (2014-2016), and mature-PBM (2017-2019) time periods. Multivariable analysis assessed the odds for composite morbidity/mortality. RESULTS: Comparing the mature-PBM to pre-PBM cohorts, transfused units per 100 discharged patients decreased by 53% for erythrocytes (155 to 73; P < .0001), 81% for plasma (79 to 15; P < .038), and 75% for platelets (10 to 2.5; P < .005). Clinical outcomes improved as well, with composite morbid event rates decreasing by more than 50%, from 236 in 1438 patients (16.4%) to 85 in 1145 patients (7.4%) (P < .0001). Mortality and length of stay remained unchanged. Compared to the pre-PBM time period, early-PBM was associated with a risk-adjusted decrease in composite morbidity/mortality (OR 0.73; 95% CI 0.57-0.93; P = .010), while mature-PBM demonstrated a further incremental decrease (OR 0.44; 95% CI 0.33-0.57; P < .0001). CONCLUSIONS: The implementation of PBM was associated with substantially decreased blood utilization in pancreatic surgery, without negatively impacting clinical outcomes.

Isolation of internal and external sphincter progenitor cells from the human anal sphincter with or without radiotherapy.

AIM: We aimed to isolate and propagate internal and external anal sphincter progenitor cells from the human anal sphincter, with or without radiotherapy, for tailored cell therapy of faecal incontinence. METHODS: Sphincter progenitor cells were isolated from normal internal and external anal sphincters collected from 10 patients with rectal cancer who had undergone abdominoperineal resection with (n = 6) or without (n = 4) preoperative chemoradiotherapy. The isolated cells and differentiated muscle fibres were identified using immunofluorescence assay, western blotting and reverse transcription polymerase chain reaction (RT-PCR). The proliferation of progenitor cells with and without radiotherapy was compared by quantitative 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RESULTS: The immunofluorescence assay before differentiation confirmed that the internal anal sphincter progenitor cells expressed CD34 and neural-glial antigen 2 (NG2), whereas the external anal sphincter progenitor cells expressed CD34 and PAX7. After differentiation, the internal anal sphincter progenitor cells expressed desmin, calponin and α-smooth muscle actin, whereas the external anal sphincter progenitor cells expressed desmin, myogenic factor 4 and myosin heavy chain. The differential expression profiles of both cell types were confirmed by western blotting and RT-PCR. MTT assays showed that the viability of internal and external anal sphincter progenitor cells was significantly lower in the radiotherapy group than that in the nonradiotherapy group. CONCLUSIONS: This study describes the differential harvest internal and external sphincter muscle progenitor cells from human anal sphincters. We confirm that radiotherapy decreases the viability of internal and external anal sphincter progenitor cells.

Evaluation of a diagnostic 18F-FDG PET/CT strategy for differentiating benign from malignant retroperitoneal soft-tissue masses.

AIM: To investigate the optimal combined 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET)/computed tomography (CT) diagnostic criteria for distinguishing between benign and malignant retroperitoneal soft-tissue masses (RPMs). MATERIALS AND METHODS: A total of 74 patients (M:F=34:40; age, 53±13.2 years) who underwent FDG PET/CT for the initial work-up of RPMs were included. The maximum standardised uptake value (SUVmax), tumour size, presence of fat or calcifications and separated hypermetabolic lesions were included as PET/CT diagnostic parameters. Receiver-operating characteristic (ROC) curves were used to compare the diagnostic performance. RESULTS: The final pathological diagnoses included 52 malignant and 22 benign tumours. High SUVmax (>4.8) and large size (>13 cm) favoured malignancy, and yielded a diagnostic accuracy and AUC of 64.9%, 0.820±0.059, and 68.9%, 0.738±0.061, respectively. In a subgroup of RPMs with a fat component, both SUVmax and size were significantly different between benign and malignant RPM, which yielded a diagnostic accuracy and AUC of 91%, 0.977±0.024 (cut-off, 1.9 cm) and 87.9%, 0.865±0.072 (cut-off, 13 cm), respectively. In a subgroup without a fat component, only SUVmax was significantly different with an accuracy of 90.2% and AUC of 0.919±0.043. The optimal diagnostic flow by combining SUVmax and tumour size after dividing patients into two groups according to the presence of fat showed a sensitivity of 90.4%, a specificity of 95.5%, and an accuracy of 91.9%. CONCLUSIONS: The combination of SUVmax and size according to the presence of a fat component may be the optimal PET/CT diagnostic criteria for distinguishing benign and malignant RPMs.

Body mass index and 20 specific cancers: re-analyses of dose-response meta-analyses of observational studies.

Background: Objectives were to provide an overview and understand the strength of evidence and extent of potential biases and validity of claimed associations between body mass index (BMI) and risk of developing cancer. Methods: We carried out an umbrella review and comprehensively re-analyzed the data of dose-response meta-analyses on associations between BMI and risk of 20 specific cancers (bladder, brain, breast, colonic, rectal, endometrial, gallbladder, gastric, leukemia, liver, lung, melanoma, multiple myeloma, non-Hodgkins lymphoma, esophagus, ovarian, pancreatic, prostate, renal, thyroid) by adding big data or missed individual studies. Convincing evidence for an association was defined as a strong statistical significance in fixed-effects and random-effects meta-analyses at P < 0.001, 95% prediction interval (PI) excluded null, there was no large between-study heterogeneity and no small study effects. Suggestive evidence was defined as meeting the significance threshold for the random summary effects of P < 0.05, but 95% PI included the null. Weak evidence was defined as meeting the significance threshold for the random summary effects at a P < 0.05, but 95% PI included the null and there was large between-study heterogeneity or there were small study effects. Results: Convincing evidence for an association with BMI was detectable for six cancers (leukemia, multiple myeloma, pancreatic, endometrial, rectal, and renal cell carcinoma). Suggestive evidence was detectable for malignant melanoma, non-Hodgkins lymphoma, and esophageal adenocarcinoma. Weak evidence was detectable for brain and central nervous system tumors, breast, colon, gall bladder, lung, liver, ovarian, and thyroid cancer. No evidence was detectable for bladder, gastric, and prostate cancer. Conclusions: The association of increased BMI and cancer is heterogeneous across cancer types. Leukemia, multiple myeloma, pancreatic, endometrial, rectal, and renal cell carcinoma are convincingly associated with an increased BMI by dose-response meta-analyses.

Quality of life with talazoparib versus physician's choice of chemotherapy in patients with advanced breast cancer and germline BRCA1/2 mutation: patient-reported outcomes from the EMBRACA phase III trial.

Background: In the EMBRACA phase III trial, talazoparib (1 mg daily, orally) demonstrated a statistically significant improvement in PFS versus physician's choice of chemotherapy (PCT; capecitabine, eribulin, gemcitabine, or vinorelbine) in patients with HER2-negative advanced breast cancer carrying a germline BRCA1/2 mutation; we evaluated patient-reported outcomes (PROs). Patients and methods: Patients were randomized 2 : 1 to receive talazoparib or PCT. PROs were assessed at day 1 (baseline), the start of each treatment cycle (every 3 weeks), and at the end of treatment, using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-30) and its breast cancer module, QLQ-BR23. Prespecified exploratory analyses included a longitudinal mixed-effect model comparing treatment arms and a time to definitive clinically meaningful deterioration (TTD) analysis carried out in the global health status/quality of life (GHS/QoL), and all functional and symptom scales from the EORTC QLQ-C30 and -BR23 questionnaires. Between-arm TTD comparisons were made using a stratified log-rank test and a Cox proportional hazards model. Results: Baseline scores were similar between arms. Statistically significant estimated overall improvement from baseline in GHS/QoL was seen for talazoparib compared with statistically significant deterioration for PCT {3.0 [95% confidence interval (CI) 1.2, 4.8] versus -5.4 [95% CI -8.8, -2.0]; between arms, P < 0.0001}. A statistically significant greater delay was observed in TTD in GHS/QoL, favoring talazoparib over PCT [hazard ratio, 0.38 (95% CI 0.26, 0.55; median, 24.3 versus 6.3 months, respectively; P < 0.0001)]. A statistically significant overall change and a statistically significant delay in TTD, all favoring talazoparib, were also observed in multiple functions and symptoms. Conclusion: Patients who received talazoparib had significant overall improvements and significant delay in TTD in multiple cancer-related and breast cancer-specific symptoms, functions, and GHS/QoL. ClinicalTrials.gov: NCT01945775.

Sensitization to various minor house dust mite allergens is greater in patients with atopic dermatitis than in those with respiratory allergic disease.

BACKGROUND: Various allergenic proteins are produced by house dust mites (HDM). However, the allergenicity and clinical implications of these allergens are unknown. OBJECTIVE: The purpose of this study was to identify allergens in Dermatophagoides farinae and elucidate the sensitization profiles to these in Korean patients suffering from respiratory (allergic rhinitis and/or asthma) and atopic dermatitis symptoms. METHODS: IgE reactivities in sera from 160 HDM allergy patients were analysed by one- and two-dimensional gel electrophoresis and immunoblotting. IgE-reactive components were identified by liquid chromatography-coupled electrospray ionization-tandem mass spectrometry. Nine recombinant mite allergens (Der f 1, Der f 2, Der f 10, Der f 11, Der f 13, Der f 14, Der f 30, Der f 32 and Der f Alt a 10) were produced, and the IgE reactivity in sera to each was determined by ELISAs. RESULTS: Der f 1 and Der f 2 were recognized by IgE in serum samples from 88.1% and 78.1% of all patients, respectively. Patients with respiratory allergies were mainly sensitized to these major allergens, whereas patients with atopic dermatitis symptoms showed polysensitization to major and minor allergen components (including Der f 11, Der f 13, Der f 14, Der f 32 and Der f Alt a 10). CONCLUSIONS: Patients with respiratory allergic disease sensitize to major allergen components of HDM. Those with atopic dermatitis were sensitized to a broader range of minor allergen components of HDM (Der f 11, Der f 13, Der f 14, Der f 32 and Der f Alt a 10).

Allergen-specific immunotherapy induces regulatory T cells in an atopic dermatitis mouse model.

BACKGROUND: Several studies have demonstrated that allergen-specific immunotherapy (SIT) can be an effective treatment for atopic dermatitis (AD). However, there is no relevant mouse model to investigate the mechanism and validate the novel modality of SIT in AD. METHODS: NC/Nga mice with induced AD-like skin lesions received a subcutaneous injection of SIT (an extract of the house dust mite Dermatophagoides farinae [DfE]) or placebo for 5 weeks). Clinical and histological improvements of AD-like skin lesions were examined. The responses of local and systemic regulatory T (Treg) cells, natural killer (NK) cells, B cells, serum immunoglobulin, and T-cell cytokine response to DfE were evaluated to determine the underlying mechanism of the observed results. RESULTS: Specific immunotherapy significantly improved AD-like skin lesions. Histologically, SIT decreased epidermal thickness and reduced inflammatory cell infiltration, especially that of eosinophils. Concomitantly, SIT suppressed Th2 responses and induced local infiltration of Treg cells into the skin. Also, SIT induced the immunoglobulin G4 and attenuated allergen-specific immunoglobulin E. Furthermore, SIT induced local and systemic IL-10-producing Treg cells and regulatory NK cells. CONCLUSION: We established a SIT model on AD mice and showed that our model correlates well with previous reports about SIT-treated patients. Also, we revealed NK cells as another possible resource of IL-10 in SIT. Based on our results, we suggest our SIT model as a useful tool to investigate mechanism of action of SIT and to validate the efficacy of new SIT modalities for the treatment of AD.

Blood utilization and mortality in victims of gun violence.

BACKGROUND: Blood transfusion can be lifesaving for patients with hemorrhage; however, transfusion requirements for victims of gun violence are poorly understood. STUDY DESIGN AND METHODS: In an urban, Level 1 trauma center, 23,422 trauma patients were analyzed in a retrospective cohort study. Patients with gunshot wounds (GSWs) (n = 2,672; 11.4% of trauma patients) were compared to those with non-GSW traumatic injuries from 2005 to 2017, to assess blood utilization. RESULTS: The GSW cohort was approximately five times more likely to require transfusion (538 of 2672 [20.1%] vs. 798 of 20,750 [3.9%]; p < 0.0001), and the number of blood component units transfused per patient was approximately 10 times greater (3.3 ± 13.5 vs. 0.31 ± 3.8 units/patient; p < 0.0001), compared to the non-GSW cohort. The risk-adjusted likelihood of requiring high-dose transfusion was greater in the GSW cohort (odds ratio, 2.38; 95% confidence interval, 1.14-5.80), and requirements were increased for all four blood components (red blood cells, platelets, plasma, and cryoprecipitate). Patients with GSWs had approximately 14 times greater overall mortality (653 of 2672 [24.4%] vs. 352 of 20,750 [1.7%]; p < 0.0001]. Compared to non-GSW penetrating injuries (e.g., stab wounds), those with GSWs had approximately four times higher transfusion requirements (3.3 ± 13.5 vs. 0.80 ± 3.8 units/patient; p < 0.0001), and approximately eight times greater overall mortality (653 of 2672 [24.4%] vs. 28 of 956 [2.9%]; p < 0.0001). CONCLUSIONS: Compared to other traumatic injuries, GSW injuries are associated with substantially greater blood utilization and mortality. Trauma centers treating GSW injuries should have ready access to all blood components and ability to implement massive transfusions.