The threaten of typhoons to the health of residents in inland areas: a study on the vulnerability of residents to death risk during typhoon "Lekima" : In Jinan, China.

BACKGROUND: Studies had suggested increased risk of death of residents was associated with typhoons, particularly coastal regions. However, these findings ignored the impact of inland typhoons on the health of residents, especially the indirect death risk caused by typhoons. This study aimed to investigate the acute death risk of residents during inland typhoon Lekima in Jinan, further identify vulnerable populations and areas. METHODS: We selected the daily death from 11 to 27th August 2019 in Jinan as case period, and conducted a time-stratified case-crossover design to match the contemporaneous data from 2016 to 2018 as control period. We used the generalized linear Poisson models to estimate the related effects of death risk during typhoon Lekima and lag days. RESULTS: During the Lekima typhoon month, there were 3,366 deaths occurred in Jinan. Compared to unexposed periods, the acute death risk of non-accidental diseases (especially circulatory diseases), female and the older adults increased significantly in the second week after the typhoon. The maximum significant effect of circulatory disease deaths, female and older adult deaths were appeared on lag9, lag9, and lag13 respectively. And the typhoon-associated RR were 1.19 (95%CI:1.05,1.34), 1.28 (95%CI:1.08,1.52), and 1.22 (95%CI:1.06,1.42) respectively. The acute death risk of residents living in TQ and CQ increased significantly on Lag2 and Lag6 after the typhoon, respectively, while those living in LX, LC, HY, JY, and SH occurred from Lag 8 to Lag 13 after the typhoon. LC lasted the longest days. CONCLUSIONS: Typhoons would increase the vulnerability of residents living in Jinan which mainly occurred from the seventh day after the typhoon. Residents suffering from non-accidental diseases (circulatory diseases), female and the older adults were more vulnerable. The vulnerability of TQ and CQ occurred on Lag2 and Lag6 after typhoon Lekima, respectively, and the other areas except ZQ and PY occurred from Lag 8 to Lag 13. LC lasted the longest duration. Our findings emphasized the importance of the emergency response, which would help policymakers to identify vulnerable regions and populations accurately during typhoons and formulate the emergency response plan.

A systematic review and meta-analysis on the prevalence of stigma in infectious diseases, including COVID-19: a call to action.

Infectious diseases, including COVID-19, are crucial public health issues and may lead to considerable fear among the general public and stigmatization of, and discrimination against, specific populations. This meta-analysis aimed to estimate the pooled prevalence of stigma in infectious disease epidemics. We systematically searched PubMed, PsycINFO, Embase, MEDLINE, Web of Science, and Cochrane databases since inception to June 08, 2021, and reported the prevalence of stigma towards people with infectious diseases including SARS, H1N1, MERS, Zika, Ebola, and COVID-19. A total of 50 eligible articles were included that contributed 51 estimates of prevalence in 92722 participants. The overall pooled prevalence of stigma across all populations was 34% [95% CI: 28-40%], including enacted stigma (36% [95% CI: 28-44%]) and perceived stigma (31% [95% CI: 22-40%]). The prevalence of stigma in patients, community population, and health care workers, was 38% [95% CI: 12- 65%], 36% [95% CI: 28-45%], and 30% [95% CI: 20-40%], respectively. The prevalence of stigma in participants from low- and middle-income countries was 37% [95% CI: 29-45%], which is higher than that from high-income countries (27% [95% CI: 18-36%]) though this difference was not statistically significant. A similar trend of prevalence of stigma was also observed in individuals with lower education (47% [95% CI: 23-71%]) compared to higher education level (33% [95% CI: 23-4%]). These findings indicate that stigma is a significant public health concern, and effective and comprehensive interventions are needed to counteract the damaging effects of the infodemics during infectious disease epidemics, including COVID-19, and reduce infectious disease-related stigma.

Quality of life assessment after total knee arthroplasty in patients with Parkinson's disease.

BACKGROUND: The number of Parkinson's patients (PD) undergoing total knee arthroplasty (TKA) is increasing. The purpose of the study was to characterize quality of life (QOL) outcomes for patients with coexisting PD and knee osteoarthritis (KOA) following TKA. METHODS: Patients with coexisting PD and KOA undergoing TKA between June 2014 and June 2020 were included. These patients were matched to controls with KOA alone by age, gender, basic social background information and Knee society score (KSS). The primary measure was to assess the QOL by the absolute changes in the EuroQOL5-Dimensions (EQ-5D), Pain and Disability Questionnaire (PDQ), and Patient Health Questionnaire-9(PHQ-9) at the last follow-up (LFU). Secondary measures were changes in QOL that exceeded the minimum clinically important difference value (MCID). Data on the health status and QOL of all patients were collected. Simple and multivariate regression analysis was used to evaluate the impact of PD on their QOL. RESULTS: Twelve KOA patients with PD were compared with 48 controls. Control patients experienced QOL improvement across all three measures:EQ-5D index (0.545-0.717, P < 0.01), PDQ (81.1-52.3, P < 0.01) and PHQ-9(8.22-5.91, P < 0.01) were significantly improved at the LFU; while in patients with PD, only PDQ (91.0-81.4, P = 0.03) slightly improved. There were significant differences in the improvement of QOL between PD patients and the control group through EQ-5D (0.531 vs.0.717, P < 0.01) and PDQ (81.4vs.52.3, P < 0.01) at the LFU. CONCLUSION: TKA has no benefit of QOL beyond a slight improvement in pain-related disability in the KOA patients with PD.

Lung CD103+dendritic cells and Clec9a signaling are required for neonatal hyperoxia-induced inflammatory responses to rhinovirus infection.

Premature infants, especially those with bronchopulmonary dysplasia (BPD), develop recurrent severe respiratory viral illnesses. We have shown that hyperoxic exposure of immature mice, a model of BPD, increases lung IL-12-producing Clec9a+ CD103+ dendritic cells (DCs), pro-inflammatory responses, and airway hyperreactivity following rhinovirus (RV) infection. However, the requirement for CD103+ DCs and Clec9a, a DAMP receptor that binds necrotic cell cytoskeletal filamentous actin (F-actin), for RV-induced inflammatory responses has not been demonstrated. To test this, 2-day-old C57BL/6J, CD103+ DC-deficient Batf3-/- or Clec9agfp-/- mice were exposed to normoxia or hyperoxia for 14 days. Also, selected mice were treated with neutralizing antibody against CD103. Immediately after hyperoxia, the mice were inoculated with RV intranasally. We found that compared with wild-type mice, hyperoxia-exposed Batf3-/- mice showed reduced levels of IL-12p40, IFN-γ, and TNF-α, fewer IFN-γ-producing CD4+ T cells, and decreased airway responsiveness following RV infection. Similar effects were observed in anti-CD103-treated and Clec9agfp-/- mice. Furthermore, hyperoxia increased airway dead cell number and extracellular F-actin levels. Finally, studies in preterm infants with respiratory distress syndrome showed that tracheal aspirate CLEC9A expression positively correlated with IL12B expression, consistent with the notion that CLEC9A+ cells are responsible for IL-12 production in humans as well as mice. We conclude that CD103+ DCs and Clec9a are required for hyperoxia-induced pro-inflammatory responses to RV infection. In premature infants, Clec9a-mediated activation of CD103+ DCs may promote pro-inflammatory responses to viral infection, thereby driving respiratory morbidity.

Machine learning based on clinico-biological features integrated 18F-FDG PET/CT radiomics for distinguishing squamous cell carcinoma from adenocarcinoma of lung.

PURPOSE: To develop and validate a clinico-biological features and 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) radiomic-based nomogram via machine learning for the pretherapy prediction of discriminating between adenocarcinoma (ADC) and squamous cell carcinoma (SCC) in non-small cell lung cancer (NSCLC). METHODS: A total of 315 NSCLC patients confirmed by postoperative pathology between January 2017 and June 2019 were retrospectively analyzed and randomly divided into the training (n = 220) and validation (n = 95) sets. Preoperative clinical factors, serum tumor markers, and PET, and CT radiomic features were analyzed. Prediction models were developed using the least absolute shrinkage and selection operator (LASSO) regression analysis. The performance of the models was evaluated and compared by the area under receiver-operator characteristic (ROC) curve (AUC) and DeLong test. The clinical utility of the models was determined via decision curve analysis (DCA). Then, a nomogram was developed based on the model with the best predictive efficiency and clinical utility and was validated using the calibration plots. RESULTS: In total, 122 SCC and 193 ADC patients were enrolled in this study. Four independent prediction models were separately developed to differentiate SCC from ADC using clinical factors-tumor markers, PET radiomics, CT radiomics, and their combination. The DeLong test and DCA showed that the Combined Model, consisting of 2 clinical factors, 2 tumor markers, 7 PET radiomics, and 3 CT radiomic parameters, held the highest predictive efficiency and clinical utility in predicting the NSCLC subtypes compared with the use of these parameters alone in both the training and validation sets (AUCs (95% CIs) = 0.932 (0.900-0.964), 0.901 (0.840-0.957), respectively) (p < 0.05). A quantitative nomogram was subsequently constructed using the independently risk factors from the Combined Model. The calibration curves indicated a good consistency between the actual observations and nomogram predictions. CONCLUSION: This study presents an integrated clinico-biologico-radiological nomogram that can be accurately and noninvasively used for the individualized differentiation SCC from ADC in NSCLC, thereby assisting in clinical decision making for precision treatment.

18F-FDG PET/CT metabolic parameters and HER2 expression in colorectal cancer.

The relationship between 18F-FDG uptake and HER2 expression in colorectal cancer has not been investigated yet. This study aimed to investigate the predictive efficiency of preoperative 18F-FDG PET/CT for HER2 expression and prognosis in colorectal cancer. We retrospectively analyzed 131 colorectal cancer patients who underwent 18F-FDG PET/CT scans in our center before surgery. HER2 positivity was defined as a score of 2+ or 3+, and HER2 negativity was defined as a score of 0 or 1+ in immunohistochemistry of HER2 expression. The relationships between 18F-FDG PET/CT metabolic parameters and HER2 expression and the prognosis of colorectal patients were systematically studied. From 131 colorectal cancer patients, there were 27 (20.6%) HER2-positive patients. SUVmax of the primary tumor (mean ± SD) in the HER2-positive and the HER2-negative group was 18.238±8.912 and 14.455±6.531, respectively. SUVmax in the HER2-positive group was higher than in the negative group (p=0.034). When the cutoff was based on 5 cm, tumor size demonstrated significant positive correlations with SUVmax (p=0.012) and HER2 expression (p=0.014). Multivariate analysis showed that both SUVmax and tumor size had a significant correlation with HER2 expression (p=0.049 vs. p=0.043, respectively). There was no statistical difference in PFS between the HER2-positive and the HER2-negative group (p=0.28). 18F-FDG metabolic parameters had a significant correlation with HER2 expression in colorectal cancer. SUVmax combined with primary tumor size were better for predicting the HER2 status of colorectal cancer. 18F-FDG metabolic parameters had a significant correlation with HER2 expression in colorectal cancer. SUVmax combined with primary tumor size were better for predicting the HER2 status of colorectal cancer.

Non-linear relationships and interactions of meteorological factors on mumps in Jinan, China.

Although vaccination is available, mumps remains a public health concern in many countries including China. Previous studies have indicated the impact of meteorological factors and mumps, but findings vary across different regions with limited evidence to inform local public health responses. We aim to examine the impacts of meteorological variables on mumps in Jinan, a temperate city of China, and explore the interactions of temperature with humidity or wind speed. Weekly meteorological data and notified cases of mumps in Jinan were collected for 2014-2018. Regression analyses using the generalized additive model were performed with considerations of multicollinearity, lag effects, school holidays, long-term trend, and seasonality. A stratification model was applied to investigate the interaction. We found a non-linear relationship between weekly mean temperature and the number of cases. Between 1.2 and 24.5 °C, the excess risk (ER) of mumps for a 1 °C increase in weekly mean temperature was 3.08% (95% CI 1.32 to 4.87%) at 0-week lag. The lagged effects could last for 3 weeks. There were interactions between mean temperature and relative humidity or wind speed. The effect of mean temperature was enhanced in days with low relative humidity or high wind speed. This study suggests that temperature is positively associated with mumps cases with thresholds in the temperate city of China, and the effect can be modified by relative humidity and wind speed and is independent of vaccine coverage. Findings could be integrated into current early warning systems of mumps in order to protect people's health from the risk of changing climate.

Career choice and influential factors among medical students majoring in psychiatry in China.

BACKGROUND: The undergraduate program of psychiatry has been widely established in recent years to improve the education and recruitment of psychiatrists in China. We aim to investigate the career choice of medical students majoring in psychiatry in China and the influential factors. METHOD: This multicenter study was conducted in 26 medical schools in China from May to October of 2019. Participants included 4610 medical students majoring in psychiatry and 3857 medical students majoring in clinical medicine. Multivariable logistic regression was used to investigate the influential factors of students' choices of psychiatry at matriculation and as a career. RESULTS: 44.08% of psychiatry majored students gave psychiatry as a first choice at matriculation, and 56.67% of them would choose psychiatry as a career, which was in sharp contrast to the proportion of clinical medicine majored students who would choose psychiatry as a career (0.69%). Personal interest (59.61%), suggestions from family members (27.96%), and experiencing mental problems (23.19%) were main reasons for choosing psychiatry major at matriculation. Personal interest (odds ratio [OR] = 2.12, 95% confidence interval [CI] = 1.87-2.40), experiencing a psychiatry clerkship (OR = 1.99, 95% CI = 1.28-3.08), being female (OR = 1.50, 95% CI = 1.30-1.68), experiencing mental problems (OR = 1.33, 95% CI = 1.28-1.56), and suggestions from family members (OR = 1.25, 95% CI = 1.08-1.46) correlated positively with students' choice of psychiatry as career. Students who lacked psychiatry knowledge (OR = 0.49, 95% CI = 0.29-0.85) or chose psychiatry because of lower admission scores (OR = 0.80, 95% CI = 0.63-0.97) were less likely to choose psychiatry as a career. CONCLUSION: More than half of psychiatry majored medical school students planned to choose psychiatry as their career, whereas very few students in the clinic medicine major would make this choice. Increasing students' interest in psychiatry, strengthening psychiatry clerkships, and popularizing psychiatric knowledge are modifiable factors to increase the psychiatry career intention. The extent to which medical students' attitudes toward psychiatry can be changed through medical school education and greater exposure to psychiatry will need further investigation.

The Predictive Value of Early Changes in 18 F-Fluoroestradiol Positron Emission Tomography/Computed Tomography During Fulvestrant 500 mg Therapy in Patients with Estrogen Receptor-Positive Metastatic Breast Cancer.

BACKGROUND: The aim of this study was to investigate the predictive value of early changes in 18 F-fluoroestradiol (FES) positron emission tomography (PET)/computed tomography (CT) during fulvestrant 500 mg therapy in patients with estrogen receptor (ER)-positive metastatic breast cancer. MATERIALS AND METHODS: Patients underwent 18 F-FES PET/CT scans at both baseline (scan 1) and day 28 (scan 2). The maximum standardized uptake value (SUVmax) of all metastatic sites was determined in each scan, and the percentage reduction in SUVmax (ΔSUVmax) was calculated as [(SUVmax on scan 1-SUVmax on scan 2)/ SUVmax on scan 1] * 100%. RESULTS: In total, 294 18 F-FES-positive lesions from 36 patients were identified. The 18 F-FES SUVmax varied widely among lesions (median 5.7; range 1.8-32.4) and patients (median 5.1; range 2.5-13.2). After treatment, the median SUVmax among lesions and patients was 2.1 and 2.1, respectively. The ΔSUVmax ranged from -5.1% to 100%, with a median reduction of 61.3%. Using receiver operating characteristic analysis, the optimal cutoff point to discriminate patients who could derive clinical benefit from fulvestrant was determined to be 38.0%. Patients with a median ΔSUVmax ≥38.0% experienced significantly longer progression-free survival (PFS) than those with ΔSUVmax <38.0% (28.0 months vs. 3.5 months, p = .003). Multivariate analysis demonstrated that ΔSUVmax ≥38.0% was an independent predictor of PFS benefit in patients receiving fulvestrant therapy. CONCLUSION: Changes in SUVmax measured by serial imaging of 18 F-FES PET/CT could be used early to predict PFS benefit in patients receiving fulvestrant therapy. IMPLICATIONS FOR PRACTICE: The aim of this study was to evaluate the role of 18 F-fluoroestradiol (FES) positron emission tomography (PET)/computed tomography (CT) in predicting response to fulvestrant 500 mg therapy in patients with hormone receptor-positive/human epidermal growth receptor 2-negative metastatic breast cancer. This study highlights the utility of FES PET/CT as a predictive factor to discriminate patients who might benefit from fulvestrant. Moreover, these findings showed that this molecular imaging technique might be a potential tool for physicians to make individualized treatment strategies.

Establishment and validation of a nomogram with intratumoral heterogeneity derived from 18F-FDG PET/CT for predicting individual conditional risk of 5-year recurrence before initial treatment of nasopharyngeal carcinoma.

BACKGROUND: Intratumoral heterogeneity has an enormous effect on patient treatment and outcome. The purpose of the current study was to establish and validate a nomogram with intratumoral heterogeneity derived from 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for prognosis of 5-Year progression-free survival (PFS) of patients with nasopharyngeal carcinoma (NPC). METHODS: A total of 171 NPC patients who underwent pretreatment 18F-FDG PET/CT were retrospectively enrolled. Data was randomly divided into training cohort (n = 101) and validation cohort (n = 70). The clinicopathologic parameters and the following PET parameters were analyzed: maximum and mean standardized uptake value (SUVmax, SUVmean), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and heterogeneity index (HI, SUVmax/SUVmean) for primary tumor and maximal neck lymph node. Cox analyses were performed on PFS in the training cohort. A prognostic nomogram based on this model was developed and validated. RESULTS: For the primary tumor, MTV-2.5, TLG-2.5, MTV-70%, and TLG-70% were significantly correlated with PFS. For the maximal neck lymph node, short diameter and HI were significantly correlated with PFS. Among the clinicopathologic parameters, M stage was a significant prognostic factor for recurrence. In multivariate analysis, M stage (P = 0.006), TLG-T-70% (P = 0.002), and HI-N (P = 0.018) were independent predictors. Based on this prognostic model, a nomogram was generated. The C-index of this model was 0.74 (95% CI: 0.63-0.85). For the cross validation, the C-index for the model was 0.73 (95% CI: 0.62-0.83) with the validation cohort. Patients with a risk score of ≥111 had poorer survival outcomes than those with a risk score of 0-76 and 77-110. CONCLUSIONS: Intratumoral heterogeneity derived from 18F-FDG PET/CT could predict long-term outcome in patients with primary NPC. A combination of PET parameters and the TNM stage enables better stratification of patients into subgroups with different PFS rates.

Sentinel node theory helps tracking of primary lesions of cancers of unknown primary.

BACKGROUND: Sentinel lymph node is the first stop of lymphatic spreading of cancer with known primary. The lymph node metastasis pattern of cancer of unknown primary (CUP) is unclear and has been presumed to follow the same pathway. To test this hypothesis, data of all 716 patients clinically diagnosed as CUP in our center were collected. METHODS: Diagnoses of lymph node metastasis were established by 18F-FDG PET-CT and/or biopsy pathology. Three hundred and forty-seven cases meeting the criteria were divided into three groups: pathology-confirmed primary with invasive biopsy or surgery of the suspicious lesion (group A, n = 64), primary still unknown even with invasive biopsy or surgery of the suspicious lesion (group B, n = 204), and others with no suspicious lesion or lesions who had not been sampled due to medical or other reasons (group C, n = 79). We assessed the clinicopathological features between these groups, and the relationship between lymph node metastasis pattern and confirmed primary site. RESULTS: In group A, the primary sites of 61 cases were compatible with sentinel node theory, resulting in a positive predictive value of 95%. No significant differences in age, sex, bone metastasis, or visceral metastasis observed between group A and group B, except that group A had a higher ratio of differentiated carcinoma (94% vs. 77%, P = 0.003). CONCLUSION: To our knowledge, this is the first evidence indicating that the majority of clinical CUP cases follow the sentinel node theory to spread in lymph nodes, which helps tracking the primary, especially for differentiated carcinoma.

WITHDRAWN: Characterization of heterogeneity of hypoxia with 18FMISO PET/CT, BOLD fMRI and immunohistochemistry in human breast tumor xenograft: initial study.

Ahead of Print article withdrawn by publisher.

Associations between Personal PM2.5 Elemental Constituents and Decline of Kidney Function in Older Individuals: the China BAPE Study.

Long-term exposure to fine particulate matter (PM2.5) is associated with kidney dysfunction. However, few studies have investigated acute effects of PM2.5 elemental constituents on renal function. We evaluated associations between personal PM2.5 and its elemental constituents and kidney function, assessed by an estimated glomerular filtration rate (eGFR) in Biomarkers of Air Pollutants Exposure in the Chinese aged 60-69 study. Seventy one older individuals were visited monthly between September 2018 and January 2019. Each participant wore a PM2.5 monitor for 72 h, responded to a questionnaire, and underwent a physical examination with blood sampling. Linear mixed-effect models were used to estimate associations between personal PM2.5 elemental constituents and eGFR. We found that significant changes in eGFR from -1.69% [95% confidence interval (CI): -3.34%, -0.01%] to -3.27% (95% CI: -5.04%, -1.47%) were associated with interquartile range (IQR) increases in individual PM2.5 exposures at various lag periods (7-12, 13-24, 0-24, 25-48, and 49-72 h). An IQR increase in 72 h moving averages of copper, manganese, and titanium in personal PM2.5 corresponded to -2.34% (95% CI: -3.67%, -0.99%) to -4.56% (95% CI: -7.04%, -2.00%) changes in eGFR. Personal PM2.5 and some of its elemental constituents are inversely associated with eGFR in older individuals.

18F-FES PET/CT Influences the Staging and Management of Patients with Newly Diagnosed Estrogen Receptor-Positive Breast Cancer: A Retrospective Comparative Study with 18F-FDG PET/CT.

PURPOSE: We compared the clinical value of 16a-18F-fluoro-17b-estradiol (18F-FES) positron emission tomography (PET)/computed tomography (CT) and 18F-fluoro-2-deoxy-D-glucose (18F-FDG) PET/CT and investigated whether and how 18F-FES PET/CT affects the implemented management of newly diagnosed estrogen receptor positive breast cancer patients. MATERIALS AND METHODS: We retrospectively analyzed 19 female patients newly diagnosed with immunohistochemistry-confirmed estrogen receptor (ER)-positive breast cancer who underwent 18F-FES and 18F-FDG PET/CT within 1 week in our center. The sensitivity of 18F-FES and 18F-FDG in diagnosed lesions were compared. To investigate the definite clinical impact of 18F-FES on managing patients with newly diagnosed ER positive breast cancer, we designed two kinds of questionnaires. Referring physicians completed the first questionnaire based on the 18F-FDG report to propose the treatment regime, and the second was completed immediately after reviewing the imaging report of 18F-FES to indicate intended management changes. RESULTS: In total, 238 lesions were analyzed in 19 patients with newly diagnosed ER-positive breast cancer. Lesion detection was achieved in 216 sites with 18F-FES PET and in 197 sites with 18F-FDG PET/CT. These results corresponded to sensitivities of 90.8% for 18F-FES versus 82.8% for 18F-FDG PET/CT in diagnosed lesions. Thirty-five physicians were given the questionnaires referring to the treatment strategy, with 27 of them completing both questionnaires. The application of 18F-FES in addition to 18F-FDG PET/CT changed the management in 26.3% of the 19 patients with newly diagnosed ER-positive breast cancer. CONCLUSION: Performing 18F-FES PET/CT in newly diagnosed ER-positive breast cancer patients increases the value of diagnosis equivocal lesions and treatment management compared with 18F-FDG PET/CT. IMPLICATIONS FOR PRACTICE: This study investigated whether 16a-18F-fluoro-17b-estradiol (18F-FES) positron emission tomography (PET)/computed tomography (CT) affects the clinical management of patients with newly diagnosed estrogen receptor (ER)-positive breast cancer. Physicians completing two questionnaires comparing the clinical impact of 18F-FES and 18F-FDG on individual management plans in patients with newly diagnosed ER-positive breast cancer confirmed that 18F-FES scans led to change in management in 26.3% of the 19 patients with newly diagnosed ER positive breast cancer. This retrospective study indicates the potential impact of 18F-FES PET/CT on intended management of patients with newly diagnosed estrogen receptor positive breast cancer in comparison to 18F-fluoro-2-deoxy-D-glucose PET/CT.

The Value of 99mTc-PSMA SPECT/CT-Guided Surgery for Identifying and Locating Lymph Node Metastasis in Prostate Cancer Patients.

BACKGROUND: This study evaluated the effect of technetium-99m (99mTc)-labeled prostate-specific membrane antigen (PSMA)-based image-guided surgery on the oncologic outcomes for patients with primary or recurrent prostate cancer (PCa). METHODS: This study retrospectively analyzed 54 consecutive patients with PCa who underwent 99mTc-labeled PSMA-based image-guided surgery between January 2016 and September 2017. These patients received a radical prostatectomy (RP) with pelvic lymph node dissection (PLND) or salvage lymph node dissection (sLND). The resected specimens were compared with findings of postoperative histologic analysis. The responses to the treatment were recorded during the follow-up period. RESULTS: In 31 patients, PSMA single-photon emission computerized tomography (SPECT) and computed tomography (CT) could find 52 suspicious lymph node metastases (LNMs). With the help of PSMA SPECT/CT, 12 patients with recurrence received sLND, 19 primary PCa patients received RP with extended PLND, and 23 primary PCa patients received RP with standard PLND. The findings showed that PSMA SPECT/CT could detect LNMs with high sensitivity and specificity. In six patients, PSMA SPECT/CT could find more LNMs that were not found by MRI and help to modify the extent of lymphadenectomy. At the latest follow-up evaluation, 39 patients showed a biochemical response (BR), 9 patients showed a biochemical recurrence (BCR) after BR, and 6 patients never exhibited BR. The patients who received RP with standard PLND or extended PLND had a better prostate-specific antigen (PSA) response than the patients who received sLND. The patients with pelvic LNMs also had a better PSA response than the patients with retroperitoneal LNMs. CONCLUSIONS: This study showed that 99mTc-PSMA SPECT/CT-guided surgery can remove more LNMs than conventional imaging with high sensitivity and specificity and delay disease progression in PCa patients.

Relationship between PSA kinetics and Tc-99m HYNIC PSMA SPECT/CT detection rates of biochemical recurrence in patients with prostate cancer after radical prostatectomy.

BACKGROUND: Prostate-specific antigen (PSA) levels should reflect or be proportional to the size and the metabolic activity of prostatic metastases. Moreover, a rapid change in PSA kinetics, either before or after treatment, is an indicator of poor prognosis after radical prostatectomy. Therefore, the purpose of this study was to investigate the effect of total PSA at the time of Tc-99m HYNIC PSMA SPECT/CT (trigger PSA), PSA velocity (PSAvel), and PSA doubling time (PSAdt) on the Tc-99m HYNIC PSMA SPECT/CT detection rate in prostate cancer patients who showed biochemical recurrence after radical prostatectomy during follow-up. METHODS: In total, 208 patients who showed an increase in PSA were evaluable for this retrospective analysis covering November 2015 to March 2017. Data were available for calculation of PSAvel in 112 patients and for PSAdt in 157 patients. Logistic regression analysis was used to determine whether there was a relationship between the PSA levels and PSA kinetics and the rate of detection of relapse using Tc-99m HYNIC PSMA SPECT/CT. RESULTS: Tc-99m HYNIC PSMA SPECT/CT detected disease relapse in 151 of 208 patients (72.6%). The PSA level (P < 0.0001) and PSAdt (P = 0.0036) were significantly different between SPECT-positive patients (higher PSA level, shorter PSAdt) and SPECT-negative patients (lower PSA, longer PSAdt). ROC analysis showed that a PSA level of 1.30 ng/mL and a PSAdt of 2.9 months were optimal cut-off values. Patients with purely local recurrence had lower PSAvel and longer PSAdt values (P < 0.001). According to the multivariate analysis, a pathological positive SPECT/CT scan was associated with the PSA level (P < 0.001), PSAdt <6 months (P < 0.05), and Gleason scores (GSC) >7 (P < 0.05). CONCLUSION: The Tc-99m HYNIC PSMA SPECT/CT detection rate is influenced by trigger PSA, PSAdt, and PSAvel. Like PSA, PSAdt is an independent predictor of Tc-99m HYNIC PSMA SPECT/CT. PSAdt should be taken into account by physicians especially when PSA <1 ng/mL.

Pretreatment 18F-FDG Uptake Heterogeneity Predicts Treatment Outcome of First-Line Chemotherapy in Patients with Metastatic Triple-Negative Breast Cancer.

BACKGROUND: Intratumoral heterogeneity of 18F-fluorodeoxyglucose (18F-FDG) uptake in primary tumor has proven to be a surrogate marker for predicting treatment outcome in various tumors. However, the value of intraindividual heterogeneity in metastatic diseases remains unknown. The aim of this study was to evaluate pretreatment positron emission tomography/computed tomography (PET/CT) 18F-FDG-based heterogeneity for the prediction of first-line treatment outcome in metastatic triple-negative breast cancer (mTNBC). MATERIALS AND METHODS: mTNBC patients from three clinical trials (NCT00601159, NCT01287624, and NCT02341911) with whole-body 18F-FDG PET/CT scan before first-line gemcitabine/platinum were included. Heterogeneity index (HI) and the maximum of FDG uptake (MAX) across total metastatic lesions (-T) on baseline PET/CT scans were assessed. HI was measured by MAX divided by the minimum FDG uptake across metastatic lesions. Optimal cutoffs were determined by time-dependent receiver operator characteristics (ROC) analysis. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method and compared by log-rank test. RESULTS: A total of 42 mTNBC patients were included in this study. The median PFS of patients with high HI-T (>1.9) and high MAX-T (>10.5) was significantly shorter than patients with low HI-T (<1.9; p = .049) and low MAX-T (<10.5; p = .001). In terms of OS, only high MAX-T was significant for poorer outcome (p = .013). ROC curve analysis confirmed the predictive value of MAX and HI in mTNBC patients. Area under the ROC curve for MAX-T and HI-T was 0.75 and 0.65, indicating a higher predictive accuracy than conventional clinical risk factors. CONCLUSION: HI and MAX measured among metastatic lesions on pretreatment 18F-FDG PET/CT scans could be potential predicators for first-line treatment outcome in patients with mTNBC. IMPLICATIONS FOR PRACTICE: Intratumoral heterogeneity of 18F-fluorodeoxyglucose (FDG) uptake in primary tumor has proven to be a robust surrogate predictive marker. A novel positron emission tomography/computed tomography (PET/CT) parameter-heterogeneity index (HI) to quantify the heterogeneous characteristics of metastatic disease is proposed. Triple-negative breast cancer (TNBC) is a highly heterogeneous disease and remains a clinical challenge. The predictive performance of HI, along with the maximum FDG uptake (MAX), measured on pretreatment PET/CT scans in patients with metastatic TNBC was evaluated. Results indicate that HI and MAX may serve as applicable imaging predicators for treatment outcome of metastatic TNBC in clinical practice.

Glutaryl Polyamidoamine Dendrimer for Overcoming Cisplatin-Resistance of Breast Cancer Cells.

OBJECTIVE: Cisplatin has limited clinical applications due to drug resistance. PAMAM dendrimer was chosen as a vehicle to counteract cisplatin-resistance and its mechanism was assessed. METHODS: Generation 5 Polyamidoamine dendrimer (G5) was modified by glutaric anhydride (GA) and then conjugated with cisplatin. The cisplatin release of G5-GA-cisplatin was evaluated at pH 5.5 and pH 7.4. The cytotoxicity of G5-GA-cisplatin and free cisplatin was compared in cisplatin-resistant breast cancer cell line MCF-7R. The intracellular platinum content of MCF-7R was determined using ICP-MS. The expression of Ctr1 and ATP7B of MCF-7R cells was also evaluated. RESULTS: An average of 75 amino groups present in the G5 PAMAM surface were converted into glutaric acid (G5-GA75) and platinum loading was 350±21 µg per 1 mg of G5-GA75. G5-Ac75-cisplatin complex exhibited controlled release of cisplatin at different pH over a period of 96 h. After 96 h incubation with G5-Ac75-cisplatin, cell viability was 27.47±2.53%, 12.18±0.65% and 11.62±0.84% using platinum concentration of 1 µg/ml, 3 µg/ml and 5 µg/ml, respectively. Meanwhile, 46.33±5.06% cells survived even in the high platinum concentration of 5 µg/ml after 96 h incubation with free cisplatin. G5-GA75 led to 3-6 times higher cisplatin accumulation than free cisplatin in MCF-7R cells, because MCF-7R cells exhibited lower Ctr1 expression and higher ATP7B expression than MCF-7 cells. CONCLUSION: The G5-GA75-cisplatin complex displayed greater anticancer activity than free cisplatin in the cisplatin-resistant breast cancer cell line MCF-7R. The low levels of Ctr1 and high levels of ATP7B in MCF-7R caused G5-GA75 to allow the accumulation of cisplatin, which in turn increased the cytotoxicity. Results indicated that glutaryl G5 PAMAM may be a potential carrier for cisplatin targeting in breast cancer.

Monitoring Apoptosis of Breast Cancer Xenograft After Paclitaxel Treatment With 99mTc-Labeled Duramycin SPECT/CT.

Our goal was to validate the feasibility of(99m)Tc-duramycin as a potential apoptosis probe for monitoring tumor response to paclitaxel in breast cancer xenografts. The binding of(99m)Tc-duramycin to phosphatidylethanolamine was validated in vitro using paclitaxel-treated human breast carcinoma MDA-MB-231 cells. Female BALB/c mice (n = 5) bearing breast cancer xenografts were randomized into 2 groups and intraperitoneally injected with 40 mg/kg paclitaxel or phosphate-buffered saline.(99m)Tc-duramycin (37-55.5 MBq) was injected at 72 hours posttreatment, and single-photon emission computed tomography/computed tomography was performed at 2 hours postinjection. Apoptotic cells and activated caspase 3 in explanted tumor tissue were measured by flow cytometry. Cellular ultrastructural changes were assessed by light and transmission electron microscopy.(99m)Tc-duramycin with radiochemical purity of >90% exhibited rapid blood clearance and predominantly renal clearance. The tumor-to-muscle ratio in the paclitaxel-treated group (5.29 ± 0.62) was significantly higher than that in the control. Tumor volume was decreased dramatically, whereas tumor uptake of(99m)Tc-duramycin (ex vivo) significantly increased following paclitaxel treatment, which was consistent with apoptotic index, histological findings, and ultrastructural changes. Our data demonstrated the feasibility of(99m)Tc-duramycin for early detection of apoptosis after paclitaxel chemotherapy in breast carcinoma xenografts.

Pim-3 contributes to radioresistance through regulation of the cell cycle and DNA damage repair in pancreatic cancer cells.

Resistance of cancer cells to chemoradiotherapy is a major clinical problem in pancreatic cancer treatment. Therefore, understanding the molecular basis of cellular resistance and identifying novel targets are essential for improving treatment efficacy for pancreatic cancer patients. Previous studies have demonstrated a significant role for Pim-3 in pancreatic cancer survival against gemcitabine-induced genotoxic stress. Here, we observed that radiation treatment enhanced Pim-3 expression in human pancreatic cancer cells in vitro. Stable overexpression of Pim-3 in pancreatic cancer cells significantly protected cells against radiation treatment by attenuating G2/M phase cell cycle arrest and DNA damage response. Silencing of Pim-3 expression significantly elevated the phosphorylation of histone variant H2AX, a marker of DNA double strand breaks, and decreased the activation of ataxia-telangiectasia-mutated (ATM) kinase, along with its downstream targets, eventually enhancing the radiosensitivity of human pancreatic cancer cells in vitro and in vivo. Hence, we demonstrated a novel function for Pim-3 in human pancreatic cancer cell survival against radiation. Targeting Pim-3 may be a promising way to improve treatment efficacy in combination with radiotherapy in human pancreatic cancer.