Immunotherapy and targeted therapy as first-line treatment for advanced gastric cancer.

For patients diagnosed with advanced gastric or gastroesophageal cancer (AGC) that is not amenable to surgical intervention, the standard of care for first-line treatment consists of fluoropyrimidine and platinum-based chemotherapy. The incorporation of novel agents into these standard first-line regimens could potentially improve patient prognosis; options for such augmentations include both immune-based and targeted therapy combinations. To provide a comparative analysis of these different first-line combination treatments, a network meta-analysis was conducted. Outcome measures comprised overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and grade 3-4 treatment-related adverse events (TRAEs). Data were drawn from 22 randomized controlled trials, encompassing 10,787 patients and 17 distinct treatment regimens. Our findings suggest that FGFR2b-targeted therapy, specifically when used in combination with chemotherapy (bemarituzumab_chemo), exhibited the greatest efficacy. This was followed by immunotherapy-based combination regimens (CPS ≥5, Sintilimab_chemo). Further, targeted combination therapy featuring CLAUDIN 18.2 (zolbetuximab_chemo) appeared beneficial based on individual patient characteristics. In the case of HER2-positive patients, the trastuzumab_chemo regimen is recommended, as most existing studies have excluded this subpopulation. These results have significant implications for both clinical decision-making and patient care in the realm of advanced gastric or gastroesophageal cancer treatment.

Oral bacterial composition associated with lung function and lung inflammation in a community-based Norwegian population.

BACKGROUND: The oral cavity is the gateway to the bacteria community in the lung. Disruption of the symbiotic balance of the oral microbiota has been associated with respiratory diseases. However, little is known about the relationship between oral bacteria and respiratory outcomes in the general population. We aimed to describe the associations between oral bacteria, lung function, and lung inflammation in a community-based population. METHODS: Oral (gingival) samples were collected concurrently with spirometry tests in 477 adults (47% males, median age 28 years) from the RHINESSA study in Bergen, Norway. Bacterial DNA from the 16S rRNA gene from gingival fluid were sequenced by Illumina®MiSeq. Lung function was measured using spirometry and measurement of fractional exhaled nitric oxide (FeNO) were performed to examine airway inflammation. Differential abundance analysis was performed using ANCOM-BC, adjusting for weight, education, and smoking. RESULTS: The abundance of the genera Clostridiales, Achromobacter, Moraxella, Flavitalea and Helicobacter were significantly different among those with low FEV1 (< lower limit of normal (LLN)) as compared to normal FEV1 i.e. ≥ LLN. Twenty-three genera differed in abundance between among those with low FVC < LLN as compared to normal FEV1 ≥ LLN. The abundance of 27 genera from phyla Actinobacteria, Bacteroidetes, Firmicutes, Proteobacteria and Sacchribacteria differed significantly between elevated FeNO levels (≥ 50 ppb) compared to FeNO ≤ 25 ppb. CONCLUSION: Oral bacterial composition was significantly different for those with low FEV or FVC as compared to those with normal lung function equal to or higher than LLN. Differential bacterial composition was also observed for elevated FeNO levels.

Pan-cancer analysis of Homeobox B9 as a predictor for prognosis and immunotherapy in human tumors.

BACKGROUND: Although several animal and cell studies have described the association between HOXB9 and cancers, there is no pan-cancer investigation of HOXB9. In this article, we explored the expression levels and prognosis of HOXB9 in pan-cancer. We evaluated the correlation of HOXB9 expression level with the efficacy of immunotherapy. METHODS: We conducted a survival analysis of HOXB9 in various types of cancer using publicly available databases. We also examined the relationship between HOXB9 expression levels and several factors including prognosis, immune infiltration, immune checkpoint genes, tumor mutational burden, microsatellite instability, mismatch repair, and DNA methylation. TIMER2.0 tool was conducted to explore the immune cell infiltrations related to HOXB9 in this analysis. RESULTS: It was discovered through a comprehensive analysis of multiple public datasets that HOXB9 expression was highly expressed in most tumor tissues and cancer cell lines and that distinct associations exist between HOXB9 expression and tumor patient prognosis. Besides, HOXB9 expression was closely associated with immune cell infiltration and checkpoint genes in many cancers. Further, HOXB9 was associated with immune cell infiltration, TMB, MSI, MMR, and DNA methylation. It was also confirmed that HOXB9 was highly expressed in clinical GBM tissues. Experiments further revealed that knockdown of HOXB9 expression could suppress proliferation, migration, and invasion of glioma cells. CONCLUSIONS: The results revealed that HOXB9, a robust tumor biomarker, has a significant prognostic value. HOXB9 may act as a new predictor to assess cancer prognosis and therapeutic efficacy of the immune in various cancers.

Impacts of bariatric surgery on adverse liver outcomes: a systematic review and meta-analysis.

BACKGROUND: Bariatric surgery has been reported to improve degeneration, inflammation, and fibrosis in nonalcoholic fatty liver disease, but the effects of bariatric surgery on the associated clinical outcomes is not known. OBJECTIVES: This work aimed to assess the impacts of bariatric surgery on adverse liver outcomes in people with obesity. SETTING: An electronic search was performed on EMBASE, PubMed, and Cochrane Central Register of Controlled Trials (CENTRAL). METHODS: The primary outcome was the incidence of adverse liver outcomes following bariatric surgery. Liver cancer, cirrhosis, liver transplantation, liver failure, and liver-related mortality were defined as adverse hepatic outcomes. RESULTS: We analyzed data from 18 studies comprising 16,800,287 post bariatric surgical patients and 10,595,752 control patients. We found that bariatric surgery reduced the risk of adverse liver outcomes in people with obesity (hazard ratio [HR] = .33, 95% confidence interval [CI] = .31-.34; I2 = 98.1%). The subgroup analysis showed that bariatric surgery reduced the risk of nonalcoholic cirrhosis (HR = .07, 95% CI = .06-.08; I2 = 99.3%) and liver cancer (HR = .37, 95% CI = .35-.39; I2 = 97.8%), although bariatric surgery may also increase the risk of postoperative alcoholic cirrhosis (HR = 1.32, 95% CI = 1.35-1.59). CONCLUSIONS: This systematic review and meta-analysis revealed that bariatric surgery lowered the incidence of adverse hepatic outcomes. However, bariatric surgery may also increase the risk of alcoholic cirrhosis after surgery. Future randomized controlled trials are required to further investigate the effects of bariatric surgery on liver of people with obesity.

Extracellular vesicles from hypoxia-pretreated adipose-derived stem cells regulate hypoxia/reoxygenation-induced human dermal microvascular endothelial apoptosis and autophagy in vitro.

Recent studies suggest hypoxia can promote adipose-derived stem cells (ADSCs) to attenuate hypoxia/reoxygenation (H/R)-induced damage to human dermal microvascular endothelial cells (HDMECs). Extracellular vesicles (EVs), isolated from ADSCs, play an-important role in the fields of regenerative medicine. Here, we aimed to investigate the effect of EVs isolated from hypoxia-pretreated ADSCs (ADSC-EVs[H]) on HDMECs to attenuate ischemia/reperfusion injury of free skin flaps. First, we characterized EVs isolated from normoxia-cultured ADSCs (ADSC-EVs[N]) and ADSC-EVs(H). Experimental data indicated that EVs isolated from ADSCs consisted of lipid-bilayer vesicles that exhibited positive expression of vascular endothelial growth factor (VEGF) and marker proteins CD9, CD63 and CD81, and the mean particle size of EVs in the hypoxia-pretreated ADSCs (ADSC[H]) group was smaller (74.17 nm) than in the normoxic-cultured ADSCs (ADSC[N]) group (93.87 nm). Hypoxic pretreatment increased the number of EVs. Later, we favorably constructed the co-culture model of EVs isolated from ADSCs (ADSC-EVs) and H/R-induced HDMECs. Cell counting kit-8, Ethynyldeoxyuridine assay, western blotting and immunofluorescence staining showed that ADSC-EVs(H) promoted the survival of HDMECs and increased LC3 level. Apoptosis, reactive oxygen species (ROS) and JC-1 mitochondrial membrane potential (MMP) assays revealed that ADSC-EVs(H) reduced the apoptosis rate and ROS accumulation and increased MMP level in HDMECs, indicating that ADSC-EVs(H) effectively attenuated H/R-induced damage in HDMECs through autophagy activation and the-inhibition of apoptosis and oxidative stress. This study confirmed that ADSC-EVs(H) could effectively regulate the proliferation, apoptosis, oxidative stress, and autophagy expression of H/R-induced HDMECs in vitro, and therefore the transplantation of ADSC-EVs(H) may provide novel insights for the transplantation of free skin flaps.

IDO-1 inhibitor INCB24360 elicits distant metastasis of basal extruded cancer cells in pancreatic ductal adenocarcinoma.

Neoplastic cells of non-immunogenic pancreatic ductal adenocarcinoma (PDAC) express indoleamine 2,3-dioxygenase 1 (IDO-1), an immunosuppressive enzyme. The metabolites of IDO-1 in cancers provide one-carbon units that annihilate effector T cells, and recruit immunosuppressive cells. In this study we investigated how IDO-1 affected the neoplastic cell behaviors in PDACs. Using multiple markers co-labeling method in 45-µm-thick tissue sections, we showed that IDO-1 expression was uniquely increased in the neoplastic cells extruded from ducts' apical or basal domain, but decreased in lymph metastatic cells. IDO-1+ extruding neoplastic cells displayed increased vimentin expression and decreased cytokeratin expression in PDACs, characteristics of epithelial-mesenchymal transition (EMT). However, IDO-1 expression was uncorrelated with immunosuppressive infiltrates and clinicopathological characteristics of grim outcome. We replicated basal extrusion with EMT in murine KPIC PDAC organoids by long-term IFN-γ induction; application of IDO-1 inhibitor INCB24360 or 1-MT partially reversed basal extrusion coupled EMT. Ido-1 deletion in KPIC cells deprived its tumorigenicity in immunocompetent mice, decreased cellular proliferation and macropinocytic ability, and increased immunogenicity. KPIC organoids with IFN-γ-induced basal extrusion did not accelerate distant metastasis, whereas inhibition IFN-γ-induced IDO-1 with INB24360 but not 1-MT in KPIC organoids elicited liver metastasis of subcutaneous KPIC organoid tumors, suggesting that lower IDO-1 activity accelerated distant metastasis, whereas IDO-1 was indispensable for tumorigenicity of PDAC cells and supports the survival of extruding cells.

The clinical diagnostic value of plasma miR-592 and miR-217-3p levels in retinoblastoma.

Background: This study was designed to investigate the abnormal expression of plasma miR-592 and miR-217-3p in retinoblastoma (Rb) and explore the clinical diagnostic value of their expression levels for Rb. Methods: The 100 Rb patients who came to Nanchang Hongdu Hospital of Traditional Chinese Medicine from January 2018 to January 2019 were selected as the Rb group, and 100 healthy patients who came to the physical examination centre during the same period were selected as the control group. Real-time fluorescence quantitative PCR (qRT-PCR) was used to detect the expression levels of plasma miR-592 and miR-217-3p in all subjects; analyse the relationship between plasma miR-592 and miR-217-3p levels and the clinicopathological characteristics of Rb. Pearson correlation analysis evaluated the relationship between plasma miR-592 and miR-217-3p levels and overall survival. Results: Plasma levels of miR-592 and miR-217-3p in the Rb group were significantly higher than those in the control group (p<0.0001), and the expression of miR-592 was significantly correlated with family genetic history (p 0.0001), tumour bias (p=0.0081), lymph node metastasis (p=0.0048) and pathological grade (p=0.0025), and the expression of miR-217-3p was significantly related to family genetic history (p 0.0001), optic nerve infiltration (p 0.0001), lymph node metastasis (p=0.0090), and pathological grade (p 0.0001). The high expression of miR-592 and miR-217-3p presents a more serious pathological manifestation of Rb, and the overall survival of patients is significantly shortened with the increase of miR-592 (r=-0.2276, p=0.0052) and miR-217-3p levels (r=-0.6461, p 0.0001). Conclusions: and miR-217-3p are highly expressed in the plasma of Rb patients, and their elevated levels present severe pathological manifestations of Rb and shortened overall survival, which is expected to become biomarkers for clinical diagnosis of Rb.

Impact of occupational exposure on job satisfaction and overall happiness among Chinese physicians and nurses: A cross-sectional study.

AIMS: This study aims to investigate the impact of occupational exposure on job satisfaction and overall happiness and to identify related factors of job satisfaction and overall happiness among physicians and nurses. BACKGROUND: Occupational exposure against physicians and nurses has become one of the most serious public health issues worldwide. METHODS: A cross-sectional study was conducted among physicians and nurses from 14 public tertiary hospitals using purposive sampling. Propensity score matching was used to compare job satisfaction and overall happiness among physicians and nurses with and without occupational exposure. Furthermore, binary logistic regression analysis was used to identify and analyse the influencing factors of job satisfaction and overall happiness. RESULTS: A total of 2139 physicians and nurses (55.59%) from 3791 participants had experienced occupational exposure hazards. Before matching, the job satisfaction and overall happiness among the physicians and nurses were 38.54% and 42.14%, respectively. Participants who experienced occupational exposure were more likely to develop job dissatisfaction (OR = 1.08, 95% confidence interval [CI]: 0.90-1.28) and overall unhappiness (OR = 1.24, 95% CI: 1.05-1.46) than those who did not. Participants' work experience, self-evaluated health status, satisfaction with the work environment, evaluation of doctor-patient relationship and stress were common factors affecting job satisfaction and overall happiness. CONCLUSIONS: Our findings suggest that physicians and nurses who experience occupational exposure are more likely to develop job dissatisfaction and overall unhappiness, especially if they have shorter work experience and a tense or neutral relationship with patients. IMPLICATIONS FOR NURSING MANAGEMENT: It is necessary to pay attention to the occupational exposure. When physicians and nurses experience occupational exposure, managers could provide support to prevent job dissatisfaction and unhappiness.

Bacteremia detection from complete blood count and differential leukocyte count with machine learning: complementary and competitive with C-reactive protein and procalcitonin tests.

BACKGROUND: Biomarkers, such as leukocyte count, C-reactive protein (CRP), and procalcitonin (PCT), have been commonly used to predict the occurrence of life-threatening bacteremia and provide prognostic information, given the need for prompt intervention. However, such diagnosis methods require much time and money. Therefore, we propose a method with a high prediction capability using machine learning (ML) models based on complete blood count (CBC) and differential leukocyte count (DC) and compare its performance with traditional CRP or PCT biomarker methods and those of models incorporating CRP or PCT biomarkers. METHODS: We collected 366,586 daily blood culture (BC) results, of which 350,775 (93.2%), 308,803 (82.1%), and 23,912 (6.4%) cases were issued CBC/DC (CBC/DC group), CRP with CBC/DC (CRP&CBC/DC group), and PCT with CBC/DC (PCT&CBC/DC group), respectively. For the ML methods, conventional logistic regression and random forest models were selected, trained, applied, and validated for each group. Fivefold validation and prediction capability were also evaluated and reported. RESULTS: Overall, the ML methods, such as the random forest model, demonstrated promising performances. When trained with CBC/DC data, it achieved an area under the ROC curve (AUC) of 0.802, which is superior to the prediction conventionally made with CRP/PCT levels (0.699/0.731). Upon evaluating the performance enhanced by incorporating CRP or PCT biomarkers, it reported no substantial AUC increase with the addition of either CRP or PCT to CBC/DC data, which suggests the predicting power and applicability of using only CBC/DC data. Moreover, it showed competitive prognostic capability compared to the PCT test with similar all-cause in-hospital mortality (45.10% vs. 47.40%) and overall median survival time (27 vs. 25 days). CONCLUSIONS: The ML models using only CBC/DC data yielded more accurate bacteremia predictions compared to those by methods using CRP and PCT data and reached similar prognostic performance as by PCT data. Thus, such models are potentially complementary and competitive with traditional CRP and PCT biomarkers for conducting and guiding antibiotic usage.

Insufficient pain control for patients with cancer and dementia during terminal cancer stages.

PURPOSE: To estimate differences in pain control between patients with cancer and with or without dementia during terminal cancer stages 3 months or 1 month before cancer death. PATIENTS AND METHODS: We conducted frequency matching cohort for age, sex, and year of death for both groups at a 1:4 ratio. The prescription prevalence, total cumulative dose, and average daily dose of opioids during the terminal cancer stages 3 months and 1 month before cancer death were estimated. RESULTS: Patients with cancer and dementia were prescribed lower amounts of opioids 3 months before death (57.5% vs. 73.9%, respectively; adjusted odds ratio [OR] 0.46; 95% confidence interval [CI] 0.44-0.49) and 1 month before death (54.4% vs. 70.3%, respectively; adjusted OR 0.50; 95% CI 0.47-0.53). The total cumulative dose of opioids (mg) was lower in patients with cancer and dementia 3 and 1 month(s) before death (3 months: 1,578 mg vs. 2,666 mg, respectively; ß=-1,125.9, P<0.001; 1 month: 921 mg vs. 1,533 mg, respectively; ß=-622.1, P<0.001). The average daily opioid dose (mg/day), patients with cancer and dementia received a lower dose 3 months before death (31 mg vs. 48 mg; ß=-22.6, P<0.001) and 1 month before death (38 mg vs. 60 mg; ß=-17.1, P<0.001). CONCLUSION: The prevalence of opioid prescription was significantly lower in patients with both cancer and dementia during their terminal cancer stages 3 months and 1 month before death.

Palliative inter-professional learning via cased based tele-videoconference: Experience from the hospice development stage in Taiwan and China.

ABSTRACT: Palliative care in rural areas can be difficult to assess and, often is of lower quality compared to more densely populated regions. A program of multicenter palliative care discussion forum via tele-videoconference may be a promising tool for exchanging valuable experience and constructing a comprehensive hospice care system in Taiwan and China.The multicenter palliative care discussion forum began 1997 and 2010 in Taiwan and China, respectively. In every forum, 1 to 2 cases were presented by multiple field specialists, and multi-dimensional problems were discussed. All of these case reports and reference materials from the forums were analyzed.The conference discussed 199 and 143 cases in Taiwan and China, including 172 and 143 cancer patients. The most common mentioned symptom was pain (66.3% in Taiwan, 96.95% in China). As time went on, the rate of discussion in pain management issues decreased, but the social and psycho-spiritual issues increased in Taiwan. After some major legal and social changes, the discussion of ethical issues increased rapidly. In China, the trends and ranking in discussion of nonpain management issues stabilized and showed most frequently in psycho-spiritual issues, followed by social, ethical and legal issues.Sharing palliative experience via tele-videoconferences is an effective tool to improve the quality of care, and also saves a significant amount of time and expense. Experts in different professions from different hospitals should discuss any palliative problems, share their valuable experience, and ponder a comprehensive hospice care.

Phase 1 study of safety, pharmacokinetics, and pharmacodynamics of tivantinib in combination with bevacizumab in adult patients with advanced solid tumors.

PURPOSE: We investigated the combination of tivantinib, a c-MET tyrosine kinase inhibitor (TKI), and bevacizumab, an anti-VEGF-A antibody. METHODS: Patients with advanced solid tumors received bevacizumab (10 mg/kg intravenously every 2 weeks) and escalating doses of tivantinib (120-360 mg orally twice daily). In addition to safety and preliminary efficacy, we evaluated pharmacokinetics of tivantinib and its metabolites, as well as pharmacodynamic biomarkers in peripheral blood and skin. RESULTS: Eleven patients received the combination treatment, which was generally well tolerated. The main dose-limiting toxicity was grade 3 hypertension, which was observed in four patients. Other toxicities included lymphopenia and electrolyte disturbances. No exposure-toxicity relationship was observed for tivantinib or metabolites. No clinical responses were observed. Mean levels of the serum cytokine bFGF increased (p = 0.008) after the bevacizumab-only lead-in and decreased back to baseline (p = 0.047) after addition of tivantinib. Tivantinib reduced levels of both phospho-MET (7/11 patients) and tubulin (4/11 patients) in skin. CONCLUSIONS: The combination of tivantinib and bevacizumab produced toxicities that were largely consistent with the safety profiles of the individual drugs. The study was terminated prior to establishment of the recommended phase II dose (RP2D) due to concerns regarding the mechanism of tivantinib, as well as lack of clinical efficacy seen in this and other studies. Tivantinib reversed the upregulation of bFGF caused by bevacizumab, which has been considered a potential mechanism of resistance to therapies targeting the VEGF pathway. The findings from this study suggest that the mechanism of action of tivantinib in humans may involve inhibition of both c-MET and tubulin expression. TRIAL REGISTRATION: NCT01749384 (First posted 12/13/2012).

Hypoxia Promotes Adipose-Derived Stem Cells to Protect Human Dermal Microvascular Endothelial Cells Against Hypoxia/Reoxygenation Injury.

BACKGROUND: Microcirculation is important for regulating ischemia-reperfusion (I/R) injury associated with skin flap transplantation surgery. We investigated whether co-culture with adipose-derived stem cells (ADSCs) could protect human dermal microvascular endothelial cells (HDMECs) from I/R injury by inhibiting cell apoptosis and enhancing cell proliferation. We also investigated the effects of hypoxic preconditioning on ADSCs. MATERIALS AND METHODS: HDMECs were divided into four groups, control, HDMECs in normoxic culture conditions; hypoxia/reoxygenation (H/R), HDMECs in a hypoxic incubator for 8 h then in saturated aerobic culture medium for 24 h; H/R + ADSC(N), HDMECs treated similar to the H/R group then co-cultured with normoxic ADSCs; and H/R + ADSC(H), HDMECs treated similar to the H/R group then co-cultured with hypoxia preconditioned ADSCs. RESULTS: The rate of HDMECs apoptosis significantly increased in the H/R group, but decreased upon co-culture with ADSCs for 24 h, especially in the H/R + ADSC(H) group. Co-culture with ADSCs, especially hypoxia preconditioned ADSCs, significantly enhanced cell proliferation ability compared with that of the H/R group after 48 h and 72 h, but not after 24 h. Vascular endothelial growth factor levels were significantly higher in the H/R + ADSC(N) and H/R + ADSC(H) groups than in the H/R group. CONCLUSIONS: ADSCs attenuated H/R injury in endothelial cells by promoting proliferation ability and reducing apoptosis, with an increase in Vascular endothelial growth factor level, especially in the context of hypoxic preconditioning. This approach suggests the potential for an easy and safe method to reduce I/R injury associated with skin flap transplantation surgery.

Epidemiological characteristics and forecasting incidence for patients with breast cancer in Shantou, Southern China: 2006-2017.

This study aimed to explore the epidemiological characteristics of breast cancer and establish an Exponential Smoothing (ETS) and Autoregressive Integrated Moving Average (ARIMA) models to predict the development of incidence in Shantou. This study has a large sample size, strong representativeness, and wide-ranging and comprehensive medical insurance information, which can fill the gaps in basic epidemiological research on breast cancer in Shantou. Successful completion of this study is a helpful tool to understand the epidemiology of Guangdong Province and Southern China. This study also provides data and scientific references for the government and future research on breast cancer prevention and control. This retrospective study was conducted to describe the epidemic intensity, epidemic distribution, and epidemic trend of breast cancer in Shantou, Guangdong Province, from 2006 to 2017, gathered from the Shantou's Medical Security Bureau covers the whole districts of Shantou. ETS and ARIMA models were used to describe the regional distribution, time distribution, and population distribution of breast cancer in Shantou. Moreover, based on the ARIMA model and ETS model, the incidence trend of breast cancer was predicted during 2018-2022. This study included 5,681 breast cancer patients, majority of whom were aged 50-59 years. The male-to-female ratio of the breast cancer patients was about 1:107 (the same ratio of the insured population was 1:1). Female patients accounted for 98.61% of the total insured population. The incidence and mortality rates of female breast cancer were 16.42/100,000 and 0.66/100,000, respectively. Based on the ARIMA model or ARIMA and ETS model, a gradually decreasing trend in the incidence of breast cancer is expected in the future. Comparing the performances of the ARIMA model and ETS model, ARIMA (4, 0, 1) (0, 1, 0) model had a lower the root mean squared error and the mean absolute percentage error than ETS (M, N) model. This population-based retrospective study showed that the high-risk age for the age-specific incidence of female breast cancer was 50-55 years. It is recommended that healthcare administration should strengthen program awareness and education regarding breast cancer prevention and control. It is also possible that feasibility of extrapolating the current methodology to other future studies or broader populations in which the cancer registry data are not available.

Neoadjuvant Pembrolizumab and High-Dose IFNα-2b in Resectable Regionally Advanced Melanoma.

PURPOSE: Neoadjuvant immunotherapy may improve the clinical outcome of regionally advanced operable melanoma and allows for rapid clinical and pathologic assessment of response. We examined neoadjuvant pembrolizumab and high-dose IFNα-2b (HDI) therapy in patients with resectable advanced melanoma. PATIENTS AND METHODS: Patients with resectable stage III/IV melanoma were treated with concurrent pembrolizumab 200 mg i.v. every 3 weeks and HDI 20 MU/m2/day i.v., 5 days per week for 4 weeks, then 10 MU/m2/day subcutaneously 3 days per week for 2 weeks. Definitive surgery followed, as did adjuvant combination immunotherapy, completing a year of treatment. Primary endpoint was safety of the combination. Secondary endpoints included overall response rate (ORR), pathologic complete response (pCR), recurrence-free survival (RFS), and overall survival (OS). Blood samples for correlative studies were collected throughout. Tumor tissue was assessed by IHC and flow cytometry at baseline and at surgery. RESULTS: A total of 31 patients were enrolled, and 30 were evaluable. At data cutoff (October 2, 2019), median follow-up for OS was 37.87 months (range, 33.2-43.47). Median OS and RFS were not reached. Radiographic ORR was 73.3% [95% confidence interval (CI): 55.5-85.8], with a 43% (95% CI: 27.3-60.1) pCR rate. None of the patients with a pCR have had a recurrence. HDI and pembrolizumab were discontinued in 73% and 43% of patients, respectively. Correlative analyses suggested that intratumoral PD-1/PD-L1 interaction and HLA-DR expression are associated with pCR (P = 0.002 and P = 0.008, respectively). CONCLUSIONS: Neoadjuvant concurrent HDI and pembrolizumab demonstrated promising clinical activity despite high rates of treatment discontinuation. pCR is a prognostic indicator.See related commentary by Menzies et al., p. 4133.

Craving and implicit attitude toward heroin use and their relationships with the levels of heroin dependence and methadone adherence in heroin users.

Craving is a core feature of heroin use disorder. Craving for heroin is a conscious cognitive process. Recently, implicit (i.e., an implicit attitude toward heroin use) cognitive processes have been thought to be precursors of cravings. This study aimed to explore the associations of craving and implicit attitude toward heroin use with the level of heroin use disorder and adherence to methadone maintenance treatment (MMT). This study recruited 213 intravenous heroin users (196 males and 17 females) from MMT clinics of two hospitals. The mean age of participants was 42.3 years. They provided details of their severity of heroin use disorder and craving for heroin via questionnaires and also completed a computerized test to assess implicit attitude toward heroin use. The relationships between implicit attitude, craving, age, heroin use disorder, and MMT adherence were examined using path analysis. Craving was positively related to heroin use disorder (beta = 0.4). Implicit attitude directly and indirectly positively contributed to heroin use disorder (betas: 0.1 and 0.3). Craving was positively related to MMT adherence (beta: 0.2), whereas implicit attitude had an indirect effect on MMT adherence (beta: 0.03). Age was negatively associated with craving but was not associated with implicit attitude toward heroin. Methadone dosage was negatively associated with craving. Craving is significantly associated with the levels of heroin use disorder and MMT adherence. Meanwhile, craving mediates the relationship between implicit attitude and heroin use disorder, as well as MMT adherence. Implicit attitude also contributes to the level of heroin use disorder directly. For reducing craving, adequate dosage may be necessary.

Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding.

Mechanisms of resistance to cancer immunotherapy remain poorly understood. Lymphocyte activation gene-3 (LAG3) signaling is regulated by a disintegrin and metalloprotease domain-containing protein-10 (ADAM10)- and ADAM17-mediated cell surface shedding. Here, we show that mice expressing a metalloprotease-resistant, noncleavable LAG3 mutant (LAG3NC) are resistant to PD1 blockade and fail to mount an effective antitumor immune response. Expression of LAG3NC intrinsically perturbs CD4+ T conventional cells (Tconvs), limiting their capacity to provide CD8+ T cell help. Furthermore, the translational relevance for these observations is highlighted with an inverse correlation between high LAG3 and low ADAM10 expression on CD4+ Tconvs in the peripheral blood of patients with head and neck squamous cell carcinoma, which corresponded with poor prognosis. This correlation was also observed in a cohort of patients with skin cancers and was associated with increased disease progression after standard-of-care immunotherapy. These data suggest that subtle changes in LAG3 inhibitory receptor signaling can act as a resistance mechanism with a substantive effect on patient responsiveness to immunotherapy.

Early- and Late-Luteal-Phase Estrogen and Progesterone Levels of Women with Premenstrual Dysphoric Disorder.

: Objective/introduction: The dynamics of ovarian hormone fluctuations during the luteal phase of the menstruation cycle were previously suggested to contribute to the development of premenstrual dysphoric disorder (PMDD) symptoms, but adequate empirical evidence has not been obtained from hormone concentration studies. We prospectively evaluated estrogen and progesterone levels in the early luteal (EL) and late luteal (LL) phases in women with PMDD and the association of these levels with PMDD symptom severity. Methods: 63 women with PMDD and 53 controls without such severe symptoms were evaluated for the estrogen and progesterone levels, and PMDD severity in the EL and LL phases. Results: The results demonstrated that the women with PMDD had a lower EL-phase estrogen level than the controls. Covariant analysis demonstrated that the interaction term between EL-phase estrogen and EL-phase progesterone level was associated with PMDD severity. Among women with lower EL estrogen levels, higher EL-phase progesterone was observed among the women with PMDD versus controls. These results suggest that low EL-phase estrogen level could moderate the provoking effect of EL progesterone in women with PMDD. Overall, these data suggest a possible role of estrogen and progesterone in the development of PMDD symptoms.

Multiple antigen-engineered DC vaccines with or without IFNα to promote antitumor immunity in melanoma.

BACKGROUND: Cancer vaccines are designed to promote systemic antitumor immunity and tumor eradication. Cancer vaccination may be more efficacious in combination with additional interventions that may build on or amplify their effects. METHODS: Based on our previous clinical and in vitro studies, we designed an antigen-engineered DC vaccine trial to promote a polyclonal CD8+ and CD4+ T cell response against three shared melanoma antigens. The 35 vaccine recipients were then randomized to receive one month of high-dose IFNα or observation. RESULTS: The resulting clinical outcomes were 2 partial responses, 8 stable disease and 14 progressive disease among patients with measurable disease using RECIST 1.1, and, of 11 surgically treated patients with no evidence of disease (NED), 4 remain NED at a median follow-up of 3 years. The majority of vaccinated patients showed an increase in vaccine antigen-specific CD8+ and CD4+ T cell responses. The addition of IFNα did not appear to improve immune or clinical responses in this trial. Examination of the DC vaccine profiles showed that IL-12p70 secretion did not correlate with immune or clinical responses. In depth immune biomarker studies support the importance of circulating Treg and MDSC for development of antigen-specific T cell responses, and of circulating CD8+ and CD4+ T cell subsets in clinical responses. CONCLUSIONS: DC vaccines are a safe and reliable platform for promoting antitumor immunity. This combination with one month of high dose IFNα did not improve outcomes. Immune biomarker analysis in the blood identified several predictive and prognostic biomarkers for further analysis, including MDSC. TRIAL REGISTRATION: NCT01622933 .