Efficacy and safety of atezolizumab and bevacizumab in appendiceal adenocarcinoma.

PURPOSE: Appendiceal Adenocarcinoma (AA) remains an orphan disease with limited treatment options for patients unable to undergo surgical resection. Evidence supporting the efficacy of combined VEGF and PD-1 inhibition in other tumor types provided a compelling rationale for investigating this combination in AA, where immune checkpoint inhibitors (ICIs) have not been previously explored. PATIENTS AND METHODS: We conducted a prospective, single arm phase 2 study evaluating efficacy and safety of atezolizumab in conjunction with bevacizumab (Atezo+Bev) in advanced, unresectable AA. RESULTS: Patients treated with the Atezo+Bev combination had 100% disease control rate (1 PR, 15 SD) with progression free survival (PFS) of 18.3 months and overall survival not-yet-reached with median duration of follow up of 40 months. These survival intervals were significantly longer relative to a clinically and molecularly matched synthetic control cohort treated with cytotoxic chemotherapy designed for colorectal cancer (PFS of 4.4 months, p = .041). CONCLUSIONS: In light of recent data demonstrating a lack of efficacy of 5-FU based chemotherapy, Atezo+Bev is a promising treatment option for patients with low-grade unresectable AA; further study is warranted.

eEF1A2 promotes PTEN-GSK3ß-SCF complex-dependent degradation of Aurora kinase A and is inactivated in breast cancer.

The translation elongation factor eEF1A promotes protein synthesis. Its methylation by METTL13 increases its activity, supporting tumor growth. However, in some cancers, a high abundance of eEF1A isoforms is associated with a good prognosis. Here, we found that eEF1A2 exhibited oncogenic or tumor-suppressor functions depending on its interaction with METTL13 or the phosphatase PTEN, respectively. METTL13 and PTEN competed for interaction with eEF1A2 in the same structural domain. PTEN-bound eEF1A2 promoted the ubiquitination and degradation of the mitosis-promoting Aurora kinase A in the S and G2 phases of the cell cycle. eEF1A2 bridged the interactions between the SKP1-CUL1-FBXW7 (SCF) ubiquitin ligase complex, the kinase GSK3ß, and Aurora-A, thereby facilitating the phosphorylation of Aurora-A in a degron site that was recognized by FBXW7. Genetic ablation of Eef1a2 or Pten in mice resulted in a greater abundance of Aurora-A and increased cell cycling in mammary tumors, which was corroborated in breast cancer tissues from patients. Reactivating this pathway using fimepinostat, which relieves inhibitory signaling directed at PTEN and increases FBXW7 expression, combined with inhibiting Aurora-A with alisertib, suppressed breast cancer cell proliferation in culture and tumor growth in vivo. The findings demonstrate a therapeutically exploitable, tumor-suppressive role for eEF1A2 in breast cancer.

Statistical and practical considerations in planning and conduct of dose-optimization trials.

The U.S. Food and Drug Administration launched Project Optimus with the aim of shifting the paradigm of dose-finding and selection toward identifying the optimal biological dose that offers the best balance between benefit and risk, rather than the maximum tolerated dose. However, achieving dose optimization is a challenging task that involves a variety of factors and is considerably more complicated than identifying the maximum tolerated dose, both in terms of design and implementation. This article provides a comprehensive review of various design strategies for dose-optimization trials, including phase 1/2 and 2/3 designs, and highlights their respective advantages and disadvantages. In addition, practical considerations for selecting an appropriate design and planning and executing the trial are discussed. The article also presents freely available software tools that can be utilized for designing and implementing dose-optimization trials. The approaches and their implementation are illustrated through real-world examples.

Blood-based Migration Signature Biomarker Panel Discriminates Early Stage New Onset Diabetes related Pancreatic Ductal Adenocarcinoma from Type 2 Diabetes.

BACKGROUND AND AIMS: While type 2 diabetes is a well-known risk factor for pancreatic ductal adenocarcinoma (PDAC), PDAC-induced new-onset diabetes (PDAC-NOD) is a manifestation of underlying PDAC. In this study, we sought to identify potential blood-based biomarkers for distinguishing PDAC-NOD from type 2 diabetes (T2DM) without PDAC. MATERIALS AND METHODS: By ELISA analysis, a migration signature biomarker panel comprising tissue factor pathway inhibitor (TFPI), tenascin C (TNC-FNIII-C) and CA 19-9 was analyzed in plasma samples from 50 PDAC-NOD and 50 T2DM controls. RESULTS: Both TFPI (area under the curve (AUC) 0.71) and TNC-FNIII-C (AUC 0.69) outperformed CA 19-9 (AUC 0.60) in distinguishing all stages of PDAC-NOD from T2DM controls. The combined panel showed an AUC of 0.82 (95% CI = 0.73-0.90) (p = 0.002). In the PDAC-NOD early stage II samples, the three biomarkers had an AUC of 0.84 (95% CI = 0.73-0.93) vs CA 19-9, AUC = 0.60, (95% CI = 0.45-0.73), which also improved significance (p = 0.0123). CONCLUSION: The migration signature panel adds significantly to CA 19-9 to discriminate PDAC-NOD from T2DM controls and warrants further validation for high-risk group stratification.

Addition of Metastasis-Directed Therapy to Intermittent Hormone Therapy for Oligometastatic Prostate Cancer: The EXTEND Phase 2 Randomized Clinical Trial.

Importance: Despite evidence demonstrating an overall survival benefit with up-front hormone therapy in addition to established synergy between hormone therapy and radiation, the addition of metastasis-directed therapy (MDT) to hormone therapy for oligometastatic prostate cancer, to date, has not been evaluated in a randomized clinical trial. Objective: To determine in men with oligometastatic prostate cancer whether the addition of MDT to intermittent hormone therapy improves oncologic outcomes and preserves time with eugonadal testosterone compared with intermittent hormone therapy alone. Design, Setting, Participants: The External Beam Radiation to Eliminate Nominal Metastatic Disease (EXTEND) trial is a phase 2, basket randomized clinical trial for multiple solid tumors testing the addition of MDT to standard-of-care systemic therapy. Men aged 18 years or older with oligometastatic prostate cancer who had 5 or fewer metastases and were treated with hormone therapy for 2 or more months were enrolled to the prostate intermittent hormone therapy basket at multicenter tertiary cancer centers from September 2018 to November 2020. The cutoff date for the primary analysis was January 7, 2022. Interventions: Patients were randomized 1:1 to MDT, consisting of definitive radiation therapy to all sites of disease and intermittent hormone therapy (combined therapy arm; n = 43) or to hormone therapy only (n = 44). A planned break in hormone therapy occurred 6 months after enrollment, after which hormone therapy was withheld until progression. Main Outcomes and Measures: The primary end point was disease progression, defined as death or radiographic, clinical, or biochemical progression. A key predefined secondary end point was eugonadal progression-free survival (PFS), defined as the time from achieving a eugonadal testosterone level (≥150 ng/dL; to convert to nanomoles per liter, multiply by 0.0347) until progression. Exploratory measures included quality of life and systemic immune evaluation using flow cytometry and T-cell receptor sequencing. Results: The study included 87 men (median age, 67 years [IQR, 63-72 years]). Median follow-up was 22.0 months (range, 11.6-39.2 months). Progression-free survival was improved in the combined therapy arm (median not reached) compared with the hormone therapy only arm (median, 15.8 months; 95% CI, 13.6-21.2 months) (hazard ratio, 0.25; 95% CI, 0.12-0.55; P < .001). Eugonadal PFS was also improved with MDT (median not reached) compared with the hormone therapy only (6.1 months; 95% CI, 3.7 months to not estimable) (hazard ratio, 0.32; 95% CI, 0.11-0.91; P = .03). Flow cytometry and T-cell receptor sequencing demonstrated increased markers of T-cell activation, proliferation, and clonal expansion limited to the combined therapy arm. Conclusions and Relevance: In this randomized clinical trial, PFS and eugonadal PFS were significantly improved with combination treatment compared with hormone treatment only in men with oligometastatic prostate cancer. Combination of MDT with intermittent hormone therapy may allow for excellent disease control while facilitating prolonged eugonadal testosterone intervals. Trial Registration: ClinicalTrials.gov Identifier: NCT03599765.

Antifungal activity of designed α-helical antimicrobial peptides.

Antimicrobial resistance (AMR) has become a major global health concern prompting the quest for new antibiotics with higher efficiency and less proneness to drug resistance. Antimicrobial peptides (AMPs) offer such properties and have therefore gained increasing attention as a new generation of antibiotics to overcome AMR. In an attempt to develop new highly selective and highly efficient antifungal peptides, a sequence (named At1) originating from the natural AMP Ponericin-W1 was used as a lead sequence for rational design of a series of short cationic antifungal peptides named At2-At12. The charge, hydrophobicity, and terminal amino acids of the peptides were modified in a systematic way to investigate the effect of such structural changes on the biological activity of the peptides. Among all the designed peptides, three peptides (coded as At3, At5 and At10) exhibited high antifungal activity without any significant hemolytic activity in human red blood cells. The higher selectivity of these peptides for fungal cells over human cells was further confirmed in cocultures of Candida albicans and human foreskin fibroblasts. These three peptides lacked any hydrophilic residues in their hydrophobic domain, contained lysine residues in their hydrophilic region and had an overall charge of 7+. They also had a higher helical content in microbial membrane mimicking DPPG SUVs than the rest of the peptides. The fungi did not develop any resistance to the designed antifungal peptides even after 25 generations indicating low AMR. At5 was also used in vivo for the treatment of wounds infected with Candida albicans in mice and showed superiority over fluconazole for treating infection and accelerating wound healing. There was an interplay between the hydrophobicity and positive charge density to determine the antifungal activity of the peptides. The results from this study suggest this class of antifungal peptides as promising candidates for antifungal drugs with high efficiency, high biocompatibility and low propensity for drug resistance.

Mass spectrometry based biomarkers for early detection of HCC using a glycoproteomic approach.

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related mortality worldwide and 80%-90% of HCC develops in patients that have underlying cirrhosis. Better methods of surveillance are needed to increase early detection of HCC and the proportion of patients that can be offered curative therapies. Recent work in novel mass spec-based methods for glycomic and glycopeptide analysis for discovery and confirmation of markers for early detection of HCC versus cirrhosis is reviewed in this chapter. Results from recent work in these fields by several groups and the progress made in developing markers of early HCC which can outperform the current serum-based markers are described and discussed. Also, recent developments in isoform analysis of glycans and glycopeptides and in various mass spec fragmentation methods will be described and discussed.

Gene expression profiling of circulating tumor cells captured by MicroCavity Array is superior to enumeration in demonstrating therapy response in patients with newly diagnosed advanced and locally advanced non-small cell lung cancer.

Background: Circulating tumor cells (CTCs) are a promising non-invasive tool for monitoring therapy response. The only Food and Drug Administration (FDA)-approved test is limited to enumeration of epithelial CTC without further characterization and is not approved for the management of non-small cell lung cancer (NSCLC). Here we use a MicroCavity Array (MCA) system to capture CTC agnostic of epithelial markers for further molecular testing in NSCLC. Methods: CTCs were enumerated by fluorescent microscopy as longitudinal sampling throughout disease management from 213 NSCLC patients. CTC-enriched samples from a subset of 127 patients were interrogated for gene expression by reverse transcription polymerase chain reaction (RT-PCR) using a customized pre-selected panel of 20 genes. Results: At least 1 CTC was detected by enumeration in 53.8% of samples. Most patients had fewer than 5 CTCs (91%) and the highest observed count was 35 CTCs. Enumeration of single CTCs was not prognostic, although detection of CTC clusters at any time point was associated with increased risk of progression [hazard ratio (HR) 3.00, 95% confidence interval (CI): 1.1-8.2, P=0.0318]. In contrast, 124 (97.6%) patients with samples interrogated for gene expression had at least 1 gene detectable in at least 1 sample, and 101 (79.5%) had at least one elevated epithelial gene in at least one timepoint. High expression of BCL2, CD274 [programmed death-ligand 1 (PD-L1)], CDH1, EPCAM, FGFR1, FN1, KRT18, MET and MUC1 were associated with poor prognosis. Patients with CTCs positive for at least 3 epithelial genes at baseline all progressed within 10 months (HR 8.2, P<0.001, 95% CI: 3.2-21.1). BCL2, CD274 (PD-L1), EPCAM and MUC1 remained significant independent prognostic factors in multivariate, time-dependent analyses of progression and death. Conclusions: The selective profile of CTC genes and identification of CTC clusters better correlated with prognosis than enumeration of enriched CTC in NSCLC patients in this study.

Tumor suppressor DEAR1 regulates mammary epithelial cell fate and predicts early onset and metastasis in triple negative breast cancer.

Triple negative breast cancer (TNBC) is a disease of poor prognosis, with the majority classified as the basal-like subtype associated with epithelial-mesenchymal transition and metastasis. Because basal breast cancers originate from proliferative luminal progenitor-like cells upon dysregulation of proper luminal differentiation, genes regulating luminal-basal transition are critical to elucidate novel therapeutic targets to improve TNBC outcomes. Herein we demonstrate that the tumor suppressor DEAR1/TRIM62 is a critical regulator of luminal cell fate. DEAR1 loss in human mammary epithelial cells results in significantly enhanced mammosphere formation that is accelerated in the presence of TGF-ß/SMAD3 signaling. Mammospheres formed following DEAR1 loss are enriched for ALDH1A1 and CK5 expression, EpCAM-/CD49f+ and CD44high/24low basal-like epithelial cells, indicating that DEAR1 regulates stem/progenitor cell properties and luminal-basal progenitor transition. We show that DEAR1 maintains luminal differentiation as a novel ubiquitin ligase for SNAI2/SLUG, a master regulator driving stemness and generation of basal-like progenitor populations. We also identify a significant inverse correlation between DEAR1 and SNAI2 expression in a 103 TNBC case cohort and show that low DEAR1 expression significantly correlates with young age of onset and shorter time to metastasis, suggesting DEAR1 could serve as a biomarker to stratify early onset TNBCs for targeted stem cell therapies.

Chinese universities' special programs supporting talents to seek a United Nations career: a center-periphery-model analysis.

In recent years, China's higher education sector has started to establish special programs to train and support talents to seek career opportunities in the United Nations (UN). To explore these special programs and understand their relationship with China's internationalization strategies and its higher education, we used the center-periphery model as the theoretical framework. We analyzed 53 institutional documents and conducted semi-structured interviews among 5 university staff members and 21 students/recent graduates who were involved in these special programs. The analysis on the special programs implied Chinese higher education's peripheral position in supporting talents to work in the UN. This was reflected by the conforming practice, including accepting current UN recruitment regulations and English's dominance in the UN recruitment practice. However, we also identified alternative dynamics that China and its higher education do not simply obey the center-periphery model and accept their peripheral status. Instead, special programs were established to achieve China's global strategy of moving to the center of international arena via multilateralism and international organizations such as the UN. This study sheds light on further explorations of the state-university relationship in China in the globalization era, especially from the perspective of cultural diplomacy and soft power.

Association between abnormal lipid profile and inflammation and progression of myelodysplastic syndrome to acute leukemia.

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with a small risk of developing hematologic malignancies and a higher risk of cardiovascular diseases (CVD). We asked whether the reverse correlation exists and cardiometabolic risk factors have an impact on the progression of myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML). We investigated the association between abnormal lipid profiles and inflammation in MDS, which shares many genetic mutations with CHIP, and the risk of developing acute leukemia. We examined the medical records of 11071 MDS patients. Among them, 5422 had at least one lipid profile or C-reactive protein (CRP) measurement. In univariate and multivariate analyses, elevated triglyceride and high-sensitive C-reactive protein (HS-CRP) were significantly associated with a diagnosis of acute leukemia in MDS patients. Next, we examined these associations in patients with available MDS prognostic scores (International Prognostic Scoring System, IPSS, or its revised version IPSS/R) (n = 2786 patients). We found that the statistical association between CRP and the progression of MDS to leukemia was independent of other variables in the scoring system. MDS patients with elevated CRP in both the high-risk and low-risk groups had a higher risk of progression to AML than those with a lower CRP. We speculate that inflammation might be a common denominator in developing hematologic malignancies and CVD in patients with clonal hematopoiesis.

Glycopeptides with Sialyl Lewis Antigen in Serum Haptoglobin as Candidate Biomarkers for Nonalcoholic Steatohepatitis Hepatocellular Carcinoma Using a Higher-Energy Collision-Induced Dissociation Parallel Reaction Monitoring-Mass Spectrometry Method.

Nonalcoholic steatohepatitis (NASH) is the fastest growing cause of hepatocellular carcinoma (HCC) in the United States. Changes in N-glycosylation on specific glycosites of serum proteins have been investigated as potential markers for the early detection of NASH-related HCC. Herein, we report a glycopeptide with a Sialyl Lewis structure derived from serum haptoglobin (Hp) as a potential marker for NASH related HCCs among 95 patients with NASH, including 46 cirrhosis, 32 early-stage HCC, and 17 late-stage HCC. Hp immuno-isolated from patient serum was analyzed using LC-HCD-PRM-MS/MS followed by data analysis via Skyline software. Two glycopeptides involving site N184 and four glycopeptides involving site N241 were significantly changed in patients with HCC vs NASH cirrhosis (P < 0.05). The two-marker panel using N-glycopeptide N241_A4G4F2S4 showed the best performance for HCC detection when combined with α-fetoprotein (AFP), with an improved estimated area under the curve (AUC) = 0.898 (95% CI: 0.835, 0.951), compared to the AUC of 0.790(95% CI, 0.697 0.872) using AFP alone (P = 0.048). At 90% specificity, the combination of N241_A4G4F2S4 + AFP had an improved sensitivity of 63.3%, compared to the sensitivity of 52.3% using AFP alone. When using three markers, the panel of AFP + N241_A2G2F1S2 + N241_A4G4F2S4 yielded an estimated AUC of 0.928 (95% CI: 0.877, 0.970). Our findings indicated that N241_A4G4F2S4 may play an important role in distinguishing HCC from NASH cirrhosis.

Highly selective performance of rationally designed antimicrobial peptides based on ponericin-W1.

Antimicrobial peptides (AMPs) or host-defence peptides act by penetrating and disrupting the bacterial membranes and are therefore less prone to antimicrobial resistance (AMR) compared to conventional antibiotics. However, there are still many challenges in the clinical application of the naturally occurring AMPs which necessitates further studies to establish the relationship between the chemical structure of AMPs and their antimicrobial activity and selectivity. Herein, we report a study on the relationship between the chemical structure and the biological activity of a series of rationally designed AMPs derived from Ponericin-W1, a naturally occurring AMP from ants. The peptides were designed by modification of the hydrophobic and hydrophilic regions of the lead peptide sequence in a systematic way. Their antibacterial and hemolytic activities were determined in vitro. The antibacterial activity of a representative peptide, At5 was also tested in a mouse model of skin wound infection. Furthermore, the relationship between the physicochemical properties of the peptides and their antibacterial activity was investigated. Replacing the cationic amino acids in the hydrophobic region of the peptides with hydrophobic amino acids enhanced their antibacterial activity and increasing the number of cationic amino acids in the hydrophilic region reduced their toxicity to human red blood cells and thus improved their selectivity for bacteria. Four of the designed peptides, coded as At3, At5, At8, and At10, displayed considerable antibacterial activity and high selectivity for bacteria. At5 also accelerated the wound healing in mice indicating high in vivo efficiency of this peptide. The peptides were more effective against Gram-negative bacteria and no AMR was developed against them in the bacteria even after 25 generations. The results from this study can provide a better understanding of the structural features required for strong antibacterial activity and selectivity, and serve as a guide for the future rational design of AMPs.

Definitive Local Consolidative Therapy for Oligometastatic Solid Tumors: Results From the Lead-in Phase of the Randomized Basket Trial EXTEND.

PURPOSE: The benefit of local consolidative therapy (LCT) for oligometastasis across histologies remains uncertain. EXTernal beam radiation to Eliminate Nominal metastatic Disease (EXTEND; NCT03599765) is a randomized phase 2 basket trial evaluating the effectiveness of LCT for oligometastatic solid tumors. We report here the prospective results of the single-arm "lead-in" phase intended to identify histologies most likely to accrue to histology-specific endpoints in the randomized phase. METHODS AND MATERIALS: Eligible histologies included colorectal, sarcoma, lung, head and neck, ovarian, renal, melanoma, pancreatic, prostate, cervix/uterine, breast, and hepatobiliary. Patients received LCT to all sites of active metastatic disease and primary/regional disease (as applicable) plus standard-of-care systemic therapy or observation. The primary endpoint in EXTEND was progression-free survival (PFS), and the primary endpoint of the lead-phase was histology-specific accrual feasibility. Adverse events were graded by Common Terminology Criteria for Adverse Events version 4.0. RESULTS: From August 2018 through January 2019, 50 patients were enrolled and 49 received definitive LCT. Prostate, breast, and kidney were the highest enrolling histologies and identified for independent accrual in the randomization phase. Most patients (73%) had 1 or 2 metastases, most often in lung or bone (79%), and received ablative radiation (62%). Median follow-up for censored patients was 38 months (range, 16-42 months). Median PFS was 13 months (95% confidence interval, 9-24), 3-year overall survival rate was 73% (95% confidence interval, 57%-83%), and local control rate was 98% (93 of 95 tumors). Two patients (4%) had Common Terminology Criteria for Adverse Events grade 3 toxic effects related to LCT; no patient had grade 4 or 5 toxic effects. CONCLUSIONS: The prospective lead-in phase of the EXTEND basket trial demonstrated feasible accrual, encouraging PFS, and low rates of severe toxic effects at mature follow-up. The randomized phase is ongoing with histology-based baskets that will provide histology-specific evidence for LCT in oligometastatic disease.

Molecular Visualization of Early-Stage Acute Kidney Injury with a DNA Framework Nanodevice.

DNA nanomachines with artificial intelligence have attracted great interest, which may open a new era of precision medicine. However, their in vivo behavior, including early diagnosis and therapeutic effect are limited by their targeting efficiency. Here, a tetrahedral DNA framework (TDF)-based nanodevice for in vivo near-infrared (NIR) diagnosis of early-stage AKI is developed. This nanodevice comprises three functional modules: a size-tunable TDF nanostructure as kidney-targeting vehicle, a binding module for the biomarker kidney injury molecule-1 (Kim-1), and a NIR signaling module. The cooperation of these modules allows the nanodevice to be selectively accumulated in injured kidney tissues with high Kim-1 level, generating strong NIR fluorescence; whereas the nanodevice with the proper size can be rapidly cleared in healthy kidneys to minimize the background. By using this nanodevice, the early diagnosis of AKI onset is demonstrated at least 6 h ahead of Kim-1 urinalysis, or 12 h ahead of blood detection. It is envisioned that this TDF-based nanodevice may have implications for the early diagnosis of AKI and other kidney diseases.

Why there are so many contradicted or exaggerated findings in highly-cited clinical research?

It is not uncommon that clinical studies of the same intervention contradicted with each other, e.g., one study produced positive results, while the other produced negative results. Ioanndis (2005a) found that among 49 highly-cited original clinical research studies, published in New England Journal of Medicine, Journal of the American Medical Association, Lancet or in a high-impact medical specialty journal, 32% of them were contradicted in subsequent large-scale studies, or were shown to have potentially overestimated the efficacy of the experimental intervention. This finding is disturbing and of serious concern given the widespread impact of these highly-cited studies and the rigorous standards used to design and conduct the studies. We perform Bayesian analysis of these highly-cited clinical studies based on Bayesian factor. We identified one cause of the issue: p values strongly overstated the experimental evidence. For the highly-cited studies, when the p value was 0.05, there was a 74.4% percentage chance that the null hypothesis was true. The use of a p value of 0.05 as the criterion for significance caused many researchers to mistakenly draw conclusions of positive findings, which were then contradicted by subsequent large-scale studies.

Assessment of Clinical Response Following Atezolizumab and Bevacizumab Treatment in Patients With Neuroendocrine Tumors: A Nonrandomized Clinical Trial.

Importance: Therapies for patients with advanced well-differentiated neuroendocrine tumors (NETs) have expanded but remain inadequate, with patients dying of disease despite recent advances in NET therapy. While patients with other cancers have seen long-term disease control and tumor regression with the application of immunotherapies, initial prospective studies of single-agent programmed cell death 1 inhibitors in NET have been disappointing. Objective: To evaluate the response rate following treatment with the combination of the vascular endothelial growth factor inhibitor bevacizumab with the programmed cell death 1 ligand 1 inhibitor atezolizumab in patients with advanced NETs. Design, Setting, and Participants: This single-arm, open-label nonrandomized clinical study in patients with rare cancers included 40 patients with advanced, progressive grade 1 to 2 NETs (20 with pancreatic NETs [pNETs] and 20 with extrapancreatic NETs [epNETs]) treated at a tertiary care referral cancer center between March 31, 2017, and February 19, 2019. Data were analyzed from June to September 2021. Interventions: Patients received intravenous bevacizumab and atezolizumab at standard doses every 3 weeks until progression, death, or withdrawal. Main Outcomes and Measures: The primary end point was objective radiographic response using Response Evaluation Criteria in Solid Tumors, version 1.1, with progression-free survival (PFS) as a key secondary end point. Results: Following treatment of the 40 study patients with bevacizumab and atezolizumab, objective response was observed in 4 patients with pNETs (20%; 95% CI, 5.7%-43.7%) and 3 patients with epNETs (15%; 95% CI, 3.2%-37.9%). The PFS was 14.9 (95% CI, 4.4-32.0) months and 14.2 (95% CI, 10.2-19.6) months in these cohorts, respectively. Conclusions and Relevance: In this nonrandomized clinical trial, findings suggest that clinical responses in patients with NET may follow treatment with the combination of bevacizumab and atezolizumab, with a PFS consistent with effective therapies. Trial Registration: ClinicalTrials.gov Identifier: NCT03074513.

Effects of Keemun and Dianhong Black Tea in Alleviating Excess Lipid Accumulation in the Liver of Obese Mice: A Comparative Study.

The chemical compositions of black teas differ greatly and may have different health benefits; however, systematic investigations into such benefits are lacking. Here, the chemical profiles of Keemun black tea (KBT) and Dianhong black tea (DBT), two common categories of tea in China, were analyzed, and their lipid-lowering effects in male C57BL/6 mice fed a high-fat diet (60% energy from fat) or the diet supplemented with 2% black tea powder for 15 weeks were investigated. The compounds most crucial in differentiating KBT and DBT were determined to be phenolic compounds, theanine, and D-psicose. DBT was more effective than KBT in preventing excess hepatic fat accumulation. Both black teas effectively and comparably altered the mRNA levels of hepatic lipid-metabolizing genes. DBT had more favorable effects in stimulating fecal fat excretion than did KBT. The differentiating compounds with the higher values of variable importance in the projection (VIP) might predominantly contribute to the different health benefits; however, the most essential compound or combination of compounds requires clarification.

A randomized group sequential enrichment design for immunotherapy and targeted therapy.

In targeted therapy or immunotherapy, it is common that only a subpopulation of patients are sensitive to and thus may benefit from the therapy. In practice, based on pre-clinical data, it is often assumed that the sensitive subpopulation is known. Subsequent clinical trial data, however, often show that this assumptions is false. We propose a randomized, group sequential enrichment (GSE) design to evaluate an experimental treatment against a control. The GSE design starts by enrolling patients under broad eligibility criteria and then alters the entry criteria to restrict enrollment to treatment-sensitive patients based on accumulating data of short-term and long-term survival endpoints. The short-term endpoint is used to facilitate enrichment when a limited number of survival events are observed, while the final determination of treatment efficacy and sensitive subpopulation is based on the survival. The group sequential approach is adopted to implement the adaptive enrichment strategy. The proposed design simultaneously achieves two primary goals of precision medicine: to determine whether the experimental drug is superior to the control and to identify the target population that is sensitive to the treatment. A simulation study shows that the proposed design well controls the type I error rate and yields substantially higher power than the conventional group sequential design and existing two-stage enrichment design.