High dose total marrow irradiation (TMI) does not increase long-term toxicity of myeloablative fludarabine/busulfan (FluBu4) conditioning regimen in allogeneic hematopoietic stem cell transplantation (HSCT).

OBJECTIVES: Based on a previous phase 1 study, total marrow irradiation (TMI) at 9Gy was added to a myeloablative FluBu4 conditioning regimen in allogeneic hematopoietic stem cell transplantation (HSCT) for myeloid malignancies. Here, we report on the long-term toxicity of TMI combined with FluBu4 and compare it to patients who received only FluBu4. METHODS: We retrospectively analyzed 38 consecutive patients conditioned with FluBu4/TMI (n = 15) or FluBu4 (n = 23, control group) who had at least 1 year follow-up post-transplant. The rate of long-term adverse events that have been previously associated with total body irradiation (TBI) was analyzed in the two groups. RESULTS: The baseline characteristics did not differ between the two groups. The control group had a longer median follow-up (71.2 mo) than the TMI group (38.5 mo) (p = .004). The most common adverse events were xerostomia, dental complications, cataracts, or osteopenia and did not differ between the two groups. Cognitive dysfunction or noninfectious pneumonitis, often detected after high dose TBI, were also not different in the two groups (p = .12 and p = .7, respectively). There was no grade 4 adverse event. CONCLUSION: Our results suggest that a conditioning regimen with TMI 9Gy and FluBu4 does not increase long-term adverse events after allogeneic HSCT.

Bayesian dose escalation with overdose and underdose control utilizing all toxicities in Phase I/II clinical trials.

Escalation with overdose control (EWOC) is a commonly used Bayesian adaptive design, which controls overdosing risk while estimating maximum tolerated dose (MTD) in cancer Phase I clinical trials. In 2010, Chen and his colleagues proposed a novel toxicity scoring system to fully utilize patients' toxicity information by using a normalized equivalent toxicity score (NETS) in the range 0 to 1 instead of a binary indicator of dose limiting toxicity (DLT). Later in 2015, by adding underdosing control into EWOC, escalation with overdose and underdose control (EWOUC) design was proposed to guarantee patients the minimum therapeutic effect of drug in Phase I/II clinical trials. In this paper, the EWOUC-NETS design is developed by integrating the advantages of EWOUC and NETS in a Bayesian context. Moreover, both toxicity response and efficacy are treated as continuous variables to maximize trial efficiency. The dose escalation decision is based on the posterior distribution of both toxicity and efficacy outcomes, which are recursively updated with accumulated data. We compare the operation characteristics of EWOUC-NETS and existing methods through simulation studies under five scenarios. The study results show that EWOUC-NETS design treating toxicity and efficacy outcomes as continuous variables can increase accuracy in identifying the optimized utility dose (OUD) and provide better therapeutic effects.

A comparison of four leukapheresis methods to harvest an optimal dose of CD34+ cells: A single center experience.

BACKGROUND: Chemokine receptor CXCR4 antagonist plerixafor (Px) as well as high volume (HV) leukapheresis have been shown to reduce hematopoietic stem progenitor cell (HSPC) mobilization failure rates. However, no direct comparisons of such methods currently exists. METHODS AND MATERIALS: We compared the HSPC collection yield based on basal peripheral blood CD34+ cell numbers in patients diagnosed with multiple myeloma or non-Hodgkin's lymphoma undergoing autologous stem cell transplantation in a retrospective chart review. The leukapheresis methods used included HV versus regular volume (RV) with or without Px. There were 116 patients in the study group while the historical control group had 34 patients. RESULTS AND CONCLUSIONS: Control group underwent RV leukapheresis without Px. Addition of Px or HV in the study group failed to display significant improvement in CD34+ cell collection yield; however, when basal CD34+ cell numbers were taken into account, both Px + RV and HV without Px increased CD34+ cell collection yield. The collection failure rates of HV without Px group were comparable to Px + RV when the basal CD34+ cell numbers were over 20/µl. Of interest, multivariate linear regression analysis did not detect any significant difference between HV versus Px + RV or other leukapheresis methods in CD34 yields or collection failure rates from a single collection after controlling for other factors (sex, age, or underlying disease). In multivariate analysis, pre apheresis CD34+ cell number was significantly and positively associated with the CD34+ cell yields from a single apheresis. In our studies, the majority of patients can be rescued without Px by HV alone as a potential cost saving approach. In summary, trend in our studies reflects that both Px and HV are capable of reducing the mobilization failure rates except the poorest mobilizers, which will need to be validated in larger studies.

Berberine Represses ß-Catenin Translation Involving 4E-BPs in Hepatocellular Carcinoma Cells.

Aberrant activation of Wnt/ß-catenin axis occurs in several gastrointestinal malignancies due to inactivating mutations of adenomatous polyposis coli (in colorectal cancer) or activating mutations of ß-catenin itself [in hepatocellular carcinoma (HCC)]. These lead to ß-catenin stabilization, increase in ß-catenin/T-cell factor (TCF)-mediated transcriptional activation, and target gene expression, many of which are involved in tumor progression. While studying pharmaceutical agents that can target ß-catenin in cancer cells, we observed that the plant compound berberine (BBR), a potent activator of AMP-activated protein kinase (AMPK), can reduce ß-catenin expression and downstream signaling in HCC cells in a dose-dependent manner. More in-depth analyses to understand the mechanism revealed that BBR-induced reduction of ß-catenin occurs independently of AMPK activation and does not involve transcriptional or post-translational mechanisms. Pretreatment with protein synthesis inhibitor cycloheximide antagonized BBR-induced ß-catenin reduction, suggesting that BBR affects ß-catenin translation. BBR treatment also antagonized mammalian target of rapamycin (mTOR) activity and was associated with increased recruitment of eukaryotic translation initiation factor 4E-binding protein (4E-BP) 1 in the translational complex, which was revealed by 7-methyl-cap-binding assays, suggesting inhibition of cap-dependent translation. Interestingly, knocking down 4E-BP1 and 4E-BP2 significantly attenuated BBR-induced reduction of ß-catenin levels and expression of its downstream target genes. Moreover, cells with 4E-BP knockdown were resistant to BBR-induced cell death and were resensitized to BBR after pharmacological inhibition of ß-catenin. Our findings indicate that BBR antagonizes ß-catenin pathway by inhibiting ß-catenin translation and mTOR activity and thereby reduces HCC cell survival. These also suggest that BBR could be used for targeting HCCs that express mutated/activated ß-catenin variants that are currently undruggable. SIGNIFICANCE STATEMENT: ß-catenin signaling is aberrantly activated in different gastrointestinal cancers, including hepatocellular carcinoma, which is currently undruggable. In this study we describe a novel mechanism of targeting ß-catenin translation via utilizing a plant compound, berberine. Our findings provide a new avenue of targeting ß-catenin axis in cancer, which can be utilized toward the designing of effective therapeutic strategies to combat ß-catenin-dependent cancers.

Surveillance imaging during first remission in follicular lymphoma does not impact overall survival.

BACKGROUND: Although many patients with follicular lymphoma (FL) undergo routine radiographic surveillance during their first remission, no consensus exists on the modality, duration, frequency, or need for routine imaging studies. The authors retrospectively examined the effect of surveillance imaging on relapse detection and overall survival (OS) in patients with FL. METHODS: Patients with newly diagnosed FL who had a response to induction therapy were identified from the Lymphoid Malignancies Enterprise Architecture Database (LEAD) at Emory University and from the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic. Patients were evaluated for both relapse and method of relapse detection (ie, clinical concerns vs radiologic detection through surveillance imaging in an asymptomatic patient). RESULTS: Of 148 patients in the LEAD cohort, 55 (37%) relapsed, and the majority (n = 35; 64%) of relapses were detected clinically. In the MER cohort, 63 of 177 relapses (54%) were detected clinically. There was no significant difference in OS from the date of diagnosis between the 2 methods of relapse detection in the LEAD (hazard ratio [HR], 0.61; 95% CI, 0.13-2.94; P = .54) and MER (HR, 1.02; 95% CI, 0.47-2.21; P = .96) cohorts. Similarly, there was no significant difference in OS from the date of relapse between the 2 methods of relapse detection in the LEAD (HR, 0.47; 95% CI, 0.10-2.27; P = .35) and MER (HR, 1.02; 95% CI, 0.47-2.21; P = .96) cohorts. CONCLUSIONS: These findings suggest a limited role for routine surveillance imaging in patients with FL who complete front-line therapy. Future studies should evaluate which patients may benefit from a more aggressive surveillance approach and should explore novel methods of relapse detection.

Mismatch Repair (MMR) Gene Alteration and BRAF V600E Mutation Are Potential Predictive Biomarkers of Immune Checkpoint Inhibitors in MMR-Deficient Colorectal Cancer.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy is highly effective in metastatic mismatch repair-deficient (MMR-D) colorectal cancer (CRC). In this study, we evaluated molecular and clinical predictors of ICI response in MMR-D CRC. MATERIALS AND METHODS: Patient databases at four cancer institutions were queried. The Fisher exact test was performed to test the association of clinical and molecular markers. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and compared by the log-rank test. Twelve- and 24-month PFS rates were compared by the Z test. RESULTS: A total of 60 patients with CRC with MMR-D/microsatellite instability-high who previously received ICIs were identified. Patients with liver metastasis had a lower overall response rate as compared with other sites of metastasis (36.4% vs. 68.7%; p = .081). Patients with MLH1/PMS2 loss had worse 1-year and 2-year PFS rates compared with patients with MSH2/MSH6 loss (84.2% vs. 57.8% and 78.2% vs. 54.2%, respectively; p < .001). There were improved 1-year and 2-year PFS rates in patients with wild-type BRAF when compared with patients with BRAF V600E mutation (73.3% vs. 40%, and 73.3% vs. 26.7%; respectively; p < .001). Patients aged >65 had significantly worse PFS rates as compared with patients aged ≤65 (p < .001). CONCLUSION: BRAF V600E mutation, MLH1 and/or PMS2 loss, as well as age >65 years and liver metastasis, may be predictive of duration of ICI response in patients with MMR-D CRC. Larger cohorts are needed to confirm our findings. IMPLICATIONS FOR PRACTICE: The results of this study reveal clinically important biomarkers that potentially predict immune checkpoint inhibitor response in patients with mismatch repair-deficient colorectal cancer.

Adaptive Bayesian phase I clinical trial designs for estimating the maximum tolerated doses for two drugs while fully utilizing all toxicity information.

The combined treatments with multiple drugs are very common in the contemporary medicine, especially for medical oncology. Therefore, we developed a Bayesian adaptive Phase I clinical trial design entitled escalation with overdoing control using normalized equivalent toxicity score for estimating maximum tolerated dose (MTD) contour of two drug combination (EWOC-NETS-COM) used for oncology trials. The normalized equivalent toxicity score (NETS) as the primary endpoint of clinical trial is assumed to follow quasi-Bernoulli distribution and treated as quasi-continuous random variable in the logistic linear regression model which is used to describe the relationship between the doses of the two agents and the toxicity response. Four parameters in the dose-toxicity model were re-parameterized to parameters with explicit clinical meanings to describe the association between NETS and doses of two agents. Noninformative priors were used and Markov chain Monte Carlo was employed to update the posteriors of the four parameters in dose-toxicity model. Extensive simulations were conducted to evaluate the safety, trial efficiency, and MTD estimation accuracy of EWOC-NETS-COM under different scenarios, using the EWOC as reference. The results demonstrated that EWOC-NETS-COM not only efficiently estimates MTD contour of multiple drugs but also provides better trial efficiency by fully utilizing all toxicity information.

[Xihuang Pills and its main components inhibit PI3K/Akt/mTOR signaling pathways and promote the apoptosis of prostate cancer cells in PC-3 tumor-bearing mice].

OBJECTIVE: To evaluate the effects of Xihuang Pills (XHP) and its main components on PI3K, AKT and mTOR signaling pathways and cell apoptosis of castration-resistant human PCa PC-3 cell subcutaneously transplanted tumors in nude mice. METHODS: We assigned 36 PC-3 tumor-bearing model mice to six groups of equal numbers to be treated with XHP, musk, calculus bovis (CB), musk + CB and docetaxel, respectively. After 14 days of intervention, we calculated the tumor-inhibition rate in different groups, observed the morphology of the tumor cells by HE staining, determined the levels of PI3K, Akt and mTOR mRNA by RT-qPCR, and determined the expressions of PI3K, Akt and mTOR signaling pathways and caspase-3 and caspase-9 proteins by Western blot. RESULTS: After 14 days of medication, the tumor-inhibition rates in the XHP, musk, CB, musk + CB and docetaxel groups were 29.67%, 5.52%, 7.26%, 12.88% and 6.26%, respectively. HE staining showed the formation of apoptotic bodies in the tumor tissues after intervention, especially in the XHP and musk + CB groups. The mRNA and phosphorylated protein expressions of PI3K, Akt and mTOR were significantly down-regulated (P < 0.01), and so were the expressions of caspase-3 and caspase-9 proteins in the XHP and musk + CB groups in comparison with the control (P < 0.01). CONCLUSIONS: Xihuang Pills, musk and calculus bovis can inhibit the growth of castration-resistant human PCa PC-3 cell subcutaneously transplanted tumors, which is associated with their effects of suppressing the abnormally activated PI3K, Akt and mTOR signaling pathways and promoting the apoptosis of PCa PC3 cells.

Efficacy and safety of immune checkpoint blockade in self-identified Black patients with advanced non-small cell lung cancer.

BACKGROUND: To the authors' knowledge, race-based differences in efficacy for the treatment of patients with advanced non-small cell lung cancer (NSCLC) have not been studied to date due to the underrepresentation of patients of minority backgrounds in pivotal trials. In the current study, the authors examined real-world differences in outcome in a diverse patient population. METHODS: The authors retrospectively analyzed the clinical outcomes of patients with advanced NSCLC who were treated with single-agent immune checkpoint blockade (ICB) between 2013 and July 2018 at Winship Cancer Institute of Emory University in Atlanta, Georgia. Primary efficacy comparison between Black patients and White patients was performed using bivariate and multivariate analyses for overall survival (OS) and progression-free survival (PFS). RESULTS: Data from 257 patients were analyzed. The median age of the patients was 69 years; 50.6% of the patients were female, 63.4% were White, 29.5% were Black, and 7.1% of the patients were of "other" race. ICB was the first-line treatment in 51 patients (19.9%), the second-line treatment in 161 patients (62.6%), and the third-line treatment in 33 patients (12.9%). The most commonly used agents were nivolumab (49.0%), pembrolizumab (25.2%), and atezolizumab (21.3%). No differences with regard to OS (P = .839) and PFS (P = .235) were noted between Black and White patients. The sample overall response rate was 20.6% (15.2% in Black patients and 23.1% in White patients). No differences with regard to OS (P = .081) and PFS (P = .176) were observed between female and male patients. The rate of immune-related adverse events was found to be similar in Black and White patients (20.0% vs 29.9%; P = .148). On multivariate analysis, race was not found to be significantly associated with OS or PFS. CONCLUSIONS: Real-world analysis of the authors' institutional experience demonstrated similar efficacy and tolerability of ICB in Black versus White patients with advanced NSCLC. Larger multi-institutional studies including other US minority populations would make the findings of the current study more generalizable.

Suppressive myeloid cells are expanded by biliary tract cancer-derived cytokines in vitro and associate with aggressive disease.

BACKGROUND: BTC is an aggressive disease exacerbated by inflammation and immune suppression. Expansion of immunosuppressive cells occurs in biliary tract cancer (BTC), yet the role of BTC-derived cytokines in this process is unclear. METHODS: Activated signalling pathways and cytokine production were evaluated in a panel of human BTC cell lines. Human peripheral blood mononuclear cells (PBMCs) were cultured with BTC supernatants, with and without cytokine neutralising antibodies, and analysed by flow cytometry or immunoblot. A human BTC tissue microarray (TMA, n = 69) was stained for IL-6, GM-CSF, and CD33+S100a9+ cells and correlated with clinical outcomes. RESULTS: Immunomodulatory factors (IL-6, GM-CSF, MCP-1) were present in BTC supernatants. BTC supernatants expanded CD33dimCD11b+HLA-DRlow/- myeloid-derived suppressor cells (MDSCs) from human PBMCs. Neutralisation of IL-6 and GM-CSF in BTC supernatants inhibited activation of STAT3/5, respectively, in PBMCs, with heterogeneous effects on MDSC expansion in vitro. Staining of a BTC TMA revealed a positive correlation between IL-6 and GM-CSF, with each cytokine and more CD33+S100a9+ cells. Increased CD33+S100a9+ staining positively correlated with higher tumour grade, differentiation and the presence of satellite lesions. CONCLUSION: BTC-derived factors promote suppressive myeloid cell expansion, and higher numbers of CD33+S100a9+ cells in resectable BTC tumours correlates with more aggressive disease.

Phase 1 safety and pharmacodynamic study of lenalidomide combined with everolimus in patients with advanced solid malignancies with efficacy signal in adenoid cystic carcinoma.

BACKGROUND: Purpose: The combination of a mammalian target of rapamycin inhibitor and lenalidomide showed enhanced preclinical cytotoxicity. We conducted a phase 1 study in advanced solid tumour patients to assess safety, efficacy and pharmacodynamic (PD) outcomes. METHODS: We employed a 3+3 dose escalation design to establish the safety and recommended phase 2 doses (RP2D) of daily everolimus and lenalidomide in patients with advanced solid tumours. The starting doses were 5 and 10 mg, respectively, with planned escalation to maximum single-agent doses of 10 and 25 mg in the absence of dose-limiting toxicity. PD endpoints of lymphocyte subsets and immune cytokines were assessed in peripheral blood using multiparameter flow cytometry and LUMINEX assay. Efficacy was evaluated by cross-sectional imaging after every two cycles of treatment. RESULTS: The study enrolled 44 patients, median age of 58 years and 28 males (63.6%). The RP2D was established as 10 and 25 mg daily continuously for everolimus and lenalidomide. Common (>5%) grade ≥3 adverse events included rash (19%), neutropenia (19%), hypokalaemia (11%) and fatigue (9%). Best efficacy outcomes in 36 evaluable patients were partial response in 5 (13.8%), stable disease in 24 (55.8%) and progressive disease in 7 (19.4%) patients. PD assessment revealed significant association of cytokine levels (interleukin-2 (IL2), IL21 and IL17), baseline activated and total CD8+ lymphocytes and change in B cell lymphocytes and activated NK cells with clinical benefit. CONCLUSIONS: The study demonstrated the safety of everolimus and lenalidomide with promising efficacy signal in thyroid and adenoid cystic cancers. CLINICAL TRIAL REGISTRATION: NCT01218555.

Vessel-specific quantification of absolute myocardial blood flow, myocardial flow reserve and relative flow reserve by means of fused dynamic 13NH3 PET and CCTA: Ranges in a low-risk population and abnormality criteria.

OBJECTIVES: The goal of the present work is to present a novel methodology for the extraction of MBF, MFR and RFR along coronary arteries by means of multimodality image fusion of dynamic PET and CCTA images. BACKGROUND: FFR is the reference standard to identify flow-limiting lesions, but its invasiveness limits broad application. New noninvasive methodologies are warranted to stratify patients and guide treatment. METHODS: A group of 16 low-risk CAD subjects who underwent both 13NH3 PET and CCTA were analyzed. Image fusion techniques were employed to align the studies and CCTA-derived anatomy used to identify coronaries trajectories. MBF was calculated by means of a 1-tissue compartmental model for the standard vascular territories and along patient-specific vessel paths from the base to the apex of the heart. RESULTS: Low-risk ranges for MBF. MFR and RFR for LAD, LCX and rPDA were computed for the entire cohort and separated by gender. Computed low-risk ranges were used to assess a prospective patient with suspected CAD. CONCLUSIONS: Our vessel-specific functional indexes and 3D displays offer promise to more closely replicate what is commonly performed during a catheterization session and have the potential of providing effective noninvasive tools for the identification of flow-limiting lesions and image-guided therapy.

Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients.

Exhausted T cells in chronic infections and cancer have sustained expression of the inhibitory receptor programmed cell death 1 (PD-1). Therapies that block the PD-1 pathway have shown promising clinical results in a significant number of advanced-stage cancer patients. Nonetheless, a better understanding of the immunological responses induced by PD-1 blockade in cancer patients is lacking. Identification of predictive biomarkers is a priority in the field, but whether peripheral blood analysis can provide biomarkers to monitor or predict patients' responses to treatment remains to be resolved. In this study, we analyzed longitudinal blood samples from advanced stage non-small cell lung cancer (NSCLC) patients (n = 29) receiving PD-1-targeted therapies. We detected an increase in Ki-67+ PD-1+ CD8 T cells following therapy in ∼70% of patients, and most responses were induced after the first or second treatment cycle. This T-cell activation was not indiscriminate because we observed only minimal effects on EBV-specific CD8 T cells, suggesting that responding cells may be tumor specific. These proliferating CD8 T cells had an effector-like phenotype (HLA-DR+, CD38+, Bcl-2lo), expressed costimulatory molecules (CD28, CD27, ICOS), and had high levels of PD-1 and coexpression of CTLA-4. We found that 70% of patients with disease progression had either a delayed or absent PD-1+ CD8 T-cell response, whereas 80% of patients with clinical benefit exhibited PD-1+ CD8 T-cell responses within 4 wk of treatment initiation. Our results suggest that peripheral blood analysis may provide valuable insights into NSCLC patients' responses to PD-1-targeted therapies.

Visualization of the Cellular Uptake and Trafficking of DNA Origami Nanostructures in Cancer Cells.

DNA origami is a promising molecular delivery system for a variety of therapeutic applications including cancer therapy, given its capability to fabricate homogeneous nanostructures whose physicochemical properties (size, shape, surface chemistry) can be precisely tailored. However, the correlation between DNA-origami design and internalization efficiency in different cancer cell lines remains elusive. We investigated the cellular uptake of four DNA-origami nanostructures (DONs) with programmed sizes and shapes in multiple human cancer cell lines. The cellular uptake efficiency of DONs was influenced by size, shape, and cell line. Scavenger receptors were responsible for the internalization of DONs into cancer cells. We observed distinct stages of the internalization process of a gold nanoparticle (AuNP)-tagged rod-shape DON, using high-resolution transmission electron microscopy. This study provides detailed understanding of cellular uptake and intracellular trafficking of DONs in cancer cells, and offers new insights for future optimization of DON-based drug delivery systems for cancer treatment.

Response to therapeutic monoclonal antibodies for multiple myeloma in African Americans versus whites.

BACKGROUND: Myeloma occurs disproportionately in African Americans, with disparities in outcomes potentially caused by access to care, cytogenetics, and immunity. A gap in knowledge of immune function dissimilarities between African Americans and whites exists. Data for other diseases suggest innate differences in immunity and inflammatory markers, with potential implications for therapeutic monoclonal antibodies reliant on secondary immune activation for activity. METHODS: Patients receiving daratumumab or elotuzumab, lenalidomide, and dexamethasone were retrospectively studied with a primary endpoint of response at 2 (daratumumab) or 4 months (elotuzumab). Secondary endpoints included stable disease or better at the same points, treatment duration, time to best response, and adverse events. RESULTS: Eighty patients were included; baseline characteristics were balanced with the exception of the stage at diagnosis, which was more advanced in African Americans. No statistically significant difference in response was seen: 37.9% in whites versus 11.8% in African Americans with daratumumab (P = .090) and 60% in whites versus 44% in African Americans with elotuzumab (P = .462). There were no differences in the duration of treatment, the time to best response, or adverse events. Common potential immune-related adverse events in both arms were fatigue (39%), back pain (30%), and infusion reactions (40%). Anemia was significantly associated with a response to daratumumab (P = .02); no patients without anemia responded at 2 months, whereas 34.4% of patients with anemia did. CONCLUSIONS: No significant difference in response, duration of treatment, or time to response was seen by race, although a trend toward greater early response rates in whites was observed. In these cohorts, as in other analyses, African American patients tended to present with later stage disease.

Phase 1b study of pasireotide, everolimus, and selective internal radioembolization therapy for unresectable neuroendocrine tumors with hepatic metastases.

BACKGROUND: Neuroendocrine tumors (NETs) metastasize to the liver. Everolimus and selective internal radioembolization (SIRT) are approved treatments. Pasireotide is a somatostatin analogue with an affinity for somatostatin receptors 1, 2, 3, and 5. Everolimus and pasireotide may potentiate SIRT radiosensitization and inhibit rebound angiogenesis. This study evaluated the safety of pasireotide, everolimus, and SIRT. METHODS: This 3 + 3 phase 1 trial evaluated 3 dose levels of everolimus (2.5, 5, and 10 mg/day), pasireotide (600 µg twice daily), and SIRT (SIR-Spheres dose on days 9 and 37). Eligibility criteria included well or moderately differentiated NETs, bilobar liver metastases, and progression on long-acting octreotide. Toxicities and responses were evaluated with the Common Terminology Criteria for Adverse Events and the Response Evaluation Criteria in Solid Tumors (version 1.1). Dose-limiting toxicities (DLTs) were defined in the first 28 days. Correlative markers-angiopoietin 1, angiopoietin 2, basic fibroblast growth factor, collagen V, insulin-like growth factor binding protein 1, insulin-like growth factor binding protein 1, interleukin 8, M30, M65, placenta growth factor, and vascular endothelial growth factor receptor 2-were assessed. The Norfolk Quality of Life-Neuroendocrine Tumor Questionnaire was used to assess the quality of life (QOL). RESULTS: Thirteen patients were enrolled; 1 was not evaluable for the primary endpoint. Eleven patients had well-differentiated tumors. The primary sites included small bowel (4), pancreas (3), lung (2), colon (1), gastric (1), and unknown primary (2) were unknown. Four had liver-only disease; 12 completed the planned treatment. No DLTs were observed. There was no treatment-related mortality. The most common toxicity was hyperglycemia. Clinically significant liver toxicity was not observed. One patient had liver progression. QOL improved on treatment. The median progression-free survival and overall survival were 18.6 and 46.3 months, respectively. CONCLUSIONS: The recommended phase 2 dose of everolimus is 10 mg daily in combination with pasireotide and SIRT. The regimen is well tolerated. Preliminary activity appears promising. Cancer 2018;124:1992-2000. © 2018 American Cancer Society.

Race-, Age-, and Gender-Based Characteristics and Toxicities of Targeted Therapies on Phase I Trials.

BACKGROUND: The impact of age-, gender-, and race-based differences on safety and efficacy in phase I clinical trials has not been well studied. METHODS: We analyzed data from phase I clinical trials evaluating targeted biologic agents in patients with advanced solid malignancies. Race and gender distribution of enrolled patients was compared to the referral population demographics at the city, metro, and state levels. The association between age, gender, and race with type, frequency, and severity of treatment-emergent toxicities and clinical benefit was assessed using univariate and multivariable models. RESULTS: Data from 117 eligible patients - Blacks/Caucasians/Others (27/85/5); male/female (66/51) - were obtained. Blacks were younger than Caucasian patients (median age of 56 vs. 62 years, p = 0.004). Nausea/vomiting was more frequent in female patients (43 vs. 24%, p = 0.03), while hematologic toxicity was more likely in Whites. While median time on treatment was comparable (113 vs. 91; p = 0.840), the median overall survival was significantly shorter for Blacks versus Caucasians (7.4 vs. 11.4 months; p = 0.0227). Black race (HR 2.11; 95% CI 1.24-3.60; p = 0.006) and older age (HR 1.03; 95% CI 1.00-1.06; p = 0.029) were associated with an increased risk of death. CONCLUSIONS: Age-, gender-, and race-based disparities were observed with specific toxicity and survival outcomes on phase I clinical trials of anticancer agents.

Lymph node metastasis in early gastric adenocarcinoma in the United States of America.

BACKGROUND AND STUDY AIMS: Localized approaches are being increasingly used in the management of early gastric adenocarcinoma; however, there are limited data on lymph node metastasis in the US population. This study examined the incidence and predictors of lymph node involvement for early-stage gastric adenocarcinomas in the USA. PATIENTS AND METHODS: Data were abstracted from the national SEER database from 2004 to 2013. Exclusion criteria included: cases with unknown tumor characteristics, unknown patient characteristics, metastatic disease, neoadjuvant radiation, and lack of surgical resection or lymph node evaluation. Univariate and multivariable analyses were conducted to assess the relationship of tumor stage, grade, and size, and patient sex, race, and age with nodal involvement. RESULTS: 43 769 cases of gastric adenocarcinoma were initially abstracted. After exclusions, 1577 patients remained for analysis. Multivariable analysis revealed that tumor stage (P < 0.001), grade (P = 0.008), and size (P < 0.001) were independent predictors of nodal metastasis. For low grade T1a tumors, nodal metastasis was present in 1.7 %, 1.7 %, 4.5 %, 4.1 %, and 20 % of tumors 0 - 1 cm, 1 - 2 cm, 2 - 3 cm, 3 - 4 cm, and ≥ 4 cm in size, respectively (P < 0.001), and in 8.4 %, 18.0 %, 19.5 %, 22.0 %, and 35.8 % of T1b tumors, respectively (P < 0.001). CONCLUSIONS: Low grade T1a tumors < 4 cm in size have low rates of nodal metastasis in the US population and may warrant consideration for local resection. Larger, higher grade T1b tumors have high rates of nodal metastasis in the US population and lymph node dissection may be indicated for patients who are surgical candidates.

Effect of personality traits on adherence with positive airway pressure therapy in obstructive sleep apnea patients.

PURPOSE: Patient adherence with positive airway pressure (PAP) therapy is a significant clinical problem in obstructive sleep apnea treatment. Personality traits may be a factor for non-adherence. The aim of this study is to investigate the relationship between PAP therapy adherence and patient personality traits. METHODS: Patients were screened and recruited during their visit to a sleep clinic. Baseline data were collected from each patient's electronic chart. Behavioral inhibition system/behavioral activation system (BIS/BAS) scales, short measure of five-factor model personality traits (mini-IPIP), positive and negative affect score (PANAS), and appetitive motivation scores (AMS) tests were used to measure personality traits. Data from the PAP device were obtained following a minimum of an initial 30 days, with adherence defined as >4 h/night on 70% of nights. Univariate and multivariate logistic regression and Pearson correlation tests were used to analyze the data. RESULTS: A total of 400 patients were recruited. Three hundred twenty-one patients had all the data and were included in the study. Behavioral activation system-fun seeking (BAS-FS) and, to a certain extent, negative affect were significantly associated with adherence. Intellect/imagination was marginally significant. Additionally, older age (>65 years), profession, PAP type, side effects, efficiency, apnea-hypopnea index (AHI), and residual AHI showed significant associations with patient adherence with PAP therapy. Multivariate analysis revealed that BAS-FS was still a significant predictor of adherence even after adjusting for other covariates. CONCLUSION: BAS-FS, negative affect, and intellect/imagination are significant factors for adherence to PAP therapy in obstructive sleep apnea patients.

Inhibiting heat shock protein 90 and the ubiquitin-proteasome pathway impairs metabolic homeostasis and leads to cell death in human pancreatic cancer cells.

BACKGROUND: Heat shock protein 90 (HSP90) and the ubiquitin-proteasome pathway play crucial roles in the homeostasis of pancreatic cancer cells. This study combined for the first time the HSP90 inhibitor ganetespib (Gan) and the proteasome inhibitor carfilzomib (Carf) to target key mechanisms of homeostasis in pancreatic cancer. It was hypothesized that Gan plus Carf would elicit potent antitumor activity by modulating complementary homeostatic processes. METHODS: In vitro and in vivo effects of this combination on mechanisms of cell growth and viability were evaluated with human pancreatic cancer cell lines (MIA PaCa-2 and HPAC). RESULTS: Combined treatment with Gan and Carf significantly decreased cell viability. The mechanism varied by cell line and involved G2 -M cell-cycle arrest accompanied by a consistent reduction in key cell-cycle regulatory proteins and concomitant upregulation of p27. Further studies revealed increased autophagy markers, including the upregulation of autophagy related 7 and light chain 3 cleavage, and evidence of apoptosis (increased Bax expression and processing of caspase 3). Immunoblot analyses confirmed the modulation of other pathways that influence cell viability, including phosphoinositide 3-kinase/Akt and nuclear factor κB. Finally, the treatment of athymic mice bearing HPAC tumors with Gan and Carf significantly reduced tumor growth in vivo. An immunoblot analysis of freshly isolated tumors from animals at the end of the study confirmed in vivo modulation of key signaling pathways. CONCLUSIONS: The results reveal Gan plus Carf to be a promising combination with synergistic antiproliferative, apoptotic, and pro-autophagy effects in preclinical studies of pancreatic cancer and will further the exploration of the utility of this treatment combination in clinical trials. Cancer 2017;123:4924-33. © 2017 American Cancer Society.