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BACKGROUND: Ofatumumab is a humanized type 1 anti-CD20 monoclonal antibody. Preclinical studies show improved complement-mediated cytotoxicity (CMC) compared to rituximab in mantle cell lymphoma (MCL). We evaluated the safety and efficacy of combining ofatumumab with HyperCVAD/MA (O-HyperCVAD) in newly diagnosed MCL. STUDY DESIGN: In this single-arm phase II study, 37 patients were treated with the combination of O-HyperCVAD for 4 or 6 cycles, followed by high dose chemotherapy and autologous stem cell transplant (HDC-ASCT). Primary objectives were overall response rate (ORR) and complete response (CR) rate at the end of therapy. Secondary objectives included minimal residual disease (MRD) negativity, progression free survival (PFS) and overall survival (OS). RESULTS: Median age was 60 years; ORR was 86% and 73% achieved a CR by modified Cheson criteria. The MRD negativity rate was 78% after 2 cycles of therapy, increasing to 96% at the end of induction; median PFS and OS were 45.5 months and 56 months respectively. Achieving a post-induction CR by both imaging and flow cytometry was associated with improved PFS and OS. Early MRD negativity (post-2 cycles) was also associated with an improved PFS but not OS. There were 3 deaths while on therapy, and grade 3 and 4 adverse events (AEs) were observed in 22% and 68% of the patients. CONCLUSION: The addition of ofatumumab to HyperCVAD/HD-MA led to high rates of MRD negativity by flow cytometry in patients with newly diagnosed MCL. Achieving a CR post-induction by both imaging and flow cytometry is associated with improved overall survival.

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Supplemental Figure 1. Tumor infiltrating Treg; Supplemental Figure 2. Treg and IFN�-CD8.

Purpose: On the basis of preclinical data suggesting that the class I selective HDAC inhibitor entinostat exerts a synergistic antitumor effect in combination with high-dose IL2 in a renal cell carcinoma model by downregulating Foxp3 expression and function of regulatory T cells (Treg), we conducted a phase I/II clinical study with entinostat and high-dose IL2 in patients with metastatic clear cell renal cell carcinoma (ccRCC).Experimental Design: Clear cell histology, no prior treatments, and being sufficiently fit to receive high-dose IL2 were the main eligibility criteria. The phase I portion consisted of two dose levels of entinostat (3 and 5 mg, orally every 14 days) and a fixed standard dose of IL2 (600,000 U/kg i.v.). Each cycle was 85 days. The primary endpoint was objective response rate and toxicity. Secondary endpoints included progression-free survival and overall survival.Results: Forty-seven patients were enrolled. At a median follow-up of 21.9 months, the objective response rate was 37% [95% confidence interval (CI), 22%–53%], the median progression-free survival was 13.8 months (95% CI, 6.0–18.8), and the median overall survival was 65.3 months (95% CI, 52.6.-65.3). The most common grade 3/4 toxicities were hypophosphatemia (16%), lymphopenia (15%), and hypocalcemia (7%), and all were transient. Decreased Tregs were observed following treatment with entinostat, and lower numbers were associated with response (P = 0.03).Conclusions: This trial suggests a promising clinical activity for entinostat in combination with high-dose IL2 in ccRCC patients and provides the first example of an epigenetic agent being rationally combined with immunotherapy. Clin Cancer Res; 23(23); 7199–208. ©2017 AACR.

Limited therapeutic options dictate the need for new classes of antimicrobials active against carbapenem-resistant Acinetobacter baumannii. Presented data confirm and extend penicillin binding protein 7/8 (PBP 7/8) as a high-value target in the CR A. baumannii strain HUMC1. PBP 7/8 was essential for optimal growth/survival of HUMC1 in ex vivo human ascites and in a rat subcutaneous abscess model; in a mouse pneumonia model, the absence of PBP 7/8 decreased lethality 11-fold. The loss of PBP 7/8 resulted in increased permeability, sensitivity to complement, and lysozyme-mediated bactericidal activity. These changes did not appear to be due to alterations in the cellular fatty acid composition or capsule production. However, a decrease in lipid A and an increase in coccoidal cells and cell aggregation were noted. The compromise of the stringent permeability barrier in the PBP 7/8 mutant was reflected by an increased susceptibility to several antimicrobials. Importantly, expression of ampC was not significantly affected by the loss of PBP 7/8 and serial passage of the mutant strain in human ascites over 7 days did not yield revertants possessing a wild-type phenotype. In summary, these data and other features support PBP 7/8 as a high-value drug target for extensively drug-resistant and CR A. baumannii. Our results guide next-stage studies; the determination that the inactivation of PBP 7/8 results in an increased sensitivity to lysozyme enables the design of a high-throughput screening assay to identify small molecule compounds that can specifically inhibit PBP 7/8 activity.

New antimicrobials are needed for the treatment of extensively drug-resistant Acinetobacter baumannii . The de novo pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated drug target for malaria and human autoimmune diseases. We provide genetic evidence that A. baumannii DHODH ( Ab DHODH) is essential for bacterial survival in rodent infection models. We chemically validate the target by repurposing a unique library of ~450 triazolopyrimidine/imidazopyrimidine analogs developed for our malaria DHODH program to identify 21 compounds with submicromolar activity on Ab DHODH. The most potent (DSM186, DHODH IC 50 28 nM) had a minimal inhibitory concentration of ≤1 µg/ml against geographically diverse A. baumannii strains, including meropenem-resistant isolates. A structurally related analog (DSM161) with a long in vivo half-life conferred significant protection in the neutropenic mouse thigh infection model. Encouragingly, the development of resistance to these compounds was not identified in vitro or in vivo. Lastly, the X-ray structure of Ab DHODH bound to DSM186 was solved to 1.4 Å resolution. These data support the potential of Ab DHODH as a drug target for the development of antimicrobials for the treatment of A. baumannii and potentially other high-risk bacterial infections.

The CORAL study highlighted the need to develop novel salvage regimens in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) previously treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. Carfilzomib (CFZ) can overcome rituximab chemotherapy resistance in lymphoma preclinical models by targeting the ubiquitin-proteasome system. We conducted an investigator initiated, single-center, open-label, prospective phase 1 study evaluating the safety and efficacy of CFZ in combination with rituximab, ifosfamide, carboplatin, and etoposide (C-R-ICE) in high-dose chemotherapy with autologous stem cell transplant (HDC-ASCT) eligible patients with R/R DLBCL (NCT01959698). In the dose-escalation phase, 18 patients were enrolled at 6 dose levels with no dose-limiting toxicities noted. CFZ 45 mg/m2 was selected as the recommended dose for expansion. Eleven additional patients were enrolled in the dose-expansion phase. Overall response rate (ORR) was 66% (48% CR; 17% PR); 52% patients underwent HDC-ASCT. An ORR of 85% was observed in patients with nongerminal center B-cell–like (non-GCB) DLBCL compared with only 13% in those with GCB DLBCL. Median progression-free survival (PFS) was 15.2 months (5.1 months, not reached [NR]), and median overall survival (OS) was 22.6 months (6.8 months, NR). Patients with non-GCB subtype had a significantly longer PFS (NR vs 6.6 months; P = .0001) and OS (NR vs 6.6 months; P = .001) than those with GCB subtype. C-R-ICE is well tolerated in patients with R/R DLBCL with toxicities comparable to rituximab, ifosfamide, carboplatin, and etoposide therapy. Our data show that patients with non-GCB DLBCL benefit significantly from incorporating CFZ into second-line therapy and HDC-ASCT.

Purpose African American (AA) men are diagnosed with Prostate cancer (PCa) approximately 3 years younger, more often in an advanced stage, and incurable, when compared to Caucasian American (CA) men. We seek to study whether this difference is due to factors related to, stress, lack of knowledge of prostate cancer, race, or the combination of all these factors. Methods A questionnaire was administered to 389 participants (234 CA and 135 AA men) for a possible diagnosis of prostate cancer over 3 years. Quantitative data was collected from patients on demographic status along with their level of knowledge of prostate cancer and anxiety related to their diagnosis and possible treatment. Exact Pearson chi-square tests were used to test the independence between race and various socio-economic factors. Results In this study, for the first time, we investigated whether knowledge of the disease and anxiety following diagnosis and treatment could play a role in the disparity of prostate cancer among AA and CA men. We also confirmed that financial disparities among AA and CA men, with AA having more financial strain. Conclusion Our study showed that lack of knowledge of PCa screening and early detection, and lack of understanding of the diagnosis in combination with increased anxiety among AA patients, can play a role in PCa disparity.

There are no effective treatments for patients with extrinsic malignant central airway obstruction (MCAO). In a recent clinical study, we demonstrated that interstitial photodynamic therapy (I-PDT) is a safe and potentially effective treatment for patients with extrinsic MCAO. In previous preclinical studies, we reported that a minimum light irradiance and fluence should be maintained within a significant volume of the target tumor to obtain an effective PDT response. In this paper, we present a computational approach to personalized treatment planning of light delivery in I-PDT that simultaneously optimizes the delivered irradiance and fluence using finite element method (FEM) solvers of either Comsol Multiphysics® or Dosie™ for light propagation. The FEM simulations were validated with light dosimetry measurements in a solid phantom with tissue-like optical properties. The agreement between the treatment plans generated by two FEMs was tested using typical imaging data from four patients with extrinsic MCAO treated with I-PDT. The concordance correlation coefficient (CCC) and its 95% confidence interval (95% CI) were used to test the agreement between the simulation results and measurements, and between the two FEMs treatment plans. Dosie with CCC = 0.994 (95% CI, 0.953–0.996) and Comsol with CCC = 0.999 (95% CI, 0.985–0.999) showed excellent agreement with light measurements in the phantom. The CCC analysis showed very good agreement between Comsol and Dosie treatment plans for irradiance (95% CI, CCC: 0.996–0.999) and fluence (95% CI, CCC: 0.916–0.987) in using patients’ data. In previous preclinical work, we demonstrated that effective I-PDT is associated with a computed light dose of ≥45 J/cm2 when the irradiance is ≥8.6 mW/cm2 (i.e., the effective rate-based light dose). In this paper, we show how to use Comsol and Dosie packages to optimize rate-based light dose, and we present Dosie’s newly developed domination sub-maps method to improve the planning of the delivery of the effective rate-based light dose. We conclude that image-based treatment planning using Comsol or Dosie FEM-solvers is a valid approach to guide the light dosimetry in I-PDT of patients with MCAO.

ImportanceThe American Institute for Cancer Research and American Cancer Society regularly publish modifiable lifestyle recommendations for cancer prevention. Whether these recommendations have an impact on high-risk breast cancer survival remains unknown.ObjectiveTo investigate whether adherence to cancer prevention recommendations before, during, and 1 and 2 years after breast cancer treatment was associated with disease recurrence or mortality.Design, Setting, and ParticipantsThe Diet, Exercise, Lifestyles, and Cancer Prognosis Study (DELCaP) was a prospective, observational cohort study designed to assess lifestyles before diagnosis, during treatment, and at 1 and 2 years after treatment completion, implemented ancillary to the Southwest Oncology Group (SWOG) S0221 trial, a multicenter trial that compared chemotherapy regimens in breast cancer. Participants were chemotherapy-naive patients with pathologic stage I to III high-risk breast cancer, defined as node-positive disease with hormone receptor–negative tumors larger than 1 cm or any tumor larger than 2 cm. Patients with poor performance status and comorbidities were excluded from S0221. The study was conducted from January 1, 2005, to December 31, 2010; mean (SD) follow-up time for those not experiencing an event was 7.7 (2.1) years through December 31, 2018. The analyses reported herein were performed from March 2022 to January 2023.ExposureAn aggregated lifestyle index score comprising data from 4 time points and 7 lifestyles, including (1) physical activity, (2) body mass index, (3) fruit and vegetable consumption, (4) red and processed meat intake, (5) sugar-sweetened beverage consumption, (6) alcohol consumption, and (7) smoking. Higher scores indicated healthier lifestyle.Main Outcomes and MeasuresDisease recurrence and all-cause mortality.ResultsA total of 1340 women (mean [SD] age, 51.3 [9.9] years) completed the baseline questionnaire. Most patients were diagnosed with hormone-receptor positive breast cancer (873 [65.3%]) and completed some education beyond high school (954 [71.2%]). In time-dependent multivariable analyses, patients with highest vs lowest lifestyle index scores experienced a 37.0% reduction in disease recurrence (hazard ratio, 0.63; 95% CI, 0.48-0.82) and a 58.0% reduction in mortality (hazard ratio, 0.42; 95% CI, 0.30-0.59).Conclusions and RelevanceIn this observational study of patients with high-risk breast cancer, strongest collective adherence to cancer prevention lifestyle recommendations was associated with significant reductions in disease recurrence and mortality. Education and implementation strategies to help patients adhere to cancer prevention recommendations throughout the cancer care continuum may be warranted in breast cancer.

DNA mismatch repair (MMR) genes (e.g., MLH1, MSH2, MSH6, PMS2, and EPCAM) play an important role in maintaining genomic stability during DNA replication and recombination. Deficiency in MMR resulting from mutations in these genes leads to mutations in microsatellite regions throughout the genome (microsatellite instability; MSI) and in cancer driver oncogenes or tumor suppressor genes, which accumulate over time and eventually lead to cancer formation. Monoallelic germline mutation in MMR genes causes Lynch syndrome (LS). Among LS-related cancer types, the lifetime risk for colorectal cancer (CRC) is the highest (~80%). Frameshift mutations (FSMs) in coding microsatellites produce neoantigens, which have been shown to elicit immune responses. It was thus postulated that they can serve as vaccine targets. To develop a prophylactic vaccine and prevention strategy for this high-risk population, we characterized a LS mouse model (Msh2LoxP/LoxP;Villin-Cre) to determine whether these mice recapitulate the human LS oncogenic process. We found that tumor development was already notable at 7-8 months of age and median survival was 11.5 months. Histopathological analysis showed that tumors were adenoma or adenocarcinoma mixed with mucinous features. Using a targeted sequencing approach, a panel of FSMs in mononucleotide regions were identified in both tumors and histologically normal mucosa, suggesting that Msh2 deletion and FSMs were not sufficient for tumor development. In addition, Apc, Ctnnb, and Trp53 mutations were also observed with low frequency in organoids derived from these tumors, indicating that other driver mutations may be required for tumor initiation and progression, and most FSMs detected in tumors and mucosa were probably passenger mutations. To determine if fecal samples can be used to monitor the FSM load, fecal DNA from different time points was sequenced. We found that FSMs can be detected at 1month of age although the number of FSMs was relatively low compared to that from older mice, indicating that FSMs accumulate over time. MSI detection via fragment analysis confirmed that these tumors were MSI-H. Interestingly, mucosa and fecal samples from a time course study showed progressive increase in microsatellite instability, suggesting the possibility of using MSI score for disease monitoring. Our preliminary data indicates that combined fecal FSM status and MSI score can be potentially used as a biomarker to monitor the tumor development and disease progression for LS colorectal cancer. Funded by the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261201500003I Citation Format: Yurong Song, Shaneen Baxter, Lisheng Dai, Chelsea Sanders, Holli Loomans-Kropp, Brandon Somerville, Ryan N. Baugher, Stephanie D. Mellott, Todd B. Young, Heidi E. Lawhorn, Teri M. Plona, Bingfang Xu, Lei Wei, Qiang Hu, Song Liu, Alan Hutson, Baktiar Karim, Simone Difilippantonio, Ligia Pinto, Matthias Kloor, Steven M. Lipkin, Shizuko Sei, Robert H. Shoemaker. Time course genomic characterization reveals progressive accumulation of mutations during tumor development in a Lynch syndrome mouse model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6518.

Background: Patients with extrabronchial tumors that induce malignant central airway obstruction (MCAO) face dire prognoses with significant morbidity and 1-7 months overall survival. These tumors are inoperable. High-dose curative radiotherapy is associated with significant toxicity. Chemotherapy has limited localized benefits and immunotherapy cannot address the immediate need to halt tumor progression. Our preliminary data suggest that image-guided interstitial photodynamic therapy (I-PDT) with porfimer sodium is safe and potentially effective in patients with extrabronchial tumors that induce MCAO and there is a need to further improve the rate of response. Here we present results showing an improved tumor response rate by augmenting I-PDT with palliative radiotherapy (p-XRT). Methods: We investigated the addition of p-XRT prior to I-PDT to sensitize the target tumor to subsequent photoreaction in mouse models. Eight- to twelve-week-old C3H and C57B/6 mice with locally advanced (400-600 mm3) SCC-VII or LLC tumors, respectively, were treated with I-PDT alone or with p-XRT followed by I-PDT. The p-XRT regimen was 10 Gy x2 over two days. At 24-26 h after the second 10 Gy fraction, the I-PDT was administered with 5 mg/kg porfimer sodium activated with 630-nm laser light at 5.0 mW/cm2 and 45 J/cm2 at tumor margins. Photoacoustic imaging and light dosimetry measurements were used to investigate the impact of p-XRT on the tumor microenvironment as it pertains to the response to I-PDT. Tumor progression was monitored over 60 days. Image-based treatment planning was used to translate the preclinical findings into a treatment in clinical settings (8 Gy x1 followed by I-PDT) for patients with extrabronchial MCAO. Results: Preceding I-PDT with p-XRT increases tumor oxygenation for 1-2 days after the last radiation fraction and improves light penetration within mouse tumors. Administering p-XRT 24-48 h before I-PDT significantly (p Conclusions: Augmenting I-PDT with p-XRT improves the rate of tumor response. Murine studies show that p-XRT increases tumor blood oxygenation and light penetration which could contribute to better response to I-PDT. I-PDT with porfimer sodium preceded by p-XRT is feasible with possible benefits in patients with extrabronchial MCAO. Citation Format: Emily Oakley, Sarah Chamberlain, Nathaniel Ivanick, Alan Hutson, Theresa Busch, Gal Shafirstein. Image-guided interstitial photodynamic therapy with palliative radiotherapy for ablating extrabronchial malignant central airway obstruction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2423.

Background Patients with hepatocellular carcinoma (HCC) have a poor prognosis with a 5-year survival rate of only 35%. Patients with locally advanced HCC (single or multinodal tumors >3 cm) may not be candidates for curative treatments such as surgical resection, liver transplant or thermal ablation due to tumor size, poor liver function, or other medical co-morbidities. The objective of this study was to investigate the potential use of interstitial chemo-phototherapy (I-CPT) to treat locally advanced HCC with a porphyrin-phospholipid (PoP) liposomal formulation of doxorubicin (Dox) that combines the targeted delivery of doxorubicin with photodynamic therapy to improve local drug delivery. We aimed to identify a safe and effective light dose for the photoactivation of Dox-Pop in the treatment of locally advanced HCC tumors in two pre-clinical models. Methods Sprague-Dawley rats were inoculated with Morris hepatoma cells directly into the left lateral liver lobe. When the tumors reached 2-2.5 cm along the longest axis, they were treated with Dox-Pop followed by light (i.e. I-CPT). For each rat, we applied our image-based treatment planning to guide the light delivery. Following treatment, tumor response was measured through weekly contrast-enhanced magnetic resonance imaging (CE-MRI). Complete response was defined as no evidence of the tumor via MRI or pathological examination. Our image-based treatment planning was used to translate the findings in the rat study to woodchucks with 1.5-4 cm hepatitis virus induced HCC. Weekly blood samples and bi-weekly CE-MRI were performed to assess tumor response up to 70 days. Results Five out of the six rats treated with I-CPT had complete response, with three of the five surviving ≥10 weeks post treatment without tumor recurrence or progression. The other two rats with complete response died between 5-7 weeks post treatment. Death was not attributed to the original treatment. Control, untreated rats were euthanized due to tumor progression within 1-2 weeks after tumors reached 2-2.5 cm. From the rat studies, we identified that a light dose rate and dose of respectively, ≥13.4 mW/cm2 and ≥25 J/cm2 can effectively activate the Dox-Pop liposomes. Of the five woodchucks treated with I-CPT using our effective light regimen, two survived ≥ 68 days post treatment without tumor progression. Another woodchuck had a complete response, but was euthanized 55 days post treatment due to the development of a second tumor. One woodchuck had progressive disease following I-CPT. One woodchuck died unexpectedly 5 days post I-CPT. Death was attributed to high tumor necrosis. Conclusions This study demonstrated the potential use of I-CPT as a treatment option for locally advanced HCC not candidate for standard of care therapies. Ongoing studies are being conducted in woodchucks to optimize the I-CPT light settings and improve tumor response. Citation Format: Emily Oakley, Minhyung Kim, Sanjana Ghosh, Hilliard Kutscher, Jonathan Lovell, Leslie Curtin, Sandra Sexton, Alan Hutson, Gal Shafirstein. Interstitial chemo-phototherapy for treatment of locally advanced hepatocellular carcinoma: A preclinical study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2420.

To uncover underlying mechanisms associated with failure of indoleamine 2,3-dioxygenase 1 (IDO1) blockade in clinical trials, we conducted a pilot, window-of-opportunity clinical study in 17 patients with newly diagnosed advanced high-grade serous ovarian cancer before their standard tumor debulking surgery. Patients were treated with the IDO1 inhibitor epacadostat, and immunologic, transcriptomic, and metabolomic characterization of the tumor microenvironment was undertaken in baseline and posttreatment tumor biopsies. IDO1 inhibition resulted in efficient blockade of the kynurenine pathway of tryptophan degradation and was accompanied by a metabolic adaptation that shunted tryptophan catabolism toward the serotonin pathway. This resulted in elevated nicotinamide adenine dinucleotide (NAD + ), which reduced T cell proliferation and function. Because NAD + metabolites could be ligands for purinergic receptors, we investigated the impact of blocking purinergic receptors in the presence or absence of NAD + on T cell proliferation and function in our mouse model. We demonstrated that A2a and A2b purinergic receptor antagonists, SCH58261 or PSB1115, respectively, rescued NAD + -mediated suppression of T cell proliferation and function. Combining IDO1 inhibition and A2a/A2b receptor blockade improved survival and boosted the antitumor immune signature in mice with IDO1 overexpressing ovarian cancer. These findings elucidate the downstream adaptive metabolic consequences of IDO1 blockade in ovarian cancers that may undermine antitumor T cell responses in the tumor microenvironment.

RationaleVaping has become a popular method of inhaling various psychoactive substances. While evaluating respiratory effects of vaping have primarily focused on nicotine-containing products, cannabidiol (CBD)-vaping is increasingly becoming popular. It currently remains unknown whether the health effects of vaping nicotine and cannabinoids are similar.ObjectivesThis study compares side by side the pulmonary effects of acute inhalation of vaporised CBD versus nicotine.MethodsIn vivo inhalation study in mice and in vitro cytotoxicity experiments with human cells were performed to assess the pulmonary damage-inducing effects of CBD or nicotine aerosols emitted from vaping devices.Measurements and main resultsPulmonary inflammation in mice was scored by histology, flow cytometry, and quantifying levels of proinflammatory cytokines and chemokines. Lung damage was assessed by histology, measurement of myeloperoxidase activity and neutrophil elastase levels in the bronchoalveolar lavage fluid and lung tissue. Lung epithelial/endothelial integrity was assessed by quantifying BAL protein levels, albumin leak and pulmonary FITC-dextran leak. Oxidative stress was determined by measuring the antioxidant potential in the BAL and lungs. The cytotoxic effects of CBD and nicotine aerosols on human neutrophils and human small airway epithelial cells were evaluated using in vitro air–liquid interface system. Inhalation of CBD aerosol resulted in greater inflammatory changes, more severe lung damage and higher oxidative stress compared with nicotine. CBD aerosol also showed higher toxicity to human cells compared with nicotine.ConclusionsVaping of CBD induces a potent inflammatory response and leads to more pathological changes associated with lung injury than vaping of nicotine.

ImportanceChanges in postsurgical opioid prescribing practices may help reduce chronic opioid use in surgical patients.ObjectiveTo investigate whether postsurgical acute pain across different surgical subspecialties can be managed effectively after hospital discharge with an opioid supply of 3 or fewer days and whether this reduction in prescribed opioids is associated with reduced new, persistent opioid use.Design, Setting, and ParticipantsIn this prospective cohort study with a case-control design, a restrictive opioid prescription protocol (ROPP) specifying an opioid supply of 3 or fewer days after discharge from surgery along with standardized patient education was implemented across all surgical services at a tertiary-care comprehensive cancer center. Participants were all patients who underwent surgery from August 1, 2018, to July 31, 2019.Main Outcomes and MeasuresMain outcomes were the rate of compliance with the ROPP in each surgical service, the mean number of prescription days and refill requests, type of opioid prescribed, and rate of conversion to chronic opioid use determined via a state-run opioid prescription program. Postsurgical complications were also measured.ResultsA total of 4068 patients (mean [SD] age, 61.0 [13.8] years; 2528 women [62.1%]) were included, with 2017 in the pre-ROPP group (August 1, 2018, to January 31, 2019) and 2051 in the post-ROPP group (February 1, 2019, to July 31, 2019). The rate of compliance with the protocol was 95%. After implementation of the ROPP, mean opioid prescription days decreased from a mean (SD) of 3.9 (4.5) days in the pre-ROPP group to 1.9 (3.6) days in the post-ROPP group (P P P = .02). There was no statistically significant difference in surgical complications. The conversion rate to chronic opioid use decreased following ROPP implementation among both opioid-naive patients with cancer (11.3% [143 of 1267] to 4.5% [118 of 2645]; P P = .02).Conclusions and RelevanceIn this cohort study, prescribing an opioid supply of 3 or fewer days to surgical patients after hospital discharge was feasible for most patients, led to a significant decrease in the number of opioids prescribed after surgery, and was associated with a significantly decreased conversion to long-term opioid use without concomitant increases in refill requests or significant compromises in surgical recovery.

Purpose This paper uses statistical analyses to quantify the effects of five major macroeconomic indicators, namely crude oil price, 30-year mortgage interest rate (IR), Consumer Price Index (CPI), Dow Jones Industrial Average (DJIA), and unemployment rate (UR), on housing prices over time. Design/methodology/approach Housing price is measured as housing price index (HPI) and is treated as a variable affecting itself. Actual housing sale prices in the Town of Amherst, New York State, USA, 1999-2008, and time-series data of the macroeconomic indicators, 2000-2017, were used in a vector autoregression statistical model to examine the data that show the greatest statistical significance and exert maximum quantitative effects of macroeconomic indicators on housing prices. Findings The analyses concluded that the 30-year IR and HPI have statistically significant effects on housing prices. IR has the highest effect, contributing 5.0 per cent of variance in the first month to 8.5 per cent in the twelfth. The UR has the next greatest influence followed by DJIA and CPI. The disturbance from HPI itself causes the greatest variability in future prices: up to 92.7 per cent in variance 1 month ahead and approximately 74.5 per cent 12 months ahead. This result indicates that current changes in house prices heavily influence people’s expectation of future prices. The total effect of the error variance of the macroeconomic indicators ranged from 7.3 per cent in the first month to 25.5 per cent in the twelfth. Originality/value The conclusions in this paper, along with related tables and figures, will be useful to the housing and real estate communities in planning their business for the next years.

BACKGROUND Newly diagnosed glioblastoma (nGBM) has dismal outcomes with survival of 15-18 months. Tumor associated “survivin” is expressed in > 95% of nGBM and targetable by SurVaxM immunotherapy. METHODS nGBM patients (pts) were enrolled in this Phase 2 study, age ≥ 18, KPS ≥ 70, IHC confirmed surviving-expression, expression of HLA-A*02, A*03, A*11 or A*24 MHC-I alleles and residual contrast enhancement of ≤1 cm3 by MRI. Pts were treated with standard TMZ chemoradiation followed by initiation of 4 priming doses of SurVaxM (500 mcg in emulsion with Montanide ISA 51, every 2 weeks) with 100 mcg sargramostim. Maintenance doses of SurVaxM-Montanide plus sargramostim given every 12 weeks with Adjuvant TMZ for at least 6 cycles. The primary endpoint was 70% progression free survival (PFS) at 6 mos. Primary analyses of median PFS (mPFS) and median overall survival (OS) were measured from the first immunization. Safety, tolerability, and immune responsiveness were also determined. RESULTS 63 pts (38 males), median age, 60 years were treated at 5 sites. SurVaxM was well tolerated, with no serious adverse events. A strong positive correlation, accounting for censoring, was observed between PFS and OS of all pts (r = 0.79; 95% CI (0.66,0.87)). SurVaxM was immunogenic and produced survivin-specific CD8+ T-cells and antibody (IgG) titers in both methylated and unmethylated MGMT pts. Both groups showed clinical benefit with PFS of 11.4 months for the for the whole group, 7.0 months for unmethylated and 17.9 months for methylated group. OS of 25.9 months for the whole group, 16.5 months for unmethylated and 41.4 months for methylated group. CONCLUSIONS SurVaxM appeared to be safe and well-tolerated in pts with nGBM. SurVaxM was effective at stimulating survivin-specific immune responses and the primary endpoint was met. SurVaxM represents a promising therapy for nGBM, randomized trial is ongoing. Clinical trial information: NCT02455557.

The objective of the present study was to develop a predictive model for Photofrin®‐mediated interstitial photodynamic therapy (I‐PDT) of locally advanced tumors. Our finite element method was used to simulate 630‐nm intratumoral irradiance and fluence for C3H mice and New Zealand White rabbits bearing large squamous cell carcinomas. Animals were treated with light only or I‐PDT using the same light settings. I‐PDT was administered with Photofrin® at 5.0 or 6.6 mg kg−1, 24 h drug‐light interval. The simulated threshold fluence was fixed at 45 J cm−2 while the simulated threshold irradiance varied, intratumorally. No cures were obtained in the mice treated with a threshold irradiance of 5.4 mW cm−2. However, 20–90% of the mice were cured when the threshold irradiances were ≥8.6 mW cm−2. In the rabbits treated with I‐PDT, 13 of the 14 VX2 tumors showed either local control or were cured when threshold irradiances were ≥15.3 mW cm−2 and fluence was 45 J cm−2. No tumor growth delay was observed in VX2 treated with light only (n = 3). In the mouse studies, there was a high probability (92.7%) of predicting cure when the initial tumor volume was below the median (493.9 mm3) and I‐PDT was administered with a threshold intratumoral irradiance ≥8.6 mW cm−2., In this study, we applied our image‐based finite element method for simulating intratumoral irradiance and fluence to guide the light delivery and dosimetry during Photofrin®‐mediated I‐PDT of locally advanced squamous cell carcinomas in C3H mice and New Zealand White rabbits. Our results demonstrated that for the same threshold intratumoral fluence, the intratumoral threshold irradiance along with the initial tumor volume is a key parameter in predicting tumor response to Photofrin®‐mediated I‐PDT.

A hypervirulent Klebsiella pneumoniae (hvKp) pathotype is undergoing global dissemination. In contrast to the usual health care-associated epidemiology of classical K. pneumoniae (cKp) infections, hvKp causes tissue-invasive infections in otherwise healthy individuals from the community, often involving multiple sites. An accurate test to identify hvKp strains is needed for improved patient care and epidemiologic studies. To fill this knowledge gap, clinical criteria or random blood isolates from North American and United Kingdom strain collections were used to assemble hvKp-rich (n = 85) and cKp-rich (n = 90) strain cohorts, respectively. The isolates were then assessed for multiple candidate biomarkers hypothesized to accurately differentiate the two cohorts. The genes peg-344, iroB, iucA, plasmid-borne rmpA gene ((p)rmpA), and (p)rmpA2 all demonstrated >0.95 diagnostic accuracy for identifying strains in the hvKp-rich cohort. Next, to validate this epidemiological analysis, all strains were assessed experimentally in a murine sepsis model. peg-344, iroB, iucA, (p)rmpA, and (p)rmpA2 were all associated with a hazard ratio of >25 for severe illness or death, additionally supporting their utility for identifying hvKp strains. Quantitative siderophore production of ≥30 μg/ml also strongly predicted strains as members of the hvKp-rich cohort (accuracy, 0.96) and exhibited a hazard ratio of 31.7 for severe illness or death. The string test, a widely used marker for hvKp strains, performed less well, achieving an accuracy of only 0.90. Last, using the most accurate biomarkers to define hvKp, prevalence studies were performed on two Western strain collections. These data strongly support the utility of several laboratory markers for identifying hvKp strains with a high degree of accuracy.

OBJECTIVES: To assess bone marrow (BM) sampling in academic medical centers. METHODS: Data from 6,374 BM samples obtained in 32 centers in 2001 and 2011, including core length (CL), were analyzed. RESULTS: BM included a biopsy (BMB; 93%) specimen, aspirate (BMA; 92%) specimen, or both (83%). The median (SD) CL was 12 (8.5) mm, and evaluable marrow was 9 (7.6) mm. Tissue contraction due to processing was 15%. BMB specimens were longer in adults younger than 60 years, men, and bilateral, staging, and baseline samples. Only 4% of BMB and 2% of BMB/BMA samples were deemed inadequate for diagnosis. BM for plasma cell dyscrasias, nonphysician operators, and ancillary studies usage increased, while bilateral sampling decreased over the decade. BM-related quality assurance programs are infrequent. CONCLUSIONS: CL is shorter than recommended and varies with patient age and sex, clinical circumstances, and center experience. While pathologists render diagnoses on most cases irrespective of CL, BMB yield improvement is desirable.

Comparing chromosomal locations of statistically significant colon and lung cancer susceptibility loci detected by linkage in mouse and rat and by GWAS in humans revealed conservation of position of most of them in spite of the 70 million years of separate rodent and primate evolution. 1. When projected onto their corresponding homologous positions in the mouse genome, 79% of human, and rat loci as well as mouse loci mapped together in 31 distinct short clusters, which indicate presence of at least 31 evolutionary conserved colon/lung cancer susceptibility genes or gene pairs. 2. These co-localizations indicate also an evolutionary conservation of the hierarchy of strength of colon and lung cancer susceptibility genes. Generally, both in linkage and in GWAS studies a subset of genes with the largest effect will reach the significance threshold early, while many other genes will remain beneath it and may reach significance only in later studies, especially meta-analyzes. As we analyzed only significant genes, the co-mapping of their majority into the 31 clusters has been possible only if the subsets of genes with the largest effects are very similar in all three species. 3. In addition, the majority of colon and lung cancer susceptibility QTLs formed linked pairs. Consequently, all 31 clusters contained both colon and lung cancer susceptibility QTLs. 4. This pair-wise genomic location of colon and lung cancer QTLs seemed to be associated with their similar quantitative effects on tumorigenesis, as tests of congenic mouse strains each carrying 87% of BALB/c genome and differing from each other in a small subset of colon cancer QTLs revealed that the two strains with very high colon cancer susceptibility and the two strains with very low colon cancer susceptibility exhibited concordantly very high and very low susceptibility to lung cancer, respectively. 5. It has to be established whether the co-mapping of colon and lung cancer susceptibility QTLs and concordant magnitude of their effect on colon and lung cancer indicate that a single gene or two paired organ-specific genes control development of colon and lung cancer. 6. In summary, genetic location and relative strength of polygenic colon and lung cancer susceptibility QTLs have been surprisingly conserved during separate evolution of rodents and primates. These QTLs exhibit frequent pairwise linkage of colon and lung cancer susceptibility loci and directionally correlated effects on both cancers. 7. The presented findings indicate that a majority of colon and lung cancer susceptibility QTLs are robust genetic and biological entities, whose individual functions in colon and lung carcinogenesis may be effectively studied. As the combined mortality of colon and lung cancers exceeds that of combined five other major cancer sources of deaths, their study can have a significant translational impact. Citation Format: Lei Quan, Alan Hutson, Peter Demant. Robust evolutionary conservation and pair-wise co-mapping of polygenic colon and lung cancer susceptibility loci [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1590.

Assessing tobacco use and providing cessation support is recommended by the American Society for Clinical Oncology (ASCO). The purpose of this study was to evaluate practice patterns and perceptions of tobacco use and barriers to providing cessation support for patients with cancer. Methods: In 2012, an online survey was sent to 18,502 full ASCO members asking about their practice patterns regarding to- bacco assessment, cessation support, perceptions of tobacco use, and barriers to providing cessation support for patients with cancer. Responses from 1,197 ASCO members are reported. Results: At initial visit, most respondents routinely ask patients about tobacco use (90%), ask patients to quit (80%), and advise patients to stop using tobacco (84%). However, only 44% rou- tinely discuss medication options with patients, and only 39% provide cessation support. Tobacco assessments decrease at fol- low-up assessments. Most respondents (87%) agree or strongly agree that smoking affects cancer outcomes, and 86% believe cessation should be a standard part of clinical cancer care. How- ever, only 29% report adequate training in tobacco cessation inter- ventions. Inability to get patients to quit (72%) and patient resistance to treatment (74%) are dominant barriers to cessation intervention, but only 8% describe cessation as a waste of time. Conclusion: Among ASCO members who responded to an online survey about their practice patterns regarding tobacco, most believe that tobacco cessation is important and frequently assess tobacco at initial visit, but few provide cessation support. Interventions are needed to increase access to tobacco cessa- tion support for patients with cancer.

A large project to collect natural gas at Dallas/Fort Worth International Airport required the rapid construction of more than 80 mi of pipeline. To overcome space limitations and other impediments to construction typical of an airport, 15 mi of the pipelines were installed by means of horizontal directional drilling.

Composite nanodevices (CNDs) are a well-studied class of multifunctional nanomaterials with several potential medical uses, including cancer imaging and therapy. Gold/ dendrimer CNDs are organic/inorganic hybrid materials consisting of physical networks of dendrimer(s) and inorganic materials. This design permits properties of dendrimers and inorganic materials to be individually modified and optimized. A detailed understanding of factors regulating toxicity is lacking. We develop and test toxicity assays for CNDs in vitro both for cancer cells and for normal endothelial cells. We show how CND surface charge (positive, negative or neutral) and exposure time affects biosafety for d = 5 nm nanodevices. We also show that formation of the CND (incorporation of gold into a dendrimer template) can lower toxicity of a dendrimer. Interestingly, we also show that tumour cells and proliferating endothelial cells have different toxicity profiles.

They say everything is bigger in Texas. So when Dallas and Fort Worth joined forces to tie-in an additional water supply for the metroplex, things got big in a hurry. The Integrated Pipeline Project (IPL) is a $2.2 billion water transmission project currently being undertaken by Tarrant Regional Water District (TRWD) and Dallas Water Utilities (DWU). In laying out a process for selecting the pipeline route, the conceptual design team started by looking at multiple corridors then took steps to narrow the focus to a preferred corridor, then a better defined route, and eventually to a final alignment. The steps taken to select the final route included: Screening of seven initial corridors to narrow selection down to four corridors; Detailed analysis of four corridors leading to the selection of a single corridor; Analysis of conflicts within the corridor to recommend a preferred route; Right-of-Entry for the preferred route; Detailed surveys including archeology, environmental and geotechnical; and Final route selection by design teams. During the course of this process, the conceptual design team implemented several technological and operational innovations which optimized the route and the route selection process. These innovative solutions included: Use of mobile Geographic Information System (GIS) technology to collect data that led to efficiencies in sharing and analyzing data; Helicopter flight with geo-referenced video of the pipeline route; Cross-connection to existing system which increased flexibility, reliability and allowed a substantial portion of the project to be postponed; and Adding a storage reservoir and tunnel section to reduce pumping during the initial years and add operational flexibility. Implementing a sequential route selection process and incorporating technological tools allowed the pipeline route to be successfully selected. The route selection reflected consideration for a large range of social, environmental, construction, operational, and sustainable criteria.

Since its formation in 1951, the North Texas Municipal Water District (NTMWD) has been charged with developing a reliable water supply source for its 13 member cities and 46 other customers (some direct and some indirect), including more than 1.6 million people in portions of Collin, Dallas, Denton, and Kaufman Counties and all of Rockwall County. The NTMWD’s Lake Texoma Water Supply Project was designed in the late 1980’s and completed in 1991 to convey raw water from Lake Texoma to Lake Lavon via a discharge point at Sister Grove Creek approximately 30 miles to the south of Lake Texoma. Sister Grove Creek then flows into Lake Lavon to the south. The City of Sherman, Texas’ water treatment plant is also supplied from the 72-inch pipeline. The NTMWD had never performed a condition assessment of the pipeline, so a condition assessment utilizing interior visual inspection, Remote Field Transformer Coupling (RFTC), and external pipeline inspection at areas where the other inspection methods identified potential issues was performed in 2009. The PCCP was designed to meet the requirements of the American Water Works Association’s 1 st Edition of the M-9 Concrete Pressure Pipe (1979). The thrust restraint design sections of M-9 underwent a major change in the 2008 edition that recognized additional stresses that are experienced in the steel cylinder of PCCP and the need to potentially increase the cylinder thicknesses to resist these stresses, especially where welded joints are used for thrust restraint. This revision of M-9 combined with the Engineer’s experience with PCCP failures at welded bends on past projects prompted an in-depth structural analysis of the existing pipeline bends and fittings at the 125 MGD flow rate. This analysis included finite element analysis, geotechnical analysis of in-situ soil conditions at 26 bends, and follow up structural analysis. After the analysis phase, several bend strengthening options were considered at the 21 bends that did not meet the criteria in M-9 at the increased flow rate. This paper will summarize the procedures and results of the condition assessment, results of the structural analysis of the PCCP bends, and the repairs necessary to strengthen the bends before increasing the flow.

Although most of the statistical methods for diagnostic studies focus on disease processes with binary disease status, many diseases can be naturally classified into three ordinal diagnostic categories, that is normal, early stage, and fully diseased. For such diseases, the volume under the ROC surface (VUS) is the most commonly used index of diagnostic accuracy. Because the early disease stage is most likely the optimal time window for therapeutic intervention, the sensitivity to the early diseased stage has been suggested as another diagnostic measure. For the purpose of comparing the diagnostic abilities on early disease detection between two markers, it is of interest to estimate the confidence interval of the difference between sensitivities to the early diseased stage. In this paper, we present both parametric and non-parametric methods for this purpose. An extensive simulation study is carried out for a variety of settings for the purpose of evaluating and comparing the performance of the proposed methods. A real example of Alzheimer’s disease (AD) is analyzed using the proposed approaches.

The Gynecologic Oncology Group (GOG) examined the association between the relative expression of the DeltaNp63alpha isoform and clinicopathologic variables, p53 status, angiogenic markers, progression-free survival (PFS) and overall survival (OS) in epithelial ovarian cancer (EOC).Immunoblot analysis was used to determine the relative expression of DeltaNp63alpha to beta-actin in lysates of frozen primary tumor from women with previously untreated, advanced stage EOC who participated in a GOG specimen banking protocol and a randomized phase III treatment protocol.DeltaNp63alpha was detected in 49/56 (87.5%) cases with relative expression ranging from 0 to 4.55 (median=0.325). A correlation was observed between the relative expression of DeltaNp63alpha and debulking status (Spearman's correlation coefficient=0.303; p=0.025) and the relative expression of vascular endothelial growth factor (VEGF) (Spearman's correlation coefficient=0.303; p=0.045), but not with p53 status (overexpression or mutation), immunoblot expression of MASPIN, or the relative expression of thrombospondin-1, basic fibroblast growth factor or VEGF receptor-1. A 1.4-fold increase was observed in the risk of disease progression for each unit increase in the relative expression of DeltaNp63alpha using an unadjusted (hazard ratio [HR]=1.459; 95% confidence interval [CI]=1.096-1.942; p=0.010), a full (HR=1.483; 95% CI=1.060-2.076; p=0.021) and a reduced (HR=1.387; 95% CI=1.025-1.877; p=0.034) Cox regression model. The relative expression of DeltaNp63alpha was not associated with OS using an unadjusted, a full or a reduced Cox model.The relative expression DeltaNp63alpha appears to be associated with debulking status and the relative expression of VEGF and PFS, and to be an independent prognostic factor for disease progression in EOC.