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Kevin F Boehnke,1 Manuel Valdivieso,2 Alejandro Bussalleu,3 Rachael Sexton,4 Kathryn C Thompson,1 Soledad Osorio,5 Italo Novoa Reyes,3 John J Crowley,4 Laurence H Baker,2 Chuanwu Xi1 1Department of Environmental Health Sciences, School of Public Health, 2Division of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; 3Departamento Académico de Clínicas Médicas, Facultad de Medicina Alberto Hurtado, Universidad Peruana Cayetano Heredia, Lima, Perú; 4Cancer Research and Biostatistics, Seattle, WA, USA; 5Dirección General de Salud Ambiental, Ministerio de Salud del Perú, Lima, Perú Objectives: Gastric carcinoma is the most common cancer and cause of cancer mortality in Peru. Helicobacter pylori, a bacterium that colonizes the human stomach, is a Group 1 carcinogen due to its causal relationship to gastric carcinoma. While eradication of H. pylori can help prevent gastric cancer, characterizing regional antibiotic resistance patterns is necessary to determine targeted treatment for each region. Thus, we examined primary antibiotic resistance in clinical isolates of H. pylori in Lima, Peru.Materials and methods: H. pylori strains were isolated from gastric biopsies of patients with histologically proven H. pylori infection. Primary antibiotic resistance among isolates was examined using E-test strips. Isolates were examined for the presence of the cagA pathogenicity island and the vacA m1/m2 alleles via polymerase chain reaction.Results: Seventy-six isolates were recovered from gastric biopsies. Clinical isolates showed evidence of antibiotic resistance to 1 (27.6%, n=21/76), 2 (28.9%, n=22/76), or ≥3 antibiotics (40.8%). Of 76 isolates, eight (10.5%) were resistant to amoxicillin and clarithromycin, which are part of the standard triple therapy for H. pylori infection. No trends were seen between the presence of cagA, vacA m1, or vacA m2 and antibiotic resistance.Conclusion: The rate of antibiotic resistance among H. pylori isolates in Lima, Peru, is higher than expected and presents cause for concern. To develop more targeted eradication therapies for H. pylori in Peru, more research is needed to better characterize antibiotic resistance among a larger number of clinical isolates prospectively. Keywords: H. pylori, antibiotic resistance, Peru, amoxicillin

Soft tissue sarcomas are a heterogeneous group of malignancies arising from mesenchymal tissues. A large number of new therapies are being evaluated in patients with sarcomas, and consensus criteria defining treatment responses are essential for comparison of results from studies completed by different research groups. The 1979 World Health Organization (WHO) handbook set forth operationally defined criteria for response evaluation in solid tumors that were updated in 2000 with the publication of the Response Evaluation Criteria in Solid Tumors (RECIST). There have been significant advances in tumor imaging, however, that are not reflected in the RECIST. For example, computed tomography (CT) slice thickness has been reduced from 10 mm to < or =2.5 mm, allowing for more reproducible and accurate measurement of smaller lesions. Combination of imaging techniques, such as positron emission tomography with fluorine-18-fluorodeoxyglucose (18FDG-PET) and CT can provide investigators and clinicians with both anatomical and functional information regarding tumors, and there is now a large body of evidence demonstrating the effectiveness of PET/CT and other newer imaging methods for the detection and staging of tumors as well as early determination of responses to therapy. The application of newer imaging methods has the potential to decrease both the sample sizes required for, and duration of, clinical trials by providing an early indication of therapeutic response that is well correlated with clinical outcomes, such as time to tumor progression or overall survival. The results summarized in this review support the conclusion that the RECIST and the WHO criteria for evaluation of response in solid tumors need to be modernized. In addition, there is a current need for prospective trials to compare new response criteria with established endpoints and to validate imaging-based response rates as surrogate endpoints for clinical trials of new agents for sarcoma and other solid tumors. [ABSTRACT FROM AUTHOR]

The electronic medical record (EMR) offers new avenues for inviting patients to become active partners in their health care. It also can become a barrier to effective communication.Connected is a 3-hour on-site program designed to provide nurses and other clinicians with tools to help them communicate effectively with patients while using exam room computers.With effective communication, patients will experience the EMIR as a valuable tool that enhances their confidence in care, encourages adherence to treatment regimens, and invites their active participation in their health care. [ABSTRACT FROM AUTHOR]

Objectives: To monitor individual mucosal immunity and identify potential risk factors of upper respiratory symptoms in elite swimmers over a competitive season., Design: Eight-month longitudinal study, observing mucosal immunity, Epstein-Barr virus status, training loads and illness symptoms of elite international swimmers, leading into the Commonwealth Games 2018., Methods: Participants were fourteen elite swimmers (age ± standard deviation = 19.9 ± 0.8 years, height = 178.9 ± 6.3 cm, and mass = 75.0 ± 7.7 kg). Self-reported upper respiratory symptoms, training load and saliva samples were collected weekly. Venous blood samples were taken at study commencement to determine Epstein-Barr virus status., Results: Throughout the study, 70 episodes of upper respiratory symptoms were recorded resulting in 34 days of missed training. Incidence (p = 0.001), severity (p = 0.022), and duration of upper respiratory symptoms (p = 0.001) were significantly higher during high training loads, compared to low. Eight swimmers (61 %) had evidence of past infection with Epstein-Barr virus, but this had no relationship with incidence, severity, or duration of upper respiratory symptoms (p > 0.05). Relative individual salivary immunoglobulin A concentration was 12 % lower when upper respiratory symptoms were present but was not statistically significant (p = 0.101)., Conclusions: This study highlights the importance of individual athlete monitoring, to identify swimmers at increased illness risk. Identification of possible risk factors for upper respiratory symptoms, such as increased training load, may allow for modifications in training or other illness preventative strategies for elite swimmers., Competing Interests: Declaration of interest statement None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Leiomyosarcoma (LMS) is an aggressive sarcoma for which standard chemotherapies achieve response rates under 30%. There are no effective targeted therapies against LMS. Most LMS are characterized by chromosomal instability (CIN), resulting in part from TP53 and RB1 co-inactivation and DNA damage repair defects. We sought to identify therapeutic targets that could exacerbate intrinsic CIN and DNA damage in LMS, inducing lethal genotoxicity., Experimental Design: We performed clinical targeted sequencing in 287 LMS and genome-wide loss-of-function screens in 3 patient-derived LMS cell lines, to identify LMS-specific dependencies. We validated candidate targets by biochemical and cell-response assays in vitro and in seven mouse models., Results: Clinical targeted sequencing revealed a high burden of somatic copy-number alterations (median fraction of the genome altered =0.62) and demonstrated homologous recombination deficiency signatures in 35% of LMS. Genome-wide short hairpin RNA screens demonstrated PRKDC (DNA-PKcs) and RPA2 essentiality, consistent with compensatory nonhomologous end joining (NHEJ) hyper-dependence. DNA-PK inhibitor combinations with unconventionally low-dose doxorubicin had synergistic activity in LMS in vitro models. Combination therapy with peposertib and low-dose doxorubicin (standard or liposomal formulations) inhibited growth of 5 of 7 LMS mouse models without toxicity., Conclusions: Combinations of DNA-PK inhibitors with unconventionally low, sensitizing, doxorubicin dosing showed synergistic effects in LMS in vitro and in vivo models, without discernable toxicity. These findings underscore the relevance of DNA damage repair alterations in LMS pathogenesis and identify dependence on NHEJ as a clinically actionable vulnerability in LMS., (©2023 American Association for Cancer Research.)

Background: Leiomyosarcoma (LMS) is the most common soft tissue and uterine sarcoma, but no standard therapy is available for recurrent or metastatic LMS. TP53, p16/RB1, and PI3K/mTOR pathway dysregulations are recurrent events, and some LMS express estrogen receptor (ER) and/or progesterone receptor (PR). To characterize relationships between these pathway perturbations, the authors evaluated protein expression in soft tissue and uterine nonprimary leiomyosarcoma (np-LMS), including local recurrences and distant metastases., Methods: TP53, RB1, p16, and PTEN expression aberrations were determined by immunohistochemistry (IHC) in tissue microarrays (TMAs) from 227 np-LMS and a comparison group of 262 primary leiomyosarcomas (p-LMS). Thirty-five of the np-LMS had a matched p-LMS specimen in the TMAs. Correlative studies included differentiation scoring, ER and PR IHC, and CDKN2A/p16 fluorescence in situ hybridization., Results: Dysregulation of TP53, p16/RB1, and PTEN was demonstrated in 90%, 95%, and 41% of np-LMS, respectively. PTEN inactivation was more common in soft tissue np-LMS than uterine np-LMS (55% vs 31%; P = .0005). Moderate-strong ER expression was more common in uterine np-LMS than soft tissue np-LMS (50% vs 7%; P < .0001). Co-inactivation of TP53 and RB1 was found in 81% of np-LMS and was common in both soft tissue and uterine np-LMS (90% and 74%, respectively). RB1, p16, and PTEN aberrations were nearly always conserved in p-LMS and np-LMS from the same patients., Conclusions: These studies show that nearly all np-LMS have TP53 and/or RB1 aberrations. Therefore, therapies targeting cell cycle and DNA damage checkpoint vulnerabilities should be prioritized for evaluations in LMS., (© 2021 American Cancer Society.)

Resource availability can powerfully influence host-parasite interactions. However, we currently lack a mechanistic framework to predict how resource fluctuations alter individual infection dynamics. We address this gap with experiments manipulating resource supply and starvation for a human parasite, Schistosoma mansoni , and its snail intermediate host to test a hypothesis derived from mechanistic energy budget theory: resource fluctuations should reduce schistosome reproduction and virulence by inhibiting parasite ingestion of host biomass. Low resource supply caused hosts to remain small, reproduce less and produce fewer human-infectious cercariae. Periodic starvation also inhibited cercarial production and prevented infection-induced castration. The periodic starvation experiment also revealed substantial differences in fit between two bioenergetic model variants, which differ in their representation of host starvation. Simulations using the best-fit parameters of the winning model suggest that schistosome performance substantially declines with resource fluctuations with periods greater than 7 days. These experiments strengthen mechanistic theory, which can be readily scaled up to the population level to understand key feedbacks between resources, host population dynamics, parasitism and control interventions. Integrating resources with other environmental drivers of disease in an explicit bioenergetic framework could ultimately yield mechanistic predictions for many disease systems.

Background: Radiation-associated osteosarcoma (RAO) is a rare, life-threatening complication from radiation. Many physicians presume RAO has a worse prognosis than sporadic osteosarcoma (SO), although limited objective data exist. We conducted a retrospective study comparing these entities. Methods: We identified adults treated at our institution with osteosarcoma (1990-2016) and categorized tumors as SO or RAO based on location within a prior radiation field. We extracted data on demographics, treatment and primary malignancy and examined available tumor samples for MTA-1 and ezrin using immunohistochemistry (IHC). Results: Of 159 identified patients, 28 had RAO, diagnosed at a median interval from radiation of 11.5 years (1.5-28 years). Median follow-up was 2.8 years (0.1-19.6 years). Median progression free survival (PFS) and overall survival (OS) were not significantly different in the small population of patients with metastases, SO ( n = 20) vs. RAO ( n = 6): PFS 10.3 months vs. 4.8 months ( p = 0.45) and OS 15.6 months vs. 6.1 months ( p = 0.96), respectively. For the larger group with localized disease, median relapse-free survival (RFS) and OS were significantly different, NR vs. 12.2 months ( p < 0.001) and NR vs. 27.6 months ( p = 0.001) in SO ( n = 111) vs. RAO ( n = 22), respectively. On IHC, there were significant differences in distribution of high, intermediate or low MTA-1 ( p = 0.015) and ezrin ( p = 0.002) between RAO and SO tumors. Conclusions: Patients with metastases at diagnosis fared poorly irrespective of prior radiation. RAO patients with localized disease had worse outcomes without detectable differences in therapy rendered or treatment effect in resected specimens. Higher expression of MTA-1 in RAO patients may suggest an underlying difference in tumor biology to explain differences in outcomes., (Copyright © 2020 Siontis, McHugh, Roberts, Zhao, Thomas, Owen, Baker, Biermann, Schuetze and Chugh.)

Aim: Cardiovascular disease is a leading cause of mortality among long-term cancer survivors treated with large total doses of doxorubicin. An increase in coronary artery disease (CAD) among childhood cancer survivors by age 45 has been observed and is driven by primarily anthracycline chemotherapy and to a lesser extent chest radiation that includes the heart in the radiation field. The risk factors and associated chronic diseases (hypertension, etc .) are well known for CAD and can be often prevented or treated, thus reducing the risk of CAD in these patients. We piloted a risk-based survivorship clinic in an academic medical center to characterize the distribution of risk factors for CAD and improve the quality of life in a population of sarcoma survivors treated with doxorubicin., Methods: We followed a prospective cohort of sixty-one survivors of bone and soft tissue sarcoma treated with doxorubicin chemotherapy (> 400 mg/m 2 ) and at least 2 years post-therapy attending the sarcoma survivorship clinic. We collected clinical, demographic data, and patient reported outcomes via PROMIS questionnaires annually., Results: We demonstrated a high burden of chronic diseases in this population. Among six chronic conditions that are known risk factors for CAD (hypertension, diabetes, obesity, chronic inflammation, kidney disease and dyslipidemia), more than one-fourth (26%, 16/61) of patients had three or more of these risk factors at baseline visit, and 49% (30/61) had two or more., Conclusion: The results of this pilot study support the presence of modifiable CAD risk factors in this population of sarcoma survivors. Evidence-based guidelines for high-risk survivors of rare cancers are needed., Competing Interests: Conflicts of interest All authors declared that there are no conflicts of interest.

Purpose: To understand the perceptions of patients with cancer regarding the role and purpose of a survivorship care plan (SCP) to inform content and delivery opportunities., Participants & Setting: A mixed-methods evaluation was conducted among patients at a survivorship clinic for high-risk survivors of sarcomas in an academic medical center., Methodologic Approach: An electronic survey was administered, followed by qualitative telephone interviews., Findings: 51 surveys were delivered, and 23 surveys were completed. Eight telephone interviews were completed. Content analysis revealed that participants value the SCP as a health management tool to address information needs and reduce fear of recurrence. Few participants shared their SCP with other healthcare providers., Implications for Nursing: Patients use their SCP as a health management tool to understand the details of their cancer history and treatment and to manage their health concerns. Nurses who care for patients with cancer are well positioned to use the SCP as a patient education tool.

Importance: Universal screening of patients with newly diagnosed cancer for hepatitis B virus (HBV), hepatitis C virus (HCV), and HIV is not routine in oncology practice, and experts disagree about whether universal screening should be performed., Objective: To estimate the prevalence of HBV, HCV, and HIV infection among persons with newly diagnosed cancer., Design, Setting, and Participants: Multicenter prospective cohort study of patients with newly diagnosed cancer (ie, identified within 120 days of cancer diagnosis) at 9 academic and 9 community oncology institutions affiliated with SWOG (formerly the Southwest Oncology Group) Cancer Research Network, a member of the National Clinical Trials Network, with enrollment from August 29, 2013, through February 15, 2017. The data analysis was conducted using data available through August 17, 2017., Main Outcomes and Measures: The accrual goal was 3000 patients and the primary end point was the presence of HBV infection (previous or chronic), HCV infection, or HIV infection at enrollment. Patients with previous knowledge of infection as well as patients with unknown viral viral status were evaluated., Results: Of 3092 registered patients, 3051 were eligible and evaluable. Median (range) age was 60.6 (18.2-93.7) years, 1842 (60.4%) were female, 553 (18.1%) were black, and 558 (18.3%) were Hispanic ethnicity. Screened patients had similar clinical and demographic characteristics compared with those registered. The observed infection rate for previous HBV infection was 6.5% (95% CI, 5.6%-7.4%; n = 197 of 3050 patients); chronic HBV, 0.6% (95% CI, 0.4%-1.0%; n = 19 of 3050 patients); HCV, 2.4% (95% CI, 1.9%-3.0%; n = 71 of 2990 patients); and HIV, 1.1% (95% CI, 0.8%-1.6%; n = 34 of 3045). Among those with viral infections, 8 patients with chronic HBV (42.1%; 95% CI, 20.3%-66.5%), 22 patients with HCV (31.0%; 95% CI, 20.5%-43.1%), and 2 patients with HIV (5.9%; 95% CI, 0.7%-19.7%) were newly diagnosed through the study. Among patients with infections, 4 patients with chronic HBV (21.1%; 95% CI, 6.1%-45.6%), 23 patients with HCV (32.4%; 95% CI, 21.8%-44.5%), and 7 patients with HIV (20.6%; 95% CI, 8.7%-37.9%) had no identifiable risk factors., Conclusions and Relevance: Results of this study found that a substantial proportion of patients with newly diagnosed cancer and concurrent HBV or HCV are unaware of their viral infection at the time of cancer diagnosis, and many had no identifiable risk factors for infection. Screening patients with cancer to identify HBV and HCV infection before starting treatment may be warranted to prevent viral reactivation and adverse clinical outcomes. The low rate of undiagnosed HIV infection may not support universal screening of newly diagnosed cancer patients.

Introduction: Primary cardiac sarcoma (PCS) has a poor prognosis compared to other sarcomas due to late presentation, challenging resection, incidence of metastases, and limited efficacy of systemic therapies., Methods: A medical record search engine was queried to identify patients diagnosed with PCS from 1992 to 2017 at the University of Michigan., Results: Thirty-nine patients with PCS had a median age of 41 years (range 2-77). Common histologies were angiosarcoma (AS, 14), high-grade undifferentiated pleomorphic sarcoma (UPS, 10), and leiomyosarcoma (LMS, 5). Sites of origin were left atrium (18), right atrium (16), and pericardium (5). AS was the most common right-sided tumor; UPS was more common on the left. Eighteen patients presented with metastases involving lung (10), bone (7), liver (5), and brain (4). Twenty-five patients underwent resection, achieving 3 R 0 resections. Patients received a median of 2 (1-6) systemic therapies. Median overall survival (OS) was 12.1 months (range 0-79). Median OS was 14.0 months and 8.2 months in patients who did or did not undergo resection, respectively ( p =0.018). Brain metastases occurred in 12 (31%) patients, 9 (75%) of whom had left heart tumors, at a median of 8.5 months (range 0-75) from diagnosis. Median OS was 5.6 months (range 0-30) after the diagnosis of brain metastases., Conclusions: PCS portends a poor prognosis, because of difficulty in obtaining complete resection of sarcoma, advanced stage at diagnosis, and high risk of brain metastases. Providers should be aware of the increased risk of brain metastases and consider brain imaging at diagnosis and follow-up.

Importance: Gastrointestinal stromal tumors (GISTs) are life-threatening when metastatic or not amenable to surgical removal. In a few patients with advanced GISTs refractory to imatinib mesylate, treatment with sunitinib malate followed by regorafenib provides tumor control; however, additional active treatments are needed for most patients., Objective: To evaluate the 6-month progression-free survival (PFS), tumor objective response, and overall survival rates in patients with GISTs treated with dasatinib., Design, Setting, and Participants: This single-arm clinical trial used a Bayesian design to enroll patients 13 years or older with measurable imatinib-refractory metastatic GISTs treated at 14 sarcoma referral centers from June 1, 2008, through December 31, 2009. A control group was not included. Patients were followed up for survival for a minimum of 5 years from date of enrollment. Tumor imaging using computed tomography or magnetic resonance imaging was performed every 8 weeks for the first 24 weeks and every 12 weeks thereafter. Tumor response was assessed by local site using the Choi criteria. Treatment was continued until tumor progression, unacceptable toxic effects after reduction in drug dose, or patient or physician decision. Archival tumor tissue was evaluated for expression of the proto-oncogene tyrosine-protein kinase Src (SRC), phosphorylated SRC (pSRC), and succinate dehydrogenase complex iron sulfur subunit B (SDHB) proteins and for mutation in the V-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) and platelet-derived growth factor receptor α (PDGFRA) genes. Data analysis was performed from May 19, 2017, through December 20, 2017., Interventions: Dasatinib, 70 mg orally twice daily., Main Outcomes and Measures: The primary end point was the 6-month PFS estimate using greater than 30% as evidence of an active drug and less than 10% as evidence of inactive treatment., Results: In this study, 50 patients were enrolled (median age, 60 years; age range, 19-78 years; 31 [62%] male and 19 [38%] female; 41 [82%] white), and 48 were evaluable for response. The estimated 6-month PFS rate was 29% in the overall population and 50% in a subset of 14 patients with pSRC in GISTs. Objective tumor response was observed in 25%, including 1 patient with an imatinib-resistant mutation in PDGFRA exon 18., Conclusions and Relevance: Dasatinib may have activity in a subset of patients with imatinib-resistant GISTs. Further study is needed to determine whether pSRC is a prognostic biomarker.

Background: Patients with advanced sarcomas have a poor prognosis and few treatment options that improve overall survival. Chemotherapy and targeted therapies offer short-lived disease control. We assessed pembrolizumab, an anti-PD-1 antibody, for safety and activity in patients with advanced soft-tissue sarcoma or bone sarcoma., Methods: In this two-cohort, single-arm, open-label, phase 2 study, we enrolled patients with soft-tissue sarcoma or bone sarcoma from 12 academic centres in the USA that were members of the Sarcoma Alliance for Research through Collaboration (SARC). Patients with soft-tissue sarcoma had to be aged 18 years or older to enrol; patients with bone sarcoma could enrol if they were aged 12 years or older. Patients had histological evidence of metastatic or surgically unresectable locally advanced sarcoma, had received up to three previous lines of systemic anticancer therapy, had at least one measurable lesion according to the Response Evaluation Criteria In Solid Tumors version 1.1, and had at least one lesion accessible for biopsy. All patients were treated with 200 mg intravenous pembrolizumab every 3 weeks. The primary endpoint was investigator-assessed objective response. Patients who received at least one dose of pembrolizumab were included in the safety analysis and patients who progressed or reached at least one scan assessment were included in the activity analysis. Accrual is ongoing in some disease cohorts. This trial is registered with ClinicalTrials.gov, number NCT02301039., Findings: Between March 13, 2015, and Feb 18, 2016, we enrolled 86 patients, 84 of whom received pembrolizumab (42 in each disease cohort) and 80 of whom were evaluable for response (40 in each disease cohort). Median follow-up was 17·8 months (IQR 12·3-19·3). Seven (18%) of 40 patients with soft-tissue sarcoma had an objective response, including four (40%) of ten patients with undifferentiated pleomorphic sarcoma, two (20%) of ten patients with liposarcoma, and one (10%) of ten patients with synovial sarcoma. No patients with leiomyosarcoma (n=10) had an objective response. Two (5%) of 40 patients with bone sarcoma had an objective response, including one (5%) of 22 patients with osteosarcoma and one (20%) of five patients with chondrosarcoma. None of the 13 patients with Ewing's sarcoma had an objective response. The most frequent grade 3 or worse adverse events were anaemia (six [14%]), decreased lymphocyte count (five [12%]), prolonged activated partial thromboplastin time (four [10%]), and decreased platelet count (three [7%]) in the bone sarcoma group, and anaemia, decreased lymphocyte count, and prolonged activated partial thromboplastin time in the soft-tissue sarcoma group (three [7%] each). Nine (11%) patients (five [12%] in the bone sarcoma group and four [10%] in the soft-tissue sarcoma group) had treatment-emergent serious adverse events (SAEs), five of whom had immune-related SAEs, including two with adrenal insufficiency, two with pneumonitis, and one with nephritis., Interpretation: The primary endpoint of overall response was not met for either cohort. However, pembrolizumab showed encouraging activity in patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma. Enrolment to expanded cohorts of those subtypes is ongoing to confirm and characterise the activity of pembrolizumab., Funding: Merck, SARC, Sarcoma Foundation of America, QuadW Foundation, Pittsburgh Cure Sarcoma, and Ewan McGregor., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Metastasis is the primary cause of cancer-related deaths. Although The Cancer Genome Atlas has sequenced primary tumour types obtained from surgical resections, much less comprehensive molecular analysis is available from clinically acquired metastatic cancers. Here we perform whole-exome and -transcriptome sequencing of 500 adult patients with metastatic solid tumours of diverse lineage and biopsy site. The most prevalent genes somatically altered in metastatic cancer included TP53, CDKN2A, PTEN, PIK3CA, and RB1. Putative pathogenic germline variants were present in 12.2% of cases of which 75% were related to defects in DNA repair. RNA sequencing complemented DNA sequencing to identify gene fusions, pathway activation, and immune profiling. Our results show that integrative sequence analysis provides a clinically relevant, multi-dimensional view of the complex molecular landscape and microenvironment of metastatic cancers.

Background: Helicobacter pylori infection has been consistently associated with lack of access to clean water and proper sanitation, but no studies have demonstrated that the transmission of viable but nonculturable (VBNC) H. pylori can occur from drinking contaminated water. In this study, we used a laboratory mouse model to test whether waterborne VBNCH. pylori could cause gastric infection., Materials and Methods: We performed five mouse experiments to assess the infectivity of VBNCH. pylori in various exposure scenarios. VBNC viability was examined using Live/Dead staining and Biolog phenotype metabolism arrays. High doses of VBNCH. pylori in water were chosen to test the "worst-case" scenario for different periods of time. One experiment also investigated the infectious capabilities of VBNC SS1 using gavage. Further, immunocompromised mice were exposed to examine infectivity among potentially vulnerable groups. After exposure, mice were euthanized and their stomachs were examined for H. pylori infection using culture and PCR methodology., Results: VBNC cells were membrane intact and retained metabolic activity. Mice exposed to VBNCH. pylori via drinking water and gavage were not infected, despite the various exposure scenarios (immunocompromised, high doses) that might have permitted infection with VBNCH. pylori. The positive controls exposed to viable, culturable H. pylori did become infected., Conclusions: While other studies that have used viable, culturable SS1 via gavage or drinking water exposures to successfully infect mice, in our study, waterborne VBNC SS1 failed to colonize mice under all test conditions. Future studies could examine different H. pylori strains in similar exposure scenarios to compare the relative infectivity of the VBNC vs the viable, culturable state, which would help inform future risk assessments of H. pylori in water., (© 2017 The Authors. Helicobacter Published by John Wiley & Sons Ltd.)

Importance: After identification of activating mutations of the KIT gene in gastrointestinal stromal tumor (GIST)-the most common sarcomaof the gastrointestinal tract-a phase 2 study demonstrated efficacy of imatinib mesylate in patients with metastatic GIST harboring a KIT exon 11 mutation. Initial results of long-term follow-up have found a survival benefit in this subgroup of patients., Obective: To assess the long-term survival of patients with GIST who were treated in SWOG study S0033 and to present new molecular data regarding treatment outcomes., Design, Setting, and Participants: In this follow-up of randomized clinical trial participants (from December 15, 2000, to September 1, 2001), patients were required to have advanced GIST that was not surgically curable. Postprotocol data collection occurred from August 29, 2011, to July 15, 2015. Using modern sequencing technologies, 20 cases originally classified as having wild-type tumors underwent reanalysis. This intergroup study was coordinated by SWOG, a cooperative group member within the National Clinical Trials Network, with participation by member/affiliate institutions. This follow-up was not planned as part of the initial study., Interventions: Patients were randomized to 1 of 2 dose levels of imatinib mesylate, including 400 mg once daily (400 mg/d) vs 400 mg twice daily (800 mg/d), and were treated until disease progression or unacceptable toxic effects of the drug occurred., Main Outcomes and Measures: The primary end point was overall survival. Updated survival data were correlated with clinical and molecular factors, and patterns of postprotocol therapies were enumerated and described in long-term survivors., Results: Of 695 eligible patients (376 men [54.1%]; 319 women [45.9%]; mean [SD] age, 60.1 [14.0] years), 189 survived 8 years or longer, including 95 in the 400-mg/d dose arm and 94 in the 800-mg/d arm. The 10-year estimate of overall survival was 23% (95% CI, 20%-26%). Among 142 long-term survivors, imatinib was the sole therapy administered in 69 (48.6%), with additional systemic agents administered to 54 patients (38.0%). Resequencing studies of 20 cases originally classified as KIT/PDGFRA wild-type GIST revealed that 17 (85.0%) harbored a pathogenic mutation, most commonly a mutation of a subunit of the succinate dehydrogenase complex., Conclusions and Relevance: A subset of patients with metastatic GIST experiences durable, long-term overall survival with imatinib treatment. Although this study provides guidance for management of GIST harboring the most common KIT and PDGFRA mutations, optimal management of other genotypic subtypes remains unclear., Trial Registration: clinicaltrials.gov Identifier: NCT00009906.

Extraskeletal myxoid chondrosarcoma (EMC) is an indolent translocation-associated soft tissue sarcoma with a high propensity for metastases. Using a clinical sequencing approach, we genomically profiled patients with metastatic EMC to elucidate the molecular biology and identify potentially actionable mutations. We also evaluated potential predictive factors of benefit to sunitinib, a multi-targeted tyrosine kinase inhibitor with reported activity in a subset of EMC patients. Between January 31, 2012 and April 15, 2016, six patients with EMC participated in the clinical sequencing research study. High quality DNA and RNA was isolated and matched normal samples underwent comprehensive next generation sequencing (whole or OncoSeq capture exome of tumor and normal, tumor PolyA+ and capture transcriptome). The expression levels of sunitinib targeted-kinases were measured by transcriptome sequencing for KDR, PDGFRA/B, KIT, RET, FLT1, and FLT4. The previously reported EWSR1-NR4A3 translocation was identified in all patient tumors; however, other recurring genomic abnormalities were not detected. RET expression was significantly greater in patients with EMC relative to other types of sarcomas except for liposarcoma (p<0.0002). The folate receptor was overexpressed in two patients. Our study demonstrated that similar to other translocation-associated sarcomas, the mutational profile of metastatic EMC is limited beyond the pathognomonic translocation. The clinical significance of RET expression in EMC should be explored. Additional pre-clinical investigations of EMC may help elucidate molecular mechanisms contributing to EMC tumorigenesis that could be translated to the clinical setting.

Background: Alveolar soft part sarcoma (ASPS), chondrosarcoma (CS), chordoma, epithelioid sarcoma, and solitary fibrous tumor (SFT) are malignant tumors that are relatively resistant to chemotherapy and for which more effective drug therapy is needed., Methods: The 5 listed subtypes were enrolled into a single indolent sarcoma cohort in a phase 2 study of dasatinib using a Bayesian continuous monitoring rule for enrollment. The primary objective was to estimate the 6-month progression-free survival (PFS) rate according to the Choi criteria with a target of ≥50%. Cross-sectional imaging was performed before the start of treatment, every 2 months for 6 months, and then every 3 months during treatment. The 2- and 5-year survival rates were determined., Results: One hundred sixteen patients were enrolled within 45 months, and 109 began treatment with dasatinib. The 6-month PFS rate and the median PFS were 48% and 5.8 months, respectively. The PFS rate at 6 months was highest with ASPS (62%) and lowest with SFT (30%). More than 10% of the patients with ASPS, CS, or chordoma had stable disease for more than 1 year. Collectively, for all 5 subtypes, the 2- and 5-year overall survival rates were 44% and 13%, respectively. An objective response was observed in 18% of the patients with CS or chordoma., Conclusions: Dasatinib failed to achieve control of sarcoma growth for at least 6 months in more than 50% of the patients in this trial according to the Choi tumor response criteria. An objective tumor response and prolonged stable disease was observed in >10% of patients with CS or chordoma. Cancer 2017;90-97. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Purpose: Despite the rapidly increasing use of [ 18 F]fluorodeoxyglucose (FDG) -positron emission tomography (PET), the comparison of anatomic and functional imaging in the assessment of clinical outcomes has been lacking. In addition, there has not been a rigorous evaluation of how common radiologic criteria or the location of the radiology reader (local v central) compare in the ability to predict benefit. In this study, we aimed to compare the effectiveness of various radiologic response assessments for the prediction of overall survival (OS) within the same data set of patients with sarcoma., Methods: We analyzed assessments made during a clinical trial of a novel IGF1R antibody in Ewing sarcoma: PET Response Criteria in Solid Tumors (PERCIST) for functional imaging and WHO criteria (performed locally and centrally), RECIST, and volumetric analysis for anatomic imaging. We compared the effectiveness of the various criteria for the prediction of progression and survival., Results: For volume analysis, progression-defined as cumulative lesion volume increase of 100% at 6 weeks-was the optimal cutoff for decreased OS (P < .001). Assessment of the day-9 FDG-PET scan was associated with reduced OS in progressors compared with nonprogressors (P = .001) and with improved OS in responders compared with nonresponders. Significant variations in response (18% to 44%) and progression (9% to 50%) were observed between the different criteria. The comparison of central and local interpretation of anatomic imaging produced similar outcomes. PET was superior to anatomic imaging in identification of a response. Volume analysis identified the most responders among the anatomic imaging criteria., Conclusion: An early signal with FDG-PET on day 9 and volume analysis were the best predictors of benefit. Validation of the volumetric analysis is required.

The Children's Cancer Survivorship Study reports more chronic illnesses in sarcoma survivors than other pediatric cancers. Chemotherapy and radiation put survivors at risk for developing chronic illnesses, including heart disease, diabetes, hypertension, and kidney failure. Sarcoma survivors may have a reduced life expectancy and signs of heart disease in their 30s and 40s. Since these medical problems occur much later in the general population, they often go undetected or misdiagnosed in sarcoma survivors, creating delays in intervention and treatment. The good news is that these chronic illnesses can often be prevented or minimized. The most common adverse effect of chemotherapy and radiation is coronary artery disease (CAD). CAD has a number of risk factors, including hypertension, diabetes, obesity, and dyslipidemia. These risk factors are modifiable with lifestyle changes, including diet and exercise, and/or pharmacological intervention. By identifying and managing risk factors like hypertension early, we in turn reduce the risk for CAD and prolong survival. This is well established in the general population; there is no reason a priori not to apply it to sarcoma survivors. Sarcoma survivors should be followed by physicians who understand the late effects and outcomes of sarcoma treatment. The University of Michigan Sarcoma Survivorship Clinic provides long-term care for sarcoma survivors by preventing, diagnosing, and treating the adverse long-term physical and psychological effects associated with sarcoma survivorship., Competing Interests: Author Disclosure Statement No competing financial interests exist.

Background: Treatment for localized soft tissue sarcoma includes surgery and radiation, while the role of chemotherapy is controversial. Biomarkers that could predict therapeutic response or prognosticate overall survival (OS) are needed to define patients most likely to benefit from systemic treatment. Serum protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein that has been evaluated as a potential biomarker in numerous malignancies given its involvement in cell adhesion, proliferation, migration, and tissue remodeling., Methods: Using primary biopsy and resection specimens from patients with high-risk localized, soft tissue sarcoma treated on a neo/adjuvant chemotherapy study, SPARC expression was assessed and compared to patient and tumor characteristics, treatment, and outcomes. Survival functions were estimated using the Kaplan-Meier method and compared using the log-rank test. The Cox model was used for multivariate analysis., Results: Fifty patients had primary tumor specimens available. High, low, and no SPARC expression was found in 22, 13, and 15 patients, respectively. There was no significant difference in time to recurrence or OS between patients in these three groups. Comparing lack of SPARC expression with any SPARC expression, there was no significant difference in time to recurrence in patients without SPARC expression (n = 15) compared to patients with SPARC expression (n = 35). Likewise, there was no statistically significant difference in OS in patients without SPARC expression versus patients whose tumors expressed SPARC., Conclusions: Although we did not find a statistically significant difference in time to recurrence and OS in patients with high-risk soft tissue sarcoma, we did identify a trend toward improved time to recurrence and OS in patients whose tumors lacked SPARC expression. However, SPARC did not demonstrate the ability to discern which high-risk patients may have a worse prognosis or greater benefit from chemotherapy., Trial Registration: The trial was registered on September 13, 2005 with ClinicalTrials.gov, number https://clinicaltrials.gov/ct2/show/NCT00189137?term=sarcoma&id=NCT00189137&state1=NA%3AUS%3AMI&phase=1&rank=1 .

Objective: Value of information (VOI) analyses can align research with areas with the greatest potential impact on patient outcome, but questions remain concerning the feasibility and acceptability of these approaches to inform prioritization decisions. Our objective was to develop a process for calculating VOI in "real time" to inform trial funding decisions within SWOG, a large cancer clinical trials group., Methods: We developed an efficient and scalable VOI modeling approach using a selected sample of 9 randomized phase II/III trial proposals from the Breast, Gastrointestinal, and Genitourinary Disease Committees reviewed by SWOG's leadership between 2008 and 2013. There was bidirectional communication between SWOG investigators and the research team throughout the modeling development. Partial expected value of sample information for the treatment effect evaluated by the proposed trial's primary endpoint was calculated using Monte Carlo simulation., Results: We derived prior uncertainty in the treatment effect estimate from the sample size calculations. Our process was feasible for 8 of 9 trial proposals and efficient: the time required of 1 researcher was <1 week per proposal. We accommodated stakeholder input primarily by deconstructing VOI metrics into expected health benefits and incremental healthcare costs and assuming treatment decisions within our simulations were based on health benefits. Following customization, feedback from over 200 SWOG members was positive regarding the overall VOI framework, specific retrospective results, and potential for VOI analyses to inform future trial proposal evaluations., Conclusions: We developed an efficient and customized process to calculate the expected VOI of cancer clinical trials that is feasible for use in decision making and acceptable to investigators. Prospective use and evaluation of this approach is currently underway within SWOG., (© The Author(s) 2016.)

Unlabelled: The aim of this study was to assess the prognostic and predictive value of early quantitative (18)F-FDG PET to monitor therapy with an antibody to the insulinlike growth factor 1 receptor (IGF-1R antibody) in patients with Ewing sarcoma family of tumors (ESFT)., Methods: (18)F-FDG PET images at baseline and approximately 9 d after initiation of IGF-1R antibody therapy in 115 patients with refractory or relapsed ESFT were prospectively obtained as part of the Sarcoma Alliance for Research through Collaboration trial. Responses were centrally evaluated by PERCIST 1.0 in 93 patients. The 9-d PET responses were correlated to overall survival (OS), progression-free survival (PFS), and clinical benefit after 6 wk of therapy based on clinical observation and CT response by World Health Organization anatomic criteria., Results: The median OS was 8.1 mo (95% confidence interval, 6.4-10.0 mo). When PERCIST was used, patients with progressive metabolic disease showed shorter OS (median, 4.7 mo) than patients without progression (median, 10.0 mo; P = 0.001). Progressive metabolic disease on day-9 PET was associated with a significantly higher risk of death (hazard ratio, 2.8; 95% confidence interval, 1.5-5.5). Changes in (18)F-FDG uptake after 9 d of therapy had an area under the curve of receiver-operating characteristic of 0.71 to predict 1-y OS. The area under the curve was 0.63 to predict progression at 3 mo and 0.79 to predict clinical benefit after 6 wk of therapy., Conclusion: Treatment response by quantitative (18)F-FDG PET assessed by PERCIST 1.0 as early as 9 d into IGF-1R antibody therapy in patients with ESFT can predict the OS, PFS, and clinical response to therapy., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

The bromodomain and extra-terminal domain inhibitor JQ1 has marked antitumor activity against several hematologic malignancies as well as solid tumor models. Here, we investigated its activity in vitro and in vivo against models of childhood rhabdomyosarcoma and Ewing sarcoma. In vitro, JQ1 (but not the inactive enantiomer JQ1R) inhibited cell proliferation and increased G1 fraction of cells, although there was no correlation between cell line sensitivity and suppression of c-MYC or MYCN. In vivo, xenografts showed significant inhibition of growth during the period of treatment, and rapid regrowth after treatment was stopped, activity typical of antiangiogenic agents. Furthermore, xenografts derived from cell lines intrinsically resistant or sensitive to JQ1 in vitro had similar sensitivity in vivo as xenografts. Further investigation showed that JQ1 reduced tumor vascularization. This was secondary to both drug-induced downregulation of tumor-derived growth factors and direct effects of JQ1 on vascular elements. JQ1 suppressed VEGF-stimulated vascularization of Matrigel plugs in mice, and in vitro suppressed differentiation, proliferation, and invasion of human umbilical cord vascular endothelial cells (HUVEC). In HUVECs, JQ1 partially suppressed c-MYC levels, but dramatically reduced AP-1 levels and activity through suppression of the AP-1-associated protein FOSL1. Our data suggest that the antitumor activity of JQ1 in these sarcoma models is largely a consequence of its antiangiogenic activity. Mol Cancer Ther; 15(5); 1018-28. ©2016 AACR., (©2016 American Association for Cancer Research.)

Background: Dasatinib exhibited activity in preclinical models of sarcoma. The Sarcoma Alliance for Research through Collaboration (SARC) conducted a multicenter, phase 2 trial of dasatinib in patients with advanced sarcoma., Methods: Patients received dasatinib twice daily. The primary objective was to estimate the clinical benefit rate (CBR) (complete response or partial response within 6 months or stable disease duration of ≥6 months) with a target of ≥25%. Patients were enrolled into 1 of 7 different cohorts and assessed by imaging every 8 weeks using Choi criteria tumor response and a Bayesian hierarchical design. For each subtype, enrollment was stopped after a minimum of 9 patients were treated if there was a <1% chance the CBR was ≥25%., Results: A total of 200 patients were enrolled. Accrual was stopped early in 5 cohorts because of low CBR. The leiomyosarcoma (LMS) and undifferentiated pleomorphic sarcoma (UPS) cohorts fully accrued and 6 of 47 and 8 of 42 evaluable patients, respectively, exhibited clinical benefit. The probability that the CBR was ≥25% in the LMS and UPS cohorts was 0.008 and 0.10, respectively. The median progression-free survival ranged from 0.9 months in patients with rhabdomyosarcoma to 2.2 months in patients with LMS. The median overall survival was 8.6 months. The most frequent adverse events were constitutional, gastrointestinal, and respiratory, and 36% of patients required dose reduction for toxicity. Serious adverse events attributed to therapy occurred in 11% of patients., Conclusions: Dasatinib may have activity in patients with UPS but is inactive as a single agent in the other sarcoma subtypes included herein. The Bayesian design allowed for the early termination of accrual in 5 subtypes because of lack of drug activity., (© 2015 American Cancer Society.)

Background: Helicobacter pylori infection has been consistently associated with lack of access to clean water and proper sanitation, but no studies have demonstrated that the transmission of H. pylori can occur from drinking contaminated water. In this study, we used a laboratory mouse model to test whether waterborne H. pylori could cause gastric infection., Materials and Methods: Groups of immunocompetent C57/BL6 Helicobacter-free mice were exposed to static concentrations (1.29 × 10(5), 10(6), 10(7), 10(8), and 10(9) CFU/L) of H. pylori in their drinking water for 4 weeks. One group of Helicobacter-free mice was exposed to uncontaminated water as a negative control. H. pylori morphology changes in water were examined using microscopy Live/Dead staining. Following exposure, H. pylori infection and inflammation status in the stomach were evaluated using quantitative culture, PCR, the rapid urease test, and histology., Results: None of the mice in the negative control or 10(5) groups were infected. One of 20 cages (one of 40 mice) of the 10(6) group, three of 19 cages (four of 38 mice) of the 10(7) CFU/L group, 19 of 20 cages (33 of 40 mice) of the 10(8) group, and 20 of 20 cages (39 of 40 mice) of the 10(9) CFU/L group were infected. Infected mice had significantly higher gastric inflammation than uninfected mice (27.86% higher inflammation, p < .0001)., Conclusions: We offer proof that H. pylori in water is infectious in mice, suggesting that humans drinking contaminated water may be at risk of contracting H. pylori infection. Much work needs to be performed to better understand the risk of infection from drinking H. pylori-contaminated water., (© 2015 John Wiley & Sons Ltd.)