bluuebunny/crossref_metadata_2025 huggingface dataset:
Features of familiality in a cohort of patients (pts) with sarcoma.
Authors: Lypas Georgios , Root Elizabeth J. , George Suzanne , Wagner Andrew J. , Butrynski James E. , Morgan Jeffrey A. , Demetri George D. , DiGianni Lisa , Masciari Serena , Rath Michelle Genevieve , Garber Judy Ellen , Raut Chandrajit P.
Published: March 2020

1547

Background: Sarcomas occur in a number of cancer predisposition syndromes, yet genetic evaluation is rarely recommended for sarcoma pts. We broadly reviewed the family cancer histories of unselected pts in a tertiary center sarcoma clinic to explore the potential relevance of genetic assessment. Methods: Between 2005 and 2008, 397 pts (median age 52 years) with documented sarcoma who consented to research use of medical records and tissues also completed a family history questionnaire. Patient and family histories were reviewed for features suggesting hereditary risk (e.g. early age at diagnosis or familial clustering of certain associated diagnoses). Results: A family history of malignancy was noted in 301 of 397 pts (76%). Seventy-six pts (19%) were diagnosed with 99 additional malignancies, most frequently breast cancer (n=23), prostate cancer (12), melanoma (12), thyroid cancer (6) or a second sarcoma (10). Sarcoma was diagnosed prior to or synchronously (within 6 months) with another malignancy in 20 pts and metachronously in 56 pts. In 18 pts, sarcoma arose within a prior radiation field. Thirty-seven pts (9%) had a sarcoma subtype associated with a recognized syndrome: desmoid fibromatosis (n=16), malignant peripheral nerve sheath tumor (11), PEComa/angiomyolipoma (6), retinoblastoma (3), and GIST with paraganglioma (1). Based on additional features, the associated syndromes were confirmed in 6 of them (1.5% of the cohort): familial adenomatous polyposis (n=1), neurofibromatosis type 1 (2), familial retinoblastoma (2), and Carney-Stratakis dyad (1). Thirty-three pts (8% of the cohort, or 16% of pts age <50) fulfilled TP53 testing criteria (Chompret, Birch or classical Li-Fraumeni Syndrome [LFS] criteria). Another 147 pts (37% of the entire cohort) did not fulfill LFS testing criteria, but were diagnosed with sarcoma before age 50 and had at least one first or second degree relative with a diagnosis of malignancy before age 50. Conclusions: Sarcomas are rare and diverse cancers. Given the potential association with cancer predisposition syndromes, genetic evaluation should be strongly considered in sarcoma pts based on age at diagnosis, histology, and family cancer history.
Ethnic difference of driver mutation frequencies and correlations between driver mutations and histologic subtypes in lung adenocarcinoma.
Authors: Yamane Yuki , Goto Koichi , Kawase Akikazu , Tsuchihara Katsuya , Mimaki Sachiyo , Ishii Genichiro , Ohmatsu Hironobu , Niho Seiji , Yoh Kiyotaka , Umemura Shigeki , Nagai Kanji , Ohe Yuichiro , Ochiai Atsushi , Esumi Hiroyasu
Published: March 2020

1552

Background: The frequencies of known driver mutation in lung adenocarcinoma from patients in the United States have been reported by the NCI’s Lung Cancer Mutation Consortium (LCMC), indicating driver mutations were detected in 54% (280/516) of tumors. In this report, mutations found: EGFR 17%, KRAS 22%, HER2 0.6%, PIK3CA 1.2%, BRAF 2%, MET amplification 0.6%, MAP2K1 0.4%, NRAS 0.4%, AKT 0%, ALK rearrangements 7%. However little is known about ethnic difference of driver mutation frequencies and correlations between driver mutations and histological subtypes in lung adenocarcinoma. Methods: Known driver mutations in tumors from 97 Japanese patients with lung adenocarcinoma who underwent surgical resection between 1999 and 2003 in National Cancer Center Hospital East were analyzed by next-generation sequencing and confirmed by Sanger sequencing. Correlations between driver mutations and histological subtypes were also assessed. Results: Driver mutations were detected in 72% of tumors. Mutations found: EGFR 57%, KRAS9%, HER2 2%, PIK3CA 2%, BRAF 1%, MET amplification 1%, MAP2K1 0%, NRAS 0%, AKT 0%. Due to the limitation of rearrangement detection by exon-sequencing, ALK rearrangements were not analyzed. Compared with the report by LCMC, the frequency of EGFR mutations was high and that of KRAS mutations was low in the present study. All mutations were mutually exclusive. The number of predominant histological subtypes of tumors harbored EGFR mutations were papillary 28, acinar 3, solid 5, lepidic 19. That with KRAS mutations showed papillary 2, acinar 2, solid 2, lepidic 3, and HER2 mutations showed papillary 1 and acinar 1. Two tumors harbored PIK3CA mutations showed both histological acinar pattern. Each of BRAF mutation and MET amplification showed lepidic and papillary pattern, respectively. Conclusions: It was suggested that there should be ethnic difference of driver mutation frequencies in lung adenocarcinoma between Asian and non-Asian patients, although the details of ethnic distribution included in LCMC study has not been opened. In addition, each driver mutations did not correspond to specific histological subtypes of lung adenocarcinoma.
Variants of uncertain significance in BRCA testing: Impact on risk perception, worry, prevention, and counseling.
Authors: Graham Tracy , Eisen Andrea , Richter Sue , Haroun Iman , Warner Ellen
Published: March 2020

1555

Background: Genetic testing for BRCA1 and BRCA2 is an instrumental tool in clinical decision-making. Variants of uncertain significance (VUS) can occur in up to 25% of individuals and pose clinical challenges. We compared i) result recall ii) risk perception iii) worry and iv) risk modifying behaviours in individuals with VUS, a pathogenic mutation (PM) or an uninformative result (UR). Care provider attitudes to VUS were also studied. Methods: A questionnaire was mailed to women testing positive for a VUS, PM or UR. Items included demographics, time from disclosure, result recall and cancer worry using the validated Trask score. Likelihood of risk modifying behaviours or intensified screening was evaluated by 5 point Likert scale. 9 regional genetic counselors and 11 referring physicians were surveyed on VUS management. Responses were evaluated by chi square and ANOVA. Results: All groups had similar age, marital status and education. Failure to correctly identify a result as uninformative occurred in 32% of VUS; 90% had low economic status. 87% (VUS) and 44% (PMC) had personal history of breast cancer. Perceived risk increased after disclosure in 29% (VUS), 70%(PM) and 10% (UR) (p<0.001). Mean Trask scores were 7.6 (VUS) and 9.8 (PMC) (p=0.006, t-test). In affected patients, mastectomy was 22% (VUS) and 55% (PMC) (p=0.01), oophorectomy 39% (VUS) and 85% (PMCs) (p<0.001) with75% and 95% intensified screening 75% in unaffected VUS and PM (p=0.16). 3% (VUS) and 6% (PMC) agreed with chemoprophylaxis (p=NS). Genetic counselors unanimously reported low comprehension in VUS vs PM. VUS was disclosed only 75% of the time with poor comprehension, perceived anxiety and negative family history as reasons. Referring physicians recommended predictive testing for relatives of VUS carriers (100%). Conclusions: Nearly 1/3 of patients fail to recall their VUS as uninformative. Perceived risk was increased after VUS disclosure but lower than PMC. Worry scores showed impact on daily functioning. Uptake of prophylactic surgery was lower in affected VUS vs PMC carriers with similar rates of intensified screening if unaffected. Patients with low economic status or anxiety are at particular risk of incomplete counseling.
First report on screening an asymptomatic population for cancer: The yield of an integrated cancer prevention center.
Authors: Sella Tal , Boursi Ben , Gat-Charlap Amira , Aroch Ilan , Liberman Eliezer , Moshkowitz Menachem , Miller Ehud , Gur Eyal , Blachar Arye , Mabjeesh Nicola J. , Sperber Fanny , Reiser Vadim , Kleinman Shlomi , Jaffa Ariel J. , Ormianer Mati , Naumov Inna , Kazanov Diana , Kraus Sarah , Galazan Lior , Arber Nadir
Published: March 2020

1564

Background: Cancer is a leading cause of mortality worldwide. Screening is a key strategy for reducing cancer morbidity and mortality. We aimed to evaluate the utility of cancer screening in an asymptomatic population at an integrated cancer prevention center. Methods: One-thousand consecutive asymptomatic, apparently healthy adults, aged 20-80 years, were screened for early detection of 11 common cancers by routine screening tests. Results: Malignant and benign lesions were found in 2.4% and 7.1% of the screenees, respectively. The most common malignant lesions were in the gastrointestinal tract and breast followed by gynecological and skin. The compliance rate for the different screening procedures was considerably higher than the general Israeli population – 78% compared to 60% for mammography (p<0.001) and 39% compared to 16% for colonoscopy (p<0.001). Advanced age, family history and certain lifestyle parameters were associated with increased risk for cancer. Moreover, polymorphisms in the APC and CD24 genes indicated high cancer risk. When two of the polymorphisms existed in an individual, the risk for a neoplastic lesion was extremely high (OR 2.3 [95% CI 0.94-5.9]). Conclusions: A significant number of neoplastic lesions were diagnosed at an early stage. Polymorphisms in the APC and CD24 genes may identify individuals at an increased risk for cancer. Cancer may be diagnosed at an early stage using the screening facilities of a multidisciplinary outpatient clinic.
Factors and trends in cancer screening in the United States from 2004 to 2010.
Authors: Reungwetwattana Thanyanan , Molina Julian R. , Ziegenfuss Jeanette Y.
Published: March 2020

1565

Background: Understanding the prevalence of cancer screening in the US and the factors associated with its accessibility is important for public health promotion. Methods: The 2004 and 2010 Behavioral Risk Factor Surveillance Systems were used to ascertain cancer screening rates among populations indicated for each test by age, gender, and the American Cancer Society recommendation for cancer screenings [fecal occult blood test (FOBT) or endoscopy for colorectal cancer (CRC) screening, digital rectal examination (DRE) or prostate specific antigen (PSA) for prostate cancer screening, clinical breast examination (CBE) or mammogram for breast cancer screening, and Papanicolaou (Pap) test for cervical cancer screening]. Results: Over this period, CRC and breast cancer screening rates significantly increased (15.9%, 13.9%) while prostate and cervical cancer screening rates significantly decreased (1.2%, 5.2%). Race/ethnicity might be an influence in CRC and cervical cancer screening accessibility. Prostate cancer screening accessibility might be influenced by education and income. The older-aged populations (70-79, >79) had high prevalence of CRC, prostate and breast cancer screenings even though there is insufficient evidence for the benefits and harms of screenings in the older-aged group. Conclusions: The disparities in age, race/ethnicity, health insurance, education, employment, and income for the accession to cancer screening of the US population have decreased since 2004. The trajectory of increasing rates of CRC and breast cancer screenings should be maintained. To reverse the trend, the causes of the decreased rate of cervical cancer screening and the high rates of screenings in older-aged populations should, however, be further explored. [Table: see text]
Patient perceptions of stool-based DNA testing across racial groups.
Authors: Huang Lily , Chen Zhengyi , Lynn Audrey , Devore Nathan , Nguyen Minh-Tri , Thompson Cheryl L , Cooper Gregory , Markowitz Sanford D. , Li Li
Published: March 2020

1569

Background: Despite the widespread acceptance of colonoscopy as the gold standard for Colorectal Cancer (CRC) screening, compliance rates with recommended CRC screening lag far behind screening for breast and cervical cancers. Patients often delay or forgo screening colonoscopy due to associated discomfort, inconvenience, anxiety, and high cost. In addition, recent data have casted doubt on its effectiveness, especially in detecting right-sided colon neoplasia. Stool-based DNA (sDNA) testing is an emerging CRC screening tool that is convenient, noninvasive, and effective in detecting both right and left sided colon cancer. The goal of this study was to evaluate patient attitudes towards sDNA testing, identify preferences in CRC screening tools, and assess racial differences in these attitudes and preferences. Methods: In a colonoscopy-based case-control study, 100 patients of average CRC risk were asked to complete (1) sDNA testing (LabCorp ColoSure test), (2) screening colonoscopy, and (3) a patient satisfaction survey. Results: Eighty patients completed the study, including 55 (69%) White, 22 (27%) African American, and 3 (4%) Others. Overall, patients rated sDNA testing favorably in all preparation and test related features, except for perceived accuracy. Patients reporting a preferred screening method favored sDNA testing (78%) to FOBT (12%) or colonoscopy (10%), and 83% of all patients reported that they are likely to repeat sDNA testing. Non-Caucasians rated sDNA testing less favorably than Caucasians – reporting more discomfort (ANOVA, p<0.004), more anxiety (ANOVA, p<0.001), and less suitability (Chi-Squared, p<0.0035). Of those patients reporting a preferred screening test, 82% of Caucasians and 64% of non-Caucasians selected sDNA testing. Conclusions: Although sDNA testing was ranked less favorably by non-Caucasians, it was well received overall as the preferred CRC screening test, as compared to FOBT and colonoscopy. The differences between racial groups may reflect the generally lower uptake of CRC screening among non-Caucasians, regardless of the test. In conclusion, sDNA testing may be an effective means to increase CRC screening in African Americans, hence preventing CRC and closing the racial disparity gap.
Assessing a prognostic model for predicting VTE occurrence in cancer patients.
Authors: Sarma Deesha , Kim So Yeon , Henry David H.
Published: March 2020

1577

Background: Venous thromboembolism (VTE) poses a significant health risk to cancer patients and is one of the leading causes of death among this population. The most effective way to prevent VTE and reduce its prominence as a public health burden is by identifying high-risk patients and administering prophylactic measures. In 2008, Khorana et al. developed a model that classified patients by risk based on clinical factors. Methods: We conducted a retrospective study to test this model’s efficacy, on 150 patients with cancer receiving chemotherapy at an outpatient oncology clinic between January 1 and August 1, 2011. We aggregated data and assigned points based on the five factors in the Khorana model: site of cancer with 2 points for very high-risk site and 1 point for high-risk site, 1 point each for leukocyte counts more than 11 x 109/L, platelet counts greater than 350 X 109/L, hemoglobin levels less than 100 g/L and/or the use of erythropoiesis-stimulating agents, and BMI greater than 35 kg/m2 (Khorana et al., Blood 2008). Based on this scoring system, patients with 0 points were grouped into the low-risk category, those with 1-2 points were considered intermediate-risk, and those with 3-4 points were classified as high-risk. Results: As shown in the table, VTE incidence for the low-risk group was 1.9%, intermediate-risk group was 3.9%, and high-risk group was 9.1%. Conclusions: High-risk patients were about 4.5 times more likely to develop a VTE than low risk patients. These results provide valuable insight in determining which patients might benefit from prophylaxis and in motivating the design of prospective clinical trials that assess the VTE predictive model in various ambulatory cancer settings. [Table: see text]
Factors associated with referral to medical oncology (MO) and subsequent use of adjuvant chemotherapy (ACT) among patients with resected non-small cell lung cancer (NSCLC): A population-based study.
Authors: Kankesan Janarthanan , Shepherd Frances A. , Peng Yingwei , Darling Gail Elizabeth , Li Gavin , Kong Weidong , Mackillop William J. , Booth Christopher M.
Published: March 2020

1583

Background: ACT for NSCLC is associated with improved survival in the general population but may be underutilized. Underutilization may relate to lack of referral from surgeon to MO, MO not offering ACT, or patient declining ACT. Here we explore factors associated with referral to MO and use of ACT among patients with resected NSCLC in Ontario Canada. Methods: The Ontario Cancer Registry was used to identify all incident cases of NSCLC diagnosed in Ontario 2004-2006. We linked electronic records of treatment to identify surgery, ACT, and MO consultation. Co-morbidity was classified using the Charlson Comorbidity Index modified for administrative data. A multivariate logistic regression model was used to evaluate factors associated with referral to MO and use of ACT. Results: 3354 cases of NSCLC were resected in Ontario 2004-2006, 1830 (55%) were seen post-operatively by MO and 1032 (31%) were treated with ACT. Cases younger than 70 were more likely to have MO consultation (age 60-69 OR 1.6; 50-59 OR 2.3; 20-49 OR 2.2, p<0.001) as were cases with stage II/III (ORs 2.7 and 2.0, p<0.01) compared to stage I disease. There was substantial geographic variation in the proportion of surgical cases referred to MO (range 32-88%, p<0.001). Among cases seen by MO, patients younger than 70 were more likely to have ACT (age 60-69 OR 3.1; 50-59 OR 4.7; 20-49 OR 6.7, p<0.001) as were cases with stage II/III (ORs 2.7 and 3.0, p<0.001) compared to stage I disease. Less co-morbidity (OR 2.1, p=0.02) and shorter post-operative stay (OR 1.4, p=0.001) were also associated with use of ACT. Among cases seen by MO, there was some geographic variation (range 46-63%, p<0.001) in rates of ACT utilization. Conclusions: The upstream decision to refer to MO is associated with age and stage of disease and these factors have an even greater effect on ACT utilization once patients are seen by MO. While co-morbidity and post-operative length of stay are not associated with referral to MO, they are associated with use of ACT among cases seen by MO. There is substantial geographic variation in referral patterns to MO and less variation in ACT utilization once patients are seen by MO.
Impact of response shift on time to quality-of-life scores deterioration in patients with breast cancer.
Authors: Hamidou Zeinab , Dabakuyo Tienhan Sandrine , Guillemin Françis , Conroy Thierry , Velten Michel , Jolly Damien , Mercier Mariette , Causeret Sylvain , Cuisenier Jean , Graesslin Olivier , Gauthier Mélanie , Bonnetain Franck
Published: March 2020

1584

Background: Time to quality of life (QoL) score deterioration (TD) is a method of longitudinal QoL data analysis that has been proposed for breast cancer (BC) patients (Hamidou et al Oncologist 2011). As for RECIST criteria, the optimal definitions dealing with reference should be explored. This study aims to study the impact of changes in internal standards (CIS) of response-shift (RS) and the influence of baseline QoL expectancies on TD. Methods: A prospective multicenter study including all women hospitalized for a primary BC was conducted. The EORTC-QLQ-C30 and BR-23 questionnaires were used to assess the QoL at baseline, at the end of 1st hospitalization, and 3 and 6 months after. CIS was investigated by the then-test method. QoL expectancy was assessed at baseline using Likert scale. Deterioration was defined as a decrease in QoL scores reaching at least the mean difference identified as minimal clinically important difference (MCID) using Jaeschke’s transition question. Sensitivity analyses were done using the then-test score as reference score, and considering 5 and 10 points as MCID. TD was estimated using Kaplan-Meier method. Cox regression analyses were used to identify factors influencing TD. Results: From February 2006 to February 2008, 381 women were included. For role functioning dimension, the median TD increased from 3.2 months [95% CI: 3.1-3.36] to 4.76 months [3.3-6.2] when adjusting on CIS. For body image when adjusting on CIS, sentinel lymph node biopsy became significantly associated with longer TD (HR: 0.64[0.43-0.94]) as compared to axillary lymph node dissection, radiotherapy to a shorter TD (HR: 0.63[0.42-0.95] and the type of surgery had no effect on TD. For global health, cognitive and social functioning dimensions, patients expecting deterioration in their QoL had a significantly shorter TD. For fatigue and breast symptom scales, patients expecting no change had a significantly shorter TD, as compared to patients expecting an improvement. Sensitivity analyses using a MDCS of 5 or 10 confirmed these results. Conclusions: Our results suggest that it would be more accurate to take into account CIS component of RS as well as QoL expectancies to estimate TD of QoL scores in patient with BC.
Renal impairment after chemotherapy in lung (LC), colorectal (CRC), and breast cancer (BC) patients (pts) from the Henry Ford Health System (HFHS) tumor registry.
Authors: Chu Laura , Ulcickas Yood Marianne , Loghman-Adham Mahmoud , Wells Karen , Casso Deborah , Oliveria Susan A. , Dong Wei
Published: March 2020

1590

Background: Renal impairment is a common comorbidity in cancer pts. It can delay excretion and alter metabolism of anticancer drugs leading to further renal toxicity. The objective of this study was to determine the proportion of pts with renal impairment, defined as the presence of proteinuria (PR), acute kidney injury (AKI), or chronic kidney disease (CKD), after chemotherapy (chemo) initiation. Methods: LC, CRC, and BC pts newly diagnosed between 2000 and 2007 (regardless of prior renal status) were identified using the HFHS tumor registry, with follow-up through Mar 2009. AKI was defined based on RIFLE (severity categories only) using lab data within 1 to 7 days after chemo initiation. CKD was defined based on NKF-KDOQI criteria and lab data up to 1 year after chemo initiation. Proteinuria was defined as protein/creatinine >30 mg/g within 3 months after chemo initiation. Descriptive statistics include proportions stratified by renal impairment status (yes, no) at cancer diagnosis. Results: We identified 1,896 LC, 1,088 CRC, 1,611 BC chemo treated pts. Median age for all pts was 66 years. For LC and CRC, 56% and 51% were men, respectively. The proportion of pts with renal impairment after chemo by tumor type was the following: LC (AKI=23.4%; CKD=48.2%; PR=0.4%); CRC (AKI=20.3%; CKD=55.7%; PR=0.1%); BC (AKI=7.8%; CKD=63.9%; PR=0.6%). Pts with pre-existing renal impairment at cancer diagnosis were more likely to have impairment after chemo (Table). Conclusions: In LC, CRC, and BC pts, the proportion of pts with renal impairment after chemo initiation was high. Extent of renal impairment, especially AKI, appears to be associated with tumor type. Older age, as in this HFHS cohort, is associated with higher prevalence of CKD. Renal function should be closely monitored, particularly among pts with pre-existing renal impairment, and preventive measures implemented to minimize further toxicity after treatment.
Evolution and landscape of clinical trials for breast cancer patients.
Authors: Dogan Semih , Goubar Aicha , Arnedos Monica , Delaloge Suzette , Andre Fabrice
Published: March 2020

1601

Background: Recent advances in cancer research are expected to have dramatically changed the way clinical trials are being done. In an effort to outline new trends of clinical research in the breast cancer area, we have evaluated the evolution of clinical trials started between 2006 and 2011. Methods: 622 clinical trials, started during the first semester 2006, the second semester 2008 and the first semester 2011, were analyzed. The data source was Clinicaltrials.gov. 30 items were included in the database. Results: The overall number of patients included in prospective clinical trials increased over these periods (n=67,820, n=91,429, n=98,417). However, when large epidemiological cohorts are excluded, a significant fall in the number of patients is seen (n=67,820, n=44,554, n=37,417). The absolute number of therapeutic trials also decreased during this time (n=93, n=99, n=78), mainly related to the dramatic fall in the number of trials testing conventional treatments (n=40, n=24, n=20). In the meantime, the number of trials testing targeted agents remained similar (n=46, n=67, n=50). Interestingly, in the same time, the number of trials testing a targeted agent in a population defined by a biomarker increased (n=1, n=6, n=14). At the opposite, prospective studies aimed at validating biomarkers did not increase, and remained only driven by large consortiums. As illustration, when we exclude RxPONDER trial, the biomarker-validation studies opened in 2011 planned to include only 2 493 patients, representing 2% of the breast cancer research field. Prospective trials testing social sciences and supportive care (n= 70, n=72, n=70) tend to become as important as therapeutic trials. Finally, large epidemiological cohorts opened in 2011 will represent more than 60% of the patients included in clinical trials. Conclusions: The part of cohorts and social sciences in breast cancer research is increasing and represents now the majority of the clinical research activity. When the analysis focuses on therapeutic trials, the breast cancer field recently shifted to targeted agents and early data suggest that therapeutic research is increasingly incorporating companion biomarker. Analysis on all 2,762 clinical trials done between 2006 and 2011 will be presented.
A retrospective analysis of all non-AIDS defining cancers (NADC): A subset analysis of the County Hospital AIDS Malignancy Project (CHAMP).
Authors: Gupta Shweta , Jain Prantesh , Mino Emilio Araujo , French Audrey L. , Rosen Fred R , Rubinstein Paul G.
Published: March 2020

1611

Background: County Hospital (CCH) with its HIV clinic, the CORE Center (CC) is the largest provider for HIV patients (pts) in Chicago, treating over 5,500 HIV pts yearly. There is paucity of data on characteristics of HIV+ cancers (ca) in the inner city. The CHAMP cohort is a retrospective study of all HIV associated cancers at CC and CCH over past 14 years (yrs). We analyzed all of the NADC from this cohort. Methods: All HIV pts with NADC were identified from the CHAMP cohort and retrospectively reviewed for HIV and cancer characteristics, overall survival (OS), and pt demographics. Statistics: Survival data was analyzed using Kaplan-Meier analysis and Cox Proportional Hazards model. Results: Of 438 pts identified, 157 were NADC representing 21 ca. The average (ave) age was 48 yrs (range 44-57), with prostate ca having highest age presentation. Over the past 10 yrs, the number of NADC has risen from 10 to over 20 each yr. Unlike historical controls (HC) where lung ca is most common, anal ca (21%) was most frequent followed by lung ca (17%). Prostate, head and neck (HNSCC), liver, and colorectal ca were seen in 9, 9, 8, and 7% respectively. 65% of pts were African Americans (AA) and 18% Caucasians. 78% of all NADC were men. 45% of anal ca present with stage IIIa/b disease, moderately to poorly differentiated ca in 48%, with a median OS of 34 mo. CD4 count did not alter OS but stage predicted better outcomes. 86% lung ca presented as stage III/IV disease with ave CD4 count 204. Histologically, 36% were SCC, 28% adenosquamous and 20% adenocarcinoma. OS was 5.5 mo and did not change by histology, CD4, or age. 68% HNSCC present with stage IVa/b but no IVc. Ave age was 48 yrs with an OS of 18mo. 50% were oropharyngeal compared to 22% in HC. Conclusions: Based on data by Sheilds et. al, CCH treats just over 1% of the country’s NADC population. We demonstrate a higher incidence of NADC over time, dominated by a younger, AA and male population. Each ca presents with advanced stage 45-86% and poorly differentiated tumors ranging from 15-30%. The OS of each cancer is consistent with HC with exception of HNSCC. As HIV pts age becoming prone to cancers of elderly, education and screening of inner city HIV pts will help improve cancer rates.
Elderly patients with primary CNS lymphoma: Results from the G-PCNSL-SG-1 trial.
Authors: Roth Patrick , Martus Peter , Kiewe Philipp M. , Moehle Robert , Klasen Hermann A. , Rauch Michael , Roeth Alexander , Kaun Stephan , Thiel Eckhard , Korfel Agnieszka , Weller Michael
Published: March 2020

2007

Background: Age is the most important therapy-independent prognostic factor in patients with primary central nervous system lymphoma (PCNSL). Here we aimed at providing an analysis of the impact of higher age on response to therapy, toxicity, and survival in the largest PCNSL trial ever performed to date. Methods: Response to therapy, toxicity and survival of PCNSL patients enrolled in the G-PCNSL-SG-1 trial evaluating the role of radiotherapy after high-dose methotrexate (HD-MTX)-based chemotherapy were monitored. Subjects aged 70 or more were compared to younger patients. Results: Of all eligible patients (n=526), 126 (24%) were aged 70 or more. In the per protocol population, 66 of 318 patients (21%) were at least 70 years old. Among the eligible patients, the rate of complete and partial responses (CR+PR) to HD-MTX-based chemotherapy was 44% in the elderly compared to 57% in the younger patients (p=0.016). A higher rate of grade III/IV leukopenia was observed in the elderly (34% versus 21%, p=0.007). Also, death on therapy was more frequent (18% versus 11%; p=0.027) in these patients. In contrast, there was no other major age-dependent toxicity. Survival analyses revealed shorter progression-free survival (PFS) (4.0 versus 7.7 months, p=0.014) and overall survival (OS) (12.5 versus 26.2 months, p<0.001) in the elderly population. The PFS of CR patients was 35.0 months in younger patients compared to 16.1 in the elderly (p=0.024). Salvage therapy was used less commonly in elderly patients. When salvage WBRT was applied in patients who had failed on HD-MTX-based chemotherapy, there was no association between age and survival (p=0.633). Conclusions: Elderly PCNSL patients have a lower response rate and higher mortality on HD-MTX-based chemotherapy. Their PFS is shorter and they receive less salvage therapy which may contribute to the poor prognosis.
Rituximab, methotrexate (MTX), procarbazine, and vincristine (R-MPV) followed by consolidation high-dose chemotherapy (HDC) and autologous stem-cell transplant (ASCT) for newly diagnosed primary CNS lymphoma (PCNSL).
Authors: Omuro Antonio Marcilio Padula , Correa Denise , Moskowitz Craig , Matasar Matthew J. , DeAngelis Lisa Marie , Kaley Thomas Joseph , Gavrilovic Igor T. , Nolan Craig , Pentsova Elena , Grommes Christian , Abrey Lauren E. , Sauter Craig Steven
Published: March 2020

2008

Background: In our previous study in newly diagnosed PCNSL, induction chemotherapy with MTX and cytarabine followed by consolidation HDC (carmustine, etoposide, cytarabine, melphalan [BEAM]) with ASCT without radiotherapy resulted in only 50% of pts transplanted, reflecting low efficacy of induction chemotherapy, and short intent-to-treat (ITT) median PFS (=6m). In this phase II trial, we sought to optimize this strategy by utilizing a more effective induction regimen (R-MPV) and a more aggressive HDC regimen (Soussain et al). Methods: Pts received 5-7 cycles of R-MPV (MTX: 3.5g/m2) and if a partial or complete response was achieved, HDC with thiothepa, cyclophosphamide and busulfan was given, followed by ASCT and no radiotherapy. The primary endpoint was ITT 1 year event-free survival (promising: 75%, non-promising: 50%; 90% power, significance=0.05). Follow-up included comprehensive neuropsychological evaluation. Results: Accrual has been completed (N=32 pts, median age 57 [range 23-67], median KPS=80). Following R-MPV, 17 pts achieved a CR, 13 pts a PR and two pts progressed. A total of 25 (78%) pts were transplanted; the reasons for not receiving transplant were progressive disease (N=2), poor performance status/ physician’s decision (N= 2), mobilization failure (N=1) and consent withdrawn (N= 2). One pt who withdrew consent relapsed and received HDCASCT for salvage. Two (8%) pts died from early complications of ASCT (Stevens-Johnson: one, sepsis: one) and one pt experienced a fatal late colitis of unknown etiology. In the ITT population, the median EFS and OS have not been reached after a median follow-up of 22 months. The 1 year EFS was 78% (95%CI 58-90) and the 2y OS was 76% (95% CI 54-89). No pt has developed delayed neurotoxicity. Conclusions: R-MPV induction regimen resulted in improved response rates, allowing 78% of pts to receive HDC-ASCT. Although more toxic, this regimen resulted in excellent disease control and survival in the ITT population, far exceeding the efficacy of our previous transplant study. The primary endpoint was met, warranting further investigation.
Effect of antiangiogenic therapy on tumor-associated macrophages in recurrent glioblastoma.
Authors: Lu-Emerson Christine , Snuderl Matija , Davidson Christian , Kirkpatrick Nathaniel D. , Huang Yuhui , Duda Dan G. , Ancukiewicz Marek , Stemmer-Rachamimov Anat , Batchelor Tracy , Jain Rakesh K.
Published: March 2020

2010

Background: Antiangiogenic therapy is associated with increased radiographic responses in glioblastoma (GBM), but tumors invariably recur. Tumor associated macrophages (TAMs) have been proposed as a mechanism of resistance to anti-angiogenic therapy in preclinical models. To examine the role of TAMs in recurrent GBM, we analyzed autopsy specimens from patients with or without history of antiangiogenic therapy. Methods: We compared autopsy brain specimens from 17 recurrent GBM patients who received anti-angiogenic treatment and chemoradiation (AAT+) to 7 patients who received chemotherapy and/or radiotherapy without anti-angiogenic therapy, or no treatment (AAT-). TAMs were morphologically and phenotypically identified with flow cytometry and immunohistochemistry (IHC) with CD68, CD11b, CD14, and CD163 markers. All specimens were obtained from the Department of Pathology at Massachusetts General Hospital and clinical information gained through review of the patients’ records. Results: Using flow cytometry, we observed an increase in CD11b+CD14+ cells in the AAT+ patients compared to AAT- patients. Using IHC analysis, we observed a significant increase in CD68+ macrophages in the tumor bulk (p<0.01) and infiltrative areas (p<0.05) in AAT+ versus AAT- patients. We also observed a significant increase in CD11b+ myeloid cells in the tumor bulk (p<0.01) and a significant increase in CD163+ cells in the infiltrative areas (p<0.05) in the AAT+ group. Finally, we noted a trend toward an increase in CD163+ cells in the tumor bulk (p=0.087) in the AAT+ versus the AAT- patients. Conclusions: Patients with recurrent GBM after antiangiogenic therapy showed a significant increase in CD68+ TAMs and in CD11b+ cells in the tumor bulk. Additionally, antiangiogenic treatment induced an increase in CD68+ and CD163+ TAMs in the infiltrative region. These data indicate that TAMs may participate in escape from antiangiogenic therapy and may represent a future therapeutic target in recurrent GBM.
Phase I safety and pharmacokinetic (PK) study of veliparib in combination with whole brain radiation therapy (WBRT) in patients (pts) with brain metastases.
Authors: Mehta Minesh P. , Curran Walter J. , Wang Ding , Wang Fen , Kleinberg Lawrence , Brade Anthony M. , Mostafa Nael , Zhou Xiangdong , Qian Jiang , Leahy Terri , Desai Bhardwaj , Giranda Vincent L.
Published: March 2020

2013

Background: Veliparib is an oral PARP-1 and -2 inhibitor that enhances the antitumor activity of DNA damaging agents including radiation therapy in vivo. In pre-clinical models, veliparib crosses the blood-brain barrier. This ongoing phase I dose-escalation study evaluates the safety, PK, and provides preliminary antitumor activity of veliparib in combination with WBRT in pts with brain metastases. Methods: Pts with brain metastases from non-CNS primary solid malignancy, adequate organ function, RPA Class 2, and KPS ≥70 were treated with WBRT (37.5 Gy in 15 fractions or 30 Gy in 10 fractions) QD with veliparib BID with every fraction of WBRT in escalating doses of 10, 20, 30, 50, 100, 150, and 200 mg; the final WBRT fraction was followed by 1 extra day of veliparib. Safety, PK, and tumor response by RECIST were assessed. Results: At the time of reporting 59 pts (M/F, 21/38; median age 57 y) had been treated. Baseline KPS was 70, 80, 90, and 100 in 6.8, 32.2, 40.7, and 20.3% pts, respectively; primary tumor types were breast (n=20), NSCLC (n=20), melanoma (n=9), colorectal (n=2), and others (n=8); 71.2% pts had multiple lesions; and 18.6% had prior brain SRS. Grade 3/4 treatment-emergent adverse events (TEAEs; ≥5%) were fatigue (6.8%), anemia (5.1%), hyponatraemia (5.1%), and thrombocytopenia (5.1%); other TEAEs (≥20%) were fatigue (57.6%), headache (42.4%), nausea (40.7%), alopecia (28.8%), vomiting (22%), radiation skin reactions (22%), and decreased appetite (22%). PK of veliparib were approximately dose-proportional, with oral clearance of 21.6 ± 14.2 L/h (mean ± SD, n=45), minimal drug accumulation at day 15, and no significant effect of food on bioavailability. Tumor response was evaluable in 48 pts. Best tumor response and median survival were 37.5% and 10 months (m) for NSCLC, and 52.9% and 12.5 m for breast cancer (excluding pts with leptomeningeal disease). Conclusions: Addition of veliparib up to 200 mg BID was well tolerated with concurrent WBRT and dose escalation ongoing. The PK of veliparib was dose proportional with no food effect. Preliminary antitumor activity is encouraging and informative for the design of more definitive trials.
APG101_CD_002: A phase II, randomized, open-label, multicenter study of weekly APG101 plus reirradiation versus reirradiation in the treatment of patients with recurrent glioblastoma.
Authors: Bendszus Martin , Debus Jürgen , Wick Wolfgang , Kobyakov Grigory , Martens Tobias , Heese Oliver , Pichler Josef , Stupp Roger , Kunz Claudia , Fricke Harald
Published: March 2020

2034

Background: Preclinical data indicate antiinvasive activity of APG101, an intravenous CD95 ligand-binding fusion protein, as well as synergistic activity together with radiotherapy in glioblastoma. Methods: Patients with recurrent glioblastoma after prior standard radiochemotherapy with temozolomide (± 1 second-line chemotherapy) were considered for re-irradiation provided a tumor diameter 1-4 cm and time since the end radiotherapy ≥ 8 months. Patients were randomized 1:2 between radiotherapy (36 Gy; 5 times 2 Gy per week) or radiotherapy plus APG101 at 400 mg weekly flat dose to be continued until progression. Radiotherapy plans were centrally evaluated. Primary endpoint was 6-months progression free survival (PFS-6). MRIs were performed every 6-weeks and centrally read. Sample size of the investigational treatment arm according to a two-stage design of Simon required 55 patients. A control arm of 28 patients was implemented to validate the assumptions on PFS-6 in a cohort of patients treated with reirradiation alone. Results: Between 12/09 and 09/11, 84 pts in 25 centers were randomized and treated, preliminary data of the current report are available on 71 patients (49 APG01 + irradiation, 22 irradiation alone). Median age was 57 years, median KPS 90%. The maximal tumor diameter was ≤ 2-5 cm in 34 patients and > 2.5 cm in 37 patients. No SUSARs have to be reported. Nine patients achieved PFS-6 in the APG101 arm and none in the radiotherapy arm. Conclusions: APG101_CD_002 is the first trial evaluating CD95-mediated pathway inhibition as a therapeutic strategy. This trial is also the prospective trial on reirradiation in glioblastoma. Side effects of the combination were minimal, and treatment could be delivered as planned. The experimental arm met the primary endpoint. The approach to block rather than stimulate the CD95 system is breaking a paradigm. Our data suggest that CD95 inhibition by APG101 should be evaluated in the management of newly diagnosed glioblastoma in combination with standard radiochemotherapy. Further molecular data and updated results will be presented.
Phase II trial of dose-dense temozolomide as initial treatment for progressive low-grade oligodendroglial tumors: A multicentric study of the Italian Association of Neuro-Oncology (AINO).
Authors: Ruda Roberta , Bertero Luca , Trevisan Elisa , Pace Andrea , Carapella Carmine Maria , Dealis Cristina , Caroli Manuela , Faedi Marina , Bomprezzi Chiara , Soffietti Riccardo
Published: March 2020

2037

Background: Standard temozolomide has been shown to be active in progressive low grade gliomas after surgery, whereas few data are available on the impact of dose dense regimens. Thus, we developed a phase II single arm multicenter study to evaluate the efficacy and toxicity of a regimen of dose dense temozolomide in progressive low grade oligodendroglial tumors. Methods: The inclusion criteria of the study were as follows: 1)biopsy-proven supratentorial WHO grade II oligodendroglioma and oligoastrocytoma; 2)progressive disease, clinically (epileptic seizures)or radiologically; 3)measurable disease on MRI (at least 1 cm); 4)age ≥18 years; 5)Karnofsky Performance Status ≥70. Temozolomide was administered at 150mg/m2 1 week on/1 week off up to a maximum of 18 cycles or unacceptable toxicity. The primary end-point was response rate (RR) according to RANO criteria, whereas secondary end-points were clinical benefit in terms of reduction of epileptic seizures ≥50%, progression-free survival (PFS), quality of life and toxicity. Results: From January 2005 until December 2010 60 patients (median age 39 and median KPS 80) have been accrued and are now evaluable for response. Response rates on T2/FLAIR images were as follows: CR 0/60, PR 21/60 (35%), MR 14/60 (23%), SD 21/60 (35%) and PD 4/60 (7%). The clinical benefit was significant in 29/34 patients (85%). As for toxicity 5/60 (8%) patients stopped treatment for lymphopenia grade IV, whereas 11/31 patients (35%) were switched to the standard regimen of temozolomide. PET with methionine was added to MRI in 17 patients: in 10/17 (59%) a disappearance or a significant reduction of uptake was observed, being the reduction of seizures better correlated with the response on PET rather than that on MRI. 1p/19q codeletion was not associated with either the response or the clinical benefit, whereas the analysis of MGMT methylation and IDH1 mutations are ongoing. Thirty-nine (65%) patients are still free of tumor progression. Conclusions: Dose-dense TMZ seems to be active, especially in terms of clinical benefit, but the myelotoxicity could be a concern.
Neuraxis imaging in leptomeningeal metastasis: A retrospective case series.
Authors: Chamberlain Marc C.
Published: March 2020

2046

Background: (and Objective) Leptomeningeal metastasis (LM) is a central nervous system metastatic complication of cancer that affects the entire neuraxis. Quantify imaging (brain and spine MRI and radio-isotope cerebrospinal fluid [CSF] flow study) abnormalities in a retrospective case series of patients with LM. Methods: 240 adult patients with LM (125 non-brain solid tumor patients with positive CSF cytology; 40 non-brain solid tumor patients with negative CSF cytology; 50 lymphoma and 40 leukemia patients with positive CSF flow cytometry) underwent prior to treatment brain and entire spine MRI and radio-isotope CSF flow studies (FS). Results: Neuraxis MRI in pathologically defined patients was more often normal in hematologic tumors (80-84%) compared to solid tumors (60%). Similarly, FS was more often normal in hematologic tumors (90-92%) compared to solid tumors (72-75%). However, neuraxis MRI and FS abnormalities (i.e. CSF flow obstruction; nodular subarachnoid or parenchymal disease; hydrocephalus) altered therapy by requiring CSF diversion, site specific radiotherapy, systemic chemotherapy or recommending no further therapy in one third of CSF cytology positive solid tumors and 15% of CSF flow cytometry positive hematologic tumors. Conclusions: Notwithstanding less frequent imaging abnormalities in hematologic tumors, similar to solid tumors imaging abnormalities frequently result in treatment alteration for patients with LM. Consequently, neuraxis imaging is recommended in both tumor categories in patients being considered for LM-directed and in particular intra-CSF chemotherapy treatment.
Predictive role of MGMT status in recurrent glioblastoma (GBM) patients (PTS) treated with antiangiogenic drug (AD) plus temozolomide (TMZ) or CPT-11.
Authors: Lombardi Giuseppe , Zustovich Fable , Farina Patrizia , Bertorelle Roberta , Della Puppa Alessandro , Gardiman Marina Paola , Fiduccia Pasquale , D'Avella Domenico , Zagonel Vittorina
Published: March 2020

2049

Background: Methylation and silencing of MGMT promoter is a favourable predictive factor in PTS with GBM treated with single alkylating agent such as TMZ. Yet, MGMT is an important resistance determinant to CPT-11 activity. AD can be administered in second line treatment as single agent or in combination to cytotoxic drugs. We analyzed the predictive role of MGMT status in PTS treated with AD plus TMZ or CPT-11 as second line treatment. Methods: Retrospectively, 55 PTS were analyzed: 36 (65%) with unmethlyated MGMT, 19 (35%) with methylated MGMT; 3 (5%) PTS with IDH1 mutations. 17 (31%) PTS performed a reoperation before the second line treatment and MGMT status was changed in 2 (18%) PTS, IDH1 status was unchanged in all PTS. 32 PTS were treated with sorafenib 800mg/die plus TMZ 40mg/m2/die, 23 with bevacizumab 10mg/Kg plus irinotecan every two weeks. Tumor response was evaluated by clinician assessment and by MRI according to RANO criteria every two months or when clinically indicated. Results: Among all PTS, median PFS was 2.7 months (95%CI 1.5-3.5), median OS from start of AD was 7.3 months (95%CI 6.02-8.5), 6-month PFS was 32%; no significant differences were observed and MGMT status was balanced between the two AD groups (p>0.05). Analyzing MGMT status at first surgery, according to univariate analyses there were no significant differences in terms of PFS (3.5ms vs 2.1ms; p=0.2), OS (6.5ms vs 7.2ms; p=0.1) and 6-PFS (HR=0.2, CI95% 0.05-1.07) between PTS with unmethylated and methylated MGMT, respectively. On multivariate analysis, adjusted for performance status, age and cytotoxic drug, MGMT status was not statistically significant in terms of PFS (p=0.8) and OS (p=0.1). Yet, no significant differences emerged with MGMT status at second surgery as well as analyzing the two AD groups, separately. Conclusions: MGMT status might not be a predictive factor in recurrent GBM patients treated with AD plus TMZ or CPT-11 as second line treatment, although MGMT status may change in some PTS between first and second surgery. In conclusion, the outcome of patients with recurrent GBM receiving AD plus TMZ or CPT-11 is not significantly influenced by MGMT methylation status.