tbuckley/cabot-search huggingface dataset:
Australian population-based study of single- versus multi-fraction palliative radiotherapy for bone metastases.
Authors: Wee Loon Ong, Farshad Foroudi, Jeremy Laurence Millar
Journal: Journal of Clinical Oncology (2019)

6568 Background: Single fraction palliative radiotherapy (SFRT) has been shown to be equivalent to multi-fraction radiotherapy (MFRT) for bone metastases symptom management. Remuneration for radiotherapy (RT) in Australia are largely determined by fractions delivered. We aim to determine the use of SFRT for bone metastases in Australia. Methods: We did a population-based linkage study of multiple administrative healthcare databases in Victoria, Australia: the Victorian Radiotherapy Minimum Data Set (VRMDS), the Victorian Cancer Registry (VCR), and the Birth, Death and Marriage registry (BDM). All patients with solid tumour (excluding primary bone cancer) who received palliative radiotherapy for bone metastases between 2012 and 2017 were included. The primary outcome was use of SFRT. The Cochrane-Armitage test for trend was used to evaluate SFRT use over time. Multivariable logistic regression was used to identify factors associated with SFRT use. Results: A total of 15,668 courses of RT for bone metastases were delivered to 10,351 patients. The overall proportion of SFRT was 18% (2,746/ 15,668). There was no significant change in SFRT use over time, from 18% in 2012 to 20% in 2017 (P = 0.06). Older patients were more likely to have SFRT (mean age 69.4 vs. 68.2, P &lt; 0.001). Patients who had lung cancer (21%) and prostate cancer (19%) were more likely to have SFRT compared to other tumour types (P &lt; 0.001). Spine RT was associated with lower use of SFRT compared to other treatment sites (14% vs. 22%, P &lt; 0.001). Patients from remote area were more likely to have SFRT compared to patients from major cities (22% vs. 17%, P &lt; 0.001). Patients treated in private institutions were less likely to have SFRT compared to those treated in public institutions (10% vs. 22%, P &lt; 0.001). In multivariate analyses, patients’ age, tumour type, area of residence, and treatment institutions were independently associated with SFRT use. Conclusions: This is the largest Australian population-based cohort treated with RT for bone metastases, with low utilisation of SFRT over time. There is large variation in SFRT use depending on patient-, tumour-, geographical and institutional factors. Further work is needed to increase uptake, and reduce unwarranted variation, in SFRT use.
Real-world outcome study among patients with renal cell carcinoma (RCC) receiving checkpoint inhibitors (CPIs).
Authors: Hemant Phatak, Ruth Kim, Ting Yu, Jill Dreyfus, Julie A. Gayle, Christina L. Wassel, Stan Krulewicz, Ying Zheng
Journal: Journal of Clinical Oncology (2019)

e16073 Background: North America has one of the highest rates of RCC, and in 2018, 65,340 new cases were diagnosed in the US alone. Tyrosine kinase inhibitors have been a mainstay treatment for RCC. However, the first CPI, nivolumab, was approved by the FDA as a second-line treatment for RCC in late 2015 and as a first-line therapy in combination with ipilimumab in 2018. In this study, real-world outcomes in patients with RCC receiving CPIs were examined. Methods: An observational study was conducted from March 1, 2015, to December 31, 2017, using the Premier Healthcare Database, a hospital discharge database. Patients with RCC aged ≥18 years were identified by ICD-9/10 codes and were included if they received a CPI during the study period, irrespective of treatment line. Comorbidities were assessed in a 6-month look-back period commencing at the time of first CPI treatment and RCC diagnosis. 34 distinct immune-related adverse events (irAEs) were identified in a 90-day look-back period from time of the irAE to determine if patients had received a CPI during that time. Patients were followed for 90 days after the irAE to determine if CPI treatment was reinitiated. Results: During the study period, 1228 patients with RCC received a CPI, of whom 719 (59%) had ≥1 irAE. Approximately 95% of patients received nivolumab and the remaining 5% received an off-label CPI. At the time of initial CPI treatment, patients who experienced any irAE during the study period had a higher Charlson Comorbidity Index (5.1±3.2 vs 4.2±3.0; p &lt; 0.001) and were more likely to be hospitalized on an emergent basis than those without an irAE (9.0% vs 5.1%; p = 0.005). Patients with an irAE also had a higher average number of previous immune-related or immunocompromised comorbid conditions (0.33±0.57 vs 0.12±0.36; p &lt; 0.001). After experiencing an irAE, 65% of patients reinitiated a CPI within 90 days. Conclusions: The majority of RCC patients receiving a CPI, mostly anti-PD-1 agents, experienced an irAE, and patients with irAEs had a higher comorbidity burden than those without irAEs. Most patients with irAEs reinitiated CPI treatment within 90 days.
Novel monoclonal antibody therapeutics for metastatic castration resistant prostate cancer.
Authors: Maloy Ghosh, Kavitha Iyer Rodrigues, Sunit Maity, Sanghamitra Bhattacharjee, Yogendra Manjunath, Subhra Prakash Chakrabarty, Ashvini Kumar Dubey, Anurag Tiwari, Sathyabalan Murugesan, Vivek Halan
Journal: Journal of Clinical Oncology (2019)

e14222 Background: Therapeutic potential of innate immunity comprising Natural killer cell based targets are beginning to unravel the complexity of immune responses. NK cells recognize and induce cytotoxicity of wide range of target cells, such as, tumor cells without prior antigen sensitization. In this study, we have studied Lectin-like transcript 1 (LLT1), a member of the C-type lectin super family, is expressed on target cells and various immune cells. LLT1 isoform 1, is known to interact with CD161, a critical receptor on NK cells. CD161 is expressed on most of human NK cells, NK-T cells, γδ T cells and so on. Tumors exploit the CD161- LLT1 interaction to evade host defense mechanism (“DO NOT KILL” signal); indicating LLT1 as an attractive immunotherapeutic strategy. Methods: Prostate cancer cell lines and other tumor cell lines were used to evaluate novel anti LLT1 antibodies for therapeutic potential - IFNγ production assays and tumor cell death assays were carried out. In vivo efficacy of these antibodies were established using PC3 xenograft in humanized mouse model (HuNOG-EXL). Results: Human androgen independent prostate cancer cell line, PC3 was studied for LLT1 expression and interactions with immune cells, to understand role of LLT1 in metastatic castration resistant prostate cancer (mCRPC). Overexpression of LLT1 on tumor cells was influenced by cytokines and various TLRs. Inhibition of CD161-LLT1 interaction with novel anti LLT1 antibodies leads to IFNγ production and consequent NK cell mediated cytotoxicity – hall mark of anti-tumor responses. Disruption of LLT1 - CD161 innate immunity axis with anti LLT1 antibody releases the break on NK cell cytotoxicity and hence, established a new therapeutic option. PC3 xenograft on HuNOG mouse revealed in vivo efficacy of LLT1 antibody. Significant tumor growth reduction was observed with specific anti LLT1 antibodies alone and in combination with check point antibodies. Thus, synergistic tumor growth reduction was established by combinatorial application of anti LLT1 antibody and PD1/PDL1 axis inhibitors. Conclusions: PC3 xenograft study and other results point to therapeutic opportunities in metastatic castration resistant prostate cancer, a disease condition which needs improved patient outcomes. The ligation of CD161/LLT1 will serve as a new immuno-oncology pair regulating innate and adaptive immune responses; novel human antibodies against LLT1 described here will bring therapeutic benefit to patients in need.
Association of baseline body mass index (BMI) with response and survival in patients (Pts) with advanced melanoma (MEL) receiving PD-1 inhibitors.
Authors: Amit Hemadri, Huang Lin, Yan Lin, Amy Rose, Cindy Sander, Yana Najjar, Hassane M. Zarour, John M. Kirkwood, Diwakar Davar
Journal: Journal of Clinical Oncology (2019)

9579 Background: Obesity promotes PD-1–mediated T cell dysfunction but also improves tumor response to PD-1 blockade. Obesity has been linked with positive outcomes in pts treated with PD-1 blockade. To evaluate the prognostic utility of BMI, we performed a retrospective evaluation of BMI and other covariates in 172 pts with stage IV cutaneous MEL. Methods: Pts with stage IV cutaneous MEL who received anti PD-1 therapy at the University of Pittsburgh between 2014-2018 were included in this analysis. PD-1 blockade was continued until progression or intolerable toxicity. Tumor assessment was performed at baseline and every 12 weeks and response classified per RECIST v1.1. Clinical and demographic data were obtained. BMI was defined based on values at the first treatment date and dichotomized into two groups: ≥30 vs. &lt; 30. Fisher exact test was used to evaluate the correlation between BMI group and ORR. Kaplan Meier method and Cox proportional hazard models were performed to analyzed the time-to-event outcomes (OS and PFS). Results: 172 pts with advanced MEL were evaluated. Greater BMI was associated with greater ORR, PFS and OS across various BMI cutoffs (BMI≥28, BMI≥30 and BMI≥35) although this effect was most obvious at BMI≥30. Pts with BMI≥30 achieved higher ORR than those with BMI &lt; 30 (74% vs. 58%, p-value = 0.04). Concordantly, pts with BMI≥30 had improved PFS and OS: median PFS (BMI≥30 21.1 mos vs. BMI &lt; 30 10.7 mos) and median OS (BMI≥30 35.4 mos vs. BMI &lt; 30 22.8 mos). Higher BMI was independently associated with improved OS (p = 0.018) and PFS (p = 0.047) adjusting for age, Breslow thickness and sex. No significant interaction was observed between the effects of BMI and that of age, sex, or Breslow thickness. Conclusions: Increased BMI was associated with greater ORR in addition to previously reported associations with PFS/OS in a large retrospective series of advanced MEL pts treated with PD-1 blockade. This data was independent of other prognostic factors and underscore the “inflammaging” effects of obesity and age in relation to anti PD-1 therapy in advanced cancer.
Microsatellite instability status in metastatic colorectal cancer and effect of immune checkpoint inhibitors on survival in MSI-high metastatic colorectal cancer.
Authors: Wataru Okamoto, Yoshiaki Nakamura, Manabu Shiozawa, Yoshito Komatsu, Tadamichi Denda, Hiroki Hara, Yoshinori Kagawa, Yukiya Narita, Hisato Kawakami, Taito Esaki, Tomohiro Nishina, Naoki Izawa, Koji Ando, Toshikazu Moriwaki, Takeshi Kato, Fumio Nagashima, Taroh Satoh, Shogo Nomura, Takayuki Yoshino, Kiwamu Akagi
Journal: Journal of Clinical Oncology (2019)

e15106 Background: Tumor mismatch repair (MMR) predicts benefit of immune checkpoint inhibitors (ICIs) in metastatic colorectal cancer (mCRC). We conducted a large-scale prospective observational trial on microsatellite instability (MSI) status in mCRC: SCRUM-Japan GI-SCREEN CRC-MSI. Methods: mCRC patients (pts) appropriate for systemic chemotherapy were eligible. Paired tumor and normal DNA extracted from FFPE samples were analyzed by the MSI Analysis System, which includes 5 mononucleotide markers. Tumors exhibiting ≥2 unstable markers were defined as MSI-H, while those with ≤1 were labelled MSI-L/MSS. Results: From 2/2016 to 3/2018, 1,711 pts were enrolled, and 1,696 samples were submitted. MSI status was determined in 1,676 pts (98.8%); 51 pts (3.0%) were MSI-H. For MSI-H vs. MSI-L/MSS pts: Median age (years) 64/64; male gender (%) 51.0 vs. 43.8, p=0.31; right-sided primary (%) 70.6 vs. 25.0, p&lt;0.001; and poorly differentiated histology (%) 33.3 vs. 8.9, p&lt;0.001. Of the 864 pts who received parallel NGS testing, median tumor mutation burdens (TMB) in MSI-H and MSI-L/MSS were 32.8 and 12.6 mt/Mb, p&lt;0.001. High TMB, defined as &gt;20 mt/Mb, was observed in 27/29 (93.1%) MSI-H pts. The frequency of representative gene mutations (%) for MSI-H vs. MSI-L/MSS pts were: TP53 17.2 vs. 66.1, p&lt;0.001; PIK3CA 48.3 vs. 13.2, p&lt;0.001; BRAF 34.5 vs. 7.5, p&lt;0.001; MSH2 17.2 vs. 0, p&lt;0.001; CTNNB1 17.2 vs. 0.6, p&lt;0.001; and ERBB2 10.3 vs. 1.4, p&lt;0.001. ERBB2 amplification was detected only in MSI-L/MSS pts (2.3%). Two-year survival rates from first-line systemic therapy in 389 pts with MSI-L/MSS, 5 pts with MSI-H treated with ICI in any-line, and 5 pts with MSI-H not treated with ICI, were 77.7, 100, and 33.3%, respectively. Conclusions: MSI-H mCRC tumors were more frequent in right-sided colon primaries and with poorly differentiated histology. Median TMB was significantly greater in MSI-H pts, and a very high burden was frequently seen. Survival in MSI-H mCRC was poor before ICIs; these agents may improve outcomes for MSI-H pts. Clinical trial #UMIN000020437.
Exploring the Association of Sex Differences and Exposure to Maternal Smoking With Low Fetal Growth
Authors: Manish K. Jha, Abu Minhajuddin, Madhukar Trivedi
Journal: JAMA Psychiatry (2019)

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Molecular basis for phenotypic similarity of genetic disorders
Authors: Vijay Kumar Pounraja, Santhosh Girirajan
Journal: Genome Medicine (2019)

The contribution of distinct genes to overlapping phenotypes suggests that such genes share ancestral origins, membership of disease pathways, or molecular functions. A recent study by Liu and colleagues identified mutations in TCF20, a paralog of RAI1, among individuals manifesting a novel syndrome that has phenotypes similar to those of Smith-Magenis syndrome (a disorder caused by disruption of RAI1). This study highlights how structural similarity among genes contributes to shared phenotypes, and shows how this relationship can contribute to our understanding of the genetic basis of complex disorders.
Impact of HCV treatment in patients with advanced hepatocellular carcinoma on sorafenib.
Authors: Michael Herman, Yuhua Zhang, Lisa Wang, Hao-Wen Sim, Jennifer J. Knox
Journal: Journal of Clinical Oncology (2019)

e15645 Background: Hepatocellular carcinoma (HCC) is the 4th leading cause of global cancer deaths. In North America, HCC is most commonly caused by Hepatitis C virus (HCV). Direct acting antivirals (DAAs) have dramatically increased sustained virologic response (SVR) rates for HCV. Studies of DAAs in early stage HCC have had conflicting results on HCC outcomes. A small Asian study of 58 advanced HCC patients treated with sorafenib demonstrated SVR improved survival, but whether the same effect occurs in North American patients is unknown. Methods: Inclusion criteria for this retrospective study were: biopsy or clinically proven advanced incurable HCC, sorafenib treatment at Princess Margaret Cancer Centre between January 1 2008-June 30 2018 and a history of HCV. Survival was analyzed using the Kaplan Meier method and a cox proportional hazards model was fit to determine the effect of SVR on OS. Results: 93 patients were included with a median duration of sorafenib therapy of 3 months. 89% were ECOG 0-1 and 96% were BCLC-C (See table 1). Of those receiving antivirals, 95% were given before sorafenib. Overall, SVR was achieved in 23 (50%) patients. Median OS of patients achieving SVR vs not in SVR was 10.3 vs 8.9 months respectively (HR 0.67, 95% CI 0.36-1.24, p = 0.20). Median PFS was 6.4 vs 5.0 months in patients with or without SVR (HR 0.66, 95% CI 0.39-1.13, p = 0.13). There was no significant difference between mean dose of sorafenib or discontinuation due to toxicity in patients by SVR status. Conclusions: Antiviral therapy with SVR lead to a non-statistically significant improvement in OS in patients with Child-Pugh A-B liver disease, advanced HCC treated with sorafenib and HCV. These results should be validated in larger data-sets. [Table: see text]
How often do metastatic brain disease patients prescribed ten fractions of whole brain radiation therapy die without completing treatment?
Authors: Shearwood McClelland, Namita Agrawal, Kevin Shiue, Gregory Bartlett, Richard C. Zellars, Gordon A Watson, Susannah G. Ellsworth
Journal: Journal of Clinical Oncology (2019)

e23146 Background: Palliative whole brain radiation therapy (WBRT) is an established treatment modality for optimizing intracranial disease control in patients with metastatic brain disease, most commonly prescribed to a dose of 30 Gy in 10 fractions. The fidelity of WBRT course completion has not been rigorously evaluated. Methods: Two prospective institutional databases evaluating patients treated from April 2015 through December 2018 identified patients who received WBRT. Information analyzed included prescribed and delivered dose/fractionation, Karnofsky Performance Status (KPS), admission status, treatment duration, and time between WBRT completion and patient hospice referral/death. Results: 52 consecutive patients prescribed WBRT to 30 Gy in 10 fractions were evaluated. Twenty-six (50%) were inpatients, and only 17 (33%) had a KPS of 70 or greater (able to care for self). More than 30% failed to finish more than 5 of their 10 scheduled fractions before either death or hospice referral; only 29 of 52 patients (56%) finished WBRT as prescribed. Twenty-five patients (48%) died within 30 days of WBRT. Of the 29 patients who finished WBRT as prescribed, 9 (31%) died within 30 days of completing treatment. Of the 23 patients who failed to complete standard fractionation WBRT, nearly 70% died within 30 days of receiving their final radiation therapy fraction. Conclusions: These findings indicate that greater than 40% of patients prescribed the standard 10 fraction regimen of WBRT do not remain well enough to tolerate the full duration of treatment. With nearly half of patients dying within 30 days of standard fraction WBRT, there should be strong incentive to reduce the physical and financial burden on this patient population by prescribing WBRT with significantly shorter (i.e. single-fraction or 20 Gy in 5 fractions) fractionation schemes.
Validation of the Immunoscore prognostic value in stage III colon cancer patients treated with oxaliplatin in the prospective IDEA France cohort study (PRODIGE-GERCOR).
Authors: Franck Pages, Thierry Andre, Julien Taieb, Dewi Vernerey, Julie Henriques, Christophe Borg, Florence Marliot, Rim Ben Jannet, Christophe Louvet, Laurent Mineur, Jaafar Bennouna, Jérôme Desrame, Roger Faroux, Alex Duval, Pierre Laurent-Puig, Magali Svrcek, Fabienne Hermitte, Aurelie Catteau, Jerome Galon, Jean-François Emile
Journal: Journal of Clinical Oncology (2019)

3513 Background: The Immunoscore (IS), which has been shown to prognostically classify Stage I-III colon cancer (CC) patients, was assessed in the IDEA France cohort study evaluating 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy in Stage III CC patients. Methods: Densities of CD3+ and cytotoxic CD8+ T cells in the tumor and invasive margin of each patient were quantified by digital pathology and converted to IS using pre-defined published cut-off. The performance of IS to predict disease-free survival (DFS) was assessed in the modified intention-to-treat population, in each study arm, and was adjusted with relevant clinical features in multivariable Cox models. Harrell’s C-statistics was used to investigate the IS performance. Results: 1322 patients were included; 82 were excluded due to pre-analytical non-conformity. IS was successfully analyzed in 1062 (85.6%) eligible patients. In a 2-category IS analysis, Low and (Int+High) IS were observed in n=599 (43.6%) and n=463 (56.4%) patients, respectively. IS was significantly correlated with T stage, T/N stage (T1-3 and N1 versus T4 and/or N2), and microsatellite instability status. The study met its primary objective of validating that Low IS identifies patients with higher-risk of relapse or death [HR=1.54; 95%CI 1.24-1.93, p=0.0001]. The 3-year DFS rates were 66.80% [95%CI 62.23-70.95] and 77.14% [95%CI 73.50-80.35] for Low IS and (Int+High) IS, respectively. In multivariable analysis, IS remained independently associated with DFS (p&lt;0.0012) when combined with T/N stage. The addition of IS to the T/N stage significantly improved the model discrimination capacity [bootstrap C index mean difference, 0.022; 95%CI 0.005-0.04]. In addition, IS in 3 categories (Low, Int, High) and as a continuous variable were also both significantly associated with DFS (all p&lt;0.001). In univariable analysis, IS was also associated with DFS in 6 months arm (p&lt;0.0001); a similar trend was observed in 3 months arm (p=0.09). Conclusions: IS was confirmed as a prognostic factor of DFS in Stage III CC patients in the prospective IDEA France cohort study. Clinical trial information: NCT03422601.