tbuckley/cabot-search huggingface dataset:
Patient preferences for maintenance PARP therapy in ovarian cancer treatment.
Authors: Laura Jean Havrilesky, Stephanie Lim, Jui-Chen Yang, Amelia Lorenzo, Jessie A Ehrisman, Angeles Alvarez Secord, Reed Johnson, Shelby D. Reed
Journal: Journal of Clinical Oncology (2019)

5558 Background: Maintenance therapy with PARP inhibitors has become prevalent in treating ovarian cancer. However, the preferences of women with ovarian cancer regarding the risks, side effects and benefits afforded by maintenance therapies are largely unstudied. Methods: A discrete choice experiment was designed to elicit the preferences of women with ovarian cancer regarding 6 attributes (levels presented in parentheses) relevant to the decision for maintenance PARP inhibitor therapy versus surveillance: (1) overall survival (36, 38, 42 months); (2) progression-free survival (15, 17, 21 months); (3) nausea (none, mild, moderate); (4) fatigue (none, mild, moderate); (5) probability of death from myelodysplastic syndrome/acute myelogenous leukemia (MDS/AML) (0%, 1%, 5%, 10%); and (6) monthly out-of-pocket cost ($0, $50, $500, $1,000). Educational material was provided, with embedded questions to test respondents’ understanding. Participants chose between 2 variable clinical scenarios and a constant scenario representing a treatment break, with multiple iterations. Random-parameters logit regression was applied to model participants’ choices as a function of attribute levels. Results: Of 150 women with ovarian cancer recruited, 95 were eligible and completed the survey. The mean age was 62, 48% had recurrent ovarian cancer, and 13% were currently taking a PARP. Participants always significantly preferred better clinical outcomes to worse (except between 0% and 1% risk of MDS/AML), preferred low out-of-pocket cost, and disliked the idea of a treatment break. Participants valued overall survival most (average importance weight 25 out of 100 total), followed by monthly out-of-pocket cost (24), risk of death from MDS/AML (18), nausea (15), PFS (10) and fatigue (8). On average, participants would tolerate a 2% additional risk of MDS/AML in exchange for 2 additional months of PFS and 7% additional risk of MDS/AML in exchange for 6 additional months of PFS. Conclusions: Women with ovarian cancer are willing to accept the side effects of PARP maintenance therapy and a higher than clinically observed risk of MDS/AML in exchange for clinically observed levels of improvement in PFS.
A cost-utility analysis of atezolizumab in the second-line treatment of metastatic urothelial carcinoma.
Authors: Ambika Parmar, Marina Richardson, Beate Sander, Susanna Y. Cheng, Kelvin K. Chan
Journal: Journal of Clinical Oncology (2019)

6639 Background: Despite early promising results, IMvigor211 failed to demonstrate an overall survival benefit for atezolizumab, compared to chemotherapy, in the second-line treatment of metastatic urothelial carcinoma. However, given improvements in adverse events (AE) and quality of life with atezolizumab, there may still be investment value. We conducted a cost-utility analysis (CUA) of atezolizumab compared to chemotherapy from a public-payer healthcare perspective. Methods: We developed a partitioned survival model to evaluate atezolizumab versus chemotherapy (i.e. docetaxel, paclitaxel or vinflunine). IMvigor211 informed rates of treatment receipt (initial and subsequent), AE, effectiveness and utility estimates. Cost for treatment, AE and death were based on published literature (adjusted to 2018 Canadian dollars). Per health state, cost of treatment (initial and subsequent) and AE were incorporated. Outcomes included quality-adjusted life-years (QALY), cost per treatment, and incremental cost-effectiveness ratio (ICER). QALY and cost were discounted at 1.5% (Canadian guidelines). Parameter uncertainty was assessed through one-way and scenario analyses. Time horizons of 2 (within trial) and 5 years (extrapolated lifetime) were evaluated. Results: QALY of atezolizumab and chemotherapy over 2 years (lifetime) were 0.65 (0.93) and 0.58 (0.64), respectively. Cost of atezolizumab and chemotherapy over 2 years (lifetime) was $77,614.64, ($92,484.34), and $62,212.35 ($67,606.65), respectively. ICER over 2 years and lifetime was $220,032.71/QALY and $85,785.14/QALY. Scenario analysis from a North American perspective with only taxane chemotherapy with and without third line immunotherapy (IO) revealed an ICER of $80,144.90/QALY, $125,332.76/QALY over a lifetime horizon, respectively. Conclusions: The difference in ICER dependent on time horizon, driven by extrapolated survival benefits, highlights the importance of long-term follow-up to examine whether early evidence for durable response translates into long-term survival and improvements in cost-effectiveness. Thus, CUA of IO require careful interpretation and warrant dynamic assessment as new data becomes available.
Animal foods can improve children’s lives
Authors: George Henderson
Journal: BMJ (2019)

Willett and Rockstrom of the EAT-Lancet Commission on Food, Planet, Health claim that “flexibility to adapt to local diets is inherent in the reference dietary targets,” yet these allow scant use of starchy root vegetables.1 In many populations—including the famously long living Okinawans, but also across Africa and those parts of the South Pacific still minimally affected by dietary transitions to modern …
The impact of nodal metastasis on survival in stage IV colon cancer: Analysis of National Cancer Database 2004-2014.
Authors: Sukamal Saha, Mohamed Elgamal, Meghan Cherry, Robin Buttar, David Wiese, Sunil Kaushal, Mustafa Alnounou, Trevor Singh, David S. Eilender, Sandeep Singh Grewal, Madan L. Arora
Journal: Journal of Clinical Oncology (2019)

e15042 Background: Lymph node (LN) metastasis (mets) is the strongest prognostic factor in colon cancer (CCa), however, its significance in Stage IV disease remains controversial. We analysed National Cancer Database (NCDB) to determine the impact of nodal mets on survival in Stage IV CCa patients (pts). Methods: From 2004-2014, NCDB pts with pathologic Stage IV CCa were divided into groups based on LN status and No. of +ve LNs. Only Stage IV CCa pts who underwent surgical resection of their primary tumor with available pathologic data as well as chemotherapy data were included. Kaplan-Meier method and log rank test were used to compare 5-year overall survival. Results: A total of 33574 pts data met the criteria of the study. Adenocarcinoma represented 82.3% of the total pts. Majority of the pts (82.61%) had +ve LN status. Mean survival was 36.3 vs 24.2 months in -ve LN vs +ve LN pts respectively. Overall 5yr survival was better in LN -ve pts ( 23.4%) versus LN +ve pts ( 10.2%) Survival for all years was inversely related to the number of +ve LN ( Table). For LN +ve or LN -ve pts, receiving any form of chemotherapy was associated with significantly improved survival when compared to no chemotherapy. Conclusions: LN status and No. of +ve LNs impact the prognosis of CCa, even in stage IV. Receiving some form of chemotherapy improves the prognosis for both pts with +ve or -ve LN status. These findings suggest that separation of Stage IV LN negative versus positive patients may be warranted in staging and treatment. 5 year survival according to LN status and No. of positive LN. [Table: see text]
Frailty among childhood cancer survivors: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Samah Hayek, Todd M. Gibson, Wendy Leisenring, Jennifer Lyn Guida, Maria Monica Gramatges, Philip Lupo, Rebecca M. Howell, Kevin C. Oeffinger, Smita Bhatia, Kim Edelstein, Melissa M. Hudson, Leslie L. Robison, Paul C. Nathan, Yutaka Yasui, Kevin R. Krull, Gregory T. Armstrong, Kirsten K. Ness
Journal: Journal of Clinical Oncology (2019)

10026 Background: Childhood cancer survivors are at increased risk for frailty, which is a loss of physiological capacity that is typically observed among older adults. Aims: Estimate the prevalence of frailty among survivors, and examine direct and indirect effects of treatment, lifestyle, and chronic disease factors on frailty. Methods: CCSS participants who were &gt; 5-year survivors of childhood cancer, diagnosed between 1970-1999 at &lt;21 years of age (n=10,899, 48% male), and siblings (n=2,097, 42% male) were included. Frailty was defined from self-reported data at mean ages of 37.6±9.4 and 42.9±9.8 years for survivors and siblings, respectively, as ≥3 of the following: low lean mass, exhaustion, low energy expenditure, slow walking, and weakness. Results: The prevalence of frailty among survivors was higher compared to siblings (5.8%, 95% CI: 5.4-6.3% vs. 1.9%, 95% CI 1.4-2.5%). Prevalence was highest in survivors of CNS tumors (9.5%, 5.2-13.8%), bone sarcomas (8.1%, 5.1-11.1%) and Hodgkin lymphoma (7.5%, 4.9-10.1%). In models adjusted for sex, age at assessment, and race/ethnicity, treatment exposures were associated with frailty (Table). After adjusting for the presence of chronic diseases and lifestyle factors, these associations were attenuated. Conclusions: The prevalence of frailty among survivors (6.0% at 38 years of age) was similar to the general population aged ≥65 years (9.0%). Radiation, platinum, amputation and thoracotomy increased risk for frailty. Findings suggest interventions to prevent, delay onset, or remediate chronic disease and/or promote healthy lifestyle are needed to preserve function in this population. [Table: see text]
Novel tetravalent bispecific T-cell engaging antibodies for cancer immunotherapy.
Authors: Sribalaji Lakshmikanthan, Timothy Wyant, Swarna Pandian, Shaun Murphy, Yangde Chen
Journal: Journal of Clinical Oncology (2019)

e12513 Background: Current immunotherapy involves redirection of T cells against tumor either by chimeric antigen receptors (CAR-T) or bispecific T-cell engagers (BiTEs). These T cell-engaging technologies have been enabled by engineering single-chain variable fragment (scFv). Most BiTEs are designed as heterodimers, with monovalent binding to tumor cell surface antigens and to CD3 + T cells. Here, we describe a novel tetravalent bispecific (TetraBi) platform: a tumor associated antigen specific, T-cell engaging antibody that provides significant advantages over traditional BiTEs. Specifically, we showcase three unique TetraBi antibodies targeted for various cancers. Methods: ABP-100 was engineered by fusing CD3-binding scFv to the c-terminus of anti-HER2 IgG1 light chain, resulting in two binding sites each for HER2 and CD3. In preclinical studies, ABP-100 was compared with a clinical-stage heterodimeric antibody that is monovalent for HER2 and CD3. We also built TetraBi for anti-Glypican 3 (GPC3, ABP-110) and Claudin 18.2 (CLDN18.2, ABP-150) for gastric cancer therapy. Results: We observed bivalent binding to the tumor antigens (HER2, GPC3, CLDN18.2) on tumor cells like the monoclonal antibodies do. Interestingly, the CD3-binding domains in our TetraBi format showed functionally monovalent binding to CD3. ABP-100 displayed comparable cytokine release to the heterodimer molecule both in vitro and in vivo. In HER2+ cancer models, ABP-100 showed highly potent antitumor activity, resulting in complete responses in tumor bearing mice at doses as low as 0.1 mg/kg with no evidence of tumor relapse. ABP110 and ABP-150 also demonstrated potent cancer cell killing in vitro. Conclusions: This novel TetraBi antibody format enables concurrent bivalent and monovalent co-engagement of distinct target antigens in tumor microenvironment with promising therapeutic implications. Furthermore, it provides a potentially larger therapeutic index than more traditional bispecific formats that feature monovalent recognition of tumor antigens.
Case 9-1986
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, Sarah H. Cheeseman, David L. Gang
Journal: New England Journal of Medicine (1986)

Presentation of CaseA 40-month-old girl was admitted to the hospital because of respiratory distress.The child was born of a full-term normal delivery, one year after her mother's tuberculin test had converted to a positive reaction, without known contact with tuberculosis, and isoniazid was administered to the mother. At the age of 12 months the child was well and thriving, with a weight of 10.4 kg (75th percentile). She was taken by her parents to visit Haiti for one month. The child experienced diarrhea and conjunctivitis during the trip but had no major illness. At 13 months a hypochromic, . . .
A retrospective analysis of clinical outcomes among patients with infiltrative hepatocellular carcinoma (iHCC): A single institution study.
Authors: Lindsay Marie Hannan, E. Gabriela Chiorean, Stacey Cohen, Andrew L. Coveler, Veena Shankaran, Kit Man Wong, Rebecca Mieloszyk, Guy E Johnson, James Oh Park, Puneet Bhargava, William Proctor Harris
Journal: Journal of Clinical Oncology (2019)

e15667 Background: iHCC is an aggressive disease with poorly characterized treatment outcomes. We sought to describe clinical and radiographic features of iHCC, describe overall survival (OS), and compare outcomes of sorafenib (SOR) use with a cohort of non-infiltrative hepatocellular carcinoma (niHCC) patients. Methods: Radiology reports from the University of Washington with an Li-RADS (LR) assignment, 2013-2017, were reviewed (5037 reports, 1954 patients (pts)) for terms indicative of iHCC. Results: : 102 cases were identified, with 43% arising from known niHCC. iHCC size is difficult to measure but when reported, median was 8cm (interquartile range 5-10cm). Other radiographic features: vascular invasion 72%, R lobe only 62%. Clinical data were obtained via medical record review. The cohort was primarily male (83%), White (65%), age &gt; 55 (88%), HCV (74.5%), heavy alcohol use (67%). At diagnosis: BCLC stage C (76%), ALBI grade 2 (62%) and 3 (21%). Median OS after diagnosis was 5.7 months (m). 38 (37%) pts were too ill to receive therapy. OS for de novo iHCC and for iHCC arising from niHCC did not differ (7.5m vs 5.1m, p = NS). All niHCC pts who received SOR in any line of therapy were identified among pts with a LR 5 lesion in at least one of the aforementioned radiology reports, 2013-2017. Pts who received SOR on trial and/or combined with another agent were excluded. Clinical data for the 83 niHCC pts were abstracted and compared to the 25 iHCC pts who received SOR, any line of therapy. Based on χ 2 analyses, the 2 groups did not differ by age, sex, race, BCLC stage at SOR initiation, ECOG status at SOR initiation, HCC etiology, ALBI grade at SOR initiation, or previous locoregional therapy. OS after initiation of SOR was 14.1m for niHCC, 10.5m for iHCC, p = NS. PFS after SOR was 3.7m for niHCC, 7m for iHCC, p = NS. AFP at the time of SOR initiation was higher in iHCC than niHCC (median 1331 vs 48, respectively, p = 0.004), with median %AFP change after 30 days -13% in iHCC and +6% in niHCC, p = NS. Decrease in AFP after 30 days of therapy was associated with improved OS among niHCC (21m versus 7m, p = 0.001) but not among iHCC pts (p = NS). Conclusions: iHCC is a poorly understood subset of HCC with underlying biology not well defined. Compared to niHCC, clinical outcomes with sorafenib do not appear to differ in this cohort. Future characterization of outcomes with Y-90 and immune checkpoint inhibitors is warranted.
AL101 mediated tumor inhibition in notch-altered TNBC PDX models.
Authors: Esther Channah Broner, Genia Alpert, Udi Gluschnaider, Adi Mondshine, Oz Solomon, Ido Sloma, Rami Rauch, Evgeny Izumchenko, Jon Christopher Aster, Matti Davis
Journal: Journal of Clinical Oncology (2019)

1064 Background: The Notch pathway is activated during mammary gland development and has been implicated as a key driver in breast cancer. There is an urgent need to identify new therapeutic strategies for triple-negative breast cancer (TNBC), a sub-type associated with poor prognosis and no available targeted therapies. Notch gain of function (GOF) genetic alterations are potential tumor drivers found in ~10% of TNBC. This motivated the development of Notch inhibitors, including AL101 a pan-Notch, gamma secretase inhibitor (J Clin Oncol 36, 2018 abstract 2515). AL101 is currently being evaluated in Adenoid Cystic Carcinoma patients with activating Notch mutations (NCT03691207, ACCURACY trial). Here, we aim to test the activity of AL101 in TNBC patient derived xenograft (PDX) models with Notch activating genetic alterations. Methods: Gene expression cluster analysis was performed for 38 TNBC PDX tumors using a list of 21 Notch target genes. Seven tumors, bearing a “Notch-on” signature, were enriched with mutated/fusion (M/F) Notch genes and clustered separately from all other tumors. Of 9 models selected for study, 4 had a Notch-on signature and were expected to respond to AL101. Tumors were implanted into female athymic nude mice. Once tumors reached an average size of 150-300 mm 3 , mice (n = 5/group) were randomized to Vehicle or AL101 treatment arms (3 mg/kg, PO, 4on/3off) until tumors reached 1500 mm 3 or day 60. Results: As measured by tumor growth inhibition (TGI), AL101 was more potent in tumors with a putative Notch-on signature. Within these 4 models, M/F genes were present in Notch1-NRR GOF (103% TGI p = 0.0004); Notch2-fusion (62%TGI p = 0.036); Notch3-fusion (75% TGI p = 0.032); or Notch4-fusion (147% TGI p &lt; 0.00001). Tumors lacking the Notch signature did not respond significantly to AL101: WT Notch (43% TGI p = 0.0104; 64% TGI p = 0.13); Notch1 with a predicted loss of function mutation (12% TGI p = 0.53), Notch1 Variant of Unknown Significance (VUS) (30% TGI p = 0.44), Notch2 VUS (41% TGI p = 0.44). Conclusions: We demonstrate that in TNBC PDX models, the presence of a Notch-on signature and Notch GOF mutations/fusions correlates with potent response to AL101. These data support the clinical development of AL101 as a targeted therapy for TNBC with Notch GOF alterations.
A pilot study of oncology massage to treat chemotherapy-induced peripheral neuropathy (CIPN).
Authors: Gabriel Lopez, Cathy Eng, Michael J. Overman, David Luis Ramirez, Wenli Liu, Curtiss M Beinhorn, Pamela A Sumler, Sarah Prinsloo, Minxing Chen, Yisheng Li, Eduardo Bruera, Lorenzo Cohen
Journal: Journal of Clinical Oncology (2019)

111 Background: Short- and long-term toxicity of platinum compounds and taxanes includes development of CIPN. With an increased interest regarding the role of complementary approaches for symptom control, we investigated massage therapy for symptomatic relief of chronic CIPN. Methods: This pilot study evaluated the optimum treatment schedule and initial efficacy of a standardized Swedish massage technique to treat lower extremity (LE) CIPN. Inclusion criteria: LE neuropathy attributed to oxaliplatin, paclitaxel, or docetaxel, no other history of attributable causes; self-reported neuropathy score ≥3, 0-10 scale; ≥ 6 months since last chemotherapy treatment; age ≥ 18. Patients (pts) were randomized to one of four groups: 1) LE massage 3 times (3X) week for 4 weeks; LE massage 2X week for 6 weeks; 3) head/neck/shoulder (control) massage 3X week for 4 weeks; or 4) control massage 2X week for 6 weeks. Massage completion rate was examined and symptoms of CIPN measured with the Pain Quality Assessment Scale [PQAS (Range: 0-10); subscales of SP (surface pain), DP (deep pain), and PP (paroxysmal pain)] at baseline and at 10 weeks. Results: 71 pts fulfilled inclusion criteria: 77.5% women; 57.7% (breast cancer), and 42.3% (GI cancer); mean age 60.3 y/o (range: 40-77). Average length of time since the end of chemotherapy was &gt; 3 yrs. Mean massage completion rates (max = 12) were 8.9 (SD 4.2) for 3X week and 9.8 (4.0) for 2X week with no statistical differences. There were no statistically significant differences in PQAS scores at follow-up between site-specific massage groups (lower extremity vs controls). Pts who had massage 3X week reported statistically and clinically significantly improved PQAS scores versus those who had massage 2X week (change scores: PQAS-SP: -2.3 vs. -0.6, p = 0.001; PQAS-DP: -2.1 vs. -0.9, p = 0.008; PQAS-PP: -2.3 vs. -1.0, p = 0.025), with sustained improvement in the 3X week group, but minimal change in the 2X week group. Conclusions: We observed sustained reduction in pts with long-term CIPN up to 6 weeks after treatment completion for the more intensive 3X week massage group, regardless of treatment site. A large-scale efficacy trial is warranted to validate the role of oncology massage therapy for CIPN. Clinical trial information: NCT02221700.
Association of Increased Youth Suicides in the United States With the Release of<i>13 Reasons Why</i>
Authors: Thomas Niederkrotenthaler, Steven Stack, Benedikt Till, Mark Sinyor, Jane Pirkis, David Garcia, Ian R. H. Rockett, Ulrich S. Tran
Journal: JAMA Psychiatry (2019)

On March 31, 2017, Netflix released the show 13 Reasons Why, sparking immediate criticism from suicide prevention organizations for not following media recommendations for responsible suicide portrayal and for possible suicide contagion by media. To date, little research has been conducted into the associations between the show and suicide counts among its young target audience.To analyze the changes in suicide counts after the release of 13 Reasons Why.For this time series analysis, monthly suicide data for the age groups 10 to 19 years, 20 to 29 years, and 30 years or older for both US males and females from January 1, 1999, to December 31, 2017, were extracted from the Centers for Disease Control and Prevention's WONDER (Wide-ranging Online Data for Epidemiologic Research) database. Twitter and Instagram posts were used as a proxy to estimate the amount of attention the show received through social media from April 1, 2017, to June 30, 2017. Autoregressive integrated moving average time series models were fitted to the pre-April 2017 period to estimate suicides among the age groups and to identify changes in specific suicide methods used. The models were fitted to the full time series with dummy variables for (1) April 2017 and (2) April 1, 2017, to June 30, 2017. Data were analyzed in December 2018 and January 2019.Suicide data before and after the release of the show in 2017.Based on social media data, public interest in the show was highest in April 2017 and was negligible after June 2017. For 10- to 19-year-old males and females, increases in the observed values from April to June 2017 were outside the 95% confidence bands of forecasts. Models testing 3-month associated suicide mortality indicated 66 (95% CI, 16.3-115.7) excess suicides among males (12.4% increase; 95% CI, 3.1%-21.8%) and 37 (95% CI, 12.4-61.5) among females (21.7% increase; 95% CI, 7.3%-36.2%). No excess suicide mortality was seen in other age groups. The increase in the hanging suicide method was particularly high (26.9% increase; 95% CI, 15.3%-38.4%).Caution must be taken in interpreting these findings; however, the suicide increase in youth only and the signal of a potentially larger increase in young females all appear to be consistent with a contagion by media and seem to reinforce the need for collaboration toward improving fictional portrayals of suicide.