tbuckley/cabot-search huggingface dataset:
Distinct patterns of response and toxicity (tox) by sites of metastases (mets) in patients (pts) treated with ipilimumab combined with PD-1 antibodies (ipi+PD1).
Authors: Ines Esteves Domingues Pires Da Silva, Serigne Lo, Maria Gonzalez, Alexander Guminski, Georgina V. Long, Alexander M. Menzies
Journal: Journal of Clinical Oncology (2018)

9553 Background: Combined ipilimumab and nivolumab has the highest response rate (RR), progression-free survival (PFS) and overall survival (OS) for any immunotherapy in metastatic melanoma (MM), but the pattern of response and tox is variable. We sought to examine the association between site and size of mets with the pattern of response and tox in pts treated with ipi+PD1. Methods: MM pts treated with first line ipi+PD1 (nivolumab or pembrolizumab) had all mets > 5 mm (brain > 1 mm, lymph nodes > 15 mm in short axis) on CT/MRI measured. Lesional response was determined by RECIST. Demographics, disease characteristics, tox and outcomes were examined. Results: 140 pts were studied with 819 mets (median 5/pt); median (med) follow-up 12.9 months (mo). Mets with complete response (CR) were significantly smaller than non-CR mets (med 13 vs 17 mm, p < 0.0001) and the rate of patient CR decreased as number of mets increased within a pt, with no CR if > 8 mets (p < 0.0001). Med tumour regression was -64%, higher in subcutis (-90%, p < 0.01), soft tissue [ST] (-87%, p < 0.01), gastrointestinal [GI] (-82%, p = 0.04) and lung (-71%, p = 0.03), and lower in liver (-7%, p = 0.06) and spleen (0%, p = 0.03). The highest RR was in lung, GI and ST mets (69%), while splenic mets had the lowest RR (33%). GI mets had the fastest time to response (2.7mo) and liver the slowest (8.2mo). In multivariate analysis, pts with lung mets had superior RR (OR 2.75, p = 0.02) and PFS (HR 0.47, p = 0.03) and pts with liver mets had inferior RR (OR 0.33, p = 0.02) and PFS (HR 3.08, p < 0.01), while OS was poorer in pts with liver (HR 4.38, p = 0.01) or brain mets (HR 2.82, p = 0.06). Pts with lung mets had more rash (31% vs 9%, p = 0.05), while pts with liver and GI mets had less rash (6% vs 33%, p = 0.02) or thyroiditis (0 vs 14%, p = 0.02) compared with pts without these mets. Disease burden and number of metastases did not associate with tox. Conclusions: Metastases in different anatomical locations display distinct response patterns with combination immunotherapy, with inferior responses in liver mets and shorter survival in patients with liver mets, similar to that seen with PD1 monotherapy. Patterns of metastasis may influence toxicity.
Margaret McCartney: A summary of four and a half years of columns in one column
Authors: Margaret McCartney
Journal: BMJ (2018)

1.  Screening is only for people with no symptoms. If you have symptoms it’s not screening.

2.  Screening is often counterintuitive. False positives proportionately rise when prevalence falls.

3.  “Case finding” is the recourse of those who do non-evidence based screening but can’t seem to admit it.

4.  Inadequately tested tech can do as much harm as inadequately tested medicine.

5.  The NHS is a pie. If you ask the NHS to do more without making the pie bigger, something else won’t get done.

6.  Apparent problems are fixed more effectively when they’re first understood.

7.  A system that uses blame to attempt improvement is likely to make good professionals miserable and leave.

8.  Earlier isn’t necessarily better. Lead time bias and overdiagnosis create mirages and do harm.

9.  If it’s not evidence based …
Abstract 12601: O-Glycosylation of ApoB100 is Associated With Enhanced Sphingomyelinase Activity and Atherogenicity of Human Electronegative LDL
Authors: Liang-Yin Ke, Hua-Chen Chan, Chih-Chieh Chen, Jonathan Lu, Gopal K. Marathe, Chih-Sheng Chu, Hsiu-Chuan Chan, Chung-Ya Wang, Shi-Hui Law, Yi-Ching Tung, Thomas M McIntyre, Jeng-Hsien Yen, Chu-Huang Chen
Journal: Circulation (2015)

Background: Among the 5 (L1-L5) chromatographically resolved subfractions of human LDL, L5 is the most electronegative and atherogenic. L5’s atherogenicity may be attributed in part to its high cer...
Changes in blood parameters of patients with laryngeal squamous cell carcinoma during polychemotherapy with cetuximab.
Authors: Liubov Yu Vladimirova, Nailya Guskova, Ludmila A. Ryadinskaya, Marina Engibaryan, Aliya K. Donskaya, Ekaterina Guskova, Marina A. Gusareva, Nadezhda Golomeeva, Svetlana V. Abakumova, Irina V. Tselishcheva, Kristina Avanesova, Anastasia Nozdricheva, Viktoria Zakharchenko, Svetlana V. Belgova, Ekaterina Gornostaeva
Journal: Journal of Clinical Oncology (2017)

e17579 Background: Our purpose was to evaluate changes in blood parameters in patients with laryngeal squamous cell carcinoma (LSCC) during polychemotherapy (PCT) with cetuximab. Methods: Levels of white blood cells (WBC), immature granulocytes (IG) and neutrophils (Ne), as well as levels of C-reactive protein (CRP), lactate dehydrogenase (LDH) and creatinine were studied in the blood of 20 patients with stage I-III LSCC before therapy with cetuximab/cisplatin+5-fluorouracil and on days 2, 9 and 16 of the therapy. The control group (21 patients) received similar PCT without cetuximab. Treatment was assessed using the RECIST criteria. Results: Partial response was observed in 16 (80%) patients of the main group and in 5 (23.8%) controls, stabilization - 4 (20%) and 12 (57.4%), respectively, progression – in 4 (19%) patients of the control group. Patients of the main group with treatment effect showed WBC increase by 2 times after every cetuximab injection (days 2, 9, 16) compared with the initial levels due to Ne and IG increase by 2.7 and 4 times, respectively. WBC and IG levels measured on days 2, 9 and 16 were 13.40±2.86×10 9 /L, 13.52±1.88×10 9 /L, 12.25±2.08×10 9 /L and 0.044±0.021×10 9 /L, 0.056±0.015×10 9 /L, 0.060±0.008×10 9 /L, respectively (p &lt; 0.001). A transient increase in the indexes was replaced by their decrease to the initial values, with the values similar to the reference ones by the end of the treatment. At the same time, we observed decrease in CRP and creatinine levels up to the reference levels (7.69±3.28 mg/L and 74.75±6.54 umol/L, respectively); LDH did not increase. Stabilization was characterized by unchanged WBC levels, positive dynamics of IG and slow decline of CRP level exceeding the reference one (10.0 mg/L) by the treatment end. Reduction of WBC and increase in IG and CRP levels were noted in the controls regardless of the PCT results which could be explained by severity of intoxication syndrome, partially due to the disease and partially due to PCT toxicity. Conclusions: A dual transient increase in WBC and IG levels, reduction of CRP and creatinine during the treatment and unchanged LDH indicate minimization of myelotoxic and general toxic effects of PCT in combination with cetuximab.
Translating prostate cancer working group (PCWG) criteria into a quantitative progression biomarker in metastatic castration resistant prostate cancer (mCRPC).
Authors: Aseem Anand, Glenn Heller, Howard I. Scher, Michael J. Morris
Journal: Journal of Clinical Oncology (2017)

5068 Background: mCRPC is a bone dominant lethal disease. A validated endpoint in mCRPC trials is bone scan progression, which is semi-quantitative and rely on the appearance of new lesions as proposed by the PCWG. The validated automated bone scan index (BSI) quantifies the bone tumor burden as the fraction of total skeletal weight. To build on the current definition of disease progression, we sought to compare the association of time to progression with overall survival (OS) using PCWG criteria and BSI increase. Methods: mCRPC patients (pts) enrolled on trials of agents targeting androgen-receptor (AR) were assessed. Pts were required to have a raw bone scan image for BSI analysis concurrent with disease assessments. The EXINI automated computing platform generated the BSI values. Thresholds for the absolute and relative increase in BSI from 1st follow-up (≤12 weeks) were explored for the time to BSI progression. The association with survival time was computed for each threshold defined time to BSI progression. Kendall’s Tau, derived from the Clayton copula, was used to associate time to BSI progression with survival time, where both endpoints may be censored. Results: A total of 257 pts were assessed, of whom 169 had raw bone scans images needed for the BSI analysis. 90 pts (53%) met progression by PCWG criteria, the association between the time to PCWG progression and OS was 0.52. The association between time to BSI progression and OS was comparable to the PCWG progression when the absolute increase in BSI was 0.6 or more (table below). Conclusions: Progression in bone can be expressed as a single quantitative metric that describes the increase in total disease burden while retaining the same association that PCWG has with OS. These data represent the first steps to a quantitative expression of bone disease progression as a clinical trials endpoint. [Table: see text]
Adjuvant radio chemotherapy for gastric cancer: Is chemotherapy alone better than combined radio chemotherapy? Results of a meta-analysis.
Authors: Jan Haussmann, Edwin Boelke, Balint Tamaskovics, Kai Kammers, Freddy Joel DjiepmoNjanang, Wilfried Budach, Christiane Matuschek
Journal: Journal of Clinical Oncology (2018)

e16030 Background: Adjuvant chemotherapy in advanced gastric cancer reduces the risk of distant metastasis and most likely increases the survival rate. Patients who are at high risk for tumor recurrence may benefit from more aggressive procedures like combined radio chemotherapy. Recently, the results of 6 randomized trials addressing this question have become available. Methods: In the 6 trials of interest, in total 1171 patients with locally advanced gastric cancer were randomly assigned to receive either adjuvant chemotherapy or combined adjuvant radio chemotherapy. Published hazard ratios and hazard ratios extracted from available survival curves for local reginal control and overall survival were basis of the meta-analysis. Meta-analysis of the effect sizes on local control and overall survival was performed using a random effects model based on parameter estimates of log hazard ratios in Cox models and their standard errors. Results: Additional radio chemotherapy did not result in a significant improvement of overall survival (n = 1171) (Hazard Ratio: 0.86, 95% confidence limits (CL) 0.72-1.04 p = 0.12) but a tendency towards a better benefit cannot be excluded. Conclusions: Combined radio chemotherapy for advanced gastric cancer did not result in a significant improvement of the overall survival rate but a modest benefit cannot be excluded.
The efficacy of addition of chemoradiotherapy to achieve resectability in locally-advanced pancreatic cancer remaining unresectable after neoadjuvant chemotherapy.
Authors: Sarbajit Mukherjee, Joshua Weir, Jordan Morton, Terence S. Herman, Bilal Khalid, Russell Postier, Hassan Hatoum
Journal: Journal of Clinical Oncology (2017)

e15761 Background: Although the efficacy of neoadjuvant chemotherapy (NACT) in achieving resectability in locally advanced pancreatic cancer (LAPC) has been 20-31%, many cases remain unresectable. The aim of this study is to evaluate the efficacy of adding chemo radiotherapy (CRT) to achieve resectability in LAPC that remained unresectable after NACT. Methods: Between January 2008 and December 2016, 38 patients with LAPC (borderline resectable or unresectable pancreatic cancer, BRPC or URPC) received NACT and remained unresectable; subsequently, all patients received CRT in an attempt to achieve resectability with curative-intent. The primary objective of this retrospective single institution study is to assess resection rate (RR) in these patients. The secondary objective is to assess overall survival (OS). Results: A total of 38 patients (22 male, 16 female) who were identified as BRPC (50%) or URPC (50%) at presentation as defined by multidisciplinary tumor board using pancreatic protocol CT scan received NACT and remained unresectable. The median age was 64 (56-70.5) years. The primary site was head of pancreas in 66% versus other sites in 34% . The T-stage distribution was T1 (2.6%), T2 (2.6%), T3 (34.2%) and T4 (60.6%). N0 and N1 were 63.1% and 36.9% respectively. The types of NACT included FOFIRINOX (39.5%), Gemcitabine-based (58%) and unknown (2.5%). The median number of NACT cycles was 4 (2.25-4). All patients received subsequent CRT. Only the primary tumor was targeted with a median dose of 5040 (4950-5400) cGy and a median number of fractions 18(18-28). Chemo used concurrently with radiation was 5-FU (52.5%), Xeloda (39.5%), Gemcitabine (5.5%) and unknown (2.5%). Of note, 36.8 % patients achieved resectablity (14/38). The R0 and R1 resections were 11 (28.9%) and 3 (7.9%) respectively. 52.6% patients received adjuvant chemotherapy. The OS was 17 (6-24) months in the R0 group versus 8 (7-9) months in the R1 group. For the whole group, median OS was 11.5 (7-18.25) months. Conclusions: The addition of CRT to NACT in LAPC may improve resectability leading to an OS that approximates the OS in those patients who had upfront resectable disease.
Radiologic predictors of response to checkpoint inhibitors in advanced head and neck SCC.
Authors: Vishwajith Sridharan, Rifaquat Rahman, Raymond Yi-kun Huang, Nicole Grace Chau, Jochen H. Lorch, Ravindra Uppaluri, Robert I. Haddad, Glenn J. Hanna, Jonathan Daniel Schoenfeld
Journal: Journal of Clinical Oncology (2018)

e15133 Background: Checkpoint blockade in advanced HNSCC benefits a minority of patients. Here we nominate radiologic parameters of response to guide patient selection. Methods: We retrospectively characterized changes in radiologic parameters in 100 consecutive HNSCC patients treated with checkpoint blockade at our institution. Tumor burden (TB) was calculated as the sum of the largest diameter of all measurable lesions by RECIST 1.1. Investigators were blinded to outcomes when radiologic data were collected. Radiologic variables were correlated with clinical parameters, and data analyzed using JMP or Prism. Results: The majority of patients were male (82%) with a median age of 57 (20-89). Locoregional disease was noted at baseline in 64% of patients; with 77% having distant disease (67% lung, 17% bone, 13% liver). Human papillomavirus (HPV) was causally associated with 42% of cases, and 49% of patients were smokers ( > 10 pack-years). Most were initially treated with chemotherapy and/or chemoradiation (81%), The median TB was 5.4 cm (range 1 – 25.9). Forty patients (40%) showed clinical benefit (CR, PR, SD), and the median overall survival (OS) on PD-1 therapy was 4.5 months. TB inversely correlated with clinical benefit (p = 0.01). Similarly, patients with a higher TB had worse OS (p < 0.01). HPV+ disease (p < 0.01) and increased total mutational burden (p = 0.03) were associated with distant disease in the absence of locoregional disease. Any overall increase in TB on first scans ( < 60 days) correlated with worse OS (p = 0.04) and predicted lack of immune-related toxicity (p < 0.01). Conclusions: Several aspects of radiologic data offer important insights regarding likelihood of anti-PD-1 response.
Phase II study of neoadjuvant IGFBP-2 vaccination with neoadjuvant carboplatin and paclitaxel in advanced ovarian cancer.
Authors: William Rayford Gwin, Jennifer Childs, Doreen Higgins, Hania Shakalia, John Ben Liao, Mary L. Disis
Journal: Journal of Clinical Oncology (2018)

TPS5613 Background: Patients with advanced ovarian cancer not amenable to primary debulking surgery are candidates for neoadjuvant chemotherapy (NACT). Patients achieving a complete pathologic response (cPR) with NACT have superior overall survival; however, the rate of cPR is only 7.5%. In ovarian cancer, tumor infiltrating lymphocytes (TIL) are critically important in prognosis. Paclitaxel and carboplatin augment Type I immunity and decrease MDSCs and Tregs. A Phase I study of an IGFBP-2 vaccine designed to augment Type 1 immunity in Stage III/IV ovarian cancer patients was safe and induced IGFBP-2 specific immunity. Vaccination during the myeloid nadir after platinum/taxane chemotherapy has shown robust Th1 immune responses. We hypothesize that vaccination against IGFBP-2 during the myeloid nadir can synergize with NACT to improve the rate of cPR through Th1 immunity, antigen specific T cells, and TIL. Methods: Trial Design: Phase II single arm study of concurrent IGFBP-2 vaccination with carboplatin and paclitaxel. Patients receive NACT IV on day 1 of each 3 week cycle and receive the IGFBP-2 vaccination on day 14. Study treatment includes 3 vaccinations, evaluations at 1 week and 6 months post vaccine and yearly follow-up for 5 years. Toxicity is assessed at baseline and through end of study. Blood and tumor tissue will be collected for immunologic monitoring and evaluation. Eligibility: Patients with newly diagnosed advanced stage ovarian cancer who will receive NACT with subsequent planned cytoreductive surgery. Specific aims: (1) Determine the rate of pCR, (2) Determine the level of TIL in residual tumor (2) Determine whether IGFBP-2 induces IGFBP-2 specific T cells, (3) Explore if there is a predictive signature for pCR when IGFBP-2 vaccination is used with NACT. Statistical Methods: (1) The sample size of 38 will provide 80% power to detect a significant increase in pCR to 20% when compared to NACT alone, (2) Tumor tissue will be evaluated for TIL, (3) IGFBP-2 specific INF-g/IL-10 ratios by ELISPOT will be evaluated, (4) Whole exome sequencing will be performed to correlate expression profiles with response to vaccination. Targeted Accrual: 7 of the planned 38 patients have been enrolled. Clinical trial information: NCT03029611.
Limited stage nodular lymphocyte predominant Hodgkin lymphoma (NLPHL): A subgroup analysis of the HD.6 clinical trial.
Authors: Bethany Monteith, Erica C. DiMaria, Michael Crump, Jeffrey B. Ames, Jane N. Winter, Marina Djurfeldt, Lois E. Shepherd, Ralph M. Meyer, Bingshu E. Chen, Annette E. Hay
Journal: Journal of Clinical Oncology (2018)

7535 Background: NLPHL is a rare subtype of Hodgkin lymphoma (HL) accounting for 5% of cases. It is rarely studied in prospective clinical trials and treatment is controversial. Methods: In the Canadian Cancer Trials Group HD.6 phase 3 trial, individuals with newly diagnosed non-bulky stage IA or IIA HL were randomly assigned to treatment with ABVD chemotherapy (CT) alone, or to radiation based (CMT/RT) therapy [Meyer NEJM 2012]. From this we identified all patients with NLPHL. A classical Hodgkin lymphoma (cHL) comparison cohort was constructed using propensity score matching 3:1 for age, sex, stage, treatment arm and number of nodal sites. Event free survival (EFS), overall survival (OS) and freedom from disease progression (FFP) were as defined in the original trial. The NLPHL cohort was analyzed according to treatment arm and compared with the cHL cohort using log-rank statistics. Secondary endpoints included toxicity and second malignancies. Results: Of 405 individuals enrolled in HD.6, 29 (7.2%) had NLPHL. Of these, median age at diagnosis was 42 yrs, 24 (83%) were male and 15 were assigned to RT. Median follow up was 120 months. For patients with NLPHL, 12-yr EFS for CMT/RT vs CT was 58% vs. 85% (HR 0.46, 95% CI 0.09-2.37) and FFP was 70% vs 85% (HR 0.72, 95% CI 0.12-4.33), respectively. There was one death in the CMT/RT arm; OS analysis by treatment arm was not conducted due to insufficient events. Eighty-seven pts were identified for the matched cHL cohort. 12-yr OS in the NLPHL and cHL groups was 95% and 87% (HR 3.43, 95% CI 0.44-26.5), EFS 70% and 81% (HR 0.73, 95% CI 0.30-1.76), FFP 78% and 90% (HR 0.51, 95% CI 0.17-1.57). Over the entire course of follow-up, there was 1 (3%) death in the NLPHL group due to unknown cause and 12 (14%) deaths in the cHL group – 3 treatment-related toxicity, 6 secondary malignancy, 3 other causes. Conclusions: We present the only prospective assessment of early-stage NLPHL treated with ABVD alone. Acknowledging limitations including small sample size, outcomes of pts with NLPHL appear very good when treated with ABVD chemotherapy alone. Clinical trial information: NCT 00002561.
Circulating neuroendocrine transcripts and gene cluster analysis to predict the efficacy of peptide radioreceptor therapy.
Authors: Lisa Bodei, Mark S. Kidd, Aviral Singh, Ignat Drozdov, Stefano Severi, Sylvia Nicolini, Richard P. Baum, Giovanni Paganelli, Dik J. Kwekkeboom, Eric Krenning, Irvin Mark Modlin
Journal: Journal of Clinical Oncology (2016)

4098 Background: Somatostatin receptors (SSR) are overexpressed by neuroendocrine tumors (NETs). Peptide receptor radionuclide therapy (PRRT) targets the tumor cells through SSRs. Prediction of efficacy is critical since SSR expression or chromogranin A (CgA) levels have limited (20-60%) predictive ability. We assessed the utility of a blood-based multigene NET transcript analysis (NETest) to predict PRRT efficacy in 2 PRRT-treated NET cohorts. The algorithm comprises > 50 genes + clusters defining growth factor signaling (GFS) and metabolism (MTB). Methods: We investigated 2 independent 177Lu-PRRT-treated groups: #1 (n= 72), median total activity 18.5GBq (6.5-27.8) and #2 (n= 24), 24.5GBq (11.4-29.7). Baseline evaluations: grade (Ki67), SSR imaging (SRI), CgA (ELISA), and NETest (qRT-PCR - multianalyte algorithmic analyses). Using #1 we mathematically devised a predictive response index (PRI) of > 50 NET genes, MTB and GFS clusters & Ki67). We then assessed this PRI for PRRT efficacy in #2. RECIST criteria were used to assess disease control (responder vs non-responder). Statistical analyses: multiple regression, Kaplan-Meier survival, Chi2. Results: Cohorts were comparable by grade, staging (IV) and SRI uptake. #2 had more advanced disease (progressive 100% vs. 74%, p< 0.01). At restaging, disease control rates were similar (68% and 83%, p= 0.23) and median PFS was not reached in either cohort (follow-up 15 and 9.5 months, respectively). Baseline CgA was not different (644±133 vs. 684±295ng/ml). NETest levels were significantly elevated in #2 (67±6% vs. 51±3%, p= 0.03), consistent with the progressive disease profile. PRRT response was not predicted by grading (p= 0.15), SRI (p= 0.41) or CgA (p= 0.12). In #1 the PRI accurately (> 90%) predicted responders (95%) and non-responders (90%), significantly better than SRI (Level 4: 43% accuracy: Chi2= 41, p< 0.0001). In #2 the PRI was also predictive (83%) and significantly more accurate than SRI (46%, Chi2= 21, p< 0.01). Conclusions: NET gene analysis in blood significantly outperformed (p< 0.01) CgA, Ki67 and SRI for prediction of PRRT efficacy. PRRT efficacy can be accurately predicted (83-94%) by pre therapy blood transcript analysis.