tbuckley/cabot-search huggingface dataset:
Practice patterns of molecular profiling in colorectal cancer.
Authors: Nkem Nweze, Ashlie Nadler, Sanjay S. Reddy, Biao Luo, Elin R. Sigurdson, Wafik S. El-Deiry, Crystal Shereen Denlinger, Michael J. Hall, Jeffrey M. Farma
Journal: Journal of Clinical Oncology (2017)

641 Background: Colorectal cancer (CRC) is a genetically heterogeneous disease. Molecular profiling (MP) using next-generation sequencing is increasingly used to personalize therapy. No guidelines currently exist regarding patient selection and optimal timing. Our goal was to describe our experience at a tertiary cancer center using MP in CRC patients. Methods: This is an IRB-approved, retrospective study in patients with CRC who underwent MP between March 2007 and August 2016. Tissue samples were sent for analysis in the following MP platforms: Foundation One, Caris, and FCCC Targeted Cancer Panel (FTCP), which tests for the 50 most common mutations. Data regarding patient demographics, mutations, and clinical outcomes were analyzed. Kaplan Meier methods were used for survival analysis using SPSS. Results: We evaluated 248 patients with CRC. 60.1% were male and 80.1% were white. The median age was 59.5 years. 66.5% had colon and 33.5% had rectal CA. Initial stages: stage 1 (2.8%), stage 2 (14.1%), stage 3 (22.9%), stage 4 (59.2%). 82.2% were tested via FTCP, 8.9% via Foundation One, and 9.3% via Caris. 60.9% had the primary tumor tested. 5.2% had no mutations, 19% had 1 mutation, 28.6% had 2 mutations, 27% had 3 mutations and 20.2% had &gt;4 mutations. The most common mutation guiding targeted therapy was KRAS (43.5%). 50% of patients had R0 resection and 19.3% went on to targeted therapy. 76.2% of resectable patients had a metastatic recurrence. 51.9% had targeted therapy for recurrence and/or stage 4 disease. The median time from diagnosis to MP was 9.9 months overall and 2.7 months for stage 4 patients. The median time from date of recurrence to MP was 7.7 months. Median length of follow up was 1.7 years. 14.9% had no evidence of disease at last follow up, 73% were alive with disease and 10.9% had died of the disease. Median overall survival was 55.8 months (CI 41.9 - 69.7). Conclusions: MP is utilized commonly in patients with stage 4 and recurrent CRC and occurs within 2.7 months and 7.7 months respectively. Further research is underway to evaluate if the information provided by MP improves outcomes in CRC, provides novel targets and will lead to increased clinical trial accrual.
High neutrophil to lymphocyte ratio (NLR) persistence during enzalutamide to predict poor clinical outcome in patients (pts) with metastatic castration-resistant prostate cancer (CRPC).
Authors: Ugo De Giorgi, Simon J. Crabb, Robert J. Jones, Orazio Caffo, Tony Elliott, Paolo Fabbri, Lisa Derosa, Francesco Massari, Gianmauro Numico, Vincenza Conteduca, Sunnya Zarif, Catherine Hanna, Francesca Maines, Helen Joyce, Emanuela Scarpi, Dino Amadori
Journal: Journal of Clinical Oncology (2015)

e16059 Background: Increased NLR, an index of systemic inflammation, is associated with poor outcome for various types of cancers, and has been recently associated with poor clinical outcome in pts with mCRPC. Here we evaluate the impact of NLR at baseline and at week 4 during enzalutamide in mCRPC. Methods: We included consecutive pts with CRPC treated with enzalutamide after docetaxel in a compassionate-use program for which NLR data were available at start of therapy, and 4 weeks thereafter. Change of NLR cut-offs (> 3 vs. ≤ 3) by week 4 were studied. Progression-free survival (PFS), overall survival (OS) and their 95% Confidence Interval (95% CI) were estimated by Kaplan-Meier method and compared with logrank test. The impact of NLR conversion on PFS and OS was evaluated by Cox regression analyses and on prostate-specific antigen response rates (PSA RR; PSA decline > 50%) was evaluated by binary logistic regression. Results: Data comprising 193 evaluable pts from 9 centers were evaluated. Median age was 73.1 years (range, 42,8 to 90.7). The median baseline PSA was 113, the median baseline NLR was 3.2. The median PFS was 3.2 months (mo) (95% CI = 2.7–4.4) in patients with baseline NLR > 3 and 8.5 mo (6.0–10.1) in those with NLR ≤ 3, P < 0.0001. The median OS was 10.4 mo (95% CI = 6.5–14.6) in patients with baseline NLR > 3 and 18.2 mo (95% CI = 11.2–not reached) in those with baseline NLR ≤ 3, P < 0.0001. Data for NLR at baseline and change in NLR by week 4 using a cut-off of 3 are shown in the table. Conclusions: An increased NLR persistent during enzalutamide seems to have both prognostic and predictive value in pts with mCRPC. NLR week 0 -> NLR week 4 (cut-off 3) L -> L H -> L H -> H Total number of cases 78 37 69 PSA RR N (%) 52 (67) 20 (54) 21 (30) OR; P 0.60; 0.494 0.21; 0.0001 PFS median (mo) 9.3 4.4 2.7 HR; P 1.51; 0.081 2.57; < 0.0001 OS Median (mo) 20.9 13.9 6.8 HR; P 2.00; 0.020 2.96; < 0.0001 Note: 9 more cases with low NLR at week 0 and high NLR at week 4 had a PSA RR= 33% (3 of 9 cases), a median PFS of 6.2 months and a median OS=8.2 months. H, high (i.e. NLR > 3); L, low (i.e. NLR ≤ 3). HR, hazard ratio; OR, odds ratio.
Enhancement of cetuximab-induced antibody-dependent cellular cytotoxicity (ADCC) with lenalidomide in advanced solid tumors: A phase 1 trial.
Authors: Erin Marie Bertino, Elizabeth L McMichael, Miguel Angel Villalona-Calero, Michael R. Grever, William Edgar Carson, Gregory Alan Otterson
Journal: Journal of Clinical Oncology (2014)

3044 Background: Antibody-dependent cellular cytotoxicity (ADCC) is one mechanism of action of monoclonal antibody therapy. ADCC occurs via the innate immune system’s ability to recognize mAb coated cancer cells and activate effector cells. Lenalidomide is an immunomodulatory agent with capacity to stimulate T cell proliferation, activate natural killer cells, and effect immune cytokines including IL-2, IL-12, and interferon gamma (INF-g). Pre-clinical and clinical data demonstrate the ability of lenalidomide to increase ADCC activity of mAb therapy. This phase 1 trial evaluated the combination of cetuximab with lenalidomide to enhance ADCC activity in advanced colorectal (CRC) and head and neck squamous cell cancers (HNSCC). Methods: This phase 1 dose escalation (3+3) trial included pts with metastatic CRC or HNSCC. Treatment consisted of cetuximab 500 mg/m2 IV every 2 weeks with lenalidomide orally days 1-21 every 28 days. Three dose levels of lenalidomide were evaluated (15, 20, and 25 mg). Correlative studies include measurement of ADCC using an in vitro chromium release assay, bioplex cytokine profiles, and Fc gamma receptor (FcR) polymorphisms. For ADCC assay, target cell line was HT29 (CRC KRAS WT cell line). Results: 22 pts were treated (19 CRC, 3 HNSCC); 20 pts had received prior cetuximab or panitumumab. Grade 3 fatigue was the only DLT. One partial response was observed and 7 patients had stable disease as best response.The recommended phase II dose is cetuximab 500 mg/m2 with lenalidomide 25 mg daily. ADCC assay demonstrated increased cell lysis with increasing doses of lenalidomide, particularly with lenalidomide 25 mg. Patient with PR demonstrated increase in ADCC as well as upregulation of IL-2, IL-12, INF-g with downregulation of FGF and VEGF. No high affinity FcR polymorphisms were identified. Conclusions: Cetuximab and lenalidomide are well-tolerated with minimal toxicity. There was evidence of anti-tumor activity and clinical efficacy. Correlative studies also demonstrate improved immunologic activity as demonstrated by ADCC assays with increasing doses of lenalidomide although no high affinity FcR polymorphisms were identified. Clinical trial information: NCT01254617.
My child matters program: A UICC-sanofi-aventis partnership to improve pediatric cancer care in developing countries
Authors: R. C. Ribeiro, T. Eden, J. Hartford, J. Lemerle, I. Magrath, H. Sancho-Garnier, E. Steliarova-Foucher, G. Thaxter, I. M. Tabah-Fisch, F. Cavalli
Journal: Journal of Clinical Oncology (2007)

9526 Background: Despite dramatic advances in curing childhood cancer in developed countries, most children with cancer live in low-income countries, where misdiagnosis, late diagnosis, lack of access to treatment and abandonment of treatment hinder progress. Methods: In 2004 the International Union against Cancer and sanofi-aventis initiated a campaign to improve childhood cancer care in developing countries through grants for local projects (up to 50,000 euros/year each), a survey of childhood cancer care (conducted by the public health consulting firm Sanisphere), and lobbying to increase political support. The projects focus on professional education, improved access to care, pain management, and psychosocial/educational support. Results: During 2006, 14 pilot projects in Bangladesh, Egypt, Honduras, Morocco, Philippines, Senegal, Tanzania, Ukraine, Venezuela, and Vietnam were selected on the basis of feasibility, expected benefit, sustainability, and potential to serve as models. Only eight countries had pediatric hematology/oncology units, ranging from 20 (Tanzania) to 350 (Egypt) beds. These units manage 100 (Senegal) to 1,000 (Bangladesh) children with cancer per year (a small fraction of actual cases in these countries). One-year outcome analysis showed that various short-term objectives were met, including improved patient care infrastructure, public and professional education, earlier detection, improved access to care, the introduction of psychosocial support, decreased abandonment and better follow up. On the basis of these results, 12 additional projects have been funded in Bolivia, Indonesia, Kenya, Mali, Peru and Romania. Conclusions: Relatively small investments, accompanied by external mentoring, can help build sustainable capacity for the diagnosis and care of children with cancer in selected institutions in developing countries. No significant financial relationships to disclose.
Soluble Urokinase-Type Plasminogen Activator Receptor Improves Risk Prediction in Patients With Chronic Heart Failure
Authors: Lorenz Koller, Stefan Stojkovic, Bernhard Richter, Patrick Sulzgruber, Christos Potolidis, Florian Liebhart, Deddo Mörtl, Rudolf Berger, Georg Goliasch, Johann Wojta, Martin Hülsmann, Alexander Niessner
Journal: JACC Heart Failure (2017)
Risk for pulmonary late effects in childhood Hodgkin lymphoma survivors.
Authors: Jennifer Elise Agrusa, Austin L Brown, Viral Kothari, Gary Lewis, Bin S. Teh, Arnold Paulino, Carl E. Allen, Philip Lupo, Maria Monica Gramatges
Journal: Journal of Clinical Oncology (2017)

112 Background: Survivors of Hodgkin lymphoma (HL) are at risk for pulmonary late effects, including pulmonary fibrosis (PF). Established risk factors such as younger age at diagnosis and specific therapeutic exposures explain a fraction of the risk for these outcomes. Notably, systemic inflammation and impaired telomere maintenance are associated with adverse pulmonary outcomes in adult populations, but have not been explored in cancer survivors. Our aim was to identify pulmonary diffusion defects in HL survivors, and evaluate the impact of short lymphocyte telomere length (LTL) and systemic inflammation on these outcomes. Methods: Blood samples, demographic and treatment data, and lung carbon monoxide diffusion capacity corrected for hemoglobin and alveolar volume (DLCO) were obtained from HL survivors ≥6 months off therapy and without history of relapse or transplant. LTL was measured by telomere flow FISH (Repeat Diagnostics), and age-based percentiles determined from population controls. Plasma elevations in pro-inflammatory cytokines (HCYTMAG panel, EMD Millipore) were detected on a Luminex platform. Associations between clinical features and most recent DLCO were determined by linear regression, adjusted for age, sex, radiation, and race/ethnicity. In a subset of subjects, cytokine levels and LTL were compared in survivors with DLCO above or below the mean using a Student t-test or Fisher’s Exact test, respectively. Results: Seventy-two HL survivors met inclusion criteria (mean age at diagnosis=14 years, range: 3-18 years). Mean off-therapy DLCO was 75% (range: 52-98%), below the lower limit of normal (76%) in healthy populations. DLCO was inversely associated with female sex (p = 0.002). Five of 24 survivors (21%) had LTL ≤10th percentile for age, but there was no difference in LTL relative to DLCO. Survivors with DLCO ≤75% had higher IL1α and IL1β levels (n = 30, p = 0.07). Conclusions: HL survivors had lower than expected DLCO, with females at highest risk for impaired pulmonary diffusion. Twice as many survivors as expected had LTL ≤10th percentile, and PF-related cytokine profiles were observed in survivors with lower DLCO, suggesting inflammation and telomere maintenance defects may contribute to late effects in HL survivors.
Plasmodium knowlesi
Authors: Peter Chiodini, Barbara J. Bain
Journal: American Journal of Hematology (2017)

Plasmodium knowlesi has been known as a parasite of South-East Asian monkeys since the first quarter of the last century. It was experimentally transmitted to humans in the 1930s and for a period was used in the treatment of neurosyphilis. Subsequently, naturally occurring human infection was described. In recent decades, human cases have been recognized in Indonesia, Borneo, Singapore, Malaysia, Myanmar, Vietnam, and the Philippines and occasional cases have occurred elsewhere in returning travellers. The morphological features share some characteristics with P. falciparum in that there are delicate ring forms, sometimes two ring forms per cell and sometimes double chromatin dots and accolé forms (left and center); the parasitized cells are not enlarged and have fine cytoplasmic dots, which were referred to as Sinton and Mulligan's dots in the older literature. The presence of young rings, accolé forms, and high parasitemia may lead to confusion with P. falciparum. However, in addition to delicate rings there are also more chunky rings and, later, somewhat ameboid trophozoites (left and center). Schizonts may also be seen with up to 16 merozoites (right), whereas these are quite uncommon in the peripheral blood in P. falciparum infection. A common problem is mis-identification of P. knowlesi as P. malariae, especially as both parasites produce band form trophozoites. If a diagnostic laboratory sees what appears to be P. malariae in a person who acquired malaria in the Asia-Pacific region, PCR for P. knowlesi should be undertaken, especially as P. knowlesi produces a much more severe infection and the treatment given should be appropriate for both those possibilities. These images are from in vitro cultured parasites kindly provided by Dr. Don Van Schalkwyk of the London School of Hygiene and Tropical Medicine. none
Endocrine therapy in patients with metastatic breast cancers (MBC): Prognosis and measures of outcome.
Authors: Pamela Driol, Marta Bonotto, Caterina Fontanella, Lorenzo Gerratana, Francesca Valent, Stefania Russo, Claudia Andreetta, Alessandro Minisini, Roberta Sottile, Mauro Mansutti, Gianpiero Fasola, Fabio Puglisi
Journal: Journal of Clinical Oncology (2012)

e13070 Background: Endocrine manipulation is the cornerstone of therapy in hormone receptor (HR)-positive breast cancer. However, a significant percentage of patients who receive endocrine therapy (ET) as metastatic treatment experience de novo or acquired resistance. New clinical trials for HR-positive MBC should be tailored around immunophenotypical and clinical features. This study evaluates different potential prognostic factors in patients treated with ET for MBC. Methods: We analyzed retrospectively data from a series of 280 consecutive patients with HR-positive MBC diagnosed from January 2004 to February 2011 at University Hospital of Udine, Italy. Multivariate analysis was performed to establish the independent value of different disease and patients’ characteristics in influencing progression-free survival (PFS), overall survival (OS) and survival post-progression (SPP). Results: Median OS was 38.44 months (mo), median PFS at first-line ET was 10.05 mo. Median SPP was 22.74 mo, 15.18 mo, and 15.47 mo after first, second and third-line ET, respectively. Age &gt;70 years and ECOG performance status &gt;1 were independent prognostic factors for both shorter OS (HR 2.55, p = 0.019; HR 2.46, p = 0.025, respectively) and shorter SPP (HR 2.99, p = 0.003; HR 2.82, p = 0.011, respectively). Number of chemotherapy lines before first ET was an independent prognostic factor for both PFS (HR 1.45, p &lt; 0.001) and OS (HR 1.62, p = 0.001). MIB-1 &gt;14% was associated with shorter PFS (HR 1.98, p = 0.012); this finding underlines the poor prognosis of luminal B subtype in comparison with luminal A disease. Conclusions: Determinants of treatment decision-making in MBC include patients’ characteristics, prognostic factors, disease biology, and mechanisms of resistance. This study confirms the worse prognosis of luminal B subtype, also in presence of endocrine manipulation. Innovative therapeutic approaches are eagerly waited in order to overcome resistance to ET. This study also provides some insights for the choice of optimal endpoints in trials that enroll patients with HR-positive MBC. In particular, based on long SPP values, OS does not seem to be an appropriate endpoint in studies involving such patients’ population.
Meta-analysis of stomatitis incidence in everolimus (EVE) clinical studies and its relationship with efficacy.
Authors: Hope S. Rugo, James C. Yao, Gabriel N. Hortobagyi, Marianne E. Pavel, David Neal Franz, Alain Ravaud, Tanya Taran, Jorge Gallo, Nicolas Rouyrre, Oezlem Anak, Robert J. Motzer
Journal: Journal of Clinical Oncology (2014)

645 Background: Stomatitis is a common adverse event with EVE. This meta-analysis of individual patient (pt) data assessed the incidence, severity, and potential impact on outcomes of stomatitis and related events in EVE pts with cancer or TSC. Methods: 7 randomized, double-blind, phase 3 studies of EVE were included: RECORD-1 (RCC), RADIANT-2 (NET), RADIANT-3 (pNET), BOLERO-2 (HR+/HER2– breast cancer), BOLERO-3 (HER2+breast cancer), and EXIST-1 and -2 (TSC). Only events from the double-blind period were included. Kaplan-Meier (KM) methods were used to analyze times to first stomatitis and recurrence. Stratified Cox regression analysis adjusted for known baseline prognostic factors was used to assess the association between stomatitis occurrence within 8 wk of EVE start and PFS in cancer pts and response rate in TSC pts. Results: 1,455 cancer and 157 TSC EVE-treated pts were analyzed. Crude stomatitis incidence was 66.9% in oncology pts (8.6% grade 3/4) and appeared early (median 0.82 mo; 95% CI 0.7-1.0; 2 mo KM estimate 60.8%). Stomatitis led to discontinuation in 1.7% of pts. Reccurence occurred in 40% and appeared less rapidly (2 mo KM estimate 28.0%). Results were similar in TSC pts. An association between stomatitis and PFS was observed in BOLERO-2 (HR 0.771; 95% CI 0.603-0.987) and RADIANT-3 (HR 0.687; 95% CI 0.465-1.014); association was maintained after correcting for exposure. A similar trend was observed in RECORD-1 (HR 0.866) but not BOLERO-3 or RADIANT-2. In all trials, EVE pts had longer PFS compared with placebo regardless of stomatitis incidence. There were too few TSC pts to reach a conclusion on the relationship between stomatitis and response. Conclusions: Stomatitis is common in EVE-treated pts and occurs in the initial wks of therapy. Most events are grade 1/2, rarely lead to discontinuation when actively managed according to recommendations, and recur in <50% of affected pts. Cancer pts treated with EVE who experienced stomatitis derived benefit consistent with that shown in the overall population, suggesting EVE continuation is beneficial. Ongoing prospective studies will determine the value of prophylactic measures to reduce EVE-induced stomatitis incidence and improve its management.
Activity of docetaxel (D) and new generation hormonotherapies (NGH) in patients with metastatic castrate-resistant prostate cancer (mCRPC) following front line cabazitaxel (C).
Authors: Damien Pouessel, Safae Aarab Terrisse, Guillaume Mouillet, Katharina Breitkopf, Christine Theodore, Florence Joly Lobbedez, Guilhem Roubaud, Aude Flechon, Jean-Marc Tourani, Christophe Massard, Antoine Thiery-Vuillemin, Stephane Oudard, Emmanuel Sevin, Sylvie Chevret, Stephane Culine
Journal: Journal of Clinical Oncology (2015)

e16094 Background: C has been developed and approved for patients with progressive mCRPC after or during D chemotherapy. No efficacy data are available concerning the use of D or NGH after C delivered as front line chemotherapy. Methods: We retrospectively reviewed 128 chemotherapy naïve patients (pts) treated in 9 French centers with C or D as front-line chemotherapy in a randomized international phase III trial: 89 and 39 pts received C + prednisone (P) and D + P, respectively. PSA (bRR) and objective (oRR) response rates to D and NGH (abiraterone [AA] + P and enzalutamide [E]) were retrospectively assessed after C as first line-chemotherapy. Results: Among 89 pts treated with C as first line chemotherapy, 24 pts received D afterward: 10, 13, and 1 pts as 2nd, 3rd and 4th line, respectively. Reasons for C discontinuation (CD) were progressive disease (PD) in 11 pts (46%) and toxicity or other causes in 13 pts (54%). Median number of D cycles was 5. Overall bRR and oRR were 29% and 10%, respectively. Biological stable disease (bSD) and objective stable disease (oSD) were both 33%. If CD was due to PD, bRR, bSD, oRR and oSD to D were 11%, 44%, 0% and 33%, respectively. If CD was due to other causes, bRR, bSD, oRR and oSD were 42%, 25%, 17% and 33%, respectively. NGH were delivered in 61, 14 and 4 pts as 2nd, 3rd and 4th line, respectively. Respectively, 65 and 14 pts received AA and E. Ten of them received both AA and E. Overall 44%, 9%, 9% and 33% had a bRR, bSD, oRR and oSD, respectively. With NGH as 2nd line, bRR, bSD and bPD were observed in 32 (52%), 5 (8%) and 18 (29%) pts, respectively. With NGH from 3rdto 4th line, bRR, bSD and bPD were observed in 3 (21%), 2 (14%) and 4 (29%) pts, respectively. Conclusions: NGH show activity in pts with mCRPC treated with C as first line chemotherapy. D appears to be also efficient after C failure. However, the bRR and oRR seem to be lower in pts with refractory disease to C than those who stopped C for other reasons. Prospective studies are needed to confirm these results.
SRSF2 Mutations Identify a Distinct Subtype of Myeloid Neoplasm Across Myelodysplastic Syndromes and Acute Myeloid Leukemia
Authors: Gabriele Todisco, Anna Gallì, Erica Travaglino, Ettore Rizzo, Elisabetta Molteni, Chiara Elena, Ilaria Ambaglio, Silvia Catricalà, Paolo Bernasconi, Virginia Valeria Ferretti, Luca Malcovati, Mario Cazzola
Journal: Blood (2016)