tbuckley/cabot-search huggingface dataset:
Final results of a randomized phase II GELA/LYSA study of rituximab plus ACVBP or CHOP, using a PET-driven consolidation strategy, in patients with high-risk diffuse large B-cell lymphoma (DLBCL).
Authors: Rene-Olivier Casasnovas, Loic Ysebaert, Catherine Thieblemont, Bertrand Coiffier, Serge Bologna, Gerard Lepeu, Alain Delmer, Isabelle Plantier, Jean Gabarre, Marc Andre, Delphine Senecal, Christophe Fruchart, Michel Meignan, Alina Berriolo-Riedinger, Stephane Bardet, Thierry Jo Molina, Jean-Philippe Jais, Corinne Haioun, Herve Tilly, Franck Morschhauser
Journal: Journal of Clinical Oncology (2014)

8503 Background: GELA standard for young patients (pts) with high-risk DLBCL (aaIPI 2-3) is R-ACVBP induction plus consolidative BEAM and autologous stem cell transplantation (ASCT). R-CHOP induction might be as efficient and possibly less toxic than R-ACVBP. Also, early PET-negative patients may not need first-line ASCT. A phase II randomized trial was designed in 2007 to test both induction regimen and a PET-driven consolidation strategy (NCT00498043). Methods: Eligible pts were 18-59 years with a previously untreated CD20+ DLBCL, an aaIPI 2-3. Pts were randomly assigned to 4 cycles of either R-ACVBP14 or R-CHOP14 induction. Consolidation treatment was driven by centrally reviewed PET assessment (IHP visual criteria) after 2 (PET2) and 4 (PET4) induction cycles. Pts classified as PET2-/PET4- received a sequential immuno-chemotherapy consolidation; PET2+/PET4- pts underwent ASCT; PET4+ pts were considered as induction treatment failure and eligible for a salvage therapy. Primary endpoint was to evaluate the complete response (CR) rate after 4 induction cycles according to IWG 07 criteria. Results: 222 pts (R-ACVBP: 114; R-CHOP: 108) with a median age of 46 yrs were included: 97% had stage III/IV, 95% elevated LDH, 24% ECOG≥2. After induction treatment, 47% of the R-ACVBP arm and 39% of the R-CHOP arm pts achieved a CR. PET2 and PET4 were negative in 30% and 53% of pts in the R-ACVBP arm, and 25% and 40% in the R-CHOP arm, respectively. PET2-/PET4- pts were 27% and 24% in the R-ACVBP and R-CHOP arms respectively. Due to more frequent PET4+, pts in the R-CHOP arm more often received salvage therapy as post-induction treatment (39%) than pts in the R-ACVBP arm (27%) (p = 0.048). With a median follow-up of 45 months, PFS and OS were similar in both arms (4y-PFS=75%; 4y-OS=83%). Conclusions: A PET driven treatment of high risk DLBCL pts is feasible in a multicenter trial setting. Based on PET visual criteria at 4 cycles, CR rate was higher in the R-ACVBP arm and salvage was more frequently used after R-CHOP, possibly explaining similar PFS and OS in the two induction arms. 25% of pts found to be PET2-/PET4- do not require ASCT. Clinical trial information: NCT00498043.
TCA Cycle Inhibition By Cpi-613 Increases Sensitivity to Chemotherapy in Older and Poor Risk Acute Myeloid Leukemia (AML)
Authors: Timothy S Pardee, Lance D Miller, Kristin Pladna, Scott Isom, Leslie Renee Ellis, Dmitriy Berenzon, Dianna Howard, Megan Manuel, Sarah Dralle, Susan Lyerly, Bayard L Powell
Journal: Blood (2016)
Prognostic and predictive value of tumor infiltrating lymphocytes (TIL) in two phase III randomized adjuvant breast cancer (BC) trials.
Authors: Maria Vittoria Dieci, Aicha Goubar, Marie-Christine Mathieu, Valentina Guarneri, Pier Franco Conte, Suzette Delaloge, Fabrice Andre
Journal: Journal of Clinical Oncology (2014)

11087 Background: TIL have been proposed as a new prognostic factor for triple negative BC [Dieci MV, 2014]. Here we seek to evaluate the prognostic and predictive role of TIL in BC patients enrolled in two prospective adjuvant trials. Methods: The % of intratumoral (It) and stromal (Str) TIL were evaluated on H&E slides of tumors from 817 patients from two randomized trials comparing anthracycline-based to no chemotherapy [Arriagada R, 2005]. Samples were classified as High-TIL if ItTIL and/or StrTIL >=50%. CD3, CD8 and CD20 were also evaluated. Association with Disease-free survival (DFS) and interaction with chemotherapy were studied. Results: 781 of 817 cases were evaluable for TIL. High-TIL patients were more likely Grade 3 and ER-negative (P<0.001 for both). In multivariate analyses including age, tumor grade, tumor size, nodal status, ER, HER2 and treatment arm, both continuous It-TIL and Str-TIL variables were significantly associated with DFS. Each 10% increase in ItTIL or StrTIL was associated with 14% and 13% reduction in risk relapse (HR 0.86, 95%CI 0.78-0.94, P=0.001; HR 0.87, 95%CI 0.80-0.94, P<0.001), respectively. There was no prognostic effect in the ER+/HER2- subgroup, whereas both continuous ItTIL and StrTIL showed a significant prognostic value in multivariate analyses for both the ER-/HER2- and the HER2+ groups (P=0.05, P=0.04 for ItTIL and P=0.02, P=0.01 for StrTIL respectively). In the ER-/HER2- group 10yrs DFS rate was 85% and 53% for High-TIL and Low-TIL patients, respectively (HR 0.43 95%CI 0.20-0.94, P =0.03), whereas in the HER2-positive group 10yrs DFS rate was 74% and 54% for the High-TIL and Low-TIL groups, respectively (HR 0.48 95%CI 0.21-1.07, P=0.07). Either continuous ItTIL or StrTIL did not predict for the efficacy of anthracyclines, either in the whole study population or in different molecular subgroups (test for interaction: P>0.2). Conclusions: TILs did not predict anthracycline efficacy. We confirmed in prospective randomised trials the prognostic value of TIL for early triple negative BC patients and we suggested a prognostic impact in HER2+ patients. Analyses of TIL composition (CD3, CD8, CD20) are ongoing and will be presented at the meeting.
Vemurafenib and aPTT prolonging: A case report.
Authors: Susanna Rossi, Buggiani Antonio, Patrizia Dentico, Paolo Bernardeschi, Matilde Destefanis, Pier Giorgio Giannessi, Maria Teresa Pirrotta, Gina Turrisi, Antonella Ninci, Giuditta Zipoli, Carlo Milandri
Journal: Journal of Clinical Oncology (2014)

e20021 Background: Metastatic melanoma (MM) is a disease with poor prognosis; Vemurafenib (V) is a potent inhibitor of BRAF with V600E mutation with well established antitumor activity in this setting of patients (P). Methods: Herein we present a case of APTT prolonging, without spontaneous bleeding, possibly due to the use of V. Results: A 49 years old woman was diagnosed with liver and splenic metastases from M. At diagnosis, 80% of parenchyma was involved but laboratory tests, however, showed no major functional impairment. When P started treatment (T) she had a total bilirubin < 2n and a good coagulation (C) profile: INR 1.3 and PTT 32’’. PLT count was reduced to 60000/mmc, due to previous cycle of full dose T with CDDP and DTIC performed whyle waiting for result of BRAF mutation. We observed a rapid fibrinogen (F) lowering to 75 mg/dL, a moderate increase in INR (1.8) and APTT (40
Light therapies for acne: abridged Cochrane systematic review including <scp>GRADE</scp> assessments
Authors: J. Barbaric, R. Abbott, P. Posadzki, M. Car, L.H. Gunn, A.M. Layton, A. Majeed, J. Car
Journal: British Journal of Dermatology (2017)

We undertook a Cochrane review of randomized controlled trials (RCTs) evaluating the effects of light‐based interventions for acne vulgaris. We searched the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, LILACS, ISI Web of Science and grey literature sources (September 2015). We used the Grading of Recommendations Assessment, Development and Evaluation Working Group approach to assess the quality of evidence (QoE). We included 71 RCTs (4211 participants, median sample size 31). Results from a single study (n = 266, low QoE) showed little or no difference in effectiveness on participants' assessment of improvement between 20% aminolaevulinic acid (ALA) photodynamic therapy (PDT), activated by blue light, vs. vehicle plus blue light, whereas another study (n = 180) comparing ALA‐PDT (red light) concentrations showed that 20% ALA‐PDT was no more effective than 15% ALA‐PDT but better than 10% and 5% ALA‐PDT. Pooled data from three studies (n = 360, moderate QoE) showed that methyl aminolaevulinate PDT, activated by red light, had a similar effect on changes in lesion counts vs. placebo cream with red light. Several studies compared yellow light with placebo or no treatment, infrared light with no treatment, gold microparticle suspension with vehicle and clindamycin/benzoyl peroxide (C/BPO) combined with pulsed dye laser with C/BPO alone. None of these showed any clinically significant effects. Most studies reported adverse effects, but inadequately, with scarring reported as absent, and blistering only in studies on intense pulsed light, infrared light and PDT (very low QoE). Carefully planned studies, using standardized outcome measures and common acne treatments as comparators, are needed.
Sodium–Glucose Cotransporter 2 Inhibitors and Diabetic Ketoacidosis: A Case Series From Three Academic Institutions
Authors: Negin Misaghian-Xanthos, Afreen I. Shariff, Kavya Mekala, Loretta R. Fearrington, Tracy L. Setji, Joseph A. Aloi, John B. Buse
Journal: Diabetes Care (2017)

Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have recently been associated with diabetic ketoacidosis (DKA). Initial case reports were largely among patients using SGLT2i off label in the setting of type 1 diabetes and were unusual because of limited associated hyperglycemia (1). More recently, the problem has been specifically noted in patients with type 2 diabetes (2). Meta-analysis of data from initial randomized controlled trials of SGLT2i suggests little risk of DKA (<0.1%) in patients with type 2 diabetes (3).

To better define the scope of the problem in clinical practice, we conducted a search of three academic health care systems’ electronic health records. The study was approved by institutional review boards. Patients were selected from all emergency and inpatient encounters between 1 January 2013 and 30 April 2016 that contained the diagnosis codes for ketosis or acidosis (ICD-9 …
Role of prophylactic regional lymph node radiation therapy on locoregional recurrence in Merkel cell carcinomas.
Authors: Ronan Tanguy, Sophie Oldrini, Laetitia Rangeard, Christian Carrie, Didier Peiffert
Journal: Journal of Clinical Oncology (2015)

e20034 Background: Merkel cell carcinoma (MCC) is a rare primary cutaneous carcinoma of the skin that has a high risk of locoregional and distant spread. The use of adjuvant radiotherapy on primary site after excision depends merely on surgical margins. The efficacy of prophylactic irradiation to regional lymph node is still debated. We studied the impact of adjuvant regional irradiation in terms of local and regional recurrence. Methods: From December 2000 to December 2012, 30 patients were treated with adjuvant radiation therapy after the surgery of cN0 Merkel cell carcinomas in two institutions. Patients had adjuvant radiation therapy to the tumor bed. The prophylactic regional lymph node radiation therapy was done on physician's habit. During the follow-up, the occurrence of local, regional and distant recurrence was observed. Results: The median age was 75 years. The MCC sites were face/head and neck (12 cases, 40%), extremities (17 cases, 57%) and trunk (1 case, 3%). The mean surgical margin was 16 mm (range 0-60 mm). A regional lymph node evaluation was performed by sentinel-lymph node biopsy, lymph node dissection or sole clinical evaluation in both 10 cases (33%). Radiation therapy to the primary bed was delivered with a mean dose of 52 Gy (range 44-60Gy) and for 15 patients (50%) the mean prophylactic dose to regional lymph node was 50Gy (44-60Gy). With a median follow-up of 49 months, 6 recurrences occurred: 2 in the tumor bed and 4 in regional lymph node bed with one case of concomitant distant recurrence. No regional lymph node recurrence occurred when a prophylactic irradiation was performed providing a significant difference in regional recurrence free survival (p = 0,024). Even if regional recurrences had an impact on overall survival (p = < 0,0001), the regional irradiation was not significantly associated with a gain on overall survival (p = 0,76). Conclusions: With all the limitations due to a retrospective study done on two centers, the prophylactic regional lymph node irradiation managed to limit the risk of regional recurrence. This gain on regional control had no impact on overall survival.
Chemotherapy use in stage III colon cancer: A National Cancer Data Base (NCDB) analysis.
Authors: Sumit Dahal, Vijaya Raj Bhatt, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2014)

3576 Background: Adjuvant chemotherapy in stage III colon cancer improves overall survival, however, prior studies have shown that it is underused. We analyzed different factors that may influence its use. Methods: This is a retrospective study of stage III colon cancer patients (n=207,718) diagnosed between 2000 and 2011 in the NCDB. NCDB contains ~70% of new cancer diagnosis from >1,500 American College of Surgeons-accredited cancer programs in the United States and Puerto Rico. Chi-square test was used to determine any difference in characteristics of patients who did or did not receive chemotherapy. Results: 35% of all stage III colon cancer patients did not receive adjuvant chemotherapy. The use of chemotherapy had increased in recent years. Its use was lower in whites, females, patients ≥60 years, patients with one or more comorbidities, non-academic centers and those with medicare insurance, lower education and income levels (all p<.0001; Table). Non-white and uninsured were more likely to be <60 years. Conclusions: This is the largest study to determine the use of chemotherapy in stage III colon cancer. More than one-third did not receive adjuvant chemotherapy, although its use has increased in more recent years. Age was one of the most important determinants of chemotherapy use, which may explain higher rates in non-white and uninsured. In addition to patient characteristics, race, gender and socioeconomic factors influence chemotherapy use. These findings have important implications for health care reform. Chemotherapy use in stage III colon cancer patients. % of cases receiving chemotherapy Treatment facilities Academic hospitals 64 Other hospitals 62 Year of treatment 2000-2002 59 2003-2006 62 2007-2011 64 Age < 60 years 82 ≥ 60 years 55 Gender Male 65 Female 60 Race/ethnicity White 61 Black 65 Hispanics 66 Insurance status Private 77 Not insured 73 Medicaid 70 Medicare 52 Education (% with high school degree) ≤ 69% 61 70-88% 62 > 88% 63 Household Income < $28,000 59 $28,000 - $48,999 62 ≥ $49,000 63 Charlson Comorbidity Score None 67 ≥1 55 Distance traveled to treatment facility < 100 miles 62 ≥ 100 miles 59 P-value significant for all comparison at <0.0001.
Predictive biomarkers of trabectedin (TR) and olaparib (OL) synergism in preclinical models of bone and soft tissue sarcoma (BSTS).
Authors: Ymera Pignochino, Federica Capozzi, Carmine Dell' Aglio, Marco Basiricò, Annalisa Lorenzato, Lorenzo D'Ambrosio, Danilo Galizia, Loretta Gammaitoni, Raimondo Piana, Maria Serena Benassi, Dario Sangiolo, Massimo Aglietta, Giovanni Grignani
Journal: Journal of Clinical Oncology (2014)

10569 Background: TR is a DNA damaging agent as 2nd line-therapy in STS. We speculated that its antitumor activity could be potentiated by a “synthetic lethality” approach targeting key molecules involved in DNA repair. PARP-1 inhibition impedes DNA repair promoting cell death.We tested the antiproliferative effect of PARP inhibitor OL in combination with TR against 20 BSTS cell lines and explored their mechanism of action. Methods: The combination of OL and TR was tested against 20 BSTS cell lines. Drug synergism was evaluated by Calcusyn software. Subcutaneous (s.c) and orthotopic BSTS models were obtained in NOD/SCID mice and tumor growth was monitored by caliper and by in vivoimaging, respectively. DNA repair machinery was studied by realtime PCR, western blot and immunocytochemistry. Silencing of PARP-1 was induced with specific siRNA. Cell cycle, apoptosis and P-H2AX were evaluated by flow cytometry. Damaged DNA was studied by comet assay. Pearson’s correlation, t distribution and p value were calculated for statistical analysis. Results: We observed a strong synergism of TR-OL in 18/20 cell lines reaching significant dose reduction index (5.5-1.001). There is a 15-fold range of sensitivity among BSTS histotypes (Ewing’s sarcoma > liposarcoma > leiomiosarcoma> osteosarcoma > UPS > fibrosarcoma). Synergism is related with increased G2/M cell cycle arrest, apoptosis and DNA damage. The antitumor and antimetastatic effects of TR-OL were confirmed in s.c and orthotopic models, respectively. Real time PCR, western blot and immunocytochemistry analysis demonstrated that PARP-1 expression and activation are higher in responsive cell lines vs. less sensitive ones. To confirm these data we down-modulated PARP-1 with silencing experiments showing a reduced TR-OL synergism (25±2%, p<0.05). mRNA expression analysis of DNA repair machinery in 20 BSTS cell lines showed that PARP-1, RAD51 and BRCA1 are significantly related to synergism. These data were confirmed at protein level in selected experiments. Conclusions: PARP-1, RAD51 and BRCA-1 are predictive of TR and OL synergism in BSTS preclinical models, and could represent good candidate biomarkers to be evaluated in clinical trials.
Phase I trial to assess the safety and pharmacokinetics of afatinib and weekly vinorelbine in patients with advanced solid tumors.
Authors: Antoine Hollebecque, Rastislav Bahleda, Yann Berge, Christophe Massard, Martina Maria Uttenreuther-Fischer, Helene De-Montserrat, Inga Tschoepe, Jean-Charles Soria, Jean-Pierre Delord
Journal: Journal of Clinical Oncology (2012)

3104 Background: Afatinib (A) is an oral, irreversible ErbB Family Blocker with activity in a wide range of tumor cell lines dependent on ErbB signaling. Vinorelbine (VNR) interferes with tubulin polymerization and spindle formation during metaphase. Additive or supra-additive activity of A or EGFR TKI with VNR has been demonstrated in preclinical models. Methods: This dose-escalation Phase I study established the safety profile, MTD and PK of A with i.v. and p.o. VNR using a modified 3+3 design. Eligible patients (pts) were ≥18 years with refractory advanced or metastatic tumors, an ECOG PS 0–1, and adequate organ and bone marrow function. VNR i.v. (25 mg/m 2 )/oral (60 mg/m 2 with escalation to 80 mg/m 2 after 3 weeks) was administered weekly on Days 1, 8, 15 and 22 with escalating oral daily doses of A 20 mg, 40 mg and 50 mg in 28-day treatment courses. Results: The study treated 55 pts: 30 pts for MTD determination and 25 pts in the PK expansion cohort (24 M/31 F), median age 54 years (range 34–72). 28/27 pts were included in the VNR i.v./p.o. cohorts, respectively. Patients had NSCLC, breast, pancreatic (n=13/5/3), head and neck, stomach or colorectal cancer (n=2 each group); 28 pts had other cancers. At 20 mg A, no DLTs occurred in the VNR i.v./p.o. cohorts; whereas, at 50 mg A, 4/6 pts and 3/5 pts experienced DLTs. At 40 mg A and VNR i.v./p.o., 1/6 pts included for MTD determination experienced DLT, as did 7/13 pts and 2/12 pts in the VNR i.v./p.o. PK expansion cohorts, respectively. Main DLTs were diarrhea and febrile neutropenia. Median treatment duration (snapshot date 9 Dec 2011) across all dose groups was 80 days (range 10–687), with 98 and 58 days in the MTD cohorts of VNR i.v./p.o., respectively. Related AEs observed in most patients were diarrhea, asthenia, nausea, vomiting, neutropenia, decreased appetite, mucositis and rash. Five pts had a PR, confirmed in 2 pts. Preliminary PK analyses suggest no drug–drug interaction between A and i.v. VNR. Conclusions: Afatinib in combination with weekly i.v./p.o. VNR is tolerated, with manageable, reversible, target-related side effects and promising signs of clinical activity in heavily pretreated patients. The MTD for A for both combinations is 40 mg daily.
Loss of HER2 positivity after anti-HER2 chemotherapy in HER2-positive gastric cancer patients: Results of GASTric cancer HER2 reassessment study 3 (GASTHER3).
Authors: Seyoung Seo, Min-Hee Ryu, Ji Yong Ahn, Yangsoon Park, Sook Ryun Park, Baek-Yeol Ryoo, Young Soo Park, Gin Hyug Lee, Hwoon-Yong Jung, Yoon-Koo Kang
Journal: Journal of Clinical Oncology (2017)

27 Background: Although discordance of HER2 positivity between primary and metastatic lesions was well known, changes of HER2 positivity after chemotherapy have not been studied in gastric cancer (GC). Methods: A total of 48 HER2-positive advanced GC (AGC) patients who were treated with trastuzumab-containing 1 st line chemotherapy and had paired biopsies at baseline and after progression were enrolled. Scores of HER2 immunohistochemistry (IHC) were reviewed and in situ hybridization (ISH) was conducted when tissues were available. Results: Thirty-nine patients were treated with capecitabine, cisplatin/oxaliplatin, and trastuzumab (XPT) while the other 9 received XPT plus pertuzumab/placebo. Objective response rate (ORR) was 76% (26 out of 34) and median progression free survival (PFS) and overall survival were 8.3 and 16.3 months, respectively. At baseline, HER2 was positive with IHC 2+ and ISH+ in 5 and with IHC 3+ in 43. Loss of HER2 positivity after progression was observed in 14 (28.6%); 10 with IHC 0 or 1+ and 4 with IHC 2+ but ISH- at 2 nd biopsy. HER2 remained positive in the other 34; 4 with IHC2+ and ISH+, and 30 with IHC 3+ at 2 nd biopsy. Applying H-score formula, mean scores decreased from 201 to 170 (Wilcoxon test; p=0.047). HER2 genetic heterogeneity (5% to &lt;50% of tumor nuclei showing a HER2:CEP17 ratio ≥2) was noted only 1 out of 34 ISH-assessable patients (2.9%) at baseline while 7 out of 32 ISH-assessable patients (21.9%) had heterogeneity at 2 nd biopsy. The mean ratio was changed from 6.5 (1.2-15.8) to 5.0 (0.4-15.2) (paired t-test, p=0.019) and all patients with genetic heterogeneity at 2 nd biopsy showed HER2 negative conversion. Among 13 who received 2 nd line T-DM1, 3 showed HER2 negative conversion. Those 3 had no objective response at all and very short PFS (1.2, 1.3 and 3.4 months), whereas the others with stable HER2 status showed 44% of ORR and median PFS of 2.7 (0.4-36.8) months. Conclusions: A substantial portion of initially HER2-positive AGC patients showed HER2 negative conversion with increased HER2 heterogeneity after trastuzumab-containing chemotherapy. Loss of HER2 positivity could be a predicting factor for 2 nd line anti-HER2 treatment.