tbuckley/cabot-search huggingface dataset:
Association of higher total nucleated cell dose with improved survival in patients receiving donor lymphocyte infusion after allogeneic stem cell transplantation.
Authors: Nathan Singh, Anita J. Kumar, Amy Gao, Marlise Rachael Luskin, Noelle V. Frey, Elizabeth O. Hexner, Alison W. Loren, Selina M. Luger, Edward Allen Stadtmauer, David L. Porter, Ran Reshef
Journal: Journal of Clinical Oncology (2015)

7028 Background: Donor lymphocyte infusion (DLI) after allogeneic stem cell transplant is an established therapy for disease relapse. Long-term survival after DLI remains poor, and identification of factors associated with improved outcomes is of significant interest. Methods: We retrospectively analyzed the total nucleated cell (TNC) dose of DLIs in 79 patients (pts) who received un-manipulated DLI at the University of Pennsylvania between 2000-2014. We included pts who received DLI for relapse or falling chimerism, but excluded those who received low dose ( ≤ 0.5x108TNC/kg) for stable mixed chimerism. Multivariable regression analyses were used to evaluate associations between cell dose, survival, best response and GVHD. Classification and Regression Tree (CART) analysis was used to identify optimal cutoff in the TNC dose. Results: Pts received DLI from sibling (61%) or unrelated (39%) donors, and 10% were HLA-mismatched. Median follow-up was 68 months (range 0.33-156.2). Median age was 53 years (21-75), and diseases included AML (47), MDS (15), NHL (8), ALL (2), CML (2), Hodgkin (2), myelofibrosis (2) and myeloma (1). Six pts received DLI for falling chimerism without overt relapse. The best response to DLI was complete response (CR) in 27 of 70 evaluable pts. Any GVHD and severe GVHD developed in 24 of 61 and 15 of 59 evaluable pts, respectively. We found that pts receiving ≥ 1.6x108 TNC/kg had improved six-month (adjusted OR = 0.25, 95% CI [0.07-0.89], p = 0.03), one-year (aOR = 0.16, [0.04-0.77], p = 0.02), and overall survival (aHR = 0.47, [0.27-0.82], p = 0.01). A survival advantage for a higher TNC dose was also significant in the subset of AML and MDS pts (aHR = 0.41, [0.22-0.76], p = 0.005). Higher TNC dose did not correlate with development of any GVHD (aOR = 0.67, [0.22-2.06], p = 0.48) or grade III-IV GVHD (aOR = 0.51, [0.10-2.68], p = 0.43). There were also no significant differences in achieving a CR (aOR = 1.56, [0.40-6.10], p = 0.52). Conclusions: TNC dose of ≥ 1.6x108 TNC/kg correlated with improved survival without an increased risk of developing GVHD, and thus higher target TNC doses should be considered in pts receiving DLI.
Characteristics of high risk breast cancer patients with mutations identified by multiplex panel testing.
Authors: Kara Noelle Maxwell, Brandon Wenz, Bradley Wubbenhorst, Kurt P D'Andrea, Bradley Garman, Benita Weathers, Noah Goodman, Christopher Colameco, Jessica M. Long, Jacquelyn Powers, Jill Stopfer, Angela R. Bradbury, Angela DeMichele, Susan M. Domchek, Katherine L. Nathanson
Journal: Journal of Clinical Oncology (2015)

1511 Background: Multiplex panel testing studies evaluating cancer susceptibility in breast cancer (BC) patients suggest that between 4-11% of BRCA1/2 negative individuals have a deleterious mutation in a high or moderate penetrance gene. The range in mutation positivity is likely due to heterogeneity of the studied patient populations. Methods: We performed targeted, massively parallel sequencing of 795 BRCA1/2 negative BC patients in a research laboratory and analyzed 18 cancer susceptibility genes.Three high risk groups were studied: multiple primary cancers (MP, n = 315), early onset breast cancer (EOBC, n = 323), and familial breast cancer (FBC, n = 415). MP was defined as at least one BC and at least one other primary malignancy excluding non-melanoma skin cancer, EOBC was defined as BC under age 40, and FBC was defined as at least three first to third degree relatives with BC under age 75. Results: Overall, 78 patients (10%) were found to have a deleterious mutation. Mutations were found most commonly in CHEK2 (n = 32, 4.0%), ATM (n = 14, 1.8%), TP53 (n = 10, 1.3%), and MSH6 (n = 4, 0.5%). One to two patients each had deleterious mutations in BARD1, BRIP1, CDKN2A, MRE11A, MSH2, NBN, PALB2, PTEN, PMS2, and RAD50; no mutations were identified in CDH1, MLH1, or STK11. Deleterious mutations were more common in MP patients versus FBC patients without MP (12% versus 7%, p = 0.04) but not EOBC patients without MP (10%, p = NS). CHEK2 and MSH6 mutations were more common in MP versus non-MP patients (6% vs 3% and 1.3% vs none, respectively, p = 0.05) whereas ATM mutations were more common in non-MP patients (0.6% vs 2.5%, p = 0.05). The most common cancers in mutation carriers were a second primary breast cancer, sarcoma, melanoma, hematological malignancies, ovarian, thyroid and uterine cancer. There was a similar distribution of malignancies in MP mutation carriers versus non-mutation carriers. Sequencing is ongoing for 276 additional MP patients to validate these findings. Conclusions: Our results indicate that multiplex panel testing may find a higher rate of mutations in patients with MP malignancies as compared to patients with FBC alone; however, the type of second primary malignancy may not be predictive of mutation status.
Clinical and pharmacodynamic (PD) results of a phase I trial with AMP-224 (B7-DC Fc) that binds to the PD-1 receptor.
Authors: Jeffrey R. Infante, John D. Powderly, Howard A. Burris, Muaiad Kittaneh, Jessica Houston Grice, James F Smothers, Sara Brett, Margaret E. Fleming, Rena May, Shannon Marshall, Martin Devenport, Stanley Pillemer, Drew M. Pardoll, Lieping Chen, Solomon Langermann, Patricia LoRusso
Journal: Journal of Clinical Oncology (2013)

3044 Background: PD-1/B7-H1 (PD-L1) axis blockade can reinvigorate T cells, and overcome tumor immune evasion of multiple tumor types. AMP-224 is the first recombinant B7-DC-Fc fusion protein tested in patients that binds to and modulates the PD-1 axis through a unique MOA. The MoA hypothesis for AMP-224 is depletion of PD-1high expressing T-cells representing exhausted effector cells. Subsequent replenishment of the T-cell pool with functional T-cells may restore immune function. Methods: Patients with advanced solid tumors received low dose CTX on Day 0, followed by AMP-224 (IV infusion) on Days 1 and 15 of each 28-day cycle in doses ranging from 0.3 to 30 mg/kg. Blood samples were assessed serially for changes in lymphocyte subsets, PD-1 HI T cells and T cell effector function. IHC staining of paired biopsies for B7-H1, CD8, PD-1, CD4 and FoxP3 was performed to assess immunological status of the tumor at baseline and following treatment and then relative to peripheral readouts. Results: 42 patients (83% melanoma) were treated with varying doses of AMP-224 [0.3 mg/kg (n = 6); 1 mg/kg (n=4); 3 mg/kg (n = 4); 10 mg/kg (n = 22); 30 mg/kg (n = 6)]. Infusion reactions were common (69% across dose cohorts) and occurred mostly at higher doses (86% at the 10 mg/kg dose). No drug-related inflammatory adverse events were identified contrary to PD-1 blocking antibodies. Fresh pre-treatment biopsies were collected from 33/42 (78.5%) patients and paired biopsies have been collected thus far from 19/36 (52.7%) patients on study. 31% of baseline tumors were B7-H1+. Several PD readouts in the periphery showed reductions in PD-1 HI cells and emergence of a functional T cell response (increases in IFNg+, TNFa+, IL-2+ CD4 and CD8 T cells) in individual patients where partial response, stable disease, and mixed responses were seen. Conclusions: Data from peripheral readouts is consistent with hypothesized AMP-224 MoA. B7-H1+ was not always predictive of functional response to AMP-224 immunotherapy. Comprehensive PD readouts and evaluation of PK/PD relationships will be presented and may ultimately predict restoration of immune competence even in the presence of initial disease progression. Clinical trial information: NCT01352884.
Endocrine therapy adherence, side effects, and risk perception among racially diverse breast cancer patients.
Authors: Stephanie B. Wheeler, Caitlin C. Murphy, Katherine Elizabeth Reeder-Hayes, Jo Anne Earp, Lisa A. Carey, Andrew Olshan
Journal: Journal of Clinical Oncology (2015)

6560 Background: Differential endocrine therapy (ET) use by race may contribute to disparities in breast cancer outcomes. The goal of this study was to examine racial variation in ET adherence, side effect experiences and perceptions about recurrence risk. Methods: We surveyed 1,507 stage I-III breast cancer patients using a mailed, self-administered questionnaire at 18-months post-diagnosis as part of the Carolina Breast Cancer Study Phase III (CBCS-III), a population-based, prospective cohort study that recruited participants via rapid case ascertainment in 2008-2013. Non-adherence was defined as not taking ET pills every day as prescribed, discontinuing ET pills, or missing > = 3 pills in the past 14 days. Bivariable analyses identified differences in adherence, side effect experiences and risk perceptions by race. Results: Overall, 994 women in our sample were prescribed ET; of these, 43% were African American (AA). The mean age at diagnosis was 54, and the majority were diagnosed with stage 1 (50%) or 2 (37%) disease. Overall, 19% were classified as non-adherent; 22% of AA women were non-adherent (vs.16% of white women, p = 0.014). Compared to white women, AA women more often forgot to take ET when traveling away from home (25% vs. 16%, p = 0.035); felt sticking to their ET treatment plan was difficult (25% vs. 14%, p < 0.0001), had trouble remembering to take their ET pills (24% vs. 13%, p = 0.0001), reported cost-related non-adherence (16% vs. 7%, p = 0.0001), and experienced bothersome side effects (25% vs. 18%, p = 0.0033). AA women more often than white women reported experiencing the following side effects frequently in the past 7 days: hot flashes (55% vs. 45%, p = 0.0017), night sweats (41% vs. 30%, p = 0.0002), breast sensitivity (24% vs. 16%, p = 0.0015), and joint pain (46% vs. 38%, p = 0.011). More AA women reported believing there would be no change in their recurrence risk if they stopped ET (20% vs. 8%, p < 0.0001). Conclusions: These data highlight important racial differences in adherence behaviors, side effect experiences and perceptions of recurrence risk. Culturally-tailored interventions that can help women taking ET to better manage side effects and reframe risk perceptions may better motivate adherence.
Junior doctor who lacked basic knowledge and skills is struck off
Authors: Clare Dyer
Journal: BMJ (2017)

A junior doctor has been struck off after a medical practitioners tribunal concluded that he lacked even the basic clinical knowledge and skills essential to any physician.

Sripathy Subramanian, who qualified in Romania in 2013, was accused of a lengthy catalogue of basic failings relating to two periods in 2015, when he first did a clinical attachment at Warrington Hospital and then worked as a locum foundation year 1 (FY1) doctor at Sandwell General Hospital in West Bromwich.

His work there so alarmed his employer that after a week he was demoted to another clinical attachment. After three months of that, Sandwell and West Birmingham Hospitals Trust terminated his employment and reported its concerns …
Phase I/II study of weekly LOC-paclitaxel (LOC-pac) injection in patients (pts) with metastatic melanoma (MM).
Authors: Rodabe Navroze Amaria, Wen-Jen Hwu, Sapna Pradyuman Patel, Kevin Kim, Nicholas E. Papadopoulos, Patrick Hwu, Agop Y. Bedikian
Journal: Journal of Clinical Oncology (2014)

9053 Background: LOC-paclitaxel (LOC-pac) is a covalent conjugate of paclitaxel linked to an omega-6 fatty acid designed to enhance uptake of paclitaxel into tumors leading to higher intra-cellular drug concentrations and potentially enhance anti-tumor activity of paclitaxel. This is a first in human, phase I, open label, dose-escalating clinical study of LOC-pac administered weekly in patients (pts) with metastatic melanoma (MM). Methods: Adult MM pts who were refractory to prior systemic therapy or were ineligible for other therapy of higher priority with normal organ function and ECOG PS 0-2 were eligible for this trial. Patients with baseline peripheral neuropathy over grade 1, prior exposure to taxane chemotherapy, hypersensitivity to cremaphor or with serious concurrent medical conditions were excluded. LOC-pac was given intravenously over 1 hour on days 1, 8, 15, 22 and 29 every 42 days. LOC-pac dosing was escalated from 100mg/m2 to 1000mg/m2 after safety of the prior dose level was confirmed in cohorts of 3 pts each. Responses were assessed by RECIST every 6 weeks. Toxicity was evaluated using CTCAE v3. Results: A total of 33 patients were treated in phase I. Median age was 69 years, median ECOG PS was 0 and 79% of enrolled patients were male. Tumor stages were IIIc/M1a/M1b/M1c in 3/3/7/20 patients respectively. The MTD is 1000mg/m2 and the recommended phase 2 dose is 880mg/m2. DLTs were primarily related to infection including pneumonia and pyelonephritis. Other common toxicities included fatigue, nausea, vomiting, pruritus, peripheral neuropathy and stomatitis. No alopecia or nail changes were appreciated. Of the 33 evaluable patients for best response, 16 had PD, 14 had SD, and 3 had PR. All 3 PRs were confirmed. One patient with PR completed 8 cycles of therapy and then underwent metastectomy showing no viable residual tumor and remains without evidence of disease over 144 weeks. Conclusions: Our phase I study demonstrated that LOC-pac is safe and is associated with milder toxicities including neuropathy, nail changes and alopecia when compared with paclitaxel. An ongoing dose expansion study will further define the anti-tumor activity of LOC-pac in MM. Clinical trial information: NCT01039844.
Changes in the tumor microenvironment associated with transformation in follicular lymphoma.
Authors: Jacob Paul Smeltzer, Jason Michael Jones, Steven Ziesmer, Deanna Grote, Zhi Zhang Yang, Anne Novak, Bing Xiu, Kay Ristow, Stephen Maxted Ansell
Journal: Journal of Clinical Oncology (2013)

8538 Background: Follicular lymphoma (FL) is a heterogeneous disease with a variable prognosis. Transformation to an aggressive lymphoma is associated with a poor prognosis. Previous studies have identified tumor microenvironment cells such as CD68+ macrophages, PD-1+ and FOXP3+ cells as prognostic in FL. However, results have been conflicting and infrequently address the risk of transformation. In this study we analyzed various components of the microenvironment and their association with transformation. Methods: Patients with FL that later transformed were identified through Mayo Clinic lymphoma database. Tissue specimens at diagnosis were stained with CD68, CD11c, CD21, CXCL13, FOXP3, PD-1 and CD14 and characterized by pattern of location and semi-quantitative cell content. Time to transformation (TTT) and overall survival (OS) were assessed by Kaplan-Meir analysis. Significant variables were further analyzed by cox proportional hazards model. Results: 58 patients were included with a median TTT of 4.7 years (range, 0.4-20). Presence of CD14+ cells vs absence and their location (follicular vs non-follicular) were associated with shorter TTT (4.5 vs 6.2 yrs., p=0.037 and 3.8 vs 5.9 yrs. p= 0.027, respectively). The quantity of PD-1+ cell content was not associated with TTT or OS. However, localization of PD-1 to the follicle compared to diffuse was associated with a longer TTT (6.1 vs 3.6 yrs. p=0.033) and superior OS (9.7 vs 4.6 yrs. p=0.009). On multivariate analysis, the pattern of CD14 and PD-1 staining remained significantly associated with shorter TTT (Table). Conclusions: In follicular lymphoma, a diffuse pattern of PD-1+ cells is associated with inferior TTT and OS. CD14+ cells localized to the follicle is associated with a shorter TTT. After accounting for FLIPI score, both these factors remained significant. These results identify two independent predictors of the rate of transformation in follicular lymphoma and suggest it is location rather than quantity of CD14+ or PD-1+ cells that influence outcomes. [Table: see text]
Never Stop Caring—Reply
Authors: Dale G. Wilson, Gregory L. Moneta
Journal: JAMA Surgery (2017)

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Circulating ProGRP and tissue thyroid transcription factor 1 (TTF1) in small-cell lung carcinoma (SCLC) limited versus extensive stages.
Authors: Haim Biran, Marina Perelman, Benny Nisman, Sayeh Ben-Arieh, Nir Peled, Jair Bar, Amir Onn, Victoria Doviner, Tamar Peretz
Journal: Journal of Clinical Oncology (2014)

e18555 Background: SCLC stage is classified as limited (LD) or extensive (ED). ED is incurable while LD patients may survive. Gastrin-releasing peptide (GRP), an SCLC autocrine growth factor, assayed as Pro-GRP, is a precursor of the neuropeptide hormone and already is a documented SCLC circulating marker. SCLC biopsies frequently express TTF1. Both factors,GRP and TTF1, are active in embryonal development of central nervous system.Aim: To examine the correlation between proGRP and TTF1 positivity in patients with LD and ED SCLC. Methods: 52 SCLC patients, were eligible for analysis, 21 LD and 31 ED stages. ProGRP was assayed in plasma by Abbott ARCHITECT system. TTF1 paraffin-embedded biopsies immunostaining , was performed using Acris antibody kit. Results: ProGRP was significantly higher in ED, compared to LD patients in all tested parameters: mean, median, IQR; 7437, 2183, 208-11190 (ED); 1667, 171, 92-915 (LD), respectively. P=0.013, Mann- Whitney test. TTF1 was positive in 15/21 LD (71.4%), vs.27/31 (87%) of ED pts (87%) ( P=0.1, Fisher's exact test), thus showing a trend correlating TTF1 and disease extent. SCLC patients were TTF1+ in 42/52 while negative in 10.With all tested parameters TTF1 positivity was associated with higher ProGRP titer: mean, median, IQR: 6282,1381, 305-8844 in TTF1(+), compared to 171, 80, 36-273 in TTF1 (-): P=0.0001, Mann-Whitney test. Conclusions: This study shows a direct relationship between growth factors (GRP/ProGRP and TTF1) and SCLC extent. Moreover, a strong correlation between the tested neuropeptide and TTF1 was observed. Further research is warranted to examine potential role(s) of these factors in designing efficient strategies for SCLC therapy.
Randomized phase III trial of customized adjuvant chemotherapy (CT) according BRCA-1 expression levels in patients with node positive resected non-small cell lung cancer (NSCLS) SCAT: A Spanish Lung Cancer Group trial (Eudract:2007-000067-15; NCTgov: 00478699).
Authors: Bartomeu Massuti, Manuel Cobo, Jose Manuel Rodriguez-Paniagua, Ana Isabel Ballesteros, Teresa Moran, Ricardo Arrabal, Jose Luis Gonzalez Larriba, Isidoro Barneto, Yat Wah Pun, Javier De Castro, Santiago Ponce Aix, Carlos Baamonde, Miguel Angel Munoz, Guillermo Lopez-Vivanco, Juan-Jose Rivas, Dolores Isla, Rafael Lopez, Jose Miguel Sanchez, Jose Sanchez-Paya, Rafael Rosell
Journal: Journal of Clinical Oncology (2015)

7507 Background: Postop platinum-based CT improves outcomes in resected NSCLC with N+ (St II-IIIA). Analysis of expression of genes involved in DNA repair could be used to individualize optimal CT. BRCA1 may act as a differential regulator of response to cisplatin (Cis) and antimicrotubule agents. Methods: Phase III multicenter trial. After surgery, patients (p) with St II and III were random 1:3 to control arm (Cis-Docetaxel) or to experimental arm with treatm. according BRCA1 express. levels (low : Cis-Gemcitabine; intermediate : Cis-Doc; high: Doc alone). Stratification factors: N1 vs N2; age < or > 65 y; non-squamous vs squamous (Sq) ; lobectomy vs pneumonectomy). Planned PORT in N2. Primary end-point OS. Secondary: DFS, toxicity, compliance, recurrence pattern. Statistical hypothesis: 20% increase 5y surv. control group (45%). Results: From June 2007 to May 2013, 591 p were screened and 500 of them were random: 108 in control, 392 experimental (110 p Cis-Gem, 127 Cis-Doc and 110 Doc alone). No disbalance between arm for prognostic factors: Median age 64 y; 79% males, 21% females; 43% Sq, 49% Adeno; pneumonectomy 26%; N1 58%, N2 48%; smoking habit: 57% former, 32% current, 11% never. Median tumor size 4.4 cm (0.8-15.5). Median mRNA BRCA1 levels 15.78 (0.73-132). Mean BRCA1 levels 6.95 Adeno vs 20.29 Sq (p < 0.001). Median f-u 30 months (0-79 m). With a cut-off of March 15th median survival has not reached both arms and no significant diffs. have been seen for OS with HR 0.866 (p = 0.45) or DFS (HR 1). In exper. group HR for OS was 0.842 (NS) comparing low with high-BRCA1 levels. In p with high-BRCA1 levels control treatm. (Cis-Doc) was superior to exper. (Doc) with HR 1.24 (NS). For p receiving all planned treatm. HR is 0.63 with p = 0.043 compared with p not able to complete treatm. P with Sq histology showed a longer DFS (HR 0.73; p = 0.05) but without diff. in OR (HR 1). Conclusions: BRCA1 based adjuvant CT does not improve OS. In p with high-BRCA1 levels Doc alone is inferior to Cis-Doc. Full dose of planned treatm. confers a survival advantage, however, longer follow-up is still warranted. Clinical trial information: 00478699.