tbuckley/cabot-search huggingface dataset:
Interactions and relevance of blast percentage and treatment strategy among younger and older patients with acute myeloid leukemia (<scp>AML</scp>) and myelodysplastic syndrome (<scp>MDS</scp>)
Authors: Courtney D. DiNardo, Guillermo Garcia‐Manero, Sherry Pierce, Aziz Nazha, Carlos Bueso‐Ramos, Elias Jabbour, Farhad Ravandi, Jorge Cortes, Hagop Kantarjian
Journal: American Journal of Hematology (2015)

Acute myeloid leukemia (AML) is defined as ≥20% myeloblasts, representing a change from original guidelines where ≤30% blasts were considered as myelodysplastic syndromes (MDS), and 20-29% blasts classified as refractory anemia with excess blasts in transformation (RAEB-T). Whether the diagnostic bone marrow blast percentage has current value with regards to patient prognostication or identification of optimal treatment strategies is unclear. We retrospectively studied 1652 treatment-naïve adults with MDS or AML and ≥10% blasts from January 2000 to April 2014. Patients with 20-29% blasts were more similar to MDS patients in terms of advanced age, increased frequency of poor-risk cytogenetics, lower WBC count, and less frequent NPM1 and FLT3-ITD mutations. Median overall survival of MDS and RAEB-T were similar, 16.0 and 16.0 months, compared to 13.5 months for AML with ≥30% blasts (P = 0.045). Multivariate analysis showed inferior survival with increased age (HR 1.81 age 60-69, HR 2.68 age ≥70, P < 0.0005); poor-risk cytogenetics (HR 2.25, P < 0.0005); therapy-related disease (HR 1.44, P < 0.0005); and markers of proliferative disease including WBC ≥25 × 10(9) /L (HR 1.35, P = 0.0003), elevated LDH count (HR 1.24, P = 0.0015), and peripheral blasts (HR 1.25, P = 0.004). Among younger patients (≤60 years), intensive AML-type therapy resulted in similar outcomes regardless of blast percentage, suggesting this to be optimal therapy in this context. Among older patients (≥70 years), patients with 20-29% blasts had similar outcomes to patients with <20% blasts, and better than those with ≥30% blasts. In addition, among older patients, epigenetic therapy provided at least equivalent outcome to intensive chemotherapy.
A pilot study of a PANVAC-V and PANVAC-F in patients (pts) with metastatic carcinoma
Authors: J. Gulley, P. M. Arlen, W. L. Dahut, K. Tsang, J. Jones, M. Pazdur, E. Jones, H. L. Kotz, J. Schlom
Journal: Journal of Clinical Oncology (2006)

2512 Background: The vast majority of carcinomas express either MUC-1 or CEA. Preclinical and clinical studies have demonstrated that induction of T-cell responses directed against CEA and MUC-1 can lead to anti-tumor activity without toxicity. Two novel vaccines have been developed: (a) PANVAC-V (V) a recombinant vaccinia virus containing CEA and MUC-1 with modified agonist epitopes and 3 costimulatory molecule transgenes, and (b) PANVAC-F (F) a similar recombinant fowlpox virus. Methods: This pilot study enrolled 25 pts with metastatic carcinoma who had progressive disease after chemotherapy. Pts received V priming followed by F boosts every 2 weeks × 3 then monthly with restaging scans every 2 months while on study. All vaccines were given with sargramostim at the vaccine site. The primary endpoint was safety. Class I and class II immune responses to CEA were analyzed. Class I responses were assayed by ELISPOT, intracellular cytokine, and tetramer binding; and class II responses were assayed by ELISA using CEA protein and class II peptides. Results: Treatment was well tolerated with 135 cycles given. Only one grade 3 toxicity (syncope during a flu-like illness) was possibly related to vaccine. Apart from injection site reactions, only 9 cycles (7%) were associated with transient grade 2 toxicity (generally flu-like syndromes). Class I and class II immunologic responses were demonstrated. A pt with metastatic breast cancer and 5 large liver metastasis had a 24% decrease in unidimensional measurement of disease for 6 months. A pt with metastatic gastric cancer had stable disease for 5 months. Furthermore, a pt with metastatic clear cell ovarian cancer s/p chemotherapy had complete disappearance of large volume, symptomatic ascites accompanied by marked improvement in the appearance of mesenteric stranding and a CA-125 reduction from 281 U/mL to continued sustained normal values (&lt; 20 U/mL). Conclusions: This vaccine can be given safely and can generate therapy specific immunologic responses. In addition 1 pt with metastatic ovarian cancer had a dramatic clinical response. Based on this, we have initiated a pilot study specifically for ovarian cancer pts to gain more information on which to base a large clinical endpoint trial. No significant financial relationships to disclose.
Correlation of serum interleukin-6 (IL-6) levels with immunohistochemical p65/nuclear factor-κB (NF-κB) expression and prediction of the clinical outcome of hormone-independent prostate cancer patients (HIPC) treated with docetaxel (D)
Authors: J. Domingo-Domenech, A. Martinez-Fernandez, X. Garcia-Albeniz, P. Fernandez, X. Filella, P. Gascon, B. Mellado
Journal: Journal of Clinical Oncology (2007)

5075 Background: We have recently reported that NF-κB/IL-6 was linked to D response in human prostate cancer cells. In this study we investigated the clinical significance of IL-6 serum levels in HIPC pts treated with D and the correlation between serum IL-6 levels and p65/NF-κB tissue expression. Methods: Pts with HIPC treated with D were prospectively tested for IL-6 levels by ELISA before chemotherapy. In patients with available specimens of hormone-independent tumor p65/NF-κB was determined by immunohistochemistry. PSA response to D, time to progression and survival were analyzed. Results: Sixty pts were included. Median follow-up time was 29.3 (5.3–55.47) months. Median time to D progression was 4.2 (0,6–15.1) months and median survival was 10.1 (1.6- 47.1) months. Median baseline IL-6 were 16 pg/ml (range 0–156). Pts that responded to D had median IL-6 of 15.1±3.9 pg/ml and patients that did not respond had median IL-6 of 34.7±6.5 (p=0.009). IL-6 correlated with the number of bone metastasis (r=0.39, p=0.002), LDH levels (r=0.53, p&lt;0.0001) and inversely with time to PSA progression (r=-0.65, p&lt;0.0001) and survival (r=-0.61, p&lt;0.0001). In the multivariate analysis IL-6 were an independent prognostic factor for time to PSA progression HR 1.026 (CI95% 1.013–1.046) and survival IL-6 levels HR 1.022 (CI 95% 1.006- 1.038, p=0.008). HIPC tissue samples from 12 pts were assessed for p65/NF-κB expression. All tissue samples showed cytoplasmatic and nuclear staining. Median percentage of nuclear p65/NF-κB stained cells was 15% (range 5–45%). P65/NF-κB nuclear staining showed correlation with serum IL-6 levels (r=0.719, p=0.009). Patients with low serum IL-6 levels (= 16 pg/ml) had a median % of nuclear p65/NF-κB staining of 5.4±2.5% and patients with high IL-6 levels had a median % of nuclear p65/NF-κB staining of 30.2±4.9% (p=0.001). Conclusions: High IL-6 serum levels were associated to a worse survival in HIPC pts treated with D. Our data suggest that the determination of serum IL-6 levels may serve as a surrogate marker of NF-κB activity in hormone-independent prostate cancer tumor and may be useful to select patients for NF-κB targeted therapy. No significant financial relationships to disclose.
Initial results of a phase II study of biweekly pemetrexed and gemcitabine in patients with advanced NSCLC
Authors: A. Dudek, T. Larson, M. McCleod, D. J. Schneider, J. E. Dowell, Z. Ye, J. Cunneen, M. Monberg, F. Tai, C. K. Obasaju
Journal: Journal of Clinical Oncology (2006)

7128 Background: Pemetrexed (P), a multi-targeted antifolate, is synergisitic with gemcitabine (G) in preclinical models. A phase I study examining a biweekly schedule established a recommended phase 2 dose of G 1500 mg/m 2 followed by P 500mg/m 2 . Methods: Patients with Stage IIIB (with pleural effusion) or IV NSCLC, ECOG PS of 0 or 1, no prior systemic chemotherapy, immunotherapy, or biological therapy were enrolled. G was infused over 30 minutes, followed immediately by P given intravenously over 10 minutes once on day 1 every 14 days. Cycles were repeated until 12 treatments or progressive disease. All patients received folic acid, vitamin B12 and steroid prophylaxis. Results: Data on 53 patients (29 male, 24 female) are currently available. Median age: 64 (range: 35, 80), ECOG performance status 0:1 = 38%:60%, Stage IIIB:IV = 19%:81%. Three hundred twelve cycles of treatment were administered with 14 dose reductions (26.4%); median number of doses was 5 for both G and P, and median dose intensity was 98.05% for both G and P. Response data included 1 complete response (1.9%), 14 partial responses (26.4%), 24 stable diseases (45.3%), and 10 progressive diseases (18.9%), with a response rate of 28.3% (95% CI: 16.8–42.3%). Patient-based Grade 3/4 hematologic events included febrile neutropenia (9.4%), neutropenia (28.3%), and thrombocytopenia (1.9%). Grade 3/4 non-hematologic events included fatigue (22.6%), dyspnea (7.5%), dehydration (7.5%), diarrhea (5.7%), constipation (3.8%), and pneumonia (1.9%). Preliminary median survival was 7.8 months (95% CI: 6.0–10.8) with 43.4% patients censored and median TTPD was 4.6 months (95% CI: 2.8–6.1). Conclusion: Biweekly G and P appear to be well tolerated in advanced NSCLC. A clinical benefit rate (ORR + SD) of 73.6% indicates activity in patients with advanced NSCLC. The dose intensity for biweekly G and P is higher than a previously reported 6-cycle, 21-day regimen with median dose intensity of 83.2% for P and 82.2% for G (West, et al. Proc ASCO 2005; 7117). [Table: see text]
Obesity in COPD, how should it be managed? - The effect of weight loss and resistance training in obese COPD patients
Authors: Vanessa McDonald, Peter Gibson, Hayley Scott, Penny Baines, Michael Hensley, Jeff Pretto, Lisa Wood
Journal: European Respiratory Journal (2014)

Obesity is a known risk factor for poor health outcomes, but paradoxically in COPD it is associated with improved survival and lung function. Weight loss can lead to loss of not only fat, but also skeletal muscle mass.  Aim: To determine if weight reduction, combined with resistance training, would reduce inflammation and improve clinical outcomes in obese COPD.  Method: In a before-after clinical trial, obese (BMI>30kg/m 2 ) COPD patients (n=36) received a 12 week weight reduction program involving meal replacements, dietary counselling and resistance training. Patients were reviewed face to face by a dietician and physiotherapist every 2 weeks.  Results: 26 participants completed the intervention. The mean (SD) age was 67.9 (6.5) years, 61% were male, and mean FEV 1 %predicted was 63.3 (20.7). Mean BMI was 36.5kg/m 2  (4.6) at baseline and reduced by 2.5kg/m 2  (p  Conclusion: In obese COPD patients, dietary energy restriction coupled with resistance strength training results in clinically significant improvements in BMI, exercise tolerance and health status, whilst preserving skeletal muscle mass. Importantly, this intervention resulted in an improved prognostic score, but longer term follow up is required. This novel study provides a framework for development of guidelines and in guiding future research.
IMCT-21UPDATES ON PHASE 1B/2 COMBINATION STUDY OF THE IDO PATHWAY IHIBITOR INDOXIMOD WITH TEMOZOLOMIDE FOR ADULT PATIENTS WITH TEMOZOLOMIDE-REFRACTORY PRIMARY MALIGNANT BRAIN TUMORS
Authors: Yousef Zakharia, Howard Colman, Frank Mott, Rimas Lukas, Nicholas Vahanian, Charles Link, Eugene Kennedy, Ramses Sadek, David Munn, Olivier Rixe
Journal: Neuro-Oncology (2015)

BACKGROUND: Indoleamine 2, 3-dioxygenase (IDO) is a key immune-modulatory enzyme within the IDO Pathway that inhibits CD8+ T cells and enhances the suppressor activity of Tregs. IDO is expressed in 50 to 90% of glioblastoma (GBM), and this high expression correlates with poor prognosis. IDO pathway inhibitors such as indoximod can improve anti-tumor T cell response slowing the tumor growth in vivo. We have demonstrated a synergistic effect of indoximod when combined with temozolomide (TMZ) and radiation in a syngeneic orthotopic brain tumor model. The purpose of this study is to determine the safety and preliminary efficacy of indoximod in combination with TMZ in recurrent refractory malignant brain tumors. METHODS: After progression on TMZ, patients are treated with indoximod (1200 mg BID orally) combined with a standard fixed dose of TMZ (150mg/m2x5 days). In the phase 2 expansion, patients are enrolled into 3 cohorts: 2a: indoximod with TMZ, 2b: indoximod with TMZ and bevacizumab (after progression on bevacizumab), 2c: indoximod with TMZ in conjunction with stereotactic radiosurgery in selected patients. Indoximod is administered for 28 days of each treatment cycle. RESULTS: 30 patients of a planned 105 are enrolled of which 12 patients completed the phase 1b cohort with no DLTs. The ready for phase 2 dose was 1200mg BID. 4 patients in phase 1b remain on study, the longest for 15 months. Best responses to date in the phase 1b component include one patient demonstrating an ongoing PR at 15 months per RANO criteria and SD in 4 patients lasting between 4 and 11 months. No severe AEs or change in TMZ dosing due to indoximod addition were documented. CONCLUSIONS: The phase 1b part has been successfully concluded with encouraging preliminary observations. Enrollment into the phase 2 portion is ongoing. Updates will be presented at the meeting. NCT02052648.
Loss of human epidermal growth factor receptor 2 (HER2) expression in HER2-overexpressing esophagogastric (EG) tumors treated with trastuzumab.
Authors: Yelena Yuriy Janjigian, Jamie Cathleen Riches, Geoffrey Yuyat Ku, Tooba Imtiaz, Marinela Capanu, Joanne F. Chou, David Paul Kelsen, David H. Ilson, Michael F. Berger, Efsevia Vakiani
Journal: Journal of Clinical Oncology (2015)

63 Background: Trastuzumab-based therapy is the standard therapeutic approach for patients with metastatic HER2+ esophagogastric (EG) tumors. While trastuzumab prolongs survival in this population, responses are rarely complete and resistance invariably develops. Loss of HER2 and presence of co-occurring molecular alterations may impact the efficacy of HER2 targeted agents in second line setting. Methods: We reviewed clinical and pathologic data of patients (pts) with metastatic HER2+ (IHC 3+ or FISH &gt;2.0) EG adenocarcinoma undergoing trastuzumab/chemotherapy treatment at MSKCC. Samples with ample tissue were analyzed using an on-site 341 cancer-associated gene bait capture, next generation sequencing (NGS) assay. When available, biopsy at the time of disease progression on trastuzumab was tested for HER2 by IHC and FISH. Results: Eighty four pts with Stage IV HER2+ EG adenocarcinoma (57 IHC 3+, 27 IHC2+/FISH+) treated with trastuzumab with chemotherapy. Median progression free survival on 1 st line trastuzumab therapy 9.4 months (mos) [95%CI: 6.9-13.3 mos]. Median overall survival 20.3 mos [95%CI: 14.7-22.4 mos]. Post-trastuzumab biopsy available in 23 of 84 (27%) pts, of those 35% (8 of 23) lost HER2 positivity (4-IHC 0, 4 FISH negative). NGS performed on 24 of 84 (28%) samples. Alterations were observed in EGFR (13%), TP53 mut (92%), cell cycle mediators such as cyclin dependent kinases (42%) and the phosphoinositide 3-kinase/AKT/mTOR axis (21%). Conclusions: Loss of HER2 expression occurs in patients with HER2+ EG cancer treated with trastuzumab and presents a possible mechanism for trastuzumab resistance. Our data suggest the need for repeat biopsies to accurately determine appropriate use of second-line HER2 directed therapy.
The self in its social context: Why resilience needs company
Authors: Hans IJzerman, Siegwart Lindenberg
Journal: Behavioral and Brain Sciences (2015)

Abstract In their target article, Kalisch et al. explicate an appraisal-based model to explain how people bounce back from stress. We posit that for their model, it is crucial to understand the begin-state φ (the “self”) – a state that is shaped by early social thermoregulation and through the social network.
Morphologic features associated with mucin and carbohydrate antigens in colorectal cancer (CCR).
Authors: M. V. Croce, A. Zwenger, A. Segal-Eiras, M. Rabassa, J. Iturbe, G. Grosman, B. A. Leone, C. T. Vallejo
Journal: Journal of Clinical Oncology (2010)

e14129 Background: Different morfologic features (MF) are associated with a poor prognosis. The aim of this research was to relate MF with antigenic expression. Methods: 90 primary CCR tumor samples (69% were colonic and 31% rectal cancer), 64 lymphatic nodes (LN) and 22 control samples (adenomas and normal colorectal mucosa). MF were: localization, type, extent of local invasion, histologic and nuclear grade, vascular and lymphatic invasion and metastatic nodes (N+). Antigens studied were: MUC2, MUC1, MUC5AC, CEA, beta-catenin; carbohydrate antigens: Lewis x (Lex), sialyl Lewis x (sLex), Lewis y (Ley), sialyl Lewis a (sLea) and Tn hapten. Standard haematoxilyn/eosin and immunohistochemistry (IH) was performed. Positive response was evaluated by means of frequency analysis (p < 0.05). A reactivity index (RI) was calculated as intensity (I) x percentage of positive area (A); RI values varied from 0-12; low (0-6) and high (7-12). Intensity, percentage of positive area, IH pattern and RI were analyzed employing Chi-Square test and ANOVA (p < 0.05). Results: 65% corresponded to pure adenocarcinoma, 23% with mucinous component, 12% pure mucinous. Local invasion was detected: muscular in 96%, subserosal in 16%, serosal in 7% and fat in 37% while 31/64 (48%) LN showed metastatic invasion. Antigenic expression: CCR samples expressed MUC2 in 52% of cases; MUC1, 94%; MUC5AC, 14%; CEA, 93%; beta-catenin, 98 %; Lex, 74%; sLe x, 66%, Ley; 91%; sLea, 90% and Tn, 41%. N+ expressed MUC2, 30%; MUC1, 89%; MUC5AC, 19%; CEA, 80%; beta-catenin, 83%; Lex, 69%; sLex, 72%; Ley, 75%; sLea, 86% while Tn, 44%. A positive significant correlation was found between tumor type and antigenic expression: pure adenocarcinoma and CEA, adenocarcinoma with mucinous component and sLea and beta-catenin, pure mucinous carcinoma and Tn hapten and MUC2. Moreover, a positive tendency was found between muscular invasion and Ley and sLex while a positive significant correlation was found between well differentiated tumors and CEA and beta-catenin; a negative significant correlation between nuclear grade and beta-catenin. Conclusions: This study revealed correlations among antigenic expression and MF that may be important considering CCR patient prognosis. No significant financial relationships to disclose.
Coaching intervention as a strategy for enhancing accrual to phase I/II clinical trials
Authors: P. M. Fracasso, M. S. Walker, K. J. Mathews, H. P. Morgan, S. A. Goodner, D. M. Foster, A. A. Hardmon, A. N. Creekmore, B. C. Springer, E. B. Fisher
Journal: Journal of Clinical Oncology (2007)

6580 Background: Lack of both trust and rapport with health care providers has been identified as possible causes for under- representation of minorities within clinical trials. Our study used a “Peer Coach” (PC) to promote trust among minority patients with advanced cancer. Methods: Minority patients with advanced breast, colorectal, lung, or prostate carcinoma were randomly assigned to receive a PC or “Usual Care” (UC). Patients completed baseline and 6-month telephone interviews to assess demographics, trust in healthcare providers, attitudes toward clinical trials, and quality of life. Patients randomized to the coaching intervention were assigned a coach, trained in health communications, who made biweekly contacts for 6 months to address general issues, progress or development in cancer care, and available resources. Patients randomized to UC received no further intervention. Results: Over 21 months, we screened 268 patients and enrolled 73 African Americans and 2 Asians (56 women and 19 men) including 38, 18, 13, and 6 patients with breast, colorectal, lung and prostate cancers, respectively. Patients were randomly assigned to PC (38) and UC (37), with no baseline differences. Longitudinal data analysis was conducted on 69 patients who completed the 6-month follow-up assessment. Trial enrollment was slightly higher in the PC group but was found to be non-significant (p=0.226). Trust in doctor (p=0.053), absence of depressed mood (p=0.032) and higher quality of life (p=0.052) predicted enrollment. Adherence to care was unrelated to the assigned group and, in the PC group, to the number of coach contacts. Baseline depression was associated with missed physician appointments (p=0.039). There was no difference between the PC and UC groups on attitudes towards clinical trials, perceptions of racism, trust in doctor, medical mistrust, depression, or quality of life. Conclusions: Psychosocial elements of trust in doctor, depression and quality of life were found to predict trial enrollment, regardless of assignment to PC or UC. Future studies should include a more structured approach to clinical trial promotion, follow patients over a longer period, and consider treatment of depression given its association with trial enrollment and adherence. No significant financial relationships to disclose.
A phase I/II study of vorinostat, an oral histone deacetylase inhibitor, in combination with azacitidine in patients with the myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Initial results of the phase I trial: A New York Cancer Consortium
Authors: L. R. Silverman, A. Verma, R. Odchimar-Reissig, A. Cozza, V. Najfeld, J. D. Licht, J. A. Zwiebel
Journal: Journal of Clinical Oncology (2008)

7000 Background: Epigenetic silencing plays a role in MDS and AML. The hypomethylating agent azacitidine (azaC) alters the natural history of MDS and improves survival (Silverman JCO 2002, Fenaux Blood 2007). In AML, azaC produces responses and appears to affect survival (Silverman JCO 2006). Time to response is slow, median 4 cycles and CR+PR ranges from 7 to 27%. Vorinostat has demonstrated single agent activity in MDS and AML (Garcia-Manero Blood 2006). In sequenced combination vorinostat synergizes with azaC to reactivate epigenetically silenced genes. Methods: For the phase I component eligible patients (pts) were entered into one of 8 cohorts with the combination of vorinostat and azaC in a 3+3 dose escalating de-escalating design (see table). Results: As of the data cut for this submission 16 pts are evaluable for toxicity and the first 6 cohorts have been completed, full data will be available for the meeting. Among the 20 pts entered: 14 have MDS, 6 AML, median age 68. Responses among evaluable pts have occurred in 9 of 11 (82%); 5 CR, 1 CRi, (CR+CRi=55%), 3 HI, 2 SD. Median time to response is 2 cycles. Among pts with poor risk cytogenetics 4/5 responded (CR, CRi, 2 HI). A total of 90 cycles have been administered, range 1 to 11 with a mean 4.7 cycles. Only 3 pts have come off study for progression, co-morbidities, or consent withdrawal. No grade 3 or 4 non-hematologic toxicities were observed. Grade 2 anorexia and fatigue occurred in cycle 1 in 31.6% and 57.9% of pts, respectively. Grade 2 fatigue occurred in 89% in cohorts 2, 3 and 4. Correlative studies of effects on gene expression and methylation are underway. Conclusion: The combination is safe, tolerated in repetitive cycles and appears superior for time to response, overall response and CR rate compared to azaC alone. The phase II study will utilize the optimal epigenetic and clinical dose to determine this. Cohort Dosing in Relation to Adverse Events and Response Cohort No of Pts AzaC dose mg/m2/d 1–7 SQ Vorinostat Dose mg/d Total Dose AzaC/Vorinostat Adverse Events anorexia/Fatigue grade Response 1 3 55 200 bid x 14d 385/5600 1;0;0/2;1;2 CR;CR;CR 2 3 55 200 tid x 14d 385/8400 2;2;2/2;2;2 CR;SD;CRi 3 3 75 200 tid x 14d 525/8400 1;0;1/2;0;2 SD;CR;HI 4 3 75 200 bid x 14d 525/5600 2;1;2/2;2;2 IE;HI;HI 5 4 75 300 bid x 7d 525/4200 1;2;0/2;1;0 TE;TE;TE 6 3 55 300 bid x 7d 385/4200 TE;TE;TE TE;TE;TE 7 1 55 200 bid x 7d 385/2800 TE TE 8 0 55 300 bid x 3d 385/1800 NA NA Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pharmion