tbuckley/cabot-search huggingface dataset:
Association between primary surgery and all-cause mortality among elderly patients with high-risk prostate cancer.
Authors: Sumedha Chhatre, David Inkoo Lee, Doyeong Yu, S. Bruce Malkowicz, Ravishankar Jayadevappa
Journal: Journal of Clinical Oncology (2017)

e576 Background: To determine the five year survival impact of primary surgery compared to radiation therapy in older men with high risk prostate cancer. Methods: This was a population-based cohort study using Surveillance, Epidemiology, and End Results (SEER)-Medicare patients 66 years or older, diagnosed for prostate cancer between 2004 and 2008. High-risk prostate cancer was identified as Gleason score of ≥ 8, or clinical stage T3a. Treatments studied were definitive local (curative intent) therapy (surgery or radiation therapy) within 180 days of prostate cancer diagnosis. The two treatment groups were retrospectively followed for one-year pre and five years post diagnosis. Main outcome measure was five-year all-cause mortality and cancer specific mortality. Sequential Cox regression was used to assess the hazard of mortality associated with surgery, compared to radiation therapy, after adjusting for socio-demographic variables, variables and propensity score. Results: We identified a cohort of 24,838 men newly diagnosed for high-risk for prostate cancer between 2004 and 2008. Forty-seven percent of these had surgery (n = 11,696) as well as radiation therapy (n = 11,724) as a primary treatment with curative intent within 180 days of diagnosis. Mean age at diagnosis of radiation therapy group was higher compared to surgery group (73.5, sd = 5.3 vs. 70.3, sd = 4.9; p = 0.020). Radiation group had higher comorbidity compared to surgery group (37% vs. 26%, p = 0.0316). Unadjusted all-cause mortality comparison over five years of follow-up showed that surgery treatment was associated with lower mortality (HR = 0.58, CI = 0.54, 0.62). After adjusting for propensity score, the hazard of all-cause five year mortality remained lower for surgery compared to radiation therapy (HR = 0.86, CI = 0.78, 9.4). Conclusions: Over a five-year follow-up, primary surgery was associated with improved survival compared to radiation therapy in high-risk prostate cancer patients. Longer follow-up is needed to determine if the survival advantage of surgery will persist as well as factors contributing to the difference in survival.
A phase Ib study of CUDC-101, a multitargeted inhibitor of EGFR, HER2, and HDAC, in patients with advanced head and neck, gastric, breast, liver, and non-small cell lung cancer.
Authors: Siqing Fu, John J. Nemunaitis, Alberto Bessudo, Julie E. Bauman, Omid Hamid, Samir E. Witta, Grace K. Dy, Cheng Lai, Robert Laliberte, Maurizio Voi
Journal: Journal of Clinical Oncology (2012)

e13101 Background: CUDC-101 is a small molecule EGFR/HER2 receptor tyrosine kinase and HDAC inhibitor that has shown promising activity in cancer cell lines and tumor xenograft models. A previous Phase 1 study showed 275 mg/m 2 to be the maximum tolerated dose when given daily for 5 days every 2 weeks (QDx5). Dose limiting toxicity included transient creatinine elevation. This expansion Phase 1b study was conducted to further evaluate safety and tolerability of the QDx5 and of a three dose per week (3x/week) schedule for 3 weeks every 4 weeks. Methods: Eligible patients (pts) ≥18 years with advanced breast, gastric, head and neck, NSCLC or liver cancer (n = 10/tumor type); adequate marrow and organ function; and an ECOG PS ≤2 were assigned to receive CUDC-101 (275 mg/m 2 ) on QDx5 or 3x/week schedule. NSCLC patients required documented EGFR exon 19 or 21 mutation/deletion with recent acquired resistance to erlotinib. Study parameters included safety (CTCAE v.3), antitumor response (RECIST v1.1), PK (blood and urine) and PD (tumor biopsy and CTC) assessments. Results: A total of 46 pts were treated (23/dose schedule), including 25 (54%) males, mean age 62 yrs, PS 0/1/2 (33/56/11%), and a median of 3 prior regimens (range, 0-7). The overall incidence and severity of treatment-related AEs were similar between the 2 dose schedules, including fatigue, transiently increased creatinine, nausea, vomiting, decreased appetite, anemia and asthenia, each occurring in &lt;20% of all pts and mostly Grade ≤ 2. Grade 3 AEs were reported in 4 pts. Overall, 15 (33%) pts had SD as their best response: 4 pts had SD for &gt;14 weeks, including 1 with head and neck (QDx5), and 2 with liver (1 lasting 47 weeks) and 1 gastric cancer (all 3 on 3x/week). Paired tumor biopsies were available for one pt showing target inhibition. CTC and PK analyses are ongoing. Conclusions: CUDC-101 was well tolerated using either dosing schedule, with preliminary evidence of antitumor activity. The more convenient 3x/week schedule was selected for an ongoing Phase 1 combination study.
Analysis of docetaxel therapy in elderly (≥70yrs) castration resistant prostate cancer (CRPC) patients enrolled in the Netherlands Prostate Study (NePro).
Authors: Maartje Los, Frank L. Gerritse, Hielke Jodie Meulenbeld, Jeanine M.L. Roodhart, Ankie M.T. van der Velden, Ronald De Wit
Journal: Journal of Clinical Oncology (2013)

e16059 Background: Prostate cancer truly is an age-associated disease, approximately half of prostate cancer patients in the Netherlands are aged 70 years or older at the time of diagnosis. However, age above 70 years has been an exclusion criterion in many clinical trials. Hence the knowledge about chemotherapy tolerance and toxicity in patients aged 70 years and above is limited. In this study we evaluated the influence of age on docetaxel chemotherapy in elderly (≥70yrs) castration resistant prostate cancer (CRPC) patients. Methods: Prostate cancer truly is an age-associated disease, approximately half of prostate cancer patients in the Netherlands are aged 70 years or older at the time of diagnosis. However, age above 70 years has been an exclusion criterion in many clinical trials. Hence the knowledge about chemotherapy tolerance and toxicity in patients aged 70 years and above is limited. In this study we evaluated the influence of age on docetaxel chemotherapy in elderly (≥70yrs) castration resistant prostate cancer (CRPC) patients. Results: We analyzed 568 patients (median age 68.1yrs, range 46-89yrs, 44.5% aged ≥70yrs). There was no relation between dosage and age (p=0.60). We found no significant differences between the number of dose reductions, TTP, overall survival, chemotherapy tolerance and toxicity up to the age of 80 years. However, when compared to younger men, men aged 80 years or above more frequently experienced grade 3/4 toxicity, were five times less likely to complete the first three treatment cycles at the intended dose (OR5.34, p=0.0052) and showed decreased overall survival (15.3mos versus 24.5mos in &lt;80yrs group, p=0.020). Conclusions: In mCRPC, and possibly other cancer patients, up to the age of 80 years docetaxel chemotherapy is well tolerated with toxicity levels, tolerance and TTP comparable to that of younger patients. However, for chemotherapeutic treatment of patients aged 80 years and above an individual assessment should be made.
A phase 1b study in cutaneous T-cell lymphoma (CTCL) with the novel topically applied skin-restricted histone deacteylase inhibitor (HDAC-i) SHP-141.
Authors: Youn H. Kim, Michael Krathen, Madeleine Duvic, Henry Wong, Pierluigi Porcu, Joselin Tacastacas, Neil J Korman, Joan Guitart, James E. Bradner, Steven B. Landau
Journal: Journal of Clinical Oncology (2014)

8525 Background: The efficacy of HDAC-i as systemic therapy in CTCL is well-established although adverse effects limit use. The topical hydroxamic acid HDAC-i SHP-141 is intentionally designed to maximize activity in skin but limit systemic exposure by rendering the drug inactive via endogenous serum esterases. Methods: A phase 1b multi-center, double-blind, placebo (PBO)-controlled, randomized trial in stage IA-IIA CTCL was conducted in the USA to assess safety, pharmacokinetic (PK), pharmacodynamic, and preliminary efficacy with SHP-141 applied twice daily to index lesions (maximum 5% BSA) for 28 days; last assessment was 42 days after start of drug. Eighteen patients were enrolled: 6 patients (5 SHP-141:1 PBO) at each escalating dose level (0.1%, 0.5%, 1.0%). In SHP-141 arms there were 3 patients with stage IA, 11 IB, and 1 IIA; PBO arm with 2 stage IA and 1 IB. Results: No DLTs, early discontinuations, serious adverse events (AEs) or systemic AEs were recorded; SHP-141 related events were predominantly CTCAE Grade 1 and limited to skin (Skin, SHP-141: 4/15, PBO: 1/3; 1 CTCAE Grade 2 dermatitis in SHP-141). Only SHP-141 patients had clinical objective response (OR; >50% improvement by CAILS) and incremental weekly CAILS improvement through dosing period (see Table). Time to OR occured as early as Day 7; 2 others at Day 21 with the last at Day 42. Based on CAILS subscore a significant reduction in lesion thickness for SHP-141 groups was measured. Skin biopsy histology confirmed increased dermal actetylation by staining with a specific acetyl–lysine antibody. PK results confirmed lack of SHP-141 peripheral blood exposure. Conclusions: This is the first skin-optimized topical HDAC-i with evidence of early clinical activity and without systemic HDAC-i related toxicity. Patients responded after few weeks of treatment; rapidity is not a typical feature of approved topical drugs for CTCL. SHP-141 may address an important unmet medical need in early stage CTCL by feasibly offering clinical benefits of a HDAC-i without safety concerns. Clinical trial information: NCT01433731. SHP-141 Placebo Objective response at day 42 4(28%) 0 Reduction in thickened lesions at day 42 89% 0% Incremental improvement to day 28 6(40%) 0
Outcomes of second line treatment in patients with advanced and metastatic biliary cancers.
Authors: Gustavo Figueiredo Marcondes Westin, Samer Alsidawi, Chandrikha Chandrasekharan, Andrew M. Briggler, Brendon Huffman, Angeline Pallante, Joleen Marie Hubbard, Steven R. Alberts, Thorvardur Ragnar Halfdanarson
Journal: Journal of Clinical Oncology (2017)

420 Background: Advanced biliary cancers respond poorly to chemotherapy and have a dismal survival. Currently gemcitabine-cisplatin (GC) is the standard of care for patients with advanced disease. The efficacy of second line treatment options is not well-defined. We retrospectively evaluated outcomes of patients undergoing second line treatment for advanced biliary cancers at Mayo Clinic. Methods: After obtaining approval from the institutional board review (IRB), we identified 42 patients with advanced and metastatic biliary cancers that progressed after first line (GC) and received second line treatment from 2007-2014. All patients had adequate follow up data. JMP software was used for statistical analysis. Kaplan-Meier method and log-rank tests were used for survival analysis, and multivariate cox proportional hazards model was used to evaluate the prognostic effect of pertinent clinical variables. All tests were two sided and a P value of &lt; 0.05 was considered significant. Results: The median age at diagnosis was 61.5 (range 26-87). The most common regimens used for second line settings were 5-FU-based (69%) followed by gemcitabine-based regimens (19%). The overall response rate (ORR) was 9.1%, while the disease control rate (DCR; stable disease and partial response) was 33%. The median overall survival (mOS) for the entire cohort from first line was 16.8 months (95% CI 12.7-21.7) and the progression-free survival (PFS) was 9.16 months (95% CI 7.3-14.7). From second line start the mOS was 10.4 months (95%; CI 7.3-23.7), and PFS was 2.8 months (95% CI 2.3-4.0). 73% of patients who received second line therapy were alive at 6 months and 50% at 12 months. 25 patients received third line treatment after progression. An univariate and multivariate analysis were performed including age, sex, stage at diagnosis, regimen used, CA19-9 and total body weight loss &gt; 5%, but no significant prognostic factors were identified. Conclusions: Patients with biliary cancers who progress after first line treatment have poor prognosis, but may benefit from second line regimens. 5-FU based regimens were the most commonly used in the second line setting, and 73% of patients who received second line therapy were alive at 6 months.
Lifelong memory responses perpetuate humoral T H 2 immunity and anaphylaxis in food allergy
Authors: Rodrigo Jiménez-Saiz, Derek K. Chu, Talveer S. Mandur, Tina D. Walker, Melissa E. Gordon, Roopali Chaudhary, Joshua Koenig, Sarah Saliba, Heather J. Galipeau, Adam Utley, Irah L. King, Kelvin Lee, Rachel Ettinger, Susan Waserman, Roland Kolbeck, Manel Jordana
Journal: Journal of Allergy and Clinical Immunology (2017)

A number of food allergies (eg, fish, shellfish, and nuts) are lifelong, without any disease-transforming therapies, and unclear in their underlying immunology. Clinical manifestations of food allergy are largely mediated by IgE. Although persistent IgE titers have been attributed conventionally to long-lived IgE+ plasma cells (PCs), this has not been directly and comprehensively tested.We sought to evaluate mechanisms underlying persistent IgE and allergic responses to food allergens.We used a model of peanut allergy and anaphylaxis, various knockout mice, adoptive transfer experiments, and in vitro assays to identify mechanisms underlying persistent IgE humoral immunity over almost the entire lifespan of the mouse (18-20 months).Contrary to conventional paradigms, our data show that clinically relevant lifelong IgE titers are not sustained by long-lived IgE+ PCs. Instead, lifelong reactivity is conferred by allergen-specific long-lived memory B cells that replenish the IgE+ PC compartment. B-cell reactivation requires allergen re-exposure and IL-4 production by CD4 T cells. We define the half-lives of antigen-specific germinal centers (23.3 days), IgE+ and IgG1+ PCs (60 and 234.4 days, respectively), and clinically relevant cell-bound IgE (67.3 days).These findings can explain lifelong food allergies observed in human subjects as the consequence of allergen exposures that recurrently activate memory B cells and identify these as a therapeutic target with disease-transforming potential.
Prognostic potential of tumoral FOXP3 expression in relation with tumor-infiltrating regulatory T cells in human gastric cancers.
Authors: Jungho Suh, Wankyu EO, Si-Young Kim
Journal: Journal of Clinical Oncology (2013)

e15036 Background: Expression of the transcription factor FOXP3 is crucial for the regulatory T cells (Tregs) that engage in the maintenance of immunological self-tolerance and immune homeostasis. Recently, expression of FOXP3 in cancer cells and its association with prognosis have been shown in clinical studies. For gastric cancer, however, prognostic significance of the tumoral FOXP3 expression and its relationship with Tregs remains unknown. We observed the tumoral FOXP3 and Tregs from the 118 gastric cancer patients who underwent surgery to explore its relationships with the prognosis. Methods: Tissue samples from 118 cases of gastric cancer were used for the present study. We investigated the tumoral expression of FOXP3 and Tregs count in human gastric cancer tissue by the use of immunohistochemical analysis using a tissue microarray to explore the relation with clinicopathological variables by retrospective manner. Results: FOXP3-positive cancer cells were observed in 62 of 118 (52.5%) patients. Positive Tregs (Tregs≥10/HPF) were observed in 66 of 118 (55.9%) patients. There was significant positive relationship between positive Tregs count and the tumoral FOXP3 expression (P=0.006).Positive tumoral FOXP3 expression was significantly related with the better disease free survival but not with the overall survival. But increased Tregs count was significantly related with the better overall survival (P&lt;0.01, P&lt;0.01, respectively). When we divide the patients into four groups by the FOXP3 expression and the Tregs count, FOXP3/Tregs(+/+) group showed the best overall survival followed by FOXP3/Tregs(-/+) group, FOXP3/Tregs(+/-,) and FOXP3/Tregs(-/-), respectively. And the survival difference between the FOXP3/Tregs(+/+)-FOXP3/Tregs(-/+) group and the FOXP3/Tregs(+/-)-FOXP3/Tregs(-/-)group became more prominent by the Tregs count. Conclusions: These results suggest that positive tumoral FOXP3 expression in relation with the high Treg count is a new prognostic marker in gastric cancer. The combination of tumoral FOXP3 and Tregs enhanced its statistical power more than separated as a prognostic marker.
Effect of prednisone and rituximab prephase on early toxicity in older DLBCL patients (pts) receiving RCHOP within a NHL specific comprehensive geriatric assessment (CGA) trial.
Authors: Colette Ngozi Owens, Augustine Iannotta, John F. Gerecitano, Matthew J. Matasar, Ariela Noy, Craig H. Moskowitz, Pamela Drullinsky, Maria Lia Palomba, David J. Straus, Steven M. Horwitz, Andrew David Zelenetz, Carol S. Portlock, Anita Kumar, Paul A. Hamlin
Journal: Journal of Clinical Oncology (2015)

8571 Background: Older pts with DLBCL are increasing in the US and are most vulnerable to treatment related toxicities and mortality (TRM). Effective tools to predict and mitigate toxicity are essential in these pts. The RICOVER-60 trial implemented a "pre-phase" of vincristine and prednisone (Pred) to reduce disease symptoms and improve KPS, reporting decreased early TRM. This prospective pilot study in older DLBCL pts employs a pre-phase of Pred and rituximab (R) as part of a larger CGA validation study in NHL (n = 200; NCT01829958). Methods: Eligible pts (n = 30) had de novo DLBCL/tDLBCL, age ≥ 70 yrs or ≥ 60 yrs with KPS < 80%, and planned RCHOP-like therapy for 2+ cycles. CGA consisted of CARG and CRASH scores as largely self administered assessments. CGA was assessed at baseline, post pre-phase, with each cycle, and at end-of-therapy. Pre-phase included Pred 50-100mg x 5-10 days and R 375mg/m2 x1 day completed in the 14 days pre-RCHOP. The study is powered to show a 15% change in CGA risk score, with secondary endpoints of toxicity, TRM, PFS/OS. Results: Of 30 pts: median age 75 (range 65-85), female 59%, DLBCL 87%, Stage III/IV 60%, aaIPI high-int/high 57%, cell of origin GC/non-GC 55%/45%, median ki67 70% (range 60-90%). 97 % completed pre-phase and 2+ cycles of chemotherapy. Median followup is 6m (range 1-18m) with 28/30 pts alive. Impact of pre-phase: KPS median increased from 70% to 80% (p = .057)post pre-phase; Timed up-and-go was not significantly changed (p = .484), but 4/7 normalized post-pre-phase; Pre-phase therapy (n = 29) improved CGA risk scores compared to baseline ( p = .024). CGA predicted risk of G3+ toxicity was 65%(range 32-89%). Toxicity risk score reduced in 31% (9/29) pts, mean 16% risk reduction for G3+ toxicity. Focusing on early toxicity (C1-C3), actual non-heme grade 3+ events were 41% and heme G4+ events 16%. Hospitalization occurred in 37%. There was no reported TLS or early TRM (n = 30). 1 pt pursued hospice after pre-phase. Conclusions: A pre-phase intervention of Pred and R may mitigate early toxicity, resulting in improved KPS and CGA risk score, with no TLS or early TRM in this pilot. Clinical trial information: NCT01829958.
Excellent Engraftment and Reduced Acute and Chronic Graft Versus Host Disease (GVHD) in ATG-Refractory Severe Aplastic Anemia (SAA) Following Transplantation of a PBSC Allograft Containing CD34+ Selected Cells Combined with Non-Mobilized Donor T-Cells
Authors: Enkhtsetseg Purev, Xin Tian, Jeremy M Pantin, Robert N Reger, Lisa Cook, Catalina Ramos, Elena Cho, Sneha Purvey, Patricia Prince, Hahn Khuu, David Stroncek, Susan Leitman, Danielle M. Townsley, Neal S. Young, Georg Aue, Richard W. Childs
Journal: Blood (2014)
Effect of lymphopenia on survival in women with cervical cancer treated with primary chemoradiation.
Authors: Emily S. Wu, Titilope Oduyebo, Lauren P. Cobb, Diana Cholakian, Kara C. Long-Roche, Edward Tanner, Stuart A. Grossman, Deborah Kay Armstrong, Akram Abdulaziz Alsahafi, Amanda Nickles Fader
Journal: Journal of Clinical Oncology (2014)

e16507 Background: Lymphopenia is an independent prognostic factor of recurrence and survival in several non-gynecologic cancers. The association between lymphopenia and survival in women with cervical cancer (CC) is unclear. Methods: This was a single institution, retrospective analysis of patients (pts) with stage IB2-IVA CC who received upfront chemoradiation (C/RT) from 1998 to 2012. Complete blood counts from pre-treatment through 10 weeks post-treatment were analyzed. In addition to known prognostic factors, the presence of pre-treatment and treatment-induced lymphopenia were evaluated for an association with progression-free (PFS) and overall survival (OS) using a univariate Cox regression model. Factors associated with survival on univariate analysis were included in a multivariate proportional hazards model. Results: Sixty five pts met study criteria and had lymphocyte counts available. The median age at diagnosis was 48 and most common histologic type was squamous cell carcinoma (82%). FIGO stage distribution was 7% IB2, 5% IIA2, 42% IIB2, 5% IIIA, 38% IIIB, and 3% IVA. The Charlson index was ≥3 in 8%, largely due to pts with HIV (6%). The median total lymphocyte count (TLC) for all patients prior to C/RT was 1580 cells/mm3, of whom 13 (20%) had lymphopenia (TLC<1000). There were no significant differences in demographic, tumor or treatment characteristics between patients with or without lymphopenia. Those with pre-treatment lymphopenia had inferior median PFS (10.3 vs 20.6 mo, p=0.023) and OS (10.6 vs 28.7 mo, p=0.011). Multivariate analysis demonstrated that pretreatment lymphopenia was an independent predictor of both PFS (HR 0.33; 95% CI 0.14-0.78, p=0.012) and OS (HR 0.27; 95% CI 0.11-0.64; p=0.003). At 4-10 weeks after initiating C/RT, 65% had TLC <500, resulting in a 73% decrease in TLC (median 426 vs 1580, p=0.0001). Treatment-induced lymphopenia was not associated with survival. Conclusions: Pre-treatment lymphopenia may be an independent predictor of inferior survival in women with cervical cancer treated with primary chemoradiation. Prospective studies are warranted to confirm these findings, which suggest that pre-treatment immune preservation is of significance in this cancer.