tbuckley/cabot-search huggingface dataset:
Influence of KRAS mutations on outcome in patients with curatively resected stage III colon cancer treated with adjuvant chemotherapy.
Authors: Piercarlo Saletti, Martina Nucifora, Sara De Dosso, Alessandra Spitale, Nora Sahnane, Maria Eugenia Riveiro, Valentina Bertolini, Eraldo Bucci, Stefano Crippa, Michele E. G. Ghielmini, Milo Frattini
Journal: Journal of Clinical Oncology (2013)

e14536 Background: Adjuvant chemotherapy improves survival in patients with stage III colon cancer (CC) after curative resection, and oxaliplatin in combination with fluoropyrimidine-based regimens has been established as a standard treatment. KRAS mutations could predict oxaliplatin sensitivity in CC cells, as recently demonstrated. Here, we profiled KRAS and correlated it with outcome in stage III CC patients who underwent adjuvant chemotherapy. Methods: Eligible patients were those with resected stage III CC who underwent 6-months adjuvant chemotherapy, either with single-agent fluoropyrimidine (FP: modulated 5FU or capecitabine) or with oxaliplatin-based regimens (O-FP: FOLFOX or XELOX). DNA extraction was performed on formalin-fixed paraffin-embedded sections, and KRAS mutations were analyzed by direct sequencing. Disease-free survival (DFS) and overall survival (OS) analyses were computed using the Kaplan-Meier method and the Log-rank test. Results: The study population included 261 patients: 115 treated with FP, 146 O-FP. We identified KRAS mutations in 71/261 (27.4%) cases, of which 33 (46.5%) received FP, and 38 (53.5%) O-FP. In wild-type (wt) KRAS cases, DFS and OS group did not significantly differ between the two treatment modalities [in months, FP vs O-FP - median OS: 62.0 vs 49.6, HR: 1.12 (95% CI: 0.65; 1.92); median DFS: 57.1 vs 44.4, HR: 0.93 (95% CI: 0.55; 1.56)]. In patients treated with FP, a worse DFS [in months, mutant vs wt - median DFS: 46.0 vs 57.1, p=0.04; HR: 1.86 (95% CI: 1.01; 3.41)] and a trend toward a worse OS in months, mutant vs wt - median OS: 56.1 vs 62.0, p=0.08; HR: 1.71 (95% CI: 0.94; 3.10)] were observed in KRAS mutated patients. On the contrary, DFS and OS were not statistically different for mutated and wt KRAS patients treated with O-FP [in months, mutant vs wt - median DFS: 43.7 vs 44.4, p=0.62; HR: 1.17 (95% CI: 0.63; 2.18); median OS: 48.9 vs 49.6, p=0.77; HR: 1.11 (95% CI: 0.55; 2.23). Conclusions: Our results suggest that curatively resected stage III CC patients exhibiting wt KRAS status might benefit from FP alone. On the contrary, an oxaliplatin-containing regimen should be recommended in KRAS mutated patients.
Availability of single-fraction palliative radiotherapy for cancer patients receiving end-of-life care within the Veterans Healthcare Administration.
Authors: Drew Moghanaki, Alice V. Cheuk, Helen Fosmire, Mitchell Steven Anscher, Michael Philip Hagan, Stephen T. Lutz, George A. Dawson
Journal: Journal of Clinical Oncology (2014)

9556 Background: Multiple randomized phase III trials have established a single fraction of palliative radiotherapy is equally effective at relieving pain when compared to longer treatment courses. However, recent surveys demonstrate <20% of radiation oncologists in the US offer this shorter treatment option. As 500,000 Veterans currently receive cancer care within the Veterans Healthcare Administration (VHA), a study was conducted to determine whether this finding held true in this healthcare system. Methods: A web-based survey was emailed to all radiation oncologists currently practicing at VHA medical centers. Associations of responses were evaluated by Fisher’s exact test. Results: The response rate was 90% (70/78). Half of respondents were full-time employees of the VHA, and the majority (70%) had thoroughly read guidelines on palliative radiotherapy for bone metastases recently published by either the American College of Radiology (ACR, 2009) or American Society of Radiation Oncology (ASTRO, 2011). Single-fraction palliative radiotherapy for bone metastases had been prescribed by 76% of respondents, and 93% had prescribed a short course of ≤6 fractions. Respondents were less likely to have prescribed a single fraction for patients who had survival estimates of either >6 months or >12 months, (66% vs 37%, p < 0.0001).Those not offering single-fraction palliative radiotherapy (24%) were more likely to be >10 years out of training (37% vs 10%, p = 0.01), and more likely to have worked in private practice at some point in their career (36% vs 12%, p = 0.03). There were no associations with employment status, history of an academic appointment, or having previously read the recently published ACR or ASTRO guidelines. Conclusions: Single fraction palliative radiotherapy is widely available in the VHA. Its use is preferred by radiation oncologists for patients with a limited life expectancy of less than 6 months. These data demonstrate rapid adoption of recently published guidelines that are designed to ensure access to care is not limited by a preference for prolonged treatment courses that may discourage patients and clinicians from seeking this care.
Effect of lenalidomide combined with R-CHOP (R2CHOP) on negative prognostic impact of nongerminal center (non-GCB) phenotype in newly diagnosed diffuse large B-cell lymphoma: A phase 2 study.
Authors: Grzegorz S. Nowakowski, Betsy LaPlant, William R Macon, Craig B. Reeder, James M. Foran, Garth D. Nelson, Carrie A. Thompson, Candido Rivera, David James Inwards, Ivana N. M. Micallef, Patrick B. Johnston, Luis F. Porrata, Stephen Maxted Ansell, Thomas Matthew Habermann, Thomas E. Witzig
Journal: Journal of Clinical Oncology (2014)

8520 Background: The non-germinal center B-cell like (non-GCB) subtype of diffuse large cell lymphoma (DLBCL) is associated with a worse outcome when treated with RCHOP chemotherapy. Lenalidomide has significant single-agent activity in relapsed DLBCL and might be particularly active in non-GCB DLBCL. We have previously reported that lenalidomide can safely be combined with RCHOP (R2CHOP). This phase 2 study evaluated the efficacy of this combination in newly diagnosed DLBCL and analyzed the outcomes based on DLBCL subtype. Methods: Eligible patients were adults with newly diagnosed, untreated, stages II-IV CD20 positive DLBCL. Patients received oral lenalidomide 25 mg days 1-10 with standard dose R-CHOP every 21 days for 6 cycles. All patients received pegfilgrastim on day 2 of each cycle and aspirin prophylaxis throughout. DLBCL molecular subtype was determined by tumor immunohistochemistry (Hans algorithm) and classified as germinal center B-cell (GCB) vs non-GCB in the R2CHOP patients and 87 control DLBCL patients from the Mayo Clinic Lymphoma Database meeting the same inclusion criteria and treated with conventional RCHOP. Results: 64 DLBCL patients were enrolled. Median age was 65 years (22-87) and 34 patients (53%) had IPI intermediate-high or high. 60 were evaluable for response. The overall response rate was 98% (59/60) with 80% (48/60) complete response (CR). 24 month EFS and OS rates (95% CI) were 59% (48%-74%) and 78% (68-90%), respectively. In RCHOP patients, 24 months PFS and OS were 28% vs 64%, p<0.001 and 46% vs 78% p<0.001 in non-GCB patients vs GCB patients respectively. In contrast, there was no difference in 24 months PFS or OS for R2CHOP treated patients based on non-GCB and GCB subtype, 60% vs. 0.59%, p= 0.83 and 83% vs. 75%, p=0.61 at 2 years respectively. Conclusions: R2CHOP shows promising efficacy in DLBCL. The addition of lenalidomide to RCHOP appears to mitigate the negative impact of non-GCB phenotype on the outcome. A randomized phase 2 study of RCHOP vs. R2CHOP utilizing gene expression profiling classification of DLBCL subtype and led by the Eastern Cooperative Oncology Group (E1412) is currently ongoing. Clinical trial information: NCT00670358.
Abstract 223: Remodeling of K-ATP Channel Expression and Function in Type-2 Diabetes Mellitus
Authors: Jun Hu, Chaoqin Xie, Fadi G Akar
Journal: Circulation Research (2015)

Diabetes mellitus (DM) is associated with enhanced propensity for ventricular tachyarrhythmias (VT). We found that DM hearts exhibit attenuated APD shortening in response to ischemia (Fig). We hypothesized that altered KATP channel expression &amp; function underlie this impaired electrophysiological (EP) adaptation. Methods: We investigated differential effects of the SUR2a activator Pinacidil (PIN, 100 uM) and the SUR1 activator Diazoxide (DZX, 30 uM) on EP properties in Zucker Diabetic Fatty (ZDF) and control (ctrl) rats at baseline and in response to no flow ischemia. We measured the mRNA expression of KATP channel subunits (Kir6.1, Kir6.2, SUR1a, SUR1b, SUR2a, and SUR2b) in normal and ZDF animals. Results: PIN caused comparable APD shortening in ctrl &amp; ZDF hearts during baseline perfusion and promoted early onset of sustained VT within 6 min of ischemia in ctrl &amp; ZDF hearts. In contrast, DZX did not alter APD (p=NS) or cause arrhythmias in either group during baseline perfusion. However, DZX accelerated APD shortening and promoted VT in all (8/8) ZDF hearts during ischemia (Fig 1). The putative molecular mechanism underlying the differential proarrhythmic sensitivity of ZDF vs ctrl hearts to DZX was investigated. We found marked upregulation of Kir6.1 (by 3.7X p&lt;0.001) and SUR1b (by 2.8X p&lt;0.001) mRNA levels with no changes in Kir6.2, SUR1a, SUR2a, or SUR2b expression in ZDF. Conclusion: Remodeling of KATP channel subunits likely underlies the differential sensitivity of ZDF hearts to DZX. Our findings indicate that this classically cardioprotective agent should be avoided in DM patients at risk of ischemic events. Upregulation of Kir6.1 &amp; SUR1b may be markers of proarrhythmia.
Correlation of immune response with clinical outcomes in melanoma patients receiving adjuvant therapy of pegylated interferon alpha-2b combined with gp100 peptide vaccine.
Authors: Luis M Vence, Dae Won Kim, Roland L. Bassett, Suzanne Cain, VanAnh Trinh, Sapna Pradyuman Patel, Nicholas E. Papadopoulos, Agop Y. Bedikian, Kevin Kim, Patrick Hwu, Willem Overwijk, Wen-Jen Hwu
Journal: Journal of Clinical Oncology (2014)

3026 Background: Vaccination using tumor-associated antigen peptides alone has shown limited clinical benefit. Preclinical studies have demonstrated interferon-alpha promotes vaccine-induced tumor-specific T-cell responses. Our randomized 3-arm study explored the optimal biological dosing (OBD) schedule of pegylated IFN-alpha-2b (PEG-IFN) when combined with gp100 vaccine in patients (pts) with resected melanoma, while demonstrating safety with acceptable toxicity. Methods: After definitive surgical resection, melanoma pts were randomized into 1 of 3 PEG-IFN arms [Induction Phase (6 mcg/kg/wk)/Maintenance Phase (3 mcg/kg/wk)]: (1) Arm 1: 4 wk/20 wk; (2) Arm 2: 8 wk/16 wk; (3) Arm 3:12 wk/12 wk. All pts were vaccinated with gp100209-2M every 3 wk x 8. Toxicity and gp100-specific T-cell responses were assessed every 3 wk. Results: 30 pts (8 stage II, 22 stage III) were enrolled and treated in 3 arms (11 Arm 1, 9 Arm 2, 10 Arm 3). All 3 dosing schedules were found to be safe and well tolerated. Despite PEG-IFN-induced lymphopenia [CD8+ T-cells decreased from average 326.5 to 169.7 cells/microL (P<0.0001)], gp100-specific CD8+ T-cell frequency increased from baseline 0 cells/ml to 15.5 cells/ml of blood at the end of 24-wk study (p = 0.0007). Arm 2 pts showed the highest median maximum gp100-specific T-cell response. Median time to reach maximum T-cell response was 16 wk for Arm 1, and 19 wk for Arms 2 and 3. At median follow-up of 3 years (range 21-54 mo), 11 pts developed recurrent disease, 4 of whom died of metastases. Although median RFS and OS were not reached, the proportion of pts alive and free of distant metastasis at 3 years was 85% among those with maximum gp100-specific T-cell response > 0.025% of CD8+ T-cells, compared to 50% among those with ≤ 0.025% T-cell response (P=0.04; HR=0.24). Conclusions: In our study, Arm 2 demonstrated the OBD schedule of PEG-IFN combined with gp100 vaccination. The increased T-cell response induced by PEG-IFN correlated with improved clinical outcomes. Clinical trial information: NCT00861406.
Cancer screening in France: Reaching a plateau? New edition of an iterative nationwide survey.
Authors: Jerome Viguier, Jean F. Morere, Chantal Touboul, François Eisinger, Sebastien Couraud, Laurent Greillier, Alexis B. Cortot, Jean-Yves Blay, Christine Lhomel, Xavier B. Pivot
Journal: Journal of Clinical Oncology (2015)

1565 Background: The EDIFICE survey program began in 2005 and set out to ascertain participation rates of the French population in cancer screening and assess changes in these rates over time. After 2005, 2008 and 2011, the latest survey was conducted in 2014, and focused on colorectal, breast, prostate, cervical and lung cancers. Methods: EDIFICE 4 was conducted by phone interviews of a representative sample of 1602 subjects (age 40-75), using the quota method. Analysis focused on target populations as defined by guidelines when these exist. Results: For breast cancer, the rate of women declaring having had ≥ 1 mammography was 93%/94%/95%/97% in 2005/2008/2011/2014 respectively, with no impact of sociodemographic criteria. As recommended in the French program, a mammography had been done in the previous 2 years for 75%/83%/83%/81%, with a lower participation rate among the 65 to 74-year age group. For colorectal cancer, the rate of individuals declaring having attended ≥ 1 screening procedure, colonoscopy or fecal occult blood (FOB) test, was 25%/38%/59%/60%. The FOB test had been performed according to the recommended timing interval for NA/15%/32%/31%. Colorectal cancer screening has now reached a plateau for both genders, the only significant increase being seen in the 70 to 74-year age group. The rate of men having undergone at least one prostate cancer screening test (PSA and/or digital rectal exam) was 36%/49%/50%/49%, with a decrease in participation rates among the 50 to 59-year age group. For cervical cancer, 99% of women declared having already undergone conventional ‘Pap’ smears or liquid-based cytology during a gynecological exam. Average age for the 1st test was 26 years. With regard to lung cancer, 11% of participants declared having already undergone a lung cancer screening procedure; this figure was 6% in the first EDIFICE survey in 2005. Conclusions: Screening participation rates have stabilized and for most tumor locations, appear to be correlated with the history of implementation of national programs or recommendations. When organized screening programs exist, such as for breast and colorectal cancer, the difference between the plateau levels raises the question of the acceptability of the test.
Smoking status (SS) and influence on the clinical behavior of transitional cell carcinoma (TCC): An epidemiologic perspective.
Authors: Anuradha Jayaram, MinYuen Teo, Sandra Deady, Harry Comber, Dearbhaile M. O'Donnell, Raymond McDermott
Journal: Journal of Clinical Oncology (2014)

e15512 Background: Published data link SS to risk of occurrence and recurrence of TCC. We investigated the association of SS with histo-pathologic stage at presentation and overall survival (OS) in a large population. Methods: Individual patient data were obtained from National Cancer Registry of Ireland. Those with histologically proven TCC were included. Analysis of SS [smoker (S), ex-smoker (ExS) and non-smoker (NS)] related to histo-pathologic factors was performed using Chi-squared test. Multivariate models were used to assess the influence of SS and other clinical-pathologic factors on OS. Data are presented as adjusted hazard ratio (aHR) with p-value. Results: Between 1994 and 2010, 4,946 patients (pts) were registered. The proportion of pts without TNM data was comparable across all smoking categories. Significant differences in the distribution of gender, age, T-stage and TNM stages were observed between the groups (Table). OS for NS was 19.6 mos compared to 20.8 mos for S [aHR 1.05 (95% CI 0.96 – 1.15), p=0.29] and 20.6 mos for ExS [aHR 1.03 (95% CI 0.93 – 1.14), p=0.55)]. No OS difference was observed between S and ExS [aHR 0.99 (95% CI 0.90 – 1.10), p=0.95)]. For resected stage I – III disease, adjuvant/neoadjuvant chemotherapy, compared to no chemotherapy, did not improve OS for NS [HR 1.22 (0.88 – 1.65), p=0.22], S [HR 1.12 (0.84 – 1.47), p=0.42] or ExS [HR 0.91 (0.65 – 1.25), p=0.57]. In stage IV disease, chemotherapy compared to no chemotherapy was significantly associated with improved OS for S [HR 0.53 (0.27 – 0.96), p=0.04] but not for NS [HR 0.62 (0.27 – 1.20), p=0.17] or ExS [HR 0.54 (0.26 = 1.03), p=0.06]. Conclusions: Smoking is known to increase the risk of TCC. In a large population, SS did not significantly affect OS, but current smoking appeared to be associated with OS benefit from chemotherapy use. Investigation of the interaction of TCC biology and SS is needed. NS % S % ExS % p % Gender Male 65 75 81 <0.01 Female 35 25 19 Age ≥70 61 44 64 <0.01 <70 39 56 36 T stage 1+ 48 44 41 0.03 2 17 17 18 3 8 10 11 4 6 6 7 Unknown 21 23 23 N stage 0 29 30 30 0.78 1 2 2 2 2 2 3 2 3 0 0 0 Unknown 66 64 66 M stage 0 37 37 38 0.49 1 3 4 4 Unknown 60 59 58 TNM (fully staged) I+ 64 59 59 0.07 II 16 13 12 III 8 12 12 IV 12 16 16
A randomized phase II trial of Interleukin-2 in combination with four different doses of bryostatin in patients with renal cell carcinoma
Authors: A. C. Peterson, H. Harlin, T. Karrison, J. A. Knost, J. W. Kugler, N. J. Vogelzang, E. E. Vokes, T. F. Gajewski, W. M. Stadler
Journal: Journal of Clinical Oncology (2004)

4608 Background: Bryostatin-1 (Bryo-1) is a partial agonist of protein kinase C (PKC) with both antiproliferative and immunomodulatory effects. Preclinical data indicated that Bryo-1 upregulates IL-2 receptor expression on lymphocytes, but that the dose response relationship for this effect is bell-shaped. We conducted a phase II trial combining IL-2 with four different doses of Bryo-1 to determine if response rates could be improved over those seen with IL-2 alone. Tolerability and T cell number and activation were also evaluated. Methods: All patients with measurable stage IV renal cell carcinoma were eligible provided they had not already received IL-2. 11 million units (IU) of IL-2 were administered sc on days 1–4, 8–11, and 15–18 of every 28 day cycle. Eight patients were treated in each randomized cohort of 5, 15, 25 or 35 mcg/m2 of Bryo-1 on days 1, 8 and 15, starting in the second cycle. Lymphocytes were analyzed weekly for number, activation status, and cytokine production of IL-2, IL-4 and IFN-γ. Response evaluation was performed every 3 cycles and according to RECIST. Results: 31 of 33 patients were evaluable. Baseline characteristics included PS 0/1 in 26/5, nephrectomy in 26, prior therapy in 11, > 2 metastatic sites in 15, anemia in 15, and hypercalcemia in 1. Confusion and hyponatremia were the only grade 4 toxicities. Common grade 3 toxicities included fatigue (5), nausea and vomiting (5), myalgias and/or arthalgias (3), myopathy (3), dyspnea (3), lightheadedness (3). Four patients demonstrated evidence of tumor shrinkage, but there was only 1 objective PR after 3 cycles that was not maintained after the 6th cycle. Four patients had SD at the completion of 6 cycles. The median time to progression was 104 days (95% CI 88–120) and the median survival was 477 days (95% CI 377–577). There was no significant effect of Bryo-1 on T cell expansion, activation or cytokine production. Conclusions: Although the addition of Bryo-1 to IL-2 was well tolerated, it did not improve clinical response rates beyond those historically reported with IL-2 alone, nor did it augment T-cell expansion in patients with metastatic renal cell carcinoma. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration NCI
Regression of follicular lymphoma with alternative therapy using Devil's Claw (DC); Coincidence or causation?
Authors: K. S. Wilson
Journal: Journal of Clinical Oncology (2009)

e19560 Background: Alternative therapies are used by c 30% of cancer pts (Ernst and Cassileth, Cancer 2000). Two follicular lymphoma (FL) pts who had objective tumor regression after taking the herb DC without cytotoxic therapy are reported here. Methods: This was a retrospective chart review. In January 2000, pt #1 presented with co-existent IgG plasma cell dyscrasia and stage 3A grade 2 FL with 5 cm cervical and R/P nodes. CT scan 10 months later showing partial regression of adenopathy. On enquiry, he was taking DC and Essiac. He developed overt myeloma in Aug 2001, when he stopped DC/Essiac and received HDCT/ASCT following which there has been no clinical progression of lymphoma. In November 2003, pt #2 presented with stage 3A grade 1 FL. CT scan showed widespread adenopathy (2.5 cm max.). He learned of pt #1 through the local Lymphoma Patient Support Group and started DC alone. CT scan 11 months later showed decreased adenopathy and splenomegaly which has been sustained. Results: CT images at baseline and follow-up confirm objective regression. Conclusions: DC (Harpagophytum procumbens) tuberous root contains Harpagoside and Beta sitosterol and has anti-inflammatory properties probably by suppressing COX-2 and iNOS expression (Jang et al, J Pharmacol Sci, 2003). There is good evidence for its use in osteoarthritis ( http://www.nlm.nih.gov/medlineplus/druginfo/natural/patient-devilsclaw.html ) but it has not been reported to have anticancer activity. COX-2 inhibition has an accepted role in cancer prevention (Steinbach et al, NEJM 2000), has been implicated in lymphomagenesis (Wun et al, Leuk Res 2004) and associated with both stage of lymphoma and response to standard treatment (Hazar et al, Leuk Lymphoma 2004). However, spontaneous regression in low grade lymphoma has been reported in 7 of 44 pts on observation only (Krikorian et al, 1980); none were on herbal medications or COX-2 inhibitors. The key issue in both these patients is whether or not the disease regression was “spontaneous” or causally related to DC therapy, but the timing of response suggests a potential therapeutic benefit. Considering the role of COX-2 inhibitors and the relation between components of DC and COX-2, further investigation is warranted, preferably with a COX-2 inhibitor of known purity. No significant financial relationships to disclose.