tbuckley/cabot-search huggingface dataset:
A phase I study of MK-2206 in combination with lapatinib in patients (pts) with advanced solid tumors.
Authors: Kari Braun Wisinski, Amye Tevaarwerk, Maria Bell, Mark E. Burkard, Jens C. Eickhoff, George Wilding, Noelle K. LoConte, Anne M. Traynor, Tien Hoang, Jennifer Heideman, Jill Kolesar, Glenn Liu
Journal: Journal of Clinical Oncology (2013)

2607 Background: The AKT protein kinase is a key mediator of signaling in the human epidermal growth factor receptor-2 (HER2) pathway. HER2 inhibition can result in feedback regulation of signaling, leading to high AKT activity. Preclinical studies demonstrate activity of combined HER2 and AKT inhibition. Lapatinib is an oral tyrosine kinase inhibitor of HER2. MK-2206 is an oral selective inhibitor of AKT with a maximum tolerated dose (MTD) of 60mg qod. Both agents cause rash and diarrhea. This study was designed to determine the MTD, dose limiting toxicities (DLTs), adverse events (AEs), clinical activity and pharmacokinetic (PK) parameters of the combination. Methods: This phase I study evaluated the safety of MK-2206 (30-60 mg qod) and lapatinib (1000-1500 mg qd) continuously. Cycles were 28 days, except cycle 1 (35 days), due to a 1 week MK-2206 lead-in to evaluate for PK interactions. Because of the continuous nature of therapy, protocol-specified intolerable grade 2 AEs were considered DLTs during cycle 1. Results: 23 pts (median age 59 [range 22-72];15 female:8 male) were enrolled. The most common malignancies were colorectal (8 pts), lung (4 pts), and breast (3 pts). 4 pts were unevaluable per protocol; 19 evaluable pts were on study a median of 8 weeks (range 3-35). 3 pts experienced DLTs. At dose level one, 1 pt had grade (gr) 3 hyponatremia and fatigue. At dose level four, 1 pt had gr 4 hyponatremia, gr 3 rash and hypocalcemia and 1 pt had intolerable gr 2 mucositis with delivery of &lt;75% of drug. The most common AEs at least possibly related to therapy included diarrhea (gr 3-4 in 3 pts; gr 1-2 in 16 pts), nausea (gr 3 in 2 pts; gr 1-2 in 14 pts) and rash (gr 3 in 2 pts; gr 1-2 in 12 pts). The MTD was 45mg po qod of MK-2206 with 1500 mg po qd of lapatinib, exceeding biologically active doses for each agent. One pt with adrenal cortical carcinoma was on study for 6 months with stable disease (SD) and 1 pt with colorectal cancer was on study for 5 months with significant tumor marker decline and SD. PK analyses are ongoing. Conclusions: MK-2206 in combination with lapatinib is well-tolerated at biologically active single agent doses. Anti-tumor activity will be evaluated further in a dose expansion cohort in pts with advanced HER2-positive breast cancer. Clinical trial information: NCT01245205.
Comparison of the international prognostic factors index (IPI) with the absolute monocyte and lymphocyte prognostic index (AMLPI) for patients (Pts) with diffuse large b-cell lymphoma (DLBCL) receiving R-CHOP.
Authors: Nicolas Batty, Elham Ghonimi, Lei Feng, Luis Fayad, Anas Younes, Maria Alma Rodriguez, Jorge Enrique Romaguera, Peter McLaughlin, Felipe Samaniego, Larry W. Kwak, Fredrick B. Hagemeister
Journal: Journal of Clinical Oncology (2012)

8067 Background: We studied the value of a proposed prognostic index (PI) generated by baseline absolute monocyte (AMC) and lymphocyte (ALC) counts for pts with DLBCL, using values as previously reported (Leukemia 25:1502-9, 2011). Methods: From 03/07 to 01/09, 245 consecutive pts with untreated DLBCL receiving standard R-CHOP from the MDACC database were evaluated. Baseline AMC and ALC were retrospectively recorded. High AMC (≥610/uL) and a low ALC (≤1000/uL) were examined as dichotomized variables for progression-free (PFS) and overall survival (OS). An AMLPI was generated, stratifying pts into 3 risk groups (RGs): low-(AMC &lt;610/uL and ALC &gt;1000/uL), intermediate-(AMC ≥610/uL or ALC ≤1000/uL), and high-risk(AMC ≥610/uL and ALC ≤1000/uL). The prognostic effect of the AMLPI and the IPI were examined by multivariate analysis (MVA). Results: Ninety (37%) had high AMC and 71 (29%) had low ALC. By univariate analysis, a high AMC was associated with inferior PFS (p=0.01) and OS (p=0.03). The frequencies of AMLPI RGs were: low-105 pts (43%), intermediate-119 (48%), and high risk-21 (9%). With a median follow-up of 22 months (range &lt;1-42), 3-year PFS and OS rates for these RGs were 80%, 61%, and 46% (p=0.007) and 92%, 76%, and 60% (p=0.006), respectively. Three-year PFS rates for IPI 0-2 and 3-5 RGs were 73% and 58%, respectively (p=0.0004); comparable OS rates were 88% and 68%(p&lt;0.0001). For pts with IPI 0-2, 1-year PFS rates for AMLPI low, intermediate, and high RGs were 92%, 89% and 80% (p=0.022); comparable 1-year OS rates were 96%, 95% and 80% (p=0.049). By MVA, AMLPI effect (low vs. high RGs) on PFS was significant (p=0.046) as was IPI effect (0-2 vs 3-5, p=0.005); similar results were observed for OS (p=0.052 and p=0.003, respectively). Conclusions: Baseline AMC and AMLPI are significant variables for PFS and OS for pts with DLBCL receiving R-CHOP. AMLPI can identify pts with low, intermediate, and high-risk disease for PFS and OS, particularly for those with IPI 0-2. AMLPI may also add prognostic value beyond that of the IPI.
Understanding among medical oncologists of the true monetary cost of therapy
Authors: K. R. Hoffman
Journal: Journal of Clinical Oncology (2009)

6629 Background: While oncologists are educated to deal with the medical complexities of their treatment, a new side effect, that of financial toxicity, has arisen over the past several years. One of the major challenges in private practice is explaining the monetary cost of treatment to the patient. Methods: 50 medical oncologists agreed to take a survey judging their knowledge of the financial cost of the treatments used in patients with the five most common tumors treated in the office: breast cancer, non-small cell lung cancer, colorectal cancer, non-Hodgkin's lymphoma, and three other commonly treated cancers: chronic myelogenous leukemia, multiple myeloma and ovarian cancer. Treatment regimens in the adjuvant and first line metastatic setting were used. Physicians were asked to calculate the cost of treatments to the patient and not the acquisition price of drugs. They were asked to calculate the cost based a patient completing their adjuvant therapy or treatment in the first-line metastatic setting, which was defined by each practicioner. If desired, this included the use of maintenance therapy. A body surface area of 1.8 M2 for men and 1.6 M2 for women was used. Results: 39 medical oncologists completed the entire survey. Of these, 11 were in solo practicie. 27/39 were in practice over 15 years, while only 4 were in practice under 5 years. In almost all cases where intravenous or oral targeted therapies were used, the physicians under-estimated the actual cost of treatment to the patient by 25–40%. When ‘conventional‘ intravenous chemotherapy was used, they were either correct or over-estimated the cost of treatment by 25 to 33%, especially when generic substitution of trade name drugs were available. More importantly, the actual dollar difference was up to $50,000 when targeted therapies were in the treatment regimen but only around $5,000 when conventional treatments were considered. Nearly all the physicians were ‘within the ballpark‘ when dealing with the cost of oral medications. Conclusions: Medical oncologists have a poor understanding of the monetary costs of the newer treatments they are prescribing. More education is needed in the economics, including monetary cost-benefit analysis, of oncology practice so that we can better serve our patients and society. No significant financial relationships to disclose.
Prognostic effects of clinical and pathologic TNM stages in patients with locally advanced rectum carcinoma after neoadjuvant chemoradiotherapy.
Authors: Bixiu Wen, Haihua Peng, Kaiyun You, Chengtao Wang, Meng-zhong Liu, Yuan-Hong Gao
Journal: Journal of Clinical Oncology (2014)

e14590 Background: To corroborate prognostic effects of clinical and pathological stages in patients with locally advanced rectal carcinoma treated with neoadjuvant chemoradiotherapy (neo-CRT) and radical surgery. Methods: 210 patients with locally advanced rectal carcinoma (cT3-4 or cN+) were retrospectively reviewed who were treated with neo-CRT followed by radical surgery. Treatment outcome was compared according to clinical and pathological TNM stages. Overall survival (OS) disease free survival (DFS), local recurrence free survival (LRFS) and distant metastasis free survival (DMFS) among patients with different clinical stage (IIA,IIB, IIIA, IIIB, and IIIC) (II and III) and pathological stage (ypT0-2N0, ypT3-4N0 and yp T0-4N+) after neo-CRT. Results: The medium follow-up was 47 months (14-98 months). The pathological stage was classified into three groups: ypT0-2N0 (91 patients, 43.3%), ypT3-4N0 (69 patients, 32.9%), and ypT0-4N+ (50 patients, 23.8%). Clinical stage (IIA-IIB-IIIA-IIIB and IIIC) was not associated with 5-year OS (p=0.760), 5-year DFS (p=0.792), 5-year LRFS (p=0.381) and DMFS (p=0.368). While pathological stage (ypT0-2 vs ypT3-4N0 vs ypT0-4N+) was associated with 5-year OS (87.8% vs 75.2% vs 65.4%; p=0.018), 5-year DFS (80.6% vs 78.2% vs 59.9%; p=0.005), 5-year DMFS (90.7 % vs 80.6% vs 64.3%; p < 0.001). Multifactorial analyses showed that ypN stage was an independent prognostic factor. Conclusions: Pathologic TNM stage is strongly associated with treatment outcome in patients with locally advanced rectal carcinoma treated with neo-CRT followed by radical surgery which may be used as guidance for further individual advent treatment.
Brain Mechanisms of the Placebo Effect: An Affective Appraisal Account
Authors: Yoni K. Ashar, Luke J. Chang, Tor D. Wager
Journal: Annual Review of Clinical Psychology (2017)

Placebos are sham medical treatments. Nonetheless, they can have substantial effects on clinical outcomes. Placebos depend on a person's psychological and brain responses to the treatment context, which influence appraisals of future well-being. Appraisals are flexible cognitive evaluations of the personal meaning of events and situations that can directly impact symptoms and physiology. They also shape associative learning processes by guiding what is learned from experience. Appraisals are supported by a core network of brain regions associated with the default mode network involved in self-generated emotion, self-evaluation, thinking about the future, social cognition, and valuation of rewards and punishment. Placebo treatments for acute pain and a range of clinical conditions engage this same network of regions, suggesting that placebos affect behavior and physiology by changing how a person evaluates their future well-being and the personal significance of their symptoms.
Multicenter trial for assessing tolerability of combination therapy with cisplatin, irinotecan, and PSK in extensive-stage small-cell lung cancer: RNCLC-01 study.
Authors: Tatsuhiko Kashii, Toshiro Miwa, Shinya Kajiura, Ichiro Kinoshita, Satoshi Oizumi, Ken Nakagawa, Seisuke Nagase, Yusaku Akashi, Minoru Takada, Yasuo Iwamoto, Masahiro Tsuboi
Journal: Journal of Clinical Oncology (2013)

3072 Background: Polysaccharide-K (PSK, Krestin) is a protein-bound polysaccharide, extracted from cultured mycelium of Coriplus versicolor, and is associated with immunostimulatory activity. Although combination use of PSK with chemotherapy has been shown to prolong the response period in patients with small-cell lung cancer (SCLC), the efficacy of PSK in combination chemotherapy including cisplatin has been less examined. We examined safety and efficacy of combination therapy with cisplatin, irinotecan, and PSK in extensive-stage (ED) SCLC. Methods: Eligible pts included: histologically confirmed ED-SCLC without prior chemotherapy, age under 75 years, ECOG performance status ≤ 1, with evaluable disease and adequate organ function. Treatment: irinotecan 60 mg/m 2 on days 1, 8, and 15 and cisplatin 60 mg/m 2 on day 1 every 4 weeks for 4 to 6 courses, and oral PSK 3,000 mg/body daily. The treatment with PSK was continued after the end of cisplatin and irinotecan administrations, and was combined as a part of second-line therapy after exacerbations. Results: Between January 2008 and July 2010, 17 patients were enrolled, and the efficacy and prognosis were evaluated in 15 of 17 patients. Response rate was 66.6%, one-year survival rate was 66.6%, and two-year survival rate was 33.2%. The major toxicities were diarrhea and myelosuppression, and the common toxicity of PSK-containing combination chemotherapy was not observed. Conclusions: The combination chemotherapy with cisplatin, irinotecan, and PSK was effective and well tolerated in ED-SCLC. Clinical trial information: NCT00546130.
Immunohistochemical expression of ezrin correlates with Event-free and overall survival in osteosarcomas
Authors: S. Salas, J. Deville, C. Bartoli, J. Gaudart, G. Bollini, G. Curvale, J. Gentet, F. Duffaud, D. Figarella-Branger, C. Bouvier
Journal: Journal of Clinical Oncology (2007)

10035 Background: Ezrin is a cytoskeleton linker protein that is actively involved in the metastatic process of cancer cells. We have searched for a pronostic value of ezrin and some of its partners: a-smooth actin and CD44H in 37 patients with an osteosarcoma. Methods: Automate immunohistochemistry (IHC) with anti-ezrin, a-smooth actin and CD44H antibodies was performed in 37 biopsies before chemotherapy, 16 resected tumors of “poor” responders and 13 metastases. In addition the mRNA levels of ezrin of 13 frozen biopies and 4 metastases were evaluated by real time quantitative RT PCR. All results were correlated to the following clinical data: response to chemotherapy, onset of metastasis, event-free survival (EFS) and overall survival (OS). Results: Ezrin expression by IHC was found in 62% of 37 biopsies in the different histological subtypes especially chondroblastic osteosarcomas while chondrosarcomas were negative. A good correlation was found between positive or negative samples by IHC and mRNA levels. Ezrin expression was recorded in 84.5% of metastastic samples. The mean expression of ezrin was higher in metastases than biopsies (mean expression 38.1% versus 17.32%; p=0.024) but the onset of metastasis was not statistically correlated to ezrin positivity on biopsy (p = 0.183). In multivariate analysis, ezrin was an independent prognostic marker for EFS and OS with p&lt;0.001 and p=0.003 respectively and a-smooth actin for OS only (p=0.024). No prognostic value was found for CD44H. Conclusions: We have shown that ezrin is expressed in the different subtypes of osteosarcomas especially chondroblastic osteosarcomas. Other studies are required to confirm that ezrin could be a useful tool for differential diagnosis with chondrosarcoma. Ezrin was an independent prognostic factor for event-free and overall survival rate in multivariate analysis and its partner a-smooth-actin was also an independent prognostic factor for overall survival only. These data confirm the role of ezrin signalling pathway for tumor dissemination in osteosarcomas in vivo. This also might be of interest for therapeutic strategy to select patient for dose intensification or to use new anticancer agents such as rapamycin which reduces experimental lung metastases through an ezrin-related pathway. No significant financial relationships to disclose.
Successful integration of genetic counseling in a comprehensive childhood cancer survivorship clinic.
Authors: Shafqat Shah, Gregory John Aune, Lindsey Mette, Natalie Poullard
Journal: Journal of Clinical Oncology (2017)

230 Background: Awareness of inherited genetic risk and cancer predisposition has markedly increased. Research has shown that germline mutations in known cancer predisposition genes are identified in ~8% of pediatric oncology patients. Patients diagnosed years ago did not meet with a Genetic counselor or undergo genetic testing. The annual comprehensive survivorship visit provides cancer survivors an opportunity to review personal and family history and receive Genetic counseling. Methods: Our group initiated a pilot project in our Childhood Cancer Survivorship clinic (CCSC) to assess the feasibility of introducing survivors to a Certified Genetic Counselor (CGC). Initially, a chart review of annual visits that took place over a 3-month period was performed. A record of documentation of family history and genetic counseling was made. During the pilot period, survivors and their families were given the option to meet with a CGC. The CGC prepared a pedigree and made specific written recommendations regarding the indication, if any, for genetic testing in the patient or family. Anonymous post-counseling surveys were mailed to the families to gauge their satisfaction. Results: Prior to the pilot, 38 survivors were seen for annual visits over a 3 month period. Chart review identified no formal genetic counseling. A note of a family history of cancer was made in 1 patient. During the 3 month implementation period, 50 survivors were seen for annual visits. Thirty-four ( ~70%) accepted the offer to see a CGC. Of the 16 that did not meet with a CGC, 3 had significant medical issues that required attention, 2 had Down syndrome and 2 had previous genetic counseling. The rest declined interest with no specific rationale. Very few (3) surveys were returned. All rated the experience highly. Conclusions: Our experience in a multi-disciplinary CCSC supports the feasibility of delivering CGC services to long-term survivors of cancer. A majority of survivors were interested in meeting with the CGC. Further development of this program will focus on educating survivors about cancer predisposition and increasing access to CGC services.
Candidate drug therapies for molecularly defined subgroups of esophageal cancer identified from high-throughput drug screening.
Authors: Irene Yu-Shing Chong, David Cunningham, Richard Elliott, Asha Konde, James Campbell, Malini Menon, Leandra Bowers, Frances Daley, Christopher J. Lord, Alan Ashworth
Journal: Journal of Clinical Oncology (2014)

4039 Background: There is a pressing clinical requirement to identify novel treatment strategies for oesophageal cancers, especially considering the rising incidence and poor patient prognosis. The use of high-throughput small molecule drug screens has the potential to identify therapies not previously acknowledged to be efficacious for individual cancer types. Methods: To identify effective drug therapies for molecularly defined subgroups of patients with oesophageal cancer, high-throughput drug screening was undertaken in 17 oesophageal cancer cell line models using a small molecule library incorporating 78 drugs. Genomic profiles regarding gene mutation and copy number variation for each of the oesophageal cell line models used in the drug screen were obtained from publically available data repositories (Cancer Cell Line Encyclopedia and COSMIC cell line project). Results: Broad spectrum sensitivity across the oesophageal cell line models was observed for targeted agents including PF03758309 (PAK4 inhibitor) and BI2536 (PLK-1 inhibitor). A differential sensitivity between the oesophageal cancer cell lines was observed for other targeted agents including BEZ235 (PIK3CA/mTOR inhibitor). The oesophageal cell lines most sensitive to BEZ235 harboured COSM760 PIK3CA p.E542K, a missense mutation located in the helicase domain. Sensitivity to small molecule tankyrase inhibitors which inhibit the Wnt pathway was most pronounced in OE19, which harbours biallelic methylation of the APC promotor 1A. Single agent in vivo efficacy of a novel tankyrase inhibitor was also demonstrated, with significant differences in tumour weight and volume between the drug and vehicle groups (P=0.0024 and P=0.0048, respectively). Conclusions: High-throughput drug screening of oesophageal cancer cell lines has identified novel sensitivities to drugs including small molecule tankyrase inhibitors. It is possible that promotor hypermethylation of APC contributes towards the activation of Wnt signallng, and may serve as a candidate predictive biomarker for tankyrase inhibitor sensitivity.
Iron deficiency anemia in gastric cancer: A single site retrospective cohort study.
Authors: Grace Tang, Rachel Hart, Michelle Sholzberg, Christine Brezden-Masley
Journal: Journal of Clinical Oncology (2017)

188 Background: Gastric cancer is highly prevalent amongst men and women. While many studies have identified the prevalence and association of iron deficiency anemia (IDA) in all cancer patients, few have focused on the gastric cancer population. The primary objective of this study was to determine the proportion of patients with gastric cancer who developed IDA, and chemotherapy induced anemia (CIA) at our institution. Secondary objectives were to identify types and frequencies of IDA therapies used. Methods: A retrospective study was carried out in 110 consecutive gastric cancer patients from 2006 to 2014 at St. Michael’s Hospital, Toronto, Canada. Patient demographics, previous history of IDA, and IDA based therapies were reviewed. IDA was defined as hemoglobin (Hb) &lt; 130 g/L in men and &lt; 120g/L in women and iron deficiency (ID) was defined as a ferritin &lt; 15m/L. SAS 9.3 was used to calculate frequencies and proportions. Results: Of the 110 patients (median age 68.5 [interquartile range (IQR): 58-76]), 72 (65%) were male. Most patients were diagnosed at stage IV (35%) with a mean Hb of 118 g/L (standard deviation (SD): 19.7 g/L). Only 18 (16%) patients had a history of IDA prior to cancer diagnosis, and 63 (57%) had IDA at time of gastric cancer diagnosis. Only 29 patients (45%) had ferritin levels tested at first oncology visit. Of the 110 patients, 71 patients had an open (32%) or laparoscopic (68%) surgery. A total of 66 patients received chemotherapy, and 50 (76%) developed CIA. In this sample, 9 (14%) experienced a chemotherapy dose delay and 20 (30%) had a dose reduction. At last follow up, 87 (79%) of patients were diagnosed with IDA. Red blood cell (RBC) transfusions were most frequently prescribed (95%), compared to oral (29%) or intravenous iron (12%). Conclusions: A total of 87 (79%) gastric cancer patients were diagnosed with IDA and nearly all patients received a RBC transfusion. We found that the diagnosis of IDA increased by 22% from the time of gastric cancer diagnosis to last follow up. There was a high proportion of IDA in our gastric cancer population despite inconsistent screening for ID. This highlights the need for consistent screening and targeted therapy for ID to reduce transfusions and improve quality of life in this patient population.