tbuckley/cabot-search huggingface dataset:
Experimental therapy of PC-3 and DU-145 human androgen-independent prostate cancers with targeted cytotoxic analog of somatostatin AN-162.
Authors: Ferenc Rick, Andrew Abi-Chaker, Luca Szalontay, Norman L. Block, Gabor Halmos, Andrew V. Schally
Journal: Journal of Clinical Oncology (2013)

236 Background: Management of castration-resistant prostate cancer (CRPC) is challenging because of limitations in efficacy of current therapies. Somatostatin receptors are expressed in human CRPC. Here we tested targeted somatostatin AN-162 analog consisting of doxorubicin (DOX) conjugated to octapeptide RC-121, acting as a carrier, in human androgen-independent prostate cancer cell lines in vitro and in vivo. Methods: Expression of mRNA for the five subtypes of the somatostatin receptor in PC-3 and DU-145 human prostate cancer cell lines was evaluated by RT-PCR. Somatostatin receptor binding was measured with radioligand assays. The effect of AN-162 and DOX on the viability of PC-3 and DU-145 cells was assessed by MTS assay. Nude mice bearing PC-3 and DU-145 tumors were randomized to 5 groups (control, AN-162, DOX, somatostatin analog RC-160 as a control, and DOX + RC-160). Treatment consisted i.v. injections of AN-162, DOX, RC-160, DOX + RC-160, or vehicle once a week for 4 weeks. Tumor volume was measured every week; the study lasted 28 days. The doses of AN-162 were equivalent to 1.45 mg/kg DOX (2.5 μmol/kg). Results: The PC-3 and DU-145 cell lines were positive for the five subtypes of the somatostatin receptor. AN-162 and DOX (0.10–10 µM) inhibited the proliferation of PC-3 and DU-145 prostate cancer cells in a dose-dependent manner. AN-162 exerted a stronger inhibition of proliferation than DOX alone, but in vitro the difference was not significant. In vivo, AN-162 significantly inhibited growth of both tumor models’ compared with the controls and the groups given equimolar doses of doxorubicin, RC-160, or doxorubicin unconjugated to RC-160. Conclusions: Our work demonstrates potent inhibitory effects of AN-162 on somatostatin receptor positive androgen-independent prostate cancers, which were greater than any of the components of AN-162. The mechanisms of action of targeted cytotoxic analog of somatostatin AN-162 in CRPC should be explored. Our findings suggest the possible use of AN-162 in patients with CRPC.
Effects of the P-glycoprotein (Pgp) antagonist tariquidar (XR-9576; TQD) on Pgp function as well as the toxicity and efficacy of combined chemotherapy in patients with metastatic adrenocortical cancer (mACC)
Authors: M. E. Menefee, H. Huang, M. Edgerly, H. Kotz, M. Merino, F. M. Balis, C. C. Chen, R. Robey, S. E. Bates, A. T. Fojo
Journal: Journal of Clinical Oncology (2008)

2543 Background: ACC is a rare tumor optimally treated surgically. ACC expresses high levels of Pgp. We added TQD to a regimen of daily oral mitotane with infusional doxorubicin, vincristine, and etoposide (MAVE) to assess the efficacy of Pgp inhibition in mACC and whether the MAVE regimen could be improved. Methods: 46 pts with mACC received daily mitotane (mean 3.99 g/day) and 96-hour infusional doxorubicin (8 mg/m2/day), etoposide (60 mg/m2/day), and vincristine (0.24 mg/m2/day). Six pts underwent surgery after achieving best chemotherapy response. 99mTc-sestamibi scans obtained before and after TQD administration and rhodamine efflux from CD56+ mononuclear cells were used to assess Pgp inhibition. Results: 46 pts were enrolled and 44 are evaluable for response and toxicity. 54% had functional tumors. A total of 210 cycles were administered. The response rate was 8.7% with a median shrinkage of 13% in the 14% of pts with measurable shrinkage. Two pts have ongoing CRs over 3 years. Two pts had PR with mean duration of response of 15 weeks; 25 pts had stable disease. The median overall survival (OS) was 13.7 months. The predominant G3/4 toxicity was neutropenia in 80% of first cycles. Pegylated G-CSF was given in subsequent cycles. Fever occurred in only 4.7% of cycles. TQD inhibition of Pgp in vivo was marked and sustained as evidenced by 99mTc-sestamibi scans demonstrating inhibition of functional Pgp with a median increase accumulation of 99mTc-sestamibi of 133% (range 10–240%) and 179% (range 38–424%) in mACC lesions and normal liver, respectively, with only a 2% change in the heart. Rhodamine efflux from CD56+ cells was blocked with a median inhibition of 92% at 24 hours and 81% at 48 hours, demonstrating excellent Pgp inhibition in vivo. Conclusions: TQD results in potent and sustained inhibition of Pgp. mACC expresses functional Pgp and this can be blocked by TQD. The myelotoxicity of this regimen was resolved by G-CSF administration. The addition of TQD does not appear to prolong OS in mACC. However, the safety of TQD and its sustained potency warrant its further investigation as a Pgp antagonist in future studies with cytotoxic and novel agents that are Pgp substrates. No significant financial relationships to disclose.
Histological tumor regression after preoperative chemotherapy for colorectal liver metastases: Correlations with radiological response and prognosis.
Authors: Ryo Inada, Shigeyoshi Iwamoto, Masaki Kaibori, Morihiko Ishizaki, Hiroya Iida, Kosuke Matsui, Masaharu Oishi, Tomoko Matsumoto, Taku Michiura, Kentaro Inoue, Masanori Kon, Madoka Hamada
Journal: Journal of Clinical Oncology (2016)

609 Background: The purpose of this study was to characterize histological tumor regression grade (TRG) to colorectal liver metastases (CLM) treated with preoperative chemotherapy followed by liver surgery, and to evaluate whether TRG correlates with radiological response and prognosis. Methods: This study included 30 patients with CLM treated by surgical resection after preoperative chemotherapy with oxaliplatin- or irrinotecan-based regimens with or without molecular target agents. TRG was determined by the amount of fibrosis and necrosis replaced from tumor cells, ranging TRG 0 (0%), 1 (1-24%), 2 (25-50%), 3 (51-99%), and 4 (100%). Results: TRG 0, 1, 2, 3, and 4 were observed in 0%, 6.7%, 10.0%, 66.7%, and 16.6% of the patients, respectively. There were no relations between TRG and regimen, including molecular target agents. As shown in the table, radiological response was not significantly correlated with TRG. Patients with histological major response (TRG 3+4) had better prognosis (MST; TRG 1+2 vs. 3+4: 20.0 vs. 50 months, P= 0.007), and a multivariate analysis identified histological major response as an independent good prognostic factor. Conclusions: In this analysis, histological TRG predicted survival after preoperative chemotherapy and resection for CLM. Preoperative radiological response could not evaluate TRG. [Table: see text]
Therapeutic effect of TAS-102 (A) in patients (pts) with metastatic colorectal cancer (mCRC) refractory to standard chemotherapy by the Köhne model (Km).
Authors: Tomohiro Nishina, Takayuki Yoshino, Nobuyuki Mizunuma, Kentaro Yamazaki, Yoshito Komatsu, Hideo Baba, Akihito Tsuji, Kensei Yamaguchi, Kei Muro, Atsushi Ohtsu
Journal: Journal of Clinical Oncology (2012)

650 Background: TAS-102 is a novel oral antitumor agent consisting of trifluorothymidine and thymidine phosphorylase inhibitor. In the TAS-102 phase II study, TAS-102 significantly improved overall survival (OS) compared with placebo (P) in pts with mCRC who had 2 or more prior regimens and refractory to fluoropyrimidine, irinotecan and oxaliplatin (A: 112pts; P: 57 pts; median OS, 9.0 vs 6.6 months (M); HR, 0.56; p = 0.0011) [K. Yamazaki et al. JSMO 2011 Abst 10428, Y. Kuboki et al. ECCO 2011 Abst 6005]. Km [Ann Oncol 2002; 13:308-317] suggested predictive prognosis marker and showed 4 parameters to classify pts with mCRC treated 5-FU-based first line chemotherapy into 3 risk groups (low risk group (L), intermediate risk group (IM) and high risk group (H)). We retrospectively evaluated TAS-102 phase II study by Km. Methods: Classification of pts into each risk group was done as follows: L is ECOG performance status (PS) 0-1, 1 tumor site; IM is (1) PS 0-1, &gt;1 tumor site, ALP &lt;300 IU/L and (2) PS &gt;1, WBC &lt;10×10 9 /L, 1 tumor site; H is (1) PS 0-1, &gt;1 tumor site, ALP ≥300 IU/L, (2) PS &gt;1, WBC &lt;10×10 9 /L, &gt;1 tumor site and (3) PS &gt;1, WBC ≥10×10 9 /L. Progression-free survival (PFS) was assessed by an independent review committee. Results: Pts were classified as L/ IM/ H in 36/ 31/ 102 pts. The median OS for TAS-102 vs Placebo were in L (not reached vs 10.1M; hazard ratio (HR), 0.62), in IM (9.0 vs 4.9 M; HR, 0.44) and in H (7.6 vs 5.6 M; HR, 0.58). This risk stratified analysis by Km demonstrated that HR of OS and PFS was similar in each risk group (Table). Conclusions: The OS and PFS of TAS-102 were superior to that of placebo in all risk groups by Km. Further prospective TAS-102 phase III study is necessary to confirm these results. [Table: see text]
Higher nuclear grade indicates an invasiveness of ductal carcinoma in breast cancer
Authors: Y. Okumura, R. Nishimura, T. Osako, N. Arima
Journal: Journal of Clinical Oncology (2008)

22228 Background: Invasive ductal carcinoma (IDC) is considered to be formed through ductal carcinoma in situ with microinvasion (DCIS-Mi) from ductal carcinoma in situ (DCIS), and it is important to identify biological factors correlated with progression to IDC from DCIS. We investigated the differences of clinicopathological factors between DCIS and IDC (DCIS-Mi and ductal carcinoma with predominant intraductal component (PIDC)). Methods: The study subjects were 65 cases with DCIS, 12 cases with DCIS-Mi and 41 cases with PIDC who underwent operations in Kumamoto City Hospital from April 2006 to December 2007. We investigated some biological factors such as Ki67, p53, HER2, ER, and PgR status using immunohistochemistry (IHC). Results: The extent of cancerous lesion was slightly wider in PIDC than those in DCIS or DCIS-Mi; 35mm, 28mm, 25mm, respectively. Although breast conservation rates were similar among them, the positive rates of cut margin were higher in PIDC with 52%. Lymph node metastasis was not seen in DCIS, 8% in DCIS-Mi, and 22% in PIDC, and this was a significant difference between DCIS and IDC. Regarding nuclear grade, grade 3 was often seen in PIDC, whereas grade 1 was prominent in DCIS. Thus, nuclear grade significantly correlated with the extent of invasiveness. Moreover, the incidence of comedo necrosis was significantly higher in IDC. In DCIS, there were many cases with low Ki67 values, PgR positive, p53 and HER2 negative. On the other hand, there was no correlation of ER status with the invasiveness. The multivariate analysis revealed that nuclear grade was a significant factor for invasiveness of ductal carcinoma. Conclusions: DCIS had low grade of malignancy compared with IDC (DCIS-Mi, PIDC). Furthermore, nuclear grade significantly correlated the extent of invasiveness of ductal carcinoma. Therefore, we should take the possibility of invasive cancer into consideration when a preoperative core needle biopsy shows features of DCIS with higher nuclear grade. No significant financial relationships to disclose.
Expression of the cap-mediated translation pathway in non-Hodgkins lymphomas: diagnostic and therapeutic implications
Authors: D. Kodali, M. R. Patel, A. Rawal, D. Knapp, H. Mesa, B. Schnitzer, R. A. Kratzke, P. Gupta
Journal: Journal of Clinical Oncology (2008)

8595 Background: The eukaryotic initiation factor (eIF) complex controls cap-mediated mRNA translation. This plays a key role in cancer by mediating expression of proteins critical for cell growth, transformation and tumorigenesis (e.g., cyclin D1, survivin, c-myc, Bcl-2 and VEGF). eIF4 complex (eIF4E, eIF4G and eIF4A) activity is inhibited by eIF4E binding protein-1 (4E-BP1) which thus has tumor suppressor activity. Hyper-phosphorylated 4E-BP1 is unable to bind eIF4E and promotes translation initiation and protein synthesis. Methods: We analyzed eIF complex expression in B-cell non-Hodgkins lymphomas (NHL) using immunohistochemistry (IHC) for total 4E-BP1 and Western immunoblotting (WB) for eIF4G (total), eIF4E and 4E-BP1 (total and phosphorylated). IHC was performed on 37 NHL (9 follicular [FL], 9 diffuse large cell [DLCL], 2 Burkitt’s, 5 mantle cell, 5 extranodal marginal zone/lymphoplasmacytoid, 7 small lymphocytic) and 8 reactive tissues (6 nodes, 2 tonsils). Staining intensity was graded from 0 to 3+. WB was performed on 6 NHL (2 FL, 4 DLCL) and 2 reactive tissues. Results: IHC showed a consistently high level (2–3+) of cytoplasmic 4E-BP1 expression in malignant cells in 36 of 37 NHL samples. In contrast, there was marked regional specificity of cytoplasmic expression in reactive tissues (3+ in the mantle and marginal zone cells but absent/minimal (0- 1+) in germinal centers and T cells). Nuclear expression was seen in 4 NHL samples but not in reactive tissues. Incipient/focal involvement by FL showed 3+ staining in neoplastic follicles. WB showed that phosphorylated:total 4E-BP1 ratio was increased (2-fold over reactive samples) in 3 of 4 DLCL, but not in FL. The levels of expression of eIF4G, total and phospho-eIF4E and total 4E-BP1 were comparable in reactive and NHL samples, as expected in whole tissue lysates. Conclusion: (1) 4E-BP1 detection by IHC offers a sensitive diagnostic tool for distinguishing reactive follicles from neoplastic B-cell proliferations. (2) 4E-BP1 hyper-phosphorylation may be a mechanism that can increase expression of growth and proliferation inducing proteins in aggressive NHL. (3) These findings provide the rationale for evaluating cap-dependent translation inhibition as a novel therapeutic strategy in NHL. No significant financial relationships to disclose.
Quantifying the psychosocial needs of cancer patients and associated provider workload to build PSO services into the funding model for systemic treatment in Ontario.
Authors: Victoria Zwicker, Tory Andrien, Irene Blais, Esther Green, Zahra Ismail, Leonard Kaizer, Carlin Lalonde, Vicky Simanovski, Reena Tabing
Journal: Journal of Clinical Oncology (2014)

18 Background: As part of a broader set of provincial health funding reforms, Cancer Care Ontario (CCO) developed a new funding model for systemic treatment. A decision was made to build dedicated funding for psychosocial oncology (PSO) services into the model. The objective of this work was to estimate the psychosocial needs of cancer patients and the associated PSO provider workload to inform the incorporation of these services into the model. Methods: PSO clinicians formed advisory groups for six disciplines: social work, psychology, nutrition, physiotherapy, occupational therapy, and speech language pathology. For each cancer type, treatment intent, and phase of the cancer journey, advisors were asked to estimate: 1) proportion of patients who need services, 2) length of an average visit, and 3) average number of visits needed to address patient needs. Groups utilized online surveys to generate estimates to serve as a starting point for discussion. Evidence was used to inform the advisory groups’ consensus when available. Results: Each group produced recommendations based on estimated patient needs and associated workload. For example, the dietitian group recommended that prior to beginning systemic treatment, 50% of lung cancer patients receive a first consult visit (~75 minutes), followed by 1-2 follow up visits (~30 minutes each). Direct activities for these visits included nutrition assessment, weight loss management, and managing symptoms such as dysphagia. Indirect activities included documentation, chart review, and making referrals. Conclusions: This was an initial attempt to measure PSO workload based on patient needs, and the consensus process used could be leveraged by other jurisdictions. This work allowed the identification of specific funding for PSO services for patients who undergo systemic treatment in Ontario. Limitations included a lack of rigorous evidence and the complex nature of the funding model. Further efforts are underway to refine the recommendations and to leverage this work for quality improvement purposes.
Axitinib: Common questions related to real-world use of a new treatment option in advanced renal cell carcinoma.
Authors: Diane Lorraine Borst, Lillian Shahied Arruda, Elizabeth A. MacLean, Yazdi K. Pithavala, James E. Morgado, Nikhil Sharma
Journal: Journal of Clinical Oncology (2014)

538 Background: Axitinib is a next generation VEGFR inhibitor approved in the US in Jan 2012 for advanced RCC after failure of one prior systemic therapy. Post approval questions may arise in the medical community regarding clinical scenarios which may not have been addressed in the clinical trials. We present the most common inquiries for axitinib submitted to Pfizer US Medical Information (MI) during the first 18 months post FDA approval and review available information that addresses these questions. Methods: MI inquiries were analyzed during the 6-mo period immediately post FDA approval and a second 6-mo period approximately 1 yr later. To gain insight into real-world dosing patterns, de-identified prescription data from Feb 2012-July 2013 obtained from the 21 specialty pharmacies (SP) in the US that distribute axitinib (Inlyta) were analyzed. Algorithms were developed to define dose modifications using dosage strengths dispensed and time between prescription fills over 2 day and 14 day windows. Results: The most frequent inquiries (&gt;5%) common to both time periods included use in patients (pts) who were unable to swallow medication, use in patients with renal impairment (RI), and general dosage and administration questions. A method for preparation of an axitinib oral suspension for NG tube administration was developed for use in pts unable to swallow axitinib tablets. No dose adjustments are recommended for pts with RI; however axitinib should be used with caution in pts with end stage renal disease. The most common dose dispensed, using a 2 day window, was 5 mg bid, comprising 9659 (70%) of all dispensed prescriptions, with 789 (6%) at the 10 mg bid dose. An assessment of the most recent 7 months in the evaluation period shows that 16% and 19% of prescriptions were for doses &gt;5 mg bid or &lt;5 mg bid, respectively. Similar findings were observed using a 14 day window. Conclusions: Axitinib questions in the medical community revolve primarily around use in specific populations and dosing. Analysis of SP data revealed that dose modifications occurred at a lower frequency than observed in clinical trials. Further analysis is needed to understand outcomes associated with the dose modifications made in these patients.
Population-attributable risks for modifiable lifestyle factors and breast cancer in New Zealand women.
Authors: James Hayes
Journal: Journal of Clinical Oncology (2013)

15 Background: Breast cancer is an important cause of illness and death in New Zealand women. It is the most commonly registered cancer in women, and the second most common cause of cancer death in women. In 2009, 2,759 women were diagnosed with breast cancer and 658 women died from breast cancer. The incidence of breast cancer is projected to stabilise in New Zealand, but the actual number of women diagnosed with breast cancer will increase because of the increasing proportion of older people and increasing size of the population. Methods: Estimates of the magnitude of modifiable lifestyle risk factors for breast cancer (relative risks and odds ratios obtained from published epidemiological studies) and the prevalence of exposure in New Zealand were used to calculate the population attributable risk percent (PAR%) for each risk factor. The PAR%s show the relative importance of these risk factors, and give an indication of the potential impact of reducing the prevalence of these lifestyle risk factors on the incidence of breast cancer in New Zealand. Results: Six modifiable lifestyle factors were identified for breast cancer. These were obesity, lack of physical activity, high alcohol intake, oral contraceptive use, hormone replacement therapy (HRT), and delayed first birth. The PAR%s for these risk factors ranged from 1% for delayed first birth to 10% for obesity (16% for Maori women and 17% for Pacific women). Conclusions: The most important primary preventive strategies to reduce the risk of breast cancer in New Zealand are promoting lifestyle changes to reduce obesity, promoting regular physical activity (which may in turn reduce the prevalence of obesity), reducing HRT use, and avoiding high alcohol intake. A strategy to promote regular physical activity and reduce obesity could also have other benefits, such as reduced risks of cardiovascular disease and diabetes.
A novel interaction of genotype, gender, and adjuvant treatment in survival after resection of stage III colon cancer: Results of CALGB 89803.
Authors: Robert S. Warren, Chloe Evelyn Atreya, Donna Niedzwiecki, Robert J. Mayer, Richard M. Goldberg, Carolyn C. Compton, Vivian K. Weinberg, Monica M. Bertagnolli
Journal: Journal of Clinical Oncology (2012)

3517 Background: The p53 tumor suppressor is frequently mutated in colon cancer, but the influence of such mutations on survival is remains undefined. We investigated whether domain-specific mutations in p53 are predictive of survival in stage III colon cancer. Methods: p53 was evaluated in an intergroup trial (CALGB 89803) of patients with stage III colon cancer who were randomized to receive adjuvant 5-fluorouracil/leucovorin (5FU/LV) or 5FU/LV with irinotecan (IFL) Tissue was collected to allow correlation of molecular markers with outcomes. p53 was genotyped in 607 patient tumors. Results: p53 mutations were identified in 274 tumors, divided ~ equally between zinc binding and non-zinc binding regions of the DNA binding domain. Overall, p53 status was not predictive of benefit from either adjuvant regimen. Unexpectedly, the 5 year overall survival (OS) of women with tumors harboring non-zinc binding mutations treated with 5FU/LV was 97% compared to OS of 72% for women with p53 wild-type (wt) tumors (p =0.004). Adding irinotecan to 5FU/LV negated this survival benefit (5 year OS of 81% vs. 72%). Conversely, 5 year OS of women harboring tumors with zinc binding mutations who received 5FU/LV was 50% compared to 72% for women with p53 wt tumors (p=0.04). Adding irinotecan to 5FU/LV reversed the poor survival of women with tumors harboring zinc binding mutations and improved 5 year OS (50% vs. 73%; p=0.1). No difference in OS was observed for men on either treatment arm or when genotype was considered. Conclusions: CALGB 89803 demonstrated a lack of survival benefit for stage III colon cancer patients when irinotecan was added to 5FU/LV (IFL). We now show that in the setting of a large clinical trial, refined stratification of women, based upon domain- specific mutations of p53 identifies subsets of patients likely to benefit from, or respond poorly to, adjuvant 5FU/LV. The interaction of p53 genotype, gender, and adjuvant therapy regimen has the potential to be paradigm changing in the treatment of colon cancer, and possibly other malignancies. These data, if validated, suggest that evaluation of p53 genotype and gender may guide clinicians to make rational choices of adjuvant therapy.