tbuckley/cabot-search huggingface dataset:
Capecitabine (C), oxaliplatin (OXP), and radiation (RT) in resectable esophagus cancer (EC): A phase II trial with gene expression profiling (GEP)
Authors: N. I. Khushalani, J. Miecznikowski, D. Wang, N. Nowak, H. Nava, M. E. Nava, W. Tan, R. Iyer, G. Yang, L. Pendyala
Journal: Journal of Clinical Oncology (2009)

e15543 Background: Novel chemotherapy regimens in combination with RT aim to improve the pathologic complete response (pCR) in EC. Following our dose-finding phase I study, the present phase II neo-adjuvant (NA) EC trial was designed to examine the pCR rate using C, OXP and RT, with secondary end-points of evaluating toxicity, quality of life, and GEP of tumor tissue for correlation to therapeutic response. Methods: EC patients (PTS) with stages II-IVa, adequate organ function and performance status (ECOG 0–1) were eligible. Treatment consisted of OXP, 85mg/m 2 iv on days 1, 15 and 29, C (oral or enteral tube) 625 mg/m 2 bid on days of RT, and 50.4 Gy RT (3-D conformal) in 28 fractions, followed by an esophagectomy (E) 4–6 weeks later. 2 cycles of OXP + C were administered post-operatively. GEP using Agilent microarrays was conducted on primary tumor tissue pre-treatment (Rx), day (D) 17 and at E; &gt; 50% viable tumor cells were required. Results: 20 PTS have been enrolled (17 male, 3 female); median age 59.5 yrs; 17 adenocarcinomas &amp; 3 squamous-cell cancers. Clinical stage: II (3), III (13) and IVa (4). 18 PTS have completed NA therapy; Grade 4 toxicity includes anemia (1), lymphopenia (2); grade 3 toxicity includes esophagitis (1), pneumonia (1), wound infection (1), anastomotic leak (2), esophageal fistula (1), bowel obstruction (1), fatigue (1), hyperbilirubinemia (1), elevated ALT, AST (1 &amp; 2, respectively), hypoalbuminemia (3), OXP hypersensitivity (2) &amp; leucopenia (1). One PT died &gt; 60d post- operatively secondary to infection. 15 PTS have undergone an E with 3 pCR (20%). Analysis on pre-Rx GEP on 17 PTS revealed a distinct pattern for pCR PTS with 325 over-expressed and 79 under-expressed genes. Ongoing functional analysis will characterize GEP changes in 1) pCR PTS pre-Rx &amp; at D17, 2) pCR &amp; non-pCR PTS pre-Rx, and 3) by histology. Validation will be performed via RT-PCR. Accrual to the trial continues. Conclusions: C, OXP &amp; RT appears to be a tolerable and efficacious NA regimen for EC. The exploratory GEP analysis may provide insight on predicting response to NA therapy. Acknowledgement: The study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support provided by Roche Laboratories, Inc. [Table: see text]
Dachshund 2 protein, a novel neuroendocrine marker associated with favorable tumor characteristics and clinical outcome in colorectal cancer.
Authors: Sakarias Wangefjord, Hans Brunnstrom, Bjorn Nodin, Mathias Uhlen, Jakob Eberhard, Karin Jirstrom
Journal: Journal of Clinical Oncology (2013)

e14580 Background: The dachshund (DACH) gene encodes a nuclear protein and transcription factor that regulates metazoan development of eyes, limbs, brain, gonads and endocrine tissue. DACH2, one of two human homologues, has recently been identified as a marker of poor prognosis in epithelial ovarian cancer, but its further role in tumorigenesis and expression in normal and cancerous human tissue has not been described. Methods: In this study, immunohistochemical expression of DACH2 was evaluated in tissue microarrays with tumours from 539 cases of incident colorectal cancer in the Malmö Diet and Cancer Study. Chi Square and Spearman’s correlation tests were used to explore the associations between DACH2 expression, clinicopathological characteristics and investigative parameters. Kaplan-Meier analysis and Cox proportional hazards modelling were used to assess the relationship between DACH2 expression and cancer specific survival (CSS). Furthermore, given its distinct expression in various endocrine normal tissues and tumours in the Human Protein Atlas, we also compared DACH2 expression with a standard panel of neuroendocrine markers in 20 carcinoid tumours. Results: DACH2 expression correlated negatively with TNM-stage, differentiation grade, vascular invasion and microsatellite instability, and positively with older age, distal tumour location and expression of p27, cyclin D1, p53 Ki-67 and beta-catenin. DACH2 expression was significantly associated with an improved CSS in the whole cohort and in cases with tumour located in the colon but not rectum. These associations did however not remain significant in multivariable analysis, adjusted for established clinicopathological factors. Furthermore, DACH2 was highly expressed in all examined carcinoid tumours, with a better diagnostic performance than the majority of established markers. Conclusions: Our findings demonstrate a strong link between DACH2 expression and favourable clinicopathological characteristics and outcome in CRC. Moreover, DACH2 is abundantly expressed in neuroendocrine tumours, and its utility as a diagnostic tool for this entity warrants further study.
Radical surgery (RS) plus intraperitoneal hyperthermic perfusion (IPHP) with oxaliplatin followed by intravenous docetaxel in the treatment of peritoneal carcinosis from platinum-sensitive recurrent ovarian cancer (OC): A pilot study
Authors: A. Fagotti, G. Ferrandina, I. Paris, A. Mari, F. Legge, F. Fanfani, G. Facchini, G. Scambia
Journal: Journal of Clinical Oncology (2007)

16077 Background: Much attention has been focused on the efficacy of radical surgery (RS) plus intraperitoneal hyperthermic perfusion (IPHP) in peritoneal carcinosis from recurrent OC. Methods: A pilot study aimed at analyzing the feasibility, morbidity, and toxicity of RS/IPHP and adjuvant chemotherapy has been carried out. Patients with recurrent, platinum-sensitive OC (PFI-&gt;6 months), have been enrolled. RS has been performed with peritonectomy procedures. The perfusion of the abdominal cavity has been achieved using 2 liters/m 2 of 5% dextrose solution with oxaliplatin 460 mg/m 2 , preheated (41.5°C), and infused through the closed abdomen technique. After RS/IPHP, patients have received systemic chemotherapy with docetaxel (75 mg/mq), day 1, every 21 days, for 6 cycles. Results: As of December 2006, 14 patients underwent RS/IPHP: median age was 48.5 yrs (range 34–62). Ten (71.4%) patients had an ECOG PS=0. Median PFI was 24 months (range 7–72). TMedian value of PCI was 6 (range 2–10). Completeness of cytoreduction was 0 in 12 cases and 1 in 2 cases. Median EBL was 700 cc (range 400–1,600) and median number of blood transfusion was 3 (range 0–11). Median length of hospitalization was 15.5 days (range 8–27). We documented 3 cases of sepsis, 1 case of wound dehiscence requiring surgical intervention, 1 case of pleural effusion requiring thoracentesis, and 6 cases of post-operative haemorrhage, treated with surgical re-intervention (n=1), endoscopic cauterization (n=3), or blood transfusions (n=2). Ten patients underwent chemotherapy (total number of cycles= 49): grade 3 and 4 leukopenia occurred in 1, and 2 cases. Three patients (21.4%) experienced severe onicolysis and conjunctivitis. No deaths from this regimen was registered. With a median follow up of 7 months (range 1–18), 2 progressions of disease were observed. Conclusions: RS/IPHP utilizing intraperitoneal oxaliplatin followed by i.v. adjuvant docetaxel was shown to be a feasible approach to peritoneal recurrence of ovarian cancer. No significant financial relationships to disclose.
Risk of second malignant neoplasms (SMN) 20 years after childhood cancer: The updated experience of the Childhood Cancer Survivor Study (CCSS)
Authors: D. L. Friedman, J. Whitton, Y. Yasui, A. C. Mertens, S. Hammond, M. Stovall, S. Donaldson, A. T. Meadows, L. L. Robison, J. P. Neglia
Journal: Journal of Clinical Oncology (2004)

8509 Background: Survivors of childhood and adolescent malignancies are at increased risk for SMN but there are limited data regarding risks 20+ years following diagnosis. Objectives: To determine the incidence and risk factors for SMNs in a well-defined cohort of childhood cancer survivors. Methods: Among the CCSS cohort of 20,720 5-yr survivors (diagnosed 1970–86), SMNs are ascertained and verified by pathology reports. Age- and sex-standardized incidence ratios (SIR) were calculated using US Surveillance, Epidemiology and End Results (SEER) data. Results: As of June 2003, there were 914 verified SMNs among 14,352 survivors with 198,277 person years of follow-up (including 404 cases of non-melanoma skin cancer (NMSC, 4.3% 20-yr cumulative incidence). Excluding NMSC from the analyses, the overall SIR is 3.9 (95% CI 3.5, 4.2) with a 20-yr cumulative incidence of 5.2%. The 20-yr cumulative incidence of SMN, by original diagnosis: Hodgkin disease (13.9%), Bone tumor (6.6%), Soft tissue sarcoma (5.8%), CNS tumor (3.1%), Leukemia (2.5%), Wilms tumor (2.8%), non-Hodgkin lymphoma (4.0%) and Neuroblastoma (2.7%). Five-year survivors are at significantly increased risk (SIR; 95% CI) for CNS tumors (9.2; 6.9, 12.1), breast cancer (12.7; 10.6, 15.2), bone tumor (14.2; 10.2, 19.9), thyroid cancer (10.5; 8.3, 13.2), soft tissue sarcoma (8.0; 6.1, 10.4), leukemia (6.5, 4.6, 9.1) and melanoma (2.2, 1.5, 3.4). Analyses according to yrs from diagnosis of original cancer demonstrates that risk of SMN remains elevated over time for all survivors, with risks highest for those exposed to radiation therapy. Conclusions: Survivors of childhood cancer are at increased risk for second malignancies for >20 yrs from diagnosis. Further study is warranted to better define risk factors, develop effective surveillance and preventive strategies and determine lifetime excess risk. No significant financial relationships to disclose.
Zoledronic acid as adjuvant therapy for women with early stage breast cancer and disseminated tumor cells in bone marrow
Authors: A. Y. Lin, J. W. Park, J. Scott, M. Melisko, A. Goga, M. M. Moasser, D. H. Moore, H. S. Rugo
Journal: Journal of Clinical Oncology (2008)

559 Background: DTC in BM is associated with an increased risk of distant recurrence (DR) and death in patients (pts) with ESBC, particularly when these cells are detected after adjuvant therapy. Bisphosphonates can act as antitumor agents by various mechanisms including induction of tumor cell apoptosis. Clodronate in pts with DTC at BC diagnosis reduced the incidence of metastases and improved survival. ZA is significantly more potent than clodronate in inhibiting bone resorption. We designed a pilot study to evaluate ZA in pts with ESBC with DTC. Decrease in DTC could serve as a surrogate marker of antitumor effect. Methods: DTCs are detected by immunomagnetic enrichment + flow cytometry (FC): BM is enriched with anti-EpCAM-conjugated iron particles, DTC are detected with EpCAM, CD45, and nucleic acid content. Pts with stage I-III BC are evaluated for DTC with a unilateral BM aspiration following neoadjuvant or adjuvant CTX; eligibility was defined as >4 DTC/ml, which is 2.5 SD > than 50 normal BM (Park, Proc ASCO 2002). Pts receive 4 mg of ZA IV monthly x 2 years (yrs). Concomitant hormone therapy is allowed. Serum creatinine and toxicity are evaluated monthly, urinary n-telopeptide is measured at 0, 2, 4, 6, 12, 24 mo, and peripheral blood (PB) DTC q 6 mo for 2 yrs. Repeat BM is performed at 1 & 2 yrs. Results: 45 pts are enrolled. We report an interim analysis of baseline, one & 2 yr BM results. The mean DTC at baseline is 25.6 DTC/ml (range 4.9–332 DTC/ml), mean FU is 19.8 mo (range: 2 to 38 mo). Baseline DTC >30 DTC/ml predicts DR (p=0.007). 35 pts have received >12 mo ZA. 32 had BM at 1 yr, 25/32 pts (66%) had a decrease in DTC (p=0.0018). 17 pts had BM at 2 yrs, 12/17 pts (71%) had a decrease in DTC (p=0.01). 26/45 pts had positive DTC in PB at baseline (mean 0.4 DTC/ml, range 0–8.6 DTC/ml). Five BC recurrences occurred in the first yr (ave TTR 5.2 mo); all pts were node+, and negative for ER, PR, HER2/neu. ZA was well tolerated with 1 pt stopping ZA with side effects. Conclusions: Serial detection of DTC in BM is feasible in pts with early stage BC. High baseline BM DTCs predicted early DR, and DTCs decreased over the treatment period. This preliminary data suggests that ZA decreases the number of DTC in ESBC. The study is ongoing, updated data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis, Novartis Oncology
A randomized, double-blinded, placebo-controlled trial of oral alpha lipoic acid to prevent platinum-induced polyneuropathy.
Authors: Y. Guo, J. L. Palmer, A. Forman, S. R. Dakhil, M. R. Velasco, M. Weiss, P. Gilman, G. M. Mills, S. J. Noga, C. Eng, M. J. Overman, M. Fisch
Journal: Journal of Clinical Oncology (2011)

9010 Background: Platinum-induced peripheral neuropathy may cause pain, function loss, and can be a dose-limiting factor for cancer treatment. The neurotoxicity can be irreversible; therefore prevention of chemotherapy-induced neuropathy is necessary. Our aim is to determine if α-lipoic acid (ALA, thioctic acid) can prevent peripheral neuropathy for patients (pts) receiving platinum-containing chemotherapy. Methods: Adult cancer pts were randomized to receive either 600 mg ALA or placebo (2 large pills) three times a day for 24 weeks while receiving platinum-base chemotherapy. Neuropathy was measured by FACT/GOG-NTX score and NCI-CTC neurotoxicity grade. Results: Of 243 pts randomized, 121 pts (51%) completed treatment for 12 weeks and 84 pts (35%) for 24 weeks. Of these, 70 pts completed FACT/GOG-NTX assessments at baseline and at 24 weeks. At baseline, the ALA (n =122) and placebo (n =121) groups were comparable for age (55±11 vs. 57±12 years), gender (54% vs 52% male), prior platinum exposure, and FACT/GOG-NTX score. At 24 weeks, only 34 evaluable pts remained in the ALA group, and 36 in the placebo group (p= 0.75). Pill size and dose frequency were frequent concerns regarding adherence. No statistical difference was noted in dose intensity for the oxaliplatin arm of the ALA group and the placebo group (median of 765 mg/m2 vs. 1020 mg/m2, p=0.18). No significant differences were noted for either FACT/GOG-NTX scores (p=0.70), neurotoxicity (p=0.87), or best tumor responses between the 2 groups (p=0.85). Conclusions: Oral ALA 600 mg PO TID was ineffective at preventing neurotoxicity caused by oxaliplatin or cisplatin. Intense schedules of oral agents in the symptom/toxicity prevention setting created adherence challenges due to pill size and frequency of administration. Poor adherence might affect the power to detect ALA’s effectiveness in this trial. Innovative drug delivery and trial designs are needed to further explore alpha lipoic acid in the prevention and/or reduction of chemotherapy-induced neuropathy.
Association between serum levels of clara cell secretory protein and lung function in adults from ECRHS
Authors: Marta Rava, Lluisa Tares, Iris Lavi, Esther Barreiro, Jan-Paul Zock, Anna Ferrer, Nerea Muniozguren, Rachel Nadif, Francine Kauffmann, Josep M. Anto, Stefano Guerra
Journal: European Respiratory Journal (2012)

The 16-kD Clara cell secretory protein (CC16) has anti-inflammatory properties and protective effects from oxidative stress on the respiratory tract and has been proposed as a biological marker of pulmonary health. Whether CC16 is associated with lung function and airflow limitation in the general population remains unknown.

We measured CC16 in serum samples of 851 participants (mean age 41 yrs; 51% women) of 3 Spanish ECRHS centres using an immunoassay. Lung function parameters (FEV1% and FVC% predicted and FEV1/FVC), airflow limitation (AL) defined by Gold criteria (FEV1/FVC<0.70) were considered. All the analyses were adjusted for center, sex, age, smoking, pack-years, body mass index (BMI), and height. Mean CC16 level was 5.8 (sd=2.9), ranging from 0.4 to 19 µg/l. FEV1% predicted and FEV1/FVC increased with increasing CC16 levels.

View this table:



This association was stronger in asthmatics (2.6% increase (95% CI 0.6-4.5) in FEV1/FVC) as compared to non-asthmatics (0.6%; CI 0.1-1.0) (p for interaction 0.01). CC16 levels were lower in subjects with moderate/severe AL (4.1 µg/l, p from multivariate multinomial regression=0.04), but not in those with mild AL (5.7 µg/l, p=0.9) compared to subjects with no AL (5.9 µg/l). This study shows that reduced CC16 levels are associated with lower lung function and moderate/severe airflow limitation in the general population.

Funded by Spanish FIS ISCIII PS09/01354 and ERS fellowship 123-2011.
SWOG S0354: A phase II trial of CNTO328, a monoclonal antibody against interleukin-6 (IL-6), in chemotherapy pretreated patients (pts) with castration- resistant prostate cancer (CRPC)
Authors: J. K. Pinski, B. Goldman, T. Dorff, P. Mack, P. Lara, P. van Veldhuizen, D. Quinn, M. H. Hussain, I. M. Thompson
Journal: Journal of Clinical Oncology (2009)

5143 Background: IL-6 facilitates cancer cell survival via pleiotrophic effects on proliferation, apoptosis, angiogenesis, differentiation, and chemo-resistance. A multicenter phase II study of CNTO328 in chemo pretreated CRPC pts was conducted. Methods: Eligible pts had one prior chemotherapy, Zubrod performance status 0–2, and adequate end-organ function. Regimen: CNTO328 6 mg/kg IV q2 weeks x 12 cycles. Response assessment was q6 weeks. Primary endpoint was PSA response rate (RR) defined as ≥50% reduction. Accrual was completed in 2 stages, with planned accrual of 20 eligible pts in the first stage and 40 overall. Plasma cytokines were measured by Luminex in 44 pts. Results: Of 62 pts, 54 were eligible; all had received prior taxane therapy. Two (3.7%; 95% CI: 0.5%, 12.8%) had PSA response. Of 47 pts evaluable by RECIST, none had a response and 10 (21%) had stable disease (SD). With median follow-up of 6.6 months, median progression-free survival is 1.6 months (95% CI: 1.6, 1.7). Grade 4 toxicity included 1 case of DIC and 1 CNS ischemia; grade 3 toxicities included elevated AST (1), gastritis/esophagitis (2), thrombocytopenia (2), pain (2), leucopenia (1), and neuropathy (2). Median baseline IL-6 levels were 12.5 pg/mL (IQR: 2.5, 41.5). Pts with levels &gt;12.5 pg/mL had worse 6-month survival vs. &lt; 12.5 pg/mL (53% vs 94%, p = 0.02). Post-cycle 1, IL-6 levels were &gt; 250-fold higher, indicating antibody-target complex formation. 33/39 pts had a decline in C-reactive protein (CRP) plasma levels at 6 weeks. Conclusions: CNTO328 was well-tolerated and resulted in a PSA RR of 3.7% and RECIST SD rate of 21%. Declining CRP levels during treatment reflect biologic activity. Elevated baseline IL-6 levels portend a poor prognosis. Additional translational studies will be presented. Additional study of CNTO328 in combination may be warranted. [Table: see text]
Using epigenetic reprogramming to target triple-negative breast cancer
Authors: D. Sharma, B. B. Knight, R. Yacoub, T. Liu, L. Taliaferro-Smith, A. Nagalingam, R. M. O'Regan
Journal: Journal of Clinical Oncology (2009)

e14565 Background: The outcome for patients with breast cancer has been significantly improved by the use of targeted agents. The prognosis of triple negative (TN) breast cancers, which do not express hormone receptors (ER, PR) or Her2, is poor, because of an aggressive clinical course and lack of targeted therapeutic agents. Epigenetic silencing of specific genes has been observed in breast cancer and some of these genes are more important due to available targeted therapies such as ER. Since all endocrine therapies are designed to block ER function in some way, the identification of new therapies or strategies that could sensitize TN breast cancers to existing endocrine therapy could provide a revolutionary means of treating this aggressive subtype of cancer Methods: We examined the efficacy of combined treatment of HDAC inhibitor LBH589 and DNMT inhibitor decitabine to regenerate ER and PR in TN breast cancer cells using RT-PCR and immunoblotting. Changes in growth and proliferation of TN breast cancer cells in response to LBH589 and decitabine treatment were determined by XTT, BrdU incorporation and colony formation assay. Changes in apoptotic proteins were determined by western blotting. Athymic nude mice were used to establish pre-clinical models for TN breast cancer cells and effectiveness of combined treatment of LBH589 and decitabine was determined. Tumors biopsies were analyzed for ER and PR re-expression by western blot analysis and immunohistochemistry at the end of the treatment. Results: Combined treatment of LBH589 and decitabine resulted in re-expression of ER and PR in TN breast cancers in vitro and in vivo. Although re-expression of ER and PR were noted following LBH589 treatment alone, re-expression was more robust with the combination. TN breast cancer cells showing re-expressed ER can be targeted with tamoxifen. Tamoxifen inhibits growth of TN breast cancer cells re- expressing ER by triggering apoptosis. Conclusions: The importance of epigenetic events such as DNA methylation and HDAC inhibition in tumor progression is becoming increasingly evident. A trial evaluating the ability of LBH589 and decitabine to re- express ER, which can then be targeted by tamoxifen, is planned in patients with metastatic TN breast cancer. No significant financial relationships to disclose.
Primary invasive melanoma on the head and neck: Distribution, ultraviolet exposure and histological subtype in 1,298 Australian patients
Authors: G. V. Long, B. K. Armstrong, M. H. Colman, H. M. Shaw, J. F. Thompson, K. A. Crotty
Journal: Journal of Clinical Oncology (2007)

8541 Background: The aim of this study was to determine the subsite distribution of invasive cutaneous melanoma of the head and neck and correlate this with the melanoma histologic type and ultraviolet exposure (UVE) at each particular subsite. Methods: This study comprised 1,298 patients seen at the Sydney Melanoma Unit (SMU) between 1990 and 2000. In each case, the histopathologic diagnosis of invasive melanoma was established by highly experienced SMU histopathologists. Histologic details, gender and patient age at diagnosis were available in all patients except in 5% in whom Breslow thickness could not be determined. Nine head and neck subsites were assigned: scalp, forehead, eyelids, nose, lips, chin, ears, face and neck. The relative tumour density (RTD) at each subsite was then examined in relation to gender and age of the patient and the relative UVE at this subsite. Relative UVE values as determined using polyusulphone UV dosimeters were used. Results: There was a direct correlation between high UVE and RTD at each subsite except the forehead (135 patients) and neck (335 patients), particularly in women, with the neck subsite prevailing in patients &lt;50 years of age. Superficial spreading melanoma was the most common histologic type at all subsites except the lips (15 patients), nose (53 patients) and chin (15 patients), where desmoplastic melanoma predominated. Lentigo maligna melanoma was not more common on subsites having high UVE, nor was there an obvious association between melanoma thickness and UVE. Conclusions: The UVE was an important determinant of melanoma distribution on the head and neck. The lower RTDs at the forehead and neck subsites in women were possibly due to gender differences in hairstyles. Paradoxically, lentigo maligna melanoma, commonly considered to occur almost exclusively on sun-damaged skin, was not more common on areas of high UVE. No significant financial relationships to disclose.