tbuckley/cabot-search huggingface dataset:
Association of elevated matrix metalloproteinase-9 (MMP-9) mRNA expression levels with resistance to chemotherapy and survival in patients with metastatic gastric cancer receiving first-line chemotherapy: Results from the FLO versus FLP gastric cancer phase III trial of the AIO
Authors: S. Al-Batran, R. M. Wirtz, C. Pauligk, K. Steinmetz, S. Probst, J. T. Hartmann, R. Hofheinz, H. M. Altmannsberger, C. Petry, E. Jäger
Journal: Journal of Clinical Oncology (2008)

4544 Background: MMP-9 has been implicated in invasion and metastasis of cancer, but little is known about its prognostic role in patients (pts) with metastatic gastric cancer undergoing chemotherapy. Methods: Tumor samples from pts who received first-line 5-fluorouracil, leucovorin and platinum for metastatic gastric cancer within a phase III trial of the AIO were prospectively collected and analyzed. The expression of MMP-9 mRNA was assessed by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Moreover, EGFR, pAKT, pMAPK, HER2/neu, Ki-67, CD8+ cell and macrophage accumulation and VEGF-A were evaluated (by qRT-PCR and/or immunohistochemistry). Results: Overall, 288 samples from 168 out of 220 pts enrolled were analyzed for at least one of the marker. 158 samples of 109 pts have been assessed for MMP9 mRNA so far; 96 pts were eligible for the analysis. In this cohort, increased MMP-9 levels were strongly associated with resistance to chemotherapy and shorter progression-free and overall survival. At the cut-off with the highest predictive value, the rate of disease progression as best response associated with elevated MMP9 expression was 50% (versus 22.4%; fisher's test p=0.0276) and the relative hazard ratio for death was 2.653 (95% CI, 2.060 - 9.268); log rank p<.0001). The prognostic value for survival was maintained when data were categorized according to the median (p=.024) or quartile (p=0.004) distributions for MMP-9 expression. Interestingly, elevated MMP-9 levels were associated with more lymph node and peritoneal and less liver involvement and correlated with increased intratumoral VEGF-A levels. Other correlative analyses will be presented at the meeting. Conclusions: The association of MMP-9 expression with poor response to chemotherapy, and shorter survival suggests that MMP-9 is linked not only to early invasion and metastases formation, but also to an aggressive clinical course in metastatic disease. Thus, MMP-9 mRNA expression levels may represent a valuable marker for novel anti-protease treatment strategies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Siemens
Prognostic markers for response and overall survival in patients with esophageal adenocarcinoma treated with neoadjuvant therapy.
Authors: J. M. Leers, G. Lurje, D. Yang, A. Oezcelik, J. A. Hagen, S. R. DeMeester, T. R. DeMeester, H. Lenz
Journal: Journal of Clinical Oncology (2010)

4123 Background: Neoadjuvant therapy has been introduced to improve survival in patients with localized esophageal adenocarcinoma (EA). Yet, the benefit of neoadjuvant for patients with EA is still under debate as only about one third of treated patients respond. The identification of molecular markers that predict response to neoadjuvant therapy will be critical to tailor the appropriate therapy for these patients. Methods: We investigated tissue samples from 104 patients (94 males and 10 females with a median age of 60 years [range: 29-86]) with localized esophageal adenocarcinoma treated with 5-FU based neoadjuvant therapy at USC. A panel of ten genes involved in DNA repairs and 5-FU metabolism were selected. DNA was isolated from formalin-fixed paraffin-embedded normal esophageal tissue samples and germline polymorphisms were analyzed using PCR-RFLP and 5′-end [γ-33P] ATP-labeled PCR methods. Fisher's exact test was used to examine the associations between polymorphism and complete pathological response. Kaplan-Meier curves, log-rank test and Cox proportional hazards model were used for their associations with overall survival. Results: 31 out of 104 patients (30%) had complete pathological response. The median overall survival was 18.5 months (95% CI: 13.5-25.7). Single nucleotide polymorphism ERCC1 118T CC (p-value = 0.031, Fisher's exact test) was identified as an adverse prognostic marker for response in univariate analysis. None of 11 carriers showed evidence of response. In Cox regression analysis adjusting for TNM category, patients carrying XPD 156 A/A (p = 0.01) and XRCC 1 399 G/G (p = 0.03) had shorter survival compared to patients with XPD 156 C/C or C/A and XRCC 1 399 G/A or A/A, respectively. Conclusions: This data supports the role of functional ERCC 1 polymorphism as a predictive marker for response and may therefore be applied as a marker for tailored therapy. Further, XPD 156 and XRCC1 399 were identified as independent prognostic markers in localized EA treated with neoadjuvant therapy. No significant financial relationships to disclose.
Phase I clinical trial of cytoreductive surgery and intraoperative intraperitoneal hyperthermic chemotherapy for the treatment of peritoneal carcinomatosis
Authors: Y. Li, X. Yang, G. Yang, J. Zhang, L. Chen
Journal: Journal of Clinical Oncology (2008)

15633 Background: Peritoneal carcinomatosis (PC) is an end-stage problem gastrointestinal and the pelvic cancers with median survival of less than 6 mon. Cytoreductive surgery (CRS) plus intraoperative peritoneal hyperthermic chemotherapy (IPHC) may improve clinical outcomes in selected pts. This study was to evaluate the safety and efficacy CRS plus IPHC using mitomycin C (MMC) and hydroxycamptothecin (HCPT) in treating PC. Methods: Eligibility criteria were: (1) pts with PC from abdominal or pelvic cancers without evidence of distant metastasis and with expected survival of over 3 mon; (2) 25–70 years old; (3) laboratory workup found no abnomalities limiting aggressive intervention; (4) pts can tolerate big surgery; and (5) written informed consent obtained. 21 pts with PC (12 from gastric cancer, 5 colorectal cancer, 2 ovarian cancer, 1 pseudomyxoma peritonei and 1 malignant mesothelioma) were treated with CRS plus IPHC using HCPT 20 mg and MMC 30 mg in 12,000 ml of normal saline at 43±0.5°C for 60∼90 min. Body temperature and heart rate were recorded for 5 d after operation. Local and systemic infections, gastrointestinal function recovery, hematological, hepatic and renal parameters, wound healing time, survival and quality of life were all analyzed. Results: The PC index was 2∼33 (median 11), the duration of operation 4∼10 h (median 8 h), and the highest temperature during 5 postoperative d 38.1°C. 2 pts developed systemic edema and were successfully treated, 5 pts developed hypoproteinemia on first postoperative d, all routine blood tests checked at 1 wk postoperatively were normal, time of gastric tube removing was 2∼7 d, liquid food intake time was 3∼8 d, and time of stitches removal was 8∼18 d. There was no infection or disruption of wounds and no intraperitoneal or systemic infections, nor grade 3/4 toxicities in the hematological, hepatic or renal functions. The median follow-up was 8∼26 mon (median 14 mon), with 6 pts died, 8 surviving with tumor, and 7 surviving free of tumor. Conclusions: CRS plus IPHC with MMC 30 and HCPT 20 mg proves to be safe with no serious adverse events; and can prolong the survival and improve the quality of life in selected pts with PC. Suggested doses for phase II study are MMC 30 mg and HCPT 20 mg. No significant financial relationships to disclose.
A randomized phase III study of irinotecan/gemcitabine combination versus gemcitabine in patients with advanced/metastatic pancreatic cancer
Authors: G. P. Stathopoulos, G. Aravantinos, K. Syrigos, K. Kalbakis, N. Karvounis, P. Papakotoulas, J. Boukovinas, A. Potamianou, A. Polyzos, C. H. Christophillakis, V. Georgoulias
Journal: Journal of Clinical Oncology (2005)

4106 Background: To compare the efficacy and tolerability of Irinotecan with Gemcitabine (GEMIRI) versus Gemcitabine (G) in patients with advanced/metastatic pancreatic cancer. Methods: Chemotherapy-naïve patients (pts) with histologically or cytologically confirmed pancreatic cancer patients (pts) and documented extrapancreatic disease were eligible to receive either gemcitabine (900mg/m2, d1+d8) and irinotecan (300mg/m2 d8) (Arm A; n= 42pts) every 21 days or gemcitabine (900mg/m2, d1+d8+d5) every 28 days (Arm B; n= 50pts). Results: Patients were well balanced in respect of age, gender, PS, stage and organ involvement. There were 177 and 166 courses of chemotherapy in Arm A and B pts, respectively. G-CSF was given because of grade III/IV neutropenia in 9.0% and 12.0% Arm A and B cycles, respectively. Treatment discontinuation due to disease progression was performed in 23.8% versus 50% in A and B Arms, respectively (p= 0.020). There was no significant difference in terms of hematological and non-hematological toxicities between the two arms. Objective responses were 12.8% (Arm A) (95% CI: 2.33%–23.31%) and 8.2% (Arm B) (p= 0.474) (95% CI: 0.50%–15.83%). Tumor growth control (CR+PR+SD) was 46.2% (95% CI: 30.51%–61.80%) and 24.5% (95% CI: 12.45%–36.53%) in Arm A and B pts, respectively (p= 0.033). Median TTP between the two arms was similar and 1-year survival 19.6% and 24.0% in Arm A and B, respectively (p= n.s). Conclusions: The combination of gemcitabine and irinotecan was more active in terms of tumor growth control than single agent gemcitabine but this could not be translated in a better survival rate. No significant financial relationships to disclose.
Long-term follow-up after intraoperative radiotherapy (IORT) for breast cancer
Authors: U. S. Kraus-Tiefenbacher, C. Herskind, L. Bauer, F. Melchert, F. Wenz
Journal: Journal of Clinical Oncology (2006)

10594 Background: IORT for breast cancer with new treatment modalities is becoming increasingly important. In our department IORT is delivered by a mobile x-ray source (Intrabeam) producing isotropic 50 kV x-ray fields. Because this treatment modality includes single high doses to the normal breast tissue, careful evaluation of early and late toxicity is mandatory. Methods: Between 2/02 and 12/05 161 patients received IORT either as a tumour-bed boost (103) before 46 Gy external beam radiotherapy (EBRT) or as partial breast irradiation (58). Median age was 64.6 years (35–95), median tumour size was 15 mm (1–45). Spherical applicators (2.0 -5.0 cm diameter) were inserted into the tumourbed, giving a single dose of 20 Gy. Follow-up (f/u) included physical examination and ultrasound 1 week, 2 months, then every 6 months after therapy and mammography at yearly intervals. Radiobiological modelling of the expected spatial distribution of late reaction was done for typical cases using the linear-quadratic model with special consideration of relative biologic effectiveness, spatial dose distribution and dose rate. Results: Mean (f/u) time was 22 months. Minor postoperative side effects included erythema (5%), delayed wound healing (4%), mastitis (1%) and hematoseroma (4%). A fibrotic induration of the tumour bed was observed in 9, 18, 22, 23 and 26% of the patients at 2, 6 12, 24 and 36 month (f/u). Reoperation was required in 2 patients after 10 and 12 months, one mastectomy due to a fibrotic change of the whole breast and one local drainage of a fat necrosis. Conclusions: Although 2/3 of the patients were treated with a combination of IORT and EBRT, acute reactions in all patients were mild. Predominant late effect was an induration of the tumour bed which slowly began to resolve 1–3 years after therapy. The low level of clinically late reactions observed so far is in agreement with radiobiologic predictions from radiobiological modelling. No significant financial relationships to disclose.
Tumor Microenvironmental Features and Outcome in Post-Transplant Lymphoproliferative Disorder
Authors: Maja Ølholm Vase, Eva Maksten, Knud Bendix, Stephen Jacques Hamilton-Dutoit, Claus Andersen, Michael B. Møller, Søren Schwartz Sørensen, Bente Jespersen, Jan Kampmann, Gabriel Rabinovich, Esben Søndergård, Patricia Switten Nielsen, Francesco d'Amore
Journal: Blood (2014)
Effect of antityrosyne kinase agents on in vitro tumor cell proliferation induced by wound drainage fluids (WDFs) of head and neck cancer (HNSCC) patients
Authors: L. F. Licitra, F. Perrone, E. Tamborini, L. Bertola, C. Ghirelli, T. Negri, M. Orsenigo, M. Pompilio, M. Nava, E. Tagliabue
Journal: Journal of Clinical Oncology (2008)

6077 Background: Recurrence of resected HNSCC is due to outgrowth of unrecognized residual cells, and/or to second field tumors. Epidermal growth factor receptor (EGFR) is overexpressed in HNSCC and in the mucosa surrounding the tumor. Evidence indicates that processes triggered by surgery stimulate recurrence of EGFR family overexpressing tumors. Methods: Tumors collected from 33 resected HNSCC patients were characterized for EGFR expression-activation using EGFR-DAKO Kit, EGFR antibody (528:sc- 120, Santa Cruz) and anti-phosphotyrosine antibody (clone 4G10, Upstate) for immunohistochemistry, immunoprecipitation/Western blott. EGFR FISH was performed on 2 tumors and surrounding dysplastic areas using the LSI EGFR/CEP 7 probe. WDFs at 24–48 hours after surgery of the 33 HNSCC patients and as control, from 23 plastic/reconstructive interventions were collected. WDFs were employed for stimulating the proliferation of two EGFR overexpressing squamous carcinoma cell lines (SCCLs) in which FISH detected gene amplification (A431) and three EGFR gene copies (CAL27). Cell proliferation induced by WDFs was measured spectrophotometrically with sulphorodamine B staining. Results: EGFR overexpression/activation was demonstrated in cancers, dysplasia, metaplasia and normal mucosa surrounding the tumors. In 2 pts both dysplasia and the tumor shared an increased EGFR gene copy number. A significant higher presence of EGFR mRNA in the HNSCC WDFs, as compared to plastic WDFs was observed. Both types of WDFs contain EGF-like growth factors that induce EGFR- mediated proliferation of SCCLs that was similarly inhibited by anti EGF antibody, gefitinib and lapatinib in A431 and CAL27. By contrast, cetuximab resulted to be more efficient to inhibit A431 growth with respect to CAL27. Conclusions: The results provide evidence that in operated HNSCC patients wound processes occur in presence of an EGFR activated enriched environment surrounding the excised tumor area, on which surgery-related release of EGF-like factors might promote cell proliferation leading to tumor recurrence. Clinical implications of our findings would suggest a role for preoperative and early maintenance of anti-EGFR treatment in HNSCC patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline, Merck Serono GlaxoSmithKline, Merck Serono
Phase I dose-finding study of BN80927 as an intravenous infusion every 21 days in patients with advanced malignant solid tumors.
Authors: T. Lesimple, F. Bertheault-Cvitkovic, P. Delavault, G. Prevost, V. Fohanno
Journal: Journal of Clinical Oncology (2010)

3072 Background: Homocamptothecins are novel camptothecin derivatives. The results of the first phase I trial of BN80927—a homocamptothecin inhibiting topoisomerase I and II—are reported. Methods: This open-label, multi-center, single-arm phase I study aimed to determine the maximum tolerated dose (MTD) and recommended dose (RD) of BN80927 when administered as a 30-minute intravenous (IV) infusion once every 21 days to adult patients with advanced progressive malignant solid tumors. Cohorts of ≥3 patients received a starting dose of 1.5 mg, which was increased by 25-100% with each successive cohort until the MTD (2/3, 2/6 or 3/9 patients experiencing dose-limiting toxicity [DLT]) was reached. Additional patients received repeated administrations at the RD. BN80927 was analyzed in plasma samples using a SPE-LC-MS/MS procedure. Results: BN80927 (1.5-75 mg) was administered to 56 patients (44 in the MTD determinations and 12 in the RD period). No DLTs were recorded at doses of 1.5-40 mg. The MTD was initially defined as 75 mg but after trialing 65 mg as the RD 2/6 patients had DLTs (1 with febrile neutropenia with grade 4 neutropenia; 1 with grade 4 neutropenia and grade 4 thrombocytopenia). Thus MTD was defined as 65 mg, and RD was defined as 60 mg. Twelve patients had a mean of 3.7 ± 2.35 cycles of BN80927 60 mg. Treatment Emergent Adverse Events (TEAEs) are listed in the Table. There were no BN80927-related serious adverse events at the RD. At the RD, Cmax was 1568 ± 429.5 ng·ml−1, AUC was 3172 ± 1053 ng·ml−1, and t3/4 was 15.05 ± 4.86 h. Stable disease was observed in 19/56 (33.9%) patients with mean duration of 92.9 ± 40.9 days (5/12 [41.7%] for 123.6 ± 43.4 days at RD). No patient had confirmed complete or partial response. Conclusions: The RD and MTD for BN80927 were 60 mg and 65 mg administered as a 30-minute IV infusion every 21 days. Grade ≥3 TEAEs occurring in ≥2 patients TEAE Incidence, n (%) Grade 3 Grade 4 All RD All RD Neutropenia 4 (7.1) 7 (12.5) 3 (25) Leukopenia 2 (3.6) 2 (3.6) Thrombocytopenia 3 (5.4) Febrile neutropenia 3 (5.4) Anemia 2 (3.6) Vomiting 4 (7.1) Nausea 3 (5.4) Asthenia 7 (12.5) Fatigue 4 (7.1) Gamma-glutamyltransferase increased 2 (3.6) Hemaglobin decreased 2 (3.6) Anorexia 2 (3.6) Back pain 2 (3.6) Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ipsen Ipsen
Impaired left ventricular diastolic function in overweight youth is associated with insulin resistance, subclinical inflammation and adipokine dysregulation: a novel cardiometabolic link
Authors: Rachana Dayiha, Sarah P. Schultz, Kristen Gibbons, Danusia Duncan, John Cardinal, Karam Kostner, Nuala Byrne, Andrew P. Hills, Mark Harris, Louise S. Conwell, Gary Martin Leong
Journal: Endocrine Reviews (2013)

Impaired left ventricular diastolic function is the first sign of obesity cardiomyopathy and is evident in obese children (1) and adolescents (2). Whether this occurs due to adiposity, obesity-induced inflammation and/or insulin resistance (IR) is unclear.Objective To evaluate if overweight and obese youth have adverse cardiovascular structure a function compared with non-overweight youth and to determine whether these changes are associated with IR and adipokine dysregulation.Methods 35 overweight and obese (15.1p1.6 y; M:F, 14:21; BMI SDS 2.0p0.8) and 30 non-overweight youth (14.9p2.3 y; M:F, 19:11; BMI SDS -0.1p0.9) participated in the study. Height (Ht), weight, waist circumference (WC) were measured with resting blood pressure. Body mass index (BMI), BMI SDS and WC/Ht were calculated as markers of adiposity. Fasting blood samples were analysed for glucose, insulin, lipid profile, hs-CRP, interleukin (IL)-1b, IL-6, IL-1 receptor antagonist (RA), TNF-a, leptin, adiponectin and resistin. A homeostatic model of assessment (HOMA-IR) was calculated for IR. Echocardiography was used to determine left atrial (LA) and left ventricular (LV) volume, LA area and LV mass. Using transthoracic Doppler echocardiography, diastolic LV function was assessed by recording EA ratio (ratio of early and late diastolic LV filling), septal E prime (LV myocardial elasticity) and E/er (LV filling pressures). Results Overweight and obese youth compared to non-overweight controls had higher fasting insulin, hs-CRP, triglycerides and cholesterol (all pl0.001), LDL (p=0.001) and lower HDL (pl0.05). Compared to non-overweight (NO) and non-insulin resistant (NIR) overweight youth (n=19), IR overweight youth (IR defined as HOMA-IRg3.0; n=16) had higher hs-CRP, resistin (both pl0.01), IL-6 (pl0.05), IL-1RA and leptin (both pl0.001) and lower adiponectin (pl0.001). Diastolic function was impaired in IR overweight youth compared with NO youth, as indicated by a lower EA ratio and septal E prime (pl0.05, pl0.001 respectively) and higher E/er (pl0.001). Septal E prime and E/er were strongly correlated with BMI SDS and WC/Ht (all pl0.001). In addition, septal E prime was significantly associated with insulin, adiponectin (both p=0.005), hs-CRP, leptin and resistin (all pl0.05) independently of blood pressure in a Spearmanrs correlation analysis.Conclusion Diastolic function of the left ventricle was impaired in overweight and obese youth compared with non-overweight controls, particularly in those with IR. These changes were correlated with measures of adiposity and adipokines. Thus, overweight youth with IR and adipokine dysregulation are more likely to have impaired left ventricular diastolic function which may predispose to premature cardiovascular disease in adulthood.
Response rate to vemurafenib in BRAF-positive melanoma brain metastases.
Authors: Marcin Radoslaw Dzienis, Victoria Atkinson
Journal: Journal of Clinical Oncology (2013)

9081 Background: Brain is a common site for melanoma metastases. Responses to dabrafenib have already been reported in over 50% of patients. We aimed at assessing response rate (RR) to vemurafenib (Vem). Methods: Patients with BRAF positive melanoma and asymptomatic brain metastases at initiation of Vem were eligible. Records were analysed retrospectively to calculate RR (at least 30% decrease in the sum of diameters of target lesions), duration of response and time to CNS progression (TTP). Results: 18 patients with CNS metastasis received Vem (M/F=8/10; median age 50); 9 received no prior therapy to the brain (group A), 6 had previous surgery and/or radiotherapy with residual disease (group B; n=6), 3 patients had prior "brain therapy" but with evidence of progression in CNS before the start of Vem and were added to group A (n=9+3=12). 50% RR was observed in group A; 5 had no prior therapy, 1 relapsed after resection/WBRT. Duration of response was: 8, 8, 8, 16, 32 weeks and 1 not reached yet. Similarly, 50% RR was observed in group B; however contribution of Vem to CNS control in this group was more difficult to assess. Duration of responses: 4, 26, 33 weeks. All except 2 patients progressed in CNS before, or at the time of, systemic progression. Median TTP in group A was: 21 weeks (16-41) in responding patients and 12 weeks (4-22) in those without a response (includes SD). Median TTP in group B = 44 weeks (16-60) in responders, 8 weeks (3-16) in non-responders. Conclusions: Vemurafenib resulted in 50% CNS response rate. Prospective comparison to dabrafenib may be warranted.