tbuckley/cabot-search huggingface dataset:
Bevacizumab and oral chemotherapy for patients with lymphangitic breast cancer: A phase II randomized study of bevacizumab with sequential versus concurrent oral vinorelbine plus capecitabine
Authors: M. A. Locatelli, G. Curigliano, L. Fumagalli, R. Ghisini, P. Mancuso, F. Bertolini, G. Viale, L. Lunghi, A. Goldhirsch
Journal: Journal of Clinical Oncology (2009)

1031 Background: Antiangiogenic agents are most likely to be effective in patients (pts) with an extensive cutaneous neo-angiogenic trait of disease. There is a compelling need to monitor the biological activity of such agents and identify markers of efficacy. Methods: We evaluated the activity and biological effects of bevacizumab (B) (15 mg/kg, iv q 3 weeks) in a phase II randomized trial in pts with locally advanced breast cancer (BC) with lymphangitic spread to the chest wall. Primary aim was to assess activity and toxicity of B administered alone followed by sequential oral vinorelbine (V) plus capecitabine (C) (arm A) or with concurrent V plus C (arm B). Secondary aim was to evaluate predictive role of circulating progenitor cells (CECs) and progenitor endothelial cells (CEPs) as surrogate markers of antiangiogenic activity. We collected blood samples of all pts at baseline, at day 12, 42, and at progression. Results: Planned accrual was of 43 pts of whom 23 were enrolled (9 pts in arm A; 14 pts in arm B). Median age was 51 years (range 35–68). Most of the pts had a “triple negative” phenotype [19/23 (82%)]. 10/23 pts (43%) received ≥ 2 previous lines of chemotherapy. 19 pts (82 %) are evaluable for response and all 23 pts are evaluable for toxicity. We observed 5 PR (45%) and 6 SD (55%) in arm B. In arm A, while on B alone, 6 (75%) of the pts had PD and 2 (25%) had a short term SD. Adding VC to B 2 PR (25%), 3 SD (37.5%), and 3 PD (37.5%) were observed. Toxicity profile was typical for use of B (hypertension). The absolute mean number of CECs was 158/ml (range 45–461) (n = 23) at baseline, 116/ml at +12 (range 47–275), and 194/ml at +42 (range 36–891). Mean absolute value of CEPs was 270 (range 28–1060) at baseline, 245/ml at D+12 (range 14–981), and 143/ml (range 5–610) at D+42. The fraction of apoptotic/necrotic CECs was 54±19% at baseline, 64±21 at+12, and 52±18 at+42. Conclusions: Preliminary data showed that B alone is not an effective treatment in pts with lymphangitic spread of BC to the chest wall. Additional data on CECs and CEPs are needed to clarify their potential usefulness as a surrogate markers of antiangiogenic activity of B-based regimen. No significant financial relationships to disclose.
Nanoparticle Delivered VEGF-A siRNA Enhances Photodynamic Therapy for Head and Neck Cancer Treatment
Authors: Rumwald Leo G Lecaros, Leaf Huang, Tsai-Chia Lee, Yih-Chih Hsu
Journal: Molecular Therapy (2015)

Photodynamic therapy (PDT) is believed to promote hypoxic conditions to tumor cells leading to overexpression of angiogenic markers such as vascular endothelial growth factor (VEGF). In this study, PDT was combined with lipid–calcium–phosphate nanoparticles (LCP NPs) to deliver VEGF-A small interfering RNA (siVEGF-A) to human head and neck squamous cell carcinoma (HNSCC) xenograft models. VEGF-A were significantly decreased for groups treated with siVEGF-A in human oral squamous cancer cell (HOSCC), SCC4 and SAS models. Cleaved caspase-3 and in situ TdT-mediated dUTP nick-end labeling assay showed more apoptotic cells and reduced Ki-67 expression for treated groups compared to phosphate buffered saline (PBS) group. Indeed, the combined therapy showed significant tumor volume decrease to ~70 and ~120% in SCC4 and SAS models as compared with untreated PBS group, respectively. In vivo toxicity study suggests no toxicity of such LCP NP delivered siVEGF-A. In summary, results suggest that PDT combined with targeted VEGF-A gene therapy could be a potential therapeutic modality to achieve enhanced therapeutic outcome for HNSCC. Photodynamic therapy (PDT) is believed to promote hypoxic conditions to tumor cells leading to overexpression of angiogenic markers such as vascular endothelial growth factor (VEGF). In this study, PDT was combined with lipid–calcium–phosphate nanoparticles (LCP NPs) to deliver VEGF-A small interfering RNA (siVEGF-A) to human head and neck squamous cell carcinoma (HNSCC) xenograft models. VEGF-A were significantly decreased for groups treated with siVEGF-A in human oral squamous cancer cell (HOSCC), SCC4 and SAS models. Cleaved caspase-3 and in situ TdT-mediated dUTP nick-end labeling assay showed more apoptotic cells and reduced Ki-67 expression for treated groups compared to phosphate buffered saline (PBS) group. Indeed, the combined therapy showed significant tumor volume decrease to ~70 and ~120% in SCC4 and SAS models as compared with untreated PBS group, respectively. In vivo toxicity study suggests no toxicity of such LCP NP delivered siVEGF-A. In summary, results suggest that PDT combined with targeted VEGF-A gene therapy could be a potential therapeutic modality to achieve enhanced therapeutic outcome for HNSCC.
The importance of pathological downstaging and the circumferential margin in rectal carcinomas treated with neoadjuvant chemoradiation
Authors: S. Mawdsley, R. Glynne-Jones
Journal: Journal of Clinical Oncology (2005)

3642 Introduction: Chemoradiation prior to surgery is now a common approach in the treatment of locally advanced rectal cancer. This report describes the resection, survival and local relapse rates of patients treated over an 8-year period at Mount Vernon Hospital and highlights the importance of pathological downstaging. Methods: Between 1994 and 2002, 155 patients with a locally advanced adenocarcinoma of the rectum were treated, with a median follow-up of 25 months. T stages were: T2:2, T3:59, T4:94. Median age 67 years, male: female ratio 73:27%. The radiotherapy dose was 45Gy in 25 fractions over 5 weeks. 5-FU was given as a 60 minutes infusion on days 1–5 and 29–33, at 350mg/m2, following low dose folinic acid. Surgery was performed in 122 patients. Actuarial survival, local control, resection margins and toxicity rates, according to CTC criteria were assessed. Results: Overall median survival (OS) was 37 months with a 34% 5-year OS. Median disease-free Survival (DFS) was 28 months with a 31% 5-year DFS. Resected specimens revealed 12% had had a complete pathological response (CPR) and pathological downstaging (PS) to pT0/1/2 was achieved in 28%. The 3-year DFS in PS was 52% compared to 9% in no PS (p<0.001), the 3-year OS was 64% versus 25% (p=0.0001). An overall R0 resection rate of 63% (98/155) was achieved. The 5-year DFS in R0 was 68% compared to 25% in R1/2 (p=0.0032). The 5-year OS was 72% versus 30% (p=0.020). 93% of patients achieved 100% compliance. Local recurrence (LR) rates were higher in the R1/2 group at 62% versus 10% in R0 and distant metastases rates were also higher in R1/2 75% versus 29% in R0. 93% of patients achieved 100% compliance. Conclusion: Survival is poor in patients with locally advanced rectal carcinoma. However, chemoradiation with 5-FU can produce effective downstaging and toxicity is manageable. This study highlights that improving the rates of pathological downstaging and R0 resections will lead to lower LR and DM rates, ultimately leading to an improved survival. No significant financial relationships to disclose.
Hospitalization with febrile neutropenia in colorectal cancer patients
Authors: E. Culakova, A. Khorana, N. M. Kuderer, J. Crawford, D. C. Dale, G. H. Lyman
Journal: Journal of Clinical Oncology (2004)

3706 Background: Chemotherapy is increasingly utilized in the management of colorectal cancer. Neutropenia represents the major dose-limiting toxicity of chemotherapy with fever and neutropenia (FN) often requiring hospitalization for empiric broad-spectrum antibiotics. Methods: Hospitalization of colorectal cancer patients with FN at 115 academic medical centers between 1995 and 2000 was studied using the discharge database of the University HealthSystem Consortium. Logistic regression analysis was used to estimate relative risk based on adjusted odds ratios (OR). Results: Over a six-year period, 957 patients with colorectal cancer experienced 1046 hospitalizations for FN. The number of FN hospitalizations increased 130% from 119 in 1995 to 272 in 2000. The mean (median) length of stay was 9.0 (6) days while the average (median) cost per hospitalization was $12,484 ($7,153). The 30% of patients hospitalized ≥ 10 days accounted for 62% of all hospital days and 66% of all costs. Clinical infection was reported in 57% of patients with microbiologically documented infection reported in 31% including gram-negative sepsis in 8.5%, gram-positive in 2.7% and other bacterial infections in 17.5%. Pneumonia was reported in 5%, while 5% presented with hypotension and 34% with evidence of hypovolemia. Death occurred in 8.5% of hospitalizations. Mortality rates were greatest in those with gram-negative sepsis (35%), gram-positive sepsis (23%), hypotension (23%) and pneumonia (32%). One or more major comorbidities were reported in 57% of patients. Mortality rates increased with the number of comorbidities (P-trend<.0001). Significant independent risk factors for mortality in multivariate analysis were gram-negative sepsis (OR=6.1), gram-positive sepsis (OR=3.8), hypovolemia (OR=2.5), pneumonia (OR=4.9), lung disease (OR=4.6), liver disease (OR=4.4), heart disease (OR=3.9) and other vascular disease (OR=13.3). Conclusions: Chemotherapy has assumed an increasingly important role in the management of colorectal cancer. Nearly one-third of patients hospitalized with FN experience complicated hospitalizations with significant morbidity and mortality. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Inc. Amgen, Inc. Amgen
Low-dose docetaxel, estramustine and thalidomide followed by maintenance thalidomide in androgen-independent prostate cancer (AIPC): Final results of a phase II community based study in elderly men
Authors: R. C. Frank, L. Versea, N. Cohen, J. Long, K. Nair
Journal: Journal of Clinical Oncology (2007)

15609 Background: The TET regimen was developed to test the potential synergy and tolerability of low dose, metronomic chemotherapy plus an anti-angiogenesis agent in the treatment of AIPC in elderly men. Preliminary results were presented in 2004 (ASCO Proceedings #4681); we now present the final results 5 years from protocol initiation. Methods: Eligible patients had progressive AIPC, an adequate PS (0–2) and were chemotherapy naïve. All patients received the TET regimen: Docetaxel (Taxotere [T]) 25 mg/m2 weekly for three weeks per month, Estramustine 140 mg po tid x 3 days per week (with T) and Thalidomide (Thal) 100–200 mg as tolerated. After six monthly cycles of TET, patients with responding or stable disease received maintenance Thal until progression. Coumadin 2 mg daily was given for thromboprophylaxis. A total of 19 patients out of an intended 25 were accrued from 6/01 to 9/05. Results: The median age was 79 (59–86); 70% of patients were ≥ 75 years of age. The median PSA was 83 (20–2266), median Gleason score 7, bone metastases were present in 14/19 patients and measurable disease in 12/19 patients. 17 patients completed at least one cycle of TET and were eligible for analysis. The PSA declined &gt;50% in 10/17 (59%); there was 1 PR and 7 SD by RECIST criteria. Of six patients that received maintenance Thal, only one had PSA stabilization for more than three months. The median survival was 17 months. The major grade ¾ toxicities included non-life threatening DVT (3 patients), asthenia (6 patients), edema and dyspnea (one patient each). Thal 200 mg was especially poorly tolerated, requiring dose reductions in over half of the patients. Conclusions: In this trial of elderly men with AIPC, low-dose TET did not seem to improve upon the results previously reported for docetaxel or docetaxel/estramustine. The observed toxicities make it doubtful that a higher dose TET regimen could be tolerated by this population. Thalidomide maintenance was ineffective in maintaining responses. No significant financial relationships to disclose.
FcγR IIIa polymorphism and anti-idiotype humoral immune response predict clinical outcome in follicular lymphoma patients receiving idiotypic vaccination
Authors: W.-K. Weng, D. Czerwinski, R. Levy
Journal: Journal of Clinical Oncology (2004)

6503 Background: The Ig idiotype (Id) expressed by B cell lymphoma is a target for immunotherapy. Id vaccination (Vac) induces humoral and/or cellular anti-Id immune response (IR). However, the clinical impact of these anti-Id IR is unknown. We have recently found that IgG Fc receptor (FcγR) polymorphisms predict the response to rituximab, due to their role in the antibody-dependent cellular cytotoxicity. We tested if anti-Id IR or FcγR polymorphisms have clinical impact in patients who received Id Vac. Methods: We analyzed 155 follicular lymphoma patients who had Id Vac between 1988 and 2001 at Stanford Medical Center. All patients received induction chemotherapy followed by Id Vac. The FcγRIIa 131 H/R and FcγRIIIa 158 V/F polymorphism was determined. Results: Humoral and cellular anti-Id IR were found after Id Vac in 51 (33%) and 35 (23%) patients, respectively. The humoral IR was associated with longer freedom from progression (FFP) after induction chemotherapy/Id Vac (humoral IR, 6.23 yrs vs other, 2.66 yrs, p=0.006). The cellular IR had no impact on the FFP. Patients with FcγRIIIa V/V genotype enjoyed longer FFP than those with V/F or F/F (median time to progression: V/V, 8.21 yrs vs V/F, 2.66 yrs, p=0.002; vs F/F, 2.89 yrs, p=0.021). In contrast, the FcγRIIa polymorphism had no impact on FFP. Multi-variant analysis using the Cox Proportional Hazards Model showed that V/V genotype and humoral IR were two independent positive predictors for disease free survival, and stage IV disease was a negative predictor, while FcγRIIa polymorphism, cellular IR, gender, age, B symptoms or time from diagnosis to therapy had no impact. The relative benefit was 4.12 (95% CI, 1.83–9.27, p=0.0006) for V/V genotype and 2.45 (95% CI, 1.50–4.00, p=0.0004) for humoral IR. Conclusions: There was clinical benefit of humoral anti-Id IR in a large group of patients vaccinated with Id. We also identified the clinical importance of FcγRIIIa polymorphism in these patients probably due to its role in anti-Id antibody-mediated cytotoxicity. No significant financial relationships to disclose.
<i>p53 Arg72Pro</i>, <i>MDM2 T309G</i>, <i>CCND1 G870A</i> polymorphisms, histology and esophageal cancer prognosis
Authors: D. W. Cescon, P. A. Bradbury, K. Asomaning, R. Zhai, M. Kulke, L. Su, R. S. Heist, J. C. Wain, T. J. Lynch, D. C. Christiani, G. Liu
Journal: Journal of Clinical Oncology (2008)

11033 Background: Regulation of cell cycle and apoptosis are central to the biology of cancer. Three key genes in these pathways contain functional single nucleotide polymorphisms (SNPs) (p53 Arg72Pro, MDM2 T309G and CCND1 G870A) which have been implicated in the behavior and prognosis of several cancers. We evaluated the prognostic significance of these SNPs on overall survival (OS) and progression-free survival (PFS) in a large cohort of patients with esophageal cancer. The role of tumor histologic subtype in these relationships was explored. Methods: 371 patients with esophageal carcinoma were genotyped for the p53, MDM2 and CCND1 SNPs. Most patients were treated with tri-modality cisplatin-based therapy. Associations between genotypes and OS and PFS were assessed using the Kaplan-Meier method with log-rank test. Cox proportional hazard models, adjusted for age, stage, performance status (PS) and smoking were developed. Stratified and interaction analyses were performed for adeno- (ADC) and squamous cell carcinoma (SCC) subgroups. Results: Median age was 64 (range 21 - 91). Patients were 86% male, 98% Caucasian, 86% PS 0–1 and Stage I (7%), II (41%), III (28%) and IV (24%). Tumor histology was ADC in 81%, SCC in 17% and poorly differentiated in 2%. At median follow-up of 33 months, median survival (MS) and PFS were 29.1 and 15.7 months respectively. p53 Pro/Pro was strongly associated with worse outcome in the entire cohort (MS 11.8 vs 29.1 mo, p<0.0001). MDM2 G/G had markedly reduced survival in SCC (MS 10.3 vs 49.4 mo; AHR 7.9 (95% CI 2.4 - 26.0), p = 0.0007 and PFS 5.3 vs. 24.8 mo; AHR 9.8 (95% CI 3.0 - 31.9), p= 0.0002) but not ADC. Results remain significant after Bonferroni correction. CCND1 genotype was not associated with outcomes in any subgroup. Conclusions: In a large prospective study of esophageal cancer prognosis, p53 Arg72Pro Pro/Pro is associated with worse outcome and MDM2 T309G G/G is associated with worse outcome in SCC. In contrast to prior studies, no association between CCND1 G870A genotype and outcome was detected. Genotypes and survival outcomes in entire study cohort Overall Survival Progression-FreeSurvival Genotype GenotypeFrequency(%) MS(mo) LogRank AHR(95% CI) p* PFS(mo) LogRank AHR(95% CI) p* p53 72 Pro/Pro(vs. Arg/Arg) 9 vs.51 11.8 vs.29.1 <0.0001 2.05 (1.30- 3.24) 0.002 7.9 vs.17.4 0.0018 2.03 (1.29- 3.18) 0.002 MDM2 309 G/G(vs. T/T) 12 vs.40 22.0 vs. 29.6 0.06 1.15 (0.76 - 1.74) 0.51 10.5 vs. 18.0 0.09 1.14 (0.76- 1.72) 0.52 CCND1 870 A/A(vs G/G) 21 vs.28 27.3 vs.33.7 0.47 1.14 (0.76- 1.70) 0.53 12.0 vs.19.7 0.24 1.17 (0.80- 1.70) 0.41 * corresponding to Cox proportional hazards model, adjusted for age, stage, PS and pack-years smoking No significant financial relationships to disclose.
VEGF-D expression in lung adenocarcinoma with or without acquired resistance to gefitinib and normal lung
Authors: Z. Wang, Y. Wu, G. Zhang, A. Guo, J. Su, Z. Chen
Journal: Journal of Clinical Oncology (2007)

18166 Background: VEGF-D is related with pathogenesis and metastasis of lung cancer, however, its relationship with resistance to gefitinib in NSCLC remains unknown. Methods: Lung adenocarcinoma, normal lung tissues adjacent to the carcinoma and adenocarcinoma with acquired resistance to gefitinib including some metastastic lymph nodes were obtained during operation. Relative quantitation of VEGF-D gene expression was performed by SYBR Green real-time PCR with beta actin gene as the endogenous control. VEGF-D expression of each group was analyzed by comparing them qualitatively and quantitatively. The expression ratios were compared by Fisher’s exact test and expression levels were compared by two-related-samples nonparametric test. Results: CVEGF-D expression ratio of lung adenocarcinoma with acquired resistance to gefitinib (16.7%, 1/6) was not different from lung adenocarcinoma (50%, 7/14, P=0.325) but was significantly lower than that of normal lung (93.8%, 15/16, P=0.001). The logarithmically transformed VEGF-D relative expression levels in six lung adenocarcinomas and the matched normal lung tissues, which were 2.214±0.376 and 3.388±0.209, were found to be significantly different from each other by the analysis of Wilcoxon signed ranks test (P=0.028). Conclusions: VEGF-D expression is in a high-level state in normal lung tissues while in low-level or absent in lung adenocarcinoma with or without acquired resistance to gefitinib, suggesting that the role VEGF-D plays in normal lung tissue could be different from in lung adenocarcinoma with or without acquired resistance to gefitinib. No significant financial relationships to disclose.
Gastrointestinal organoid cultures for functional evaluation of oncogenic loci.
Authors: Ameen Abdulla Salahudeen, Xingnan Li, Michael Cantrell, Calvin Jay Kuo
Journal: Journal of Clinical Oncology (2015)

85 Background: Novel in vitro methods surpassing limitations of current gastrointestinal cancer models such as gastric and esophagus cancer are required to functionally validate putative oncogenic loci discovered by genome sequencing efforts. The in vitro culture of primary, non-transformed tissues as three-dimensional organoids that accurately recapitulate organ structure and physiology has diverse applications including cancer biology. Methods: Mouse wild type, or p53 flox/flox in tandem with lox-stop-lox KRAS G12D upper digestive tract tissue containing epithelial and mesenchymal components were cultured in an air-liquid-interface and subjected to adenovirus expressing either immunoglobulin Fc (control) or GFP tagged Cre recombinase. Results: 3-dimensional organoids were generated with histological adherence to normal tissue architecture including that seen in esophagus and were able to be maintained in long term culture. Organoids exposed to GFP tagged Cre adenovirus demonstrated green fluorescence not seen in organoids exposed to control virus. Conditional allele organoids that were exposed to Cre adenovirus demonstrated increased rate of growth compared to controls. Histology of these rapidly growing organoids demonstrated cellular features consistent with dysplasia. Conclusions: 3-dimensional organoids can be generated from upper digestive tract tissues, can undergo adenoviral mediated transfection to achieve oncogenic gene expression or inactivation resulting in dysplastic morphology. 3-dimensional organoids are therefore an attractive model to study or identify candidate oncogenic loci identified by recent genomic sequencing studies.
A phase II study of gefitinib monotherapy for chemotherapy-naive patients with non-small cell lung cancer
Authors: K. Kasahara, H. Kimura, A. Yoshimoto, T. Sone, K. Shibata, Y. Ishiura, H. Kunitoh, K. Nishio, T. Tamura, M. Fujimura, S. Nakao
Journal: Journal of Clinical Oncology (2005)

7074 Background: Gefitinib is effective as a 2nd or 3rd line treatment for non-small cell lung cancer (NSCLC), but efficacy for chemotherapy-naïve patients (pts) with NSCLC has not been established. Recently, EGFR gene mutation reported to be a predictor of response to gefitinib. Methods: We conducted a phase II study evaluating the efficacy and safety of gefitinib in chemotherapy-naïve NSCLC. The primary endpoint was response rate (RR). We also investigated whether the15-bp deletion of EGFR (E746 A750del) could be observed in serum DNA and served as a noninvasive source of information of genotype of tumor cells. Eligibility criteria were stage IIIB or IV chemotherapy-naïve NSCLC, PS 0–2, measurable lesion(s), age ≥20 years-old, adequate organ functions, and written informed consent. This study, with a sample size of 25, had 80% power to support the hypothesis that the true RR was >30%, and 5% significance to deny the hypothesis that true RR was <10%. If 5 or more of 25 pts responded, gefitinib was concluded to be effective. Assuming an inevaluability rate < 20%, we projected an accrual of 30 pts. Results: From Oct. 2002 to Aug, 2003, 30 pts were enrolled and all 30 pts were eligible. The RR was 33.3% (95% CI, 16.2–49.8%) and disease control rate of 63.3% (95% CI, 46.0–80.5%). Median time to progression (TTP) was 3.3 months (0-3-23), median overall survival was 10.0 months (1.7–26) and 1-year survival rate was 43.3% (median follow-up, 13 months). Grade 3 toxicities were observed in 7 pts (2 skin, 1 diarrhea, 2 liver, and 2 lung). Both E746 A750del (10/27) and wild-type EGFR (22/27) were detected in pretreatment samples. No correlations were seen between presence of E746 A750del in pretreatment samples and response or gender. E746 A750del was significantly more frequent in post-treatment samples from pts with PR and SD than in pts with PD (p<0.05), and correlated with TTP (p<0.05). Conclusions: Gefitinib in chemotherapy-naïve NSCLC was active with acceptable tolerability. E746 A750del in circulating tumor cells was detectable in serum samples. While E746 A750del in serum of untreated pts was not a predictor of gefitinib response, detection of E746 A750del correlated with disease control and TTP. No significant financial relationships to disclose.