bluuebunny/crossref_metadata_2025 huggingface dataset:
Total blockade of the epidermal growth factor receptor with the combination of cetuximab and gefitinib: A phase I study for patients with recurrent non-small cell lung cancer (NSCLC)
Authors: Naret C. L. , Ramalingam S. , Beattie L. , Mayfield S. D. , Lu H. , Langer C. , Belani C. P.
Published: March 2020

17045

Background: Cetuximab and gefitinib inhibit the epidermal growth factor receptor (EGFR) through different mechanisms. Preclinical evidence suggests that the combination of cetuximab and Gefitinib is synergistic and has shown antitumor activity in vitro and in xenografts (Matar et al, Clin Cancer Res, 2004). We are conducting a phase I study to determine the doses of the two agents that can be administered in combination. Methods: Patients (pts) with advanced NSCLC were eligible upon progression following 1 or 2 prior chemotherapy regimens. Gefitinib was administered at a dose of 250 mg/day for all cohorts. The dose of cetuximab was escalated in sequential cohorts of patients ( table ) and there will be no dose escalation above the approved doses for both agents (dose level 3). Paraffin-embedded tissue samples of the primary cancer were collected from all patients for analysis of EGFR mutations, gene amplification and protein expression. Results: From March to December 2005, 11 patients have been entered to the 3 planned cohorts. Patient characteristics include: 3 women and 8 men, with a median age of 63 years (range 51–77) and ECOG performance status (PS) of: 0 = 50%, 1 = 50%. A total of 26 treatment cycles were administered to the 11 pts with a median of 2 cycles per pt (range 1–8). Other observed adverse events include grade 1/2 skin rash and diarrhea. Of 8 evaluable patients, 4 had stable disease. No DLT has been experienced so far at the projected recommended phase 2 dose (dose level 3). The results of correlative studies will be presented at the meeting. Conclusions: The novel combination of cetuximab and gefitinib is safe and is associated with promising anti-cancer activity in recurrent NSCLC.

[Table: see text]

[Table: see text]
The role of methylation leading to capecitabine resistant malignant mesothelioma
Authors: Kosuri K. V. , Wu X. , Otterson G.
Published: March 2020

17105

Background: Malignant mesothelioma is a deadly malignancy whose global incidence continues to be on the rise. Established therapies have been less than optimal. The current therapeutic standard is intravenous pemetrexed, an antifolate medication. Yet, another folate antimetabolite, capecitabine, is significantly less effective than pemetrexed. The enzymes thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and thymidylate phosphatase (TP) are critical to the efficacy of antifolates. Specifically, for capecitabine to be converted into a potent cytotoxic agent, the enzyme TP must be present and active. In one of four mesothelioma cell lines examined, the gene that encodes for TP, extracellular growth factor-1 (ECGF-1), is methylated. Methylation of this gene and the subsequent downregualtion of the TP enzyme confer a diminished cytotoxic effect by a capecitabine prodrug, dioxyfluridine (DFUR). Methods: Cells were cultured treated with and without 1uM decitabine (DAC) under identical conditions. DNA, RNA, and protein lysates were collected after 72 hours. Bisulfite-treated DNA was examined by MS-PCR for evidence of methylation of TS, DPD, and TP. RNA was collected and cDNA was synthesized. Real time PCR was utilized to detect the relative difference in RNA quantity. Western blots were done to evaluate the differences in protein expression between DAC treated and untreated cells. MTT assay was performed with DAC pretreated and untreated cell lines subsequently treated with DFUR and 5-fluorouracil. Results: One of the four mesothelioma cell lines showed consistent evidence of TP methylation by MS-PCR. The addition of 1uM DAC to the cell lines conferred a six-fold difference in expression of the methylated gene by both real time PCR as well as by Western blot. The prodrug DFUR subsequently shows increased cytotoxicity in the methylated cell line by MTT assay when pretreated with DAC compared when not exposed to the DAC. Conclusion: By demethylating the ECGF-1 gene with DAC, the now upregulated TP enzyme has an increased ability to convert DFUR to 5-FU; thus enhancing the cytotoxicity of a drug thought to be ineffective in malignant mesothelioma.

No significant financial relationships to disclose.
Sleeve lobectomy an affidable lung sparing procedure
Authors: Cavallesco G. , Maniscalco P. , Quarantotto F. , Acerbis F. , Santini M. , Brombin C. , Valieri L. , Azzena G.
Published: March 2020

17159

Background: Sleeve Lobectomy (Sl) is generally considered a surgical alternative of choice to Pneumonectomy (Pn) for the treatment of central NSCLC. The aim of this study is to value if the Sl could be really a Lung saving procedure that warrants right survivals, according to stage of disease, with acceptable perioperative risks. Methods: In 165 patients (67 Sl and 98 Pn) operated from 1995 to 2003 for NSCLC of main bronchus we have analyzed the hospital stay, morbidity and mortality within 30 days, long term survival. In 39 Sl and 46 Pn we compared spyrometric volume’s changes at a distance of 6–24 months from operation. Sl was performed where it was technically possible. Long term survivals had been separated and comparated according to pathologic stadium (TNM 1997) and lymphonodal involvement: all these data were estimated by Kaplan-Meier method and log rank test. All statistical data underwent SPSS elaboration and significant assumption for p < 0.05. Results: In our population of study we didn’t check any statistically significant’s differences comparing age, sex or preoperative Fev1. Complications occurred in 28% of cases where Sl was performed and in 36.7% after Pn with a mortality rate of 2.9% vs 5.1%. Average hospital staying was longer in patients underwent to Pneumonectomy. Long term survival (5 years) in Sl group is 36% and 24% in Pn group with a statistically significant difference P = 0.016, but this difference is not evident from the comparison between the two group’s survivals based on pathological stadium or lymphonodal involvement. Spyrometric values showed a global Fev1 reduction of 245 ml (−10%) after Sl procedure and 884ml (36.3%) after Pn with a significant difference of p = 0.0042. Conclusions: In this study Sl got similar survival results if not better, with those obtained after Pn. Moreover, Sl showed to be a lung sparing procedure with an acceptable operative risk. These data confirmed that SL is the gold standard surgical procedure in the treatment of central tumors where if technically possible.

[Table: see text]

No significant financial relationships to disclose.
Clinical and biological implication of defective p53 pathway in multiple myeloma (MM)
Authors: Chng W. J. , Price-Troska T. , Van Wier S. , Jacobus S. , Blood E. , Henderson K. , Oken M. M. , Van Ness B. , Greipp P. , Fonseca R.
Published: March 2020

17516

Background: The p53 tumor suppressor is commonly inactivated by mutations. Even in tumors without mutations, there are defects in the response to p53 activation. In MM, the prognostic significance of p53 mutation is unknown, while there has been no systematic study of p53 function. We seek to address these issues in this study. Methods: p53 mutation was studied by conformation sensitive gel electrophoresis with primers encompassing exons 1 to 10 followed by sequencing of DNA fragments with altered electrophoretic pattern in newly diagnosed MM patients entered into ECOG E9486 trial where patients were randomized to receive variations of melphalan-based conventional chemotherapy (VBMCP). Fisher’s exact tests were used to compare variables between patients. Kaplan-Meier survival curves were compared using the log-rank test. To investigate p53 function, we analyzed the expression of p53, and 3 of its transcriptional targets, APAF1, p21 and MDM2, in a separate cohort of 15 normal plasma cells (PC), 14 MGUS, 13 smoldering myeloma (SMM) and 101 MM (73 new and 28 relapsed) from the Mayo Clinic who had gene expression profiling performed on the Affymetrix U133A chip (Santa Clara, Ca). Results: Two hundred and sixty-eight patients had enough materials for study and were included in the analysis. The prevalence of p53 mutation was 3% (n = 9). Five of the 9 patients (56%, p = 0.001) with mutations also had p53 deletion (studied by fluorescent in-situ hybridization) resulting in bi-allelic loss of p53. Soft tissue plasmacytomas (37% v 7%, p = 0.018), and among the common translocations, t(4;14) and t(14;16) (50% v 18%) were more common in patients with p53 mutations. Despite similar response to treatment, those with p53 mutation had very short OS (16.7 v 41.4 months, p < 0.001). There was induction of p53 expression in MGUS and SMM with concurrent induction of APAF1, p21 and MDM2 whereas loss of this pattern was frequent in MM (45% in new MM and 60% in relapse MM compared to 15% in MGUS/SMM (p = 0.03)). Conclusions: p53 mutations are relatively rare in newly diagnosed MM patients but portend a short survival. However, functional abnormalities of p53 are prevalent and may be important in progression from MGUS/SMM to MM.

[Table: see text]
Bronchial-associated lymphoid tissue (BALT) lymphoma: a retrospective analysis
Authors: Steffanoni S. , Pruneri G. , Spaggiari L. , Preda L. , Laszlo D. , Calabrese L. , Zucca E. , Bassi S. , Martinelli G.
Published: March 2020

17547

Background: Systemic CT in BALT lymphoma is the accepted therapy for those pts where surgery isn’t radical or possible. There is not a standard systemic treatment for this uncommon lymphoma however its indolent behavior and the relative asymptomatic outcome, allows on systemic therapy delay and may justify the use of less toxic CT agents. Methods: Here we reported our experience on 19 pts (10 men and 9 women) with biopsy-proven BALT lymphoma, median age was 61 yrs; 8 pts presented a symptomatic disease at diagnosis. 15 pts had a localized pulmonary disease (stage IE); 4 pts had stage IVE disease for peripheral blood and bone marrow involvement (3 pts) and gastric involvement (1 pt). Of 16 pts valuable for response, 3 pts received radical surgery (1 wedge resection and 2 lobectomy) as definitive treatment and 13 pts received systemic treatment (Chl containing regimen in 6, Rituximab ± Chl in 6; CVP regimen in 1) because of symptomatic disease or relapse after major surgery. Results: 6/13 pts achieved CR: 5/6 are still alive and disease free: 1 pt in CR died for other causes. 3 pts in asymptomatic PR don’t need further therapy while the additional 4 pts in PR need subsequent treatment because of symptomatic progression after a median TTP of 40 months. With a median follow up of 39 months, the OS and RFS observed are 85% and 63% respectively. Hematology and non-hematology toxicity was in general mild: transient G3 neutropenia occurred in only two pts; no pt discontinued the treatment because of treatment-related toxicity and no toxic death was recorded. Conclusions: Our analysis seem to confirm that surgery could be considered as unique treatment only for minority of pts with BALT lymphoma. Systemic chemotherapy with Chl containing regimen may achieve a clinical control of disease with about 50% of CR as well as other reported with more aggressive CT regimen. A larger retrospective analysis on pathological figure and clinical outcome is planned on behalf of IELSG.

No significant financial relationships to disclose.
A phase I/IIa clinical trial of CLAOP21 and CLAOP14 in patients with high grade non-Hodgkins lymphoma and cardiac risk factors
Authors: Busse A. , Huetter G. , Siehl J. M. , Schmittel A. , Keilholz U.
Published: March 2020

17548

Background: CHOP combination chemotherapy is the most effective and least toxic regimen for high-grade Non-Hodgkin’s-lymphoma (NHL). Doxorubicin, however, presents a problem in patients at risk for cardiotoxicity. Pegliposomal doxorubicin is a liposomal preparation of doxorubicin with minimal cardiotoxicity. In the CLAOP regimen reported here, we substituted conventional doxorubicin in the CHOP regimen by pegliposomal doxorubicin. Methods: An open-label phase I/IIa study was performed evaluating CLAOP21/20 with 20 mg/m2 of pegliposomal doxorubicin every 21 days, and a dose-dense CLAOP14 regimen supported by G-CSF or pegylated G-CSF every 14 days with escalating doses of pegliposomal doxorubicin in elderly high-grade lymphoma patients. Results: A total of 12 patients were enrolled for CLAOP 21/20, and 24 patients for CLAOP 14/20. CLAOP21/20 was well tolerated with a degree of hematotoxicity similar to that reported with regular CHOP. In the CLAOP14 cohort, a trend towards cumulative hematotoxicity. Palmar plantar erythema (PPE) exceeding grade II and other non-hematological toxicities exceeding grade I, except of alopecia, were not observed. A pegliposomal doxorubicin dose of 25 mg/m2 (CLAOP14/25) was associated with dose-limiting haematotoxicity, febrile episodes, and PPE. Both, the 3-weekly and the 2-weekly regimens were active with an overall response rate of 60% and 77%, respectively. Cardiotoxicity attributable to doxorubicin was not observed in any patient. Conclusions: The recommended dose of pegliposomal doxorubicin in the biweekly CLAOP regimen for Phase II/III testing is 20 mg/m2, a regimen that can safely be administered to old patients without apparent cardiotoxicity.

[Table: see text]
Level of circulating endothelial cells as new biomarker in patients with multiple myeloma, treated with bortezomib-pegylated liposomal doxorubicin-dexamethasone combination
Authors: Gevorgyan A. , Pitini V. , Arrigo C. , Altavilla G. , Naro C. , Alu M. , Procopio G. , Verzoni E. , Platania M. , Bajetta E.
Published: March 2020

17551

Background: Bortezomib is a proteasome inhibitor and has effects on both multiple myeloma (MM) tumor cells and stromal cells. Recent data suggests that relative levels of circulating endothelial cells (CECs) may serve as surrogate markers of myeloma activity. Hence, we assay the number of CECs by cell phenotype, to explore the activity and response to treatment with BMD (Bortezomib, Myocet, Dexametasone) in previously untreated MM patients. Methods: Twelve pts. with newly diagnosed multiple myeloma were enrolled in this study. Panel of monoclonal antibodies and appropriate analysis gates were used to enumerate CECs. Patients received Bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11, pegylated liposomal doxorubicin (30 mg/m2-Myocet) on day 1 and dexamethasone (40 mg/daily for 4days) for four cycles (q21) before Cyclophosphamide (5 g/m2) and G-CSF mobilization, followed by peripheral blood stem cell collection. The pts received high-dose Melphalan (MEL200) with PBSC transplantation. Samples of healthy controls were used to compare CECs levels. Results: After the treatment with BMD 4 patients had a complete remission, 2 nCR, 5 VGPR and 1 PD. All pts. underwent PBSC mobilization and 11 out of 12 were mobilized, with a median of 3.50 × 106 CD34+ cells/Kg collected with a median of 2 (range 1–4) collection procedures. Responding pts. (11) received high-dose Melphalan with stem cell transplantation. The median time to reach neutrophil and platelet regeneration was 13.5 days and 13 days respectively. In healthy controls (N° 18) mean values of CECs were 0.05% (0.1–0.62). Before treatment with BMD mean CECs level in study patients was 0.79% (0.54–1.53). After BMD treatment CECs in responding pts. was 0.07% (0.1–0.70; p < 0.01). Conclusion: BMD combination therapy in newly diagnosed MM pts. has a high response rate, it does not influence on subsequent stem cell collection, is associated with modest toxicity, furthermore, CECs value can serve as new biomarker for myeloma activity.

No significant financial relationships to disclose.
A study of tolerance to treatment among the most frequent cancer in the elderly
Authors: Pilnik N. G. , Werbin R. , Dirienzo J.
Published: March 2020

18609

Background: Besides, aging may influence pharmacological aspects due to functional reserve deterioration and comorbidities, affecting tolerance to treatment and increasing the likelihood of complications. Methods: 166 cancer pts (56 lung, 64 breast, and 46 colon), mean age 72 yrs, treated with Ch/Rt were studied. Lung cancer pts had PS 0:1 (2%); PS 1:17 (30%); and PS2:38 (68%). Breast cancer pts had PS 0:6 (9%); PS 1:25 (39%); PS 2:33 (52%). Colon cancer pts had PS 0:6 (13%); PS 1:17 (37%); PS 2:23 (50%). Comorbidities were hypertension, diabetes, arrhythmia, EPOC, coronary and gastrointestinal disease. All of the pts had adequate cardiac, hepatic, renal and bone marrow functions. Allergy, cardiovascular, gastrointestinal, hepatic, neurological, haematological and renal toxicities, and infection were evaluated following the WHO criteria. Toxicities were studied according to age and comorbidities, and correlated with the use of other medicines. QoL was studied through the improvement of symptoms and PS evolution. The Chi Square test was used for statistical analyses. Results: The prevalence of common toxicities in the lung cancer pts were anemia, 39 pts (70%), infection, 37 pts (66%), leukopenia 33 pts (59%), gastrointestinal 28 pts (50%). The most common toxicities in breast cancer, were leukopenia 43 pts (67%), gastrointestinal 37 pts (58%), infection 36 pts (56%), and anemia 32 pts (50%), while in colon cancer pts the toxicities found were gastrointestinal 38 pts (83%), anemia 33 pts (72%), leukopenia 32 pts (70%), and infection 25 pts (54%). There was no correlation between age and the most frequent toxicities. Grade 2 was the most common level of toxicity reached in all types of cancer studied. There was improvement in QoL when symptoms evolution and PS were evaluated independently of cancer type, 81% (134 pts) for symptoms (p < 0.0001), and 72% (120 pts) for PS (p < 0.0001) respectively. There was no association between age and toxicity grade, irrespective of toxicity type, age and comorbidities. Conclusions: Older pts in good general condition and with controlled morbidities may receive Ch/Rt if this treatment modality results in improvement of their QoL.-Low toxicities occurred in most of these pts, probably due to the fact that pts were adequately selected.

No significant financial relationships to disclose.
Death predicictive factor in terminal cancer patients
Authors: Koh S. , Lee K. , Hong Y. , Kang J. , Woo I. , Lee M. , Chang S.
Published: March 2020

18627

Background: One of the most important role of a end-of-life care is to control physical symptoms of patients and help them to face comfortable end. In terminally ill cancer patients, accurate prediction of survival is necessary for clinical and ethical reasons, especially in helping to avoid harm, discomfort and inappropriate therapies and in planning specific care strategies. The aim of the study was to investigate prognostic factor of death for the patients with terminal cancer. Methods: We enrolled 121 patients with the terminal cancer of Kangnam St. Mary’s Hospital from September 2004 until their death. We observed symptoms shown in dying patients and assess 17 common symptoms shown in terminally ill cancer patients, performance status, pain and analgesic use. The common symptoms were measured in a score of 0-none, 1-mild, 2-moderate, 3-severe or 4-severe by objective criteria. Results: Mean period from enrollment to death was 34.7days. The most important prognostic factor is performance status (KPS), average KPS at enrollment is 52.2% and at last 48hours is 29.8%. Physical symptoms that have significant prognostic importance are weakness, anorexia, dry mouth, dysphagia, dyspnea. VAS and analgesic use dose not impact on the prognosis. But cognitive impairment and delirium are the reliable prognostic factor. Especially weakness, dry mouth, poor oral intake, drowsiness, edema, dyspnea, ascites, icterua gradually worsened with significance. Dying patients showed markedly decreased blood pressure, cyanosis, cold extremity, death rattle, abnormal respiration frequently at 48hours before death. Conclusions: Terminally ill cancer patients have various prognostic factor and the most important factor is performance status. The death predictive symptoms such as markedly decreased pressure, cyanosis, cold extremity, death rattle, abnormal respiration appeared at last 48hours. If we assess the symptoms more carefully, we can predict the more accurate prognosis. The communication about the prognostic information will influence the personal therapeutic decision and specific care planning.

No significant financial relationships to disclose.
Distress and breast cancer anxiety (BCA) among BRCA mutation carriers participating in MRI-based screening
Authors: Hill K. , Warner E. , Esplen M. , Bigenwald R.
Published: March 2020

20001

Background: MRI has consistently been shown to be a more sensitive screening tool than mammography (M) but its lower specificity could have negative psychological effects. In a pilot study (SABCS 2004) no adverse psychological effects of MRI screening were found. A larger study was then done to look particularly at the impact of imaging recalls and biopsies. Methods: BRCA mutation carriers having breast screening with annual M, MRI, and ultrasound (US) + 6monthly clinical breast examination (CBE) were asked to complete questionnaires: 1 - 2 wks pre, 4 - 6 weeks after, and 6 months after their imaging. Questionnaires included the hospital anxiety and depression scale (HADS), a modified Kash breast cancer anxiety scale (BCAS), the monitor/blunter scale, a rating of overall health on a linear analog scale, a 4 category rating of anxiety related to each screening modality, and a description of any recent life altering events. Results: 54 women (29 BRCA1, 25 BRCA2) completed at least 2 questionnaires (median 3, range 2–5). Mean age was 44 (range 28–64). 26% were surveyed during their 1st round of screening. There was a very strong correlation between the BCAS and HADS anxiety with 19 (35%) having baseline BCA of whom 15 (79%) were monitors compared to 60% monitors among the patients without BCA. At baseline 41 (76%) indicated moderate/high MRI related anxiety compared to 61%, 46%, and 43% for M, U/S and CBE. Of the 16 patients (30%) who had recalls ± biopsy (n = 5) while on this study, 10 (63%) had elevated BCA and 3(19%) increased depression at baseline. In all but 2 women whose anxiety increased due to life events, no scores changed significantly after recall or biopsy. Only 1 cancer was diagnosed during the study period. In the other 38 women scores changed significantly only as a result of life events. Conclusions: Despite a high false positive rate, MRI-based screening had no detectable adverse psychological effects on BRCA mutation carriers in this study.

No significant financial relationships to disclose.
Prognostic significance of plasma Epstein-Barr virus (EBV) DNA level in patients with locally advanced head and neck carcinoma treated with concurrent cisplatin and concomitant boost radiotherapy (CBRT)
Authors: Yu K. H. , Chan A. K. , Tse G. M. , Kam M. K. , Hui E. P. , King A. D. , Vlantis A. C. , Wong K. T. , Lo D. Y. , Chan A. T.
Published: March 2020

20003

Background: EBV DNA is detectable in the plasma in most patients (Pts) with lymphoepithelial carcinoma (LECA) and in some Pts with squamous cell carcinoma (SCC) of the HN. We investigated the prognostic significance of plasma EBV DNA level in a prospective phase II trial of concurrent cisplatin and CBRT for locally advanced HN carcinomas. Methods: Eligibility criteria included newly-diagnosed SCC or LECA of non-nasopharyngeal HN sites; stage III or IV disease; ECOG performance status ≤ 1; and age ≤ 70 years. Plasma EBV DNA levels were measured by real-time quantitative polymerase chain reaction (PCR) before treatment and at 6 weeks post-treatment. Pre-treatment gross tumor volume (GTV) was measured on CT, and invasion of bone and cartilage was assessed on CT and MRI. Cisplatin 40–50 mg/m2 was given on days 1, 8, 15 and 22 of CBRT. Radiotherapy consisted of 54 Gy/30 fractions/6 weeks and a concomitant boost (18 Gy/12 fractions) in the last 12 treatment days. The primary endpoint was overall survival (OS) and the secondary endpoint was progression-free survival (PFS). Survival curves were compared by the log-rank test and multivariate analysis was performed with Cox regression. Results: Between March 2001 and January 2005, 46 Pts were recruited (36 with SCC and 10 with LECA). Thirty-four Pts had stage III and 12 had stage IV disease. Pre-treatment plasma EBV DNA level was > 0 copy/ml in all Pts with LECA (range, 37 - 211737 copies/ml) and in 8 Pts with SCC (range, 10 - 48734 copies/ml). Ten Pts had plasma EBV DNA level > 0 copy/ml at 6 weeks post-treatment. With a median follow-up of 1.6 years, the 1-year OS rate was 87.7 % and 1-year PFS rate was 68.3%. On multivariate analysis, plasma EBV DNA > 0 copy/ml at 6 weeks post-treatment was the only independent predictive factor of decreased OS [hazard ratio (HR) 3.59, p = 0.04] for the entire group. In the subgroup of Pts with SCC, pre-treatment EBV DNA > 0 copy/ml was the only independent predictive factor of decreased locoregional PFS (HR 7.08, p = 0.03). Conclusions: Plasma EBV DNA level is a prognostic factor in Pts with locally advanced HN SCC and LECA. Further studies are warranted to confirm the finding and to elucidate its biological basis.

No significant financial relationships to disclose.
Breast cancer risk estimates using the Gail Model in women from an annual screening program in Southern Brazil
Authors: Belo Reyes V. , Skonieski G. , Zignani J. , Bedin A. , Giugliani R. , Palmero E. I. , Kalakun L. , Schuler-Faccini L. , Ashton-Prolla P. , Caleffi M.
Published: March 2020

20045

Background: The Gail model is widely used to estimate breast cancer (BC) risk. It has been validated as a reliable risk predictor in North America, but very few studies have been done in other countries. This study intends to examine the estimated BC risk using the Gail Model in a sample of women from Southern Brazil a region with the highest BC incidence and mortality rates of the country. Methods: Lifetime and 5-year BC risk estimates were obtained for the first 1002 asymptomatic women (ages 40–69 years) enrolled in an annual BC screening program. The frequency of each of the model’s variables was recorded and compared to other studies. Information about family history (FH) included: presence of bilateral BC, male BC, first degree relative with BC and/or ovarian cancer (OC), relative with BC under age 50 and ≥ 2 relatives with either BC, OC or colorectal cancer (CRC). Other potential risk factors for BC such as body mass index and smoking were recorded. Results: Mean (± SD) values for age, age at menarche and age at birth of the first live child were 50.4 (± 7.75), 13.0 (± 1.80), and 21.6 (± 5.00) years, respectively. Only 50 (5.0%) women were nulliparous and 62 (6.2%) reported their first live birth after age 30. History of at least one first-degree relative (FDR) affected with BC was reported by 52 (5.2%), and 31 (3.1%) had a previous breast biopsy. The mean estimated BC risk in 5 years was 0.92% (± 0.49); for those under age 60, 24 (2.8%) had an estimated 5-yr risk over 1.66%. The mean estimated lifetime BC risk was 7.80 (± 3.2). Interestingly, a history of cancer in a FDR was reported by 32.6% of the women, and evidence of familial BC was observed in 20.4%. The estimated BC risk using the Gail model was significantly higher in women with a family history of BC < 50ys and with ≥ 2 relatives with either BC, OC or CRC. Smoking and overweight were reported by 28% and 65% of the women, respectively. Conclusions: BC risk estimates obtained with the Gail Model did not differ significantly from those described in other populations. However, specific findings in cancer FH were associated with higher risk estimates. The importance of FH and overweight will be further explored in a larger sample. Population-specific risk factors for BC should be sought in different communities to ensure proper risk estimates.

No significant financial relationships to disclose.
Evaluation of HER-2 in serum and tissue: correlation with clinical-pathological parameters and outcome in early stage breast cancer (BC) patients (pts)
Authors: Ludovini V. , Gori S. , Mosconi A. , Pistola L. , Rulli E. , Rulli A. , Anastasi P. , Pacifico E. , Sidoni A. , Tofanetti F. R. , Colozza M.
Published: March 2020

20066

Background: HER2 is amplified and/or overexpressed in approximately 20–30% of invasive BC and is associated with poor prognosis. It is also a predictive marker of response to trastuzumab. The extracellular domain of the HER2 protein (sHER2) is frequently cleaved and released into the circulation where it can be detected by ELISA in up to 45% of advanced BC. We evaluated HER2 expression in paired serum and tissue samples of operable BC pts to analyze 1) the correlation between sHER2 and HER2 tumor status 2) their relationship with clinical-pathological parameters and 3) their impact on the outcome. Methods: 188 consecutive stage I-III BC pts were included in this study from May 2000 to July 2005. sHER2 was measured by ELISA (manual Kit “Oncogene Science Diagnostics” and automated version “ADVIA Centaur”) before the local treatment. Tumor tissue was analyzed by IHC with CB11 antibody and scored with Dako Hercept-test. HER2 amplification was determined using the Ventana FISH assay in patients with 2+ by IHC. Chi-squared test was used to evaluate the association between HER2 and patients’ clinical-pathological features. Survival outcomes were analyzed using Cox’s model. Results: Median age was 56.6 years; 122 pts received adjuvant chemotherapy, 54 endocrine therapy and 83 both. Forty-three pts (23%) had HER2 overexpression/amplification in tumor tissue and 25 pts (13%) had sHER2 levels ≥15 ng/ml (cut-off level) with a concordance of 85%. Both high sHER2 levels and HER2 tumor expression were associated with high histological grade (p = .02 and p < .0001 respectively) and negativity of ER (p = .0035 and p < .0001) and PgR (p = .0056 and p =. 002). At a median follow-up of 2.4 years we observed 8 deaths and 19 relapses. At univariate analysis high sHER2 levels (evaluated as continuous variable) were significantly correlated with shorter DFS (p = 0.0002) even if at multivariate analysis high sHER2 levels, after adjustment for stage and ER status, were associated with a shorter DFS with borderline significance (p = 0.06). Conclusion: Our preliminary data indicate that the evaluation of sHER2 at diagnosis defines a small subgroup of early BC pts with a poor prognosis even if it needs to be confirmed in a longer follow up.

No significant financial relationships to disclose.
Phase I study of intravenous (IV) milataxel in adult patients with advanced malignant tumors
Authors: Bourbouloux E. , Campone M. , Vermorken J. B. , Martin M. , Sessa C. , Perotti A.
Published: March 2020

2037

Background: M (TL139, MAC-321) is a novel taxane with activity in human xenograft models against tumors resistant to paclitaxel. The maximum tolerated dose (MTD) when given IV every 3 weeks was 35 mg/m2. The current study was designed to determine if the dose intensity of M could be increased by a weekly IV schedule. Methods: The primary objective of the study was to determine the maximum tolerated dose (MTD), the dose limiting toxicity (DLT) and the recommended dose (RD) for phase II. Secondary objectives were pharmacokinetic (PK)/pharmacodynamic (PD) parameters of M given IV weekly and a preliminary estimate of efficacy in an expanded cohort at the RD. Key pt eligibility criteria included in adult pts with refractory malignant tumors, ECOG PS <3 and adequate hematologic, hepatic and renal function. Patients were not allowed concurrent strong inhibitors of cytochrome p450 3A4. Dose escalation was based on Fibonacci method. At the RD, additional pts with tumors that typically respond to taxane treatment were added. PK data were obtained on day 1 and 15. Results: A total of 32 pts were treated, 15 (6 females, 9 males) in the dose escalation part and 17 (15 females, 2 males) in the MTD confirmation part. The median number of doses was 11 (range 1–18). In the dose escalation phase, 3, 4, and 3 pts were treated at 8, 12, and 16 mg/m2 IV weekly without DLT. At 20 mg/m2, 2 of 5 pts developed DLT (1 pt - myalgia and neuropathy, 1 pt grade 4 neutropenia > 5 days in duration). The RD was 16 mg/m2 weekly. 17 more pts were treated at the RD. The most frequent grade 3 or 4 adverse events were asthenia (19%), nausea (9%), parethesia (9%) and neuropathy (9%). Of the 10 pts with breast cancer who were evaluable for response, one had a PR. Another breast cancer pt with a PR was a protocol violation and was not evaluable. In 20 pts at the MTD, the Tmax was 4 hr, the Cmax was 51.97 ng/mL, AUC 2711 ng*hr/mL, and the Vss was 1496 L/m2. Conclusions: Milataxel had an RD of 16 mg/m2 IV per week. Objective responses were observed in pts with metastatic breast cancer.

No significant financial relationships to disclose.
Therapeutic activity of neutralizing monoclonal antibodies targeting hepatoma-derived growth factor in cancer xenograft models
Authors: Mao L. , Ren H. , Chu Z. , Yuan P.
Published: March 2020

2517

Background: Hepatoma-derived growth factor (HDGF) is a mitogen for endothelial cells, vessel smooth muscle cells, fibroblasts, as well as some epithelial cells. It is overexpressed in a number of human cancers and its overexpression in tumors strongly correlates with tumor progression, recurrence, and metastasis. We recently showed that down-regulation of HDGF in lung cancer cells reduces tumorigenecity in both in vitro cell and in vivo animal models suggesting HDGF may be of a therapeutic target for cancer. Methods: Recombinant HDGF was used to develop a panel of monoclonal antibodies specifically bind to HDGF. Four antibodies were tested for their therapeutic activity in lung and pancreatic cancer xenograft models. The monoclonal antibodies were administered 250μg/animal (5 mice per group) every 3 days IP when the subcutaneous tumors reached approximately 50 mm3. Results: Two antibodies (C1 and H3) exhibited significant therapeutic activity in A549 lung cancer model whereas H3 also showed a therapeutic effect in MiaPaca-2 pancreatic cancer model. No sign of toxicity in the living animals and histology of major organs were observed in the antibody treated animals. In the A549 model, the mean tumor burden was 960 mm3 for control-IgG treated mice 22 days after tumor inoculation, whereas the mean tumor burdens were 224 mm3 for C1 and 266 mm3 for H3 treated mice (P < 0.05) respectively. In the MiaPaca-2, the mean tumor burden was 994 mm3 for control-IgG treated mice 21 days after tumor inoculation in contrast to 345 mm3 for H3 treated mice (P < 0.05). Consistent with known biologic functions of HDGF, our early morphologic and biomarker analyses suggest that H3 may neutralize tumor cell released HDGF resulting in disruption of tumor stroma and extracellular matrix structures. Conclusions: HDGF is a novel therapeutic target for multiple human cancers and neutralizing monoclonal antibodies targeting HDGF are effective in treating lung and pancreatic cancers in animal models. (Supported by DoD grant DAMD17–01–1-01689–1)

No significant financial relationships to disclose.
Efficacy of SMIP-016, a novel CD37-directed biologic therapy, in human NHL tumor xenograft models
Authors: Barone D. S. , Nilsson C. , Ledbetter J. , Hayden-Ledbetter M. , Mohler K.
Published: March 2020

2565

Background: Small Modular Immuno-Pharmaceuticals (SMIP) biopharmaceuticals belong to a novel proprietary biologic compound class that retain Fc mediated effector functions and are smaller than monoclonal antibodies. SMIP-016 is a SMIP product candidate that binds to CD37 on human B cells and has potent ADCC and apoptotic activity in vitro. CD-37 is known to be over-expressed in non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). We have evaluated the activity of SMIP-016 in established human tumor xenograft models in nude mice. Methods: Nude mice were injected subcutaneously with either Ramos or Daudi tumor cells. At approximately 7 days post tumor inoculation the mice were randomized to groups with roughly equivalent mean tumor volumes (>200mm3) and were treated with SMIP-016 or rituximab as a comparator. Groups were evaluated for median survival time (MST), tumor volume and percentage of tumor-free animals. Results: In nude mice bearing Daudi tumors, SMIP-016 treated mice showed a significant improvement in MST compared to control mice (p < 0.0001). Nude mice bearing Ramos tumors treated with SMIP-016 also demonstrated a significant enhancement in their median survival time (MST) in comparison to control mice (p < 0.0001). In addition, mice receiving SMIP-016 administered in combination with rituximab in this model demonstrated improvements in survival time over either single agent therapy alone. Conclusions: SMIP-016 is effective in treating established tumors in these human tumor xenograft models. Addition of SMIP-016 to rituximab therapy resulted in enhanced survival times compared to animals treated with rituximab alone.

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Phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor MS-275 in combination with 13-cis retinoic acid in patients with advanced solid tumors
Authors: Pili R. , Rudek M. , Altiok S. , Qian D. , Zhao M. , Donehower R. , Anderson A. , Halter M. , McFarland H. , Zwiebel J. , Carducci M.
Published: March 2020

3055

Background: Preclinical studies suggest that histone deacetylase (HDAC) inhibitors may restore tumor sensitivity to retinoids. The objective of this study was to determine the maximum-tolerated dose (MTD), the dose-limiting toxicity (DLT), and the pharmacokinetic (PK)/pharmacodynamic (PD) profiles of the HDAC inhibitor MS-275 in combination with 13-cis retinoic acid (CRA). Methods: Patients (pts) with advanced solid tumors were treated with MS-275 orally once weekly and CRA orally twice daily x 3 weeks every 4 weeks. The starting dose for MS-275 was 4 mg/m2 and the dose was escalated based on toxicity assessments. The fixed dose for CRA was 1 mg/kg/day. PK concentrations of MS-275 and CRA were determined by LC/MS/MS. Western Blot analysis on peripheral-blood mononuclear cells (PBMCs) and tumor samples (when feasible) were performed to evaluate target inhibition. Results: To date thirteen pts have been enrolled. Tumor types include prostate (4 pts), bladder and renal cell (2 pts), and others. The MTD was exceeded at the 5 mg/m2 dose level (G3 hyponatremia, neutropenia and anemia). Fatigue (G1 or G2) is a common side effect. MS-275 peak concentrations were 141.6±75.7ng/mL at 4mg/m2 and 139.5±30.9 ng/mL at 5mg/m2. MS-275 half-life and clearance were 108.2±47.9h and 9.4±6.0L/h/m2, which is consistent with prior reports for MS-275 as single agent. Median CRA steady-state trough levels were 182.4 ng/mL. The MTD was 4 mg/m2 MS-275 and 1 mg/kg CRA. Five pts remained on treatment for ≥ 4 months including pts with prostate cancer (3), pancreatic cancer (6 months) and a pt with renal cell carcinoma (12 months) who presented a partial response in the lungs. Histones isolated from PBMCs showed transient but consistent protein acetylation post-therapy. Tumor biopsy of a liver lesion from prostate carcinoma revealed post-therapy induced histone acetylation and decreased phosphorylated ERK and STAT3 protein expression consistent with HDAC inhibitory activity. Conclusions: Combination of MS-275 with CRA is reasonably well tolerated and 4 mg/m2 is the Phase II recommended dose for MS-275 in combination with CRA. Tumor response and PD data suggest clinical and biological activity for this combination strategy.

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A pooled safety and efficacy analysis of the FOLFOX4 regimen (bi-monthly oxaliplatin plus fluorouracil/leucovorin) in elderly compared to younger patients with colorectal cancer
Authors: Sargent D. J. , Goldberg R. M. , Bleiberg H. , De Gramont A. , Tournigand C. , Andre T. , Rothenberg M. L. , Tabah-Fisch I. M.
Published: March 2020

3517

Background: The combination of oxaliplatin, fluorouracil, and leucovorin is effective in many patients with colon cancer treated in either the advanced or adjuvant disease setting. To better identify the risks & benefits of this regimen for elderly patients we compared safety & efficacy data for the FOLFOX4 regimen (oxaliplatin plus fluorouracil/leucovorin administered bimonthly) in patients over & under 70 years of age. Methods: We conducted a retrospective analysis of 3742 patients (614 aged ≥ 70) with colorectal cancer enrolled in four clinical trials using the same FOLFOX4 regimen as adjuvant therapy, or as first- or second-line therapy in advanced disease. Endpoints included grade ≥ 3 adverse events, response rate (RR) (in studies of advanced disease), progression (metastatic)/relapse free (adjuvant) survival (P/RFS), overall survival (OS), and dose intensity. Results: Age ≥ 70 was associated with slightly higher rates of neutropenia and thrombocytopenia but no other grade ≥ 3 adverse events (see table). There was no difference in 60-day mortality (1.1% vs 2.3%, p=0.20). We observed no significant difference in any measure of therapeutic impact of FOLFOX based on age, including P/RFS, OS, response rate, or dose intensity (see table). Conclusions: The FOLFOX4 regimen maintains its efficacy/safety ratio in elderly patients with colorectal cancer, and was administered per protocol at similar drug doses compared to the younger patients enrolled on these trials. Age alone should not be a factor limiting the use of FOLFOX4 provided patients are carefully evaluated and monitored. This analysis was supported by Sanofi-Aventis

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A phase II study of celecoxib (C) with irinotecan (I), 5-fluorouracil (F), and leucovorin (L) in patients (pts) with advanced or metastatic colorectal cancer (CRC)
Authors: Sanborn R. E. , Lenz H. , Haller D. G. , Benson A. B. , Dragovich T. , Robles C. , McMahon M. , Li H. , Mori M. , Mattek N. , Blanke C. D.
Published: March 2020

3588

Background: Expression of cyclooxygenase-2 (COX-2), present in most CRC, is associated with a worse prognosis. C, a selective COX-2 inhibitor, has inhibitory effects against CRC which appear at least additive with chemotherapy preclinically. A multi-institutional phase II trial was conducted to evaluate C plus standard IFL as first-line treatment for pts with incurable CRC. Methods: C 400mg po BID starting Day #1; I 125mg/m2 iv weekly starting Day #15; F 500mg/m2 iv bolus weekly starting Day #15; L 20mg/m2 iv weekly bolus starting Day #15. Patients received IFL for 4 weeks followed by a two-week rest. C was continued during the rest. Pts were treated until disease progression or unacceptable toxicity. Primary endpoint was response with planned sample size of 47 patients. Results: 47 pts were consented and treated. Evaluable pt characteristics: Male/female (no.) = 34/13; mean age = 59.7; ECOG PS 0/1/2 (no.) = 31/14/2; cancer stage locally-advanced/distant/unknown (no.) = 10/28/9. Due to concerns of risk of excess cardiovascular (CV) toxicity the protocol was amended halfway through enrollment to exclude pts with PS 2, and to require low-dose aspirin (ASA) for pts at high risk for CV events. Pre-and post-modification (mod) results are shown in the table . In general hematologic toxicity was moderate. Non-hematologic toxicity was mostly gastrointestinal, but 25% experienced cardiac or vascular toxicity (1 cardiac arrest, 1 MI, 1 CHF, 3 arrhythmias, 2 DVT, 2 CVA, 1 hyper- and 1 hypotension). All cardiac events occurred before modification of the protocol. There was 1 treatment-related death from cardiac arrest. Conclusions: C may be given safely with IFL chemotherapy, if pts are carefully selected. Addition of low-dose ASA may reduce cardiac toxicity. Post-mod TTP and survival for C plus IFL appear superior to historical results for IFL, but a phase III study would be required for confirmation.

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Phase III randomized controlled trial of hypotonic intraperitoneal cisplatin combined with oral UFT/PSK for the adjuvant treatment of gastric cancer invading the serosa
Authors: Tsujitani S. , Saito H. , Tatebe S. , Ikeguchi M.
Published: March 2020

4027

Background: Peritoneal seeding is the most common pattern of recurrence in patients with gastric cancer invading the serosa who underwent curative gastrectomy. We developed hypotonic intraperitoneal cisplatin for preventing peritoneal recurrence in experimental models. Hypotonic cisplatin had a significant tumorcidal effect in vitro and in vivo. Hypotonic intraperitoneal cisplatin was tolerable in phase I clinical study. Now, we investigated the efficacy of the treatment in a multicenter prospective randomized controlled trial. Methods: 134 pts treated with curative resection for gastric cancer invading the serosa were randomized during surgery to one of 2 treatment arms. As per protocol, eligibility was confirmed by pathology and treatment course in 108 pts as follows: A -Hypotonic intraperitoneal cisplatin (100mg/m2) during surgery and systemic UFT (300mg/day) + PSK (protein-bound polysaccharide, 3g/day) (n=54) and B-Systemic UFT + PSK (n=48). Cisplatin diluted in 1,000 ml of warmed distilled water was injected to the abdominal cavity before closure of the abdomen. Drains were closed for 1 hour after injection of cisplatin. Results: Median follow up was 6.8 years. Postoperative complication rate and side effects were 21.3% and 30.8% in A-arm and 22.4% and 24.0% in B-arm. Tolerance was good in both arms. Peritoneal recurrence rate was 26.9% in A-arm and 40.0% in B-arm (chi-square p=0.16). Overall survival at 5 years was 62.0% and 31.0% in pts with or without hypotonic intraperitoneal cisplatin (log-rank p=0.03). Conclusions: Combining hypotonic intraperitoneal cisplatin and systemic oral chemotherapy improves the efficacy of oral chemotherapy after curative surgery for gastric cancer invading the serosa.

No significant financial relationships to disclose.