bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cetuximab reversal of resistance to chronomodulated chemotherapy in heavily-pretreated patients with metastatic colorectal cancer (MCC) without amplification of epidermal growth factor receptor (EGFR) gene
Authors: Lévi F. A. , Karaboué A. , Bralet M. , Innominato P. , Herelle M. O. , Giacchetti S. , Adam R. , Jasmin C. , Guettier C. , Bouchahda M. 
Published: March 2020

13104 Background Skin toxicity and EGFR amplification reportedly predicted for Cetux-reversal of MCC resistance to standard chemotherapy. We explored these relations for Cetux reversal of resistance to chronomodulated chemotherapy (Chrono) with irinotecan (CPT11, peak at 5 am), 5-fluorouracil-leucovorin (FU-LV, peak at 4 am) and oxaliplatin (l-OHP, peak at 4 pm). Methods: 40 pts with progressive MCC on 3 prior chemotherapy lines received weekly Cetux (250 mg/m2) and q2–3 wks CPT11-based (30 pts) or oxaliplatin-based (10 pts) Chrono. Toxicities and response were assessed q2–3 wks and q2 months (mo) respectively. Tumor EGFR expression was determined by immunohistochemistry for all pts and gene copies by fluorescent in situ hybridization (FISH) for 25 pts. Results: All pts had prior progression on CPT11, FU-LV and l-OHP. Median age: 61 yo; M/F: 24/16; WHO PS 0/1/2: 27/9/4; colon/rectum: 21/19; M sites 1/2/≥ 3: 12/15/13; liver/lung: 32/29; pre-existing peripheral sensory neuropathy grade ≥ 2: 11 pts. A median of 8 courses of Cetux-Chrono was given (1 to 22). Three pts withdrew for grade 4 allergy. 37 pts were assessable for other toxicities and 36 for response (1 too early). Gr 2–3 acneiform skin rash occurred in 27 pts (73%), with gr3 in 11 pts (29.7%). Other main gr 3–4 toxicities were diarrhea (27% of the pts), neutropenia (24.3%) and neuropathy (21.6%). Disease progressed in 12 pts (33.3%) and was controlled in 24 pts (66.7%) including 13 stable disease (36.1%) and 10 objective responses (8 PR and 2 CR) - 27.8% [95% C.L. 12.9 to 42.7]. EGFR was expressed in 32 pts (80%), with >10% + tumor cells for 14 pts (35%). 3/6 EGFR- pts (50%) and 7/32 EGFR+ pts (21.9%) responded. No gene amplification was documented in the 25 tumors (7 responders). A positive correlation between skin rash and disease control was suggested (p from χ2 = 0.08). Median progression free and overall survival (mo) are 5.3 [2.9–8.4] and 11.1 [8.6–13.6] respectively. Conclusions: Cetux partly alleviated MCC resistance to Chrono, independently of tumor EGFR protein expression or gene amplification, possibly through interfering with TGFα. This EGFR ligand carries poor prognosis for MCC and alters circadian clock function. [Table: see text]
Thymidylate synthase and MDR1 mRNA levels predict response to chemotherapy with S-1 in metastatic colorectal cancer
Authors: Fujita I. , Hayashi K. , Uchida K. , Kuramochi H. , Kudo K. , Miyakura S. , Yamamoto M. , Takasaki K. 
Published: March 2020

13107 Background: To test the hypotheses of whether the relative mRNA expression of the thymidylate synthase (TS) gene and multidrug resistance 1 (MDR1) gene are associated with response to chemotherapy with S-1 in metastatic colorectal cancer. Methods: Eighteen patients with progressive stage IV CRC were treated with S-1 twice daily (BSA = 1.5 m2, 60 mg/day) for 28 days, followed by a 2-week period rest. cDNA was derived from frozen tumor specimens to determine TS and MDR1 mRNA expression relative to the internal reference gene GAPDH using fluorescence-based, real-time reverse transcriptase polymerase chain reaction (Taqman) system. Results: The median TS gene expression level from 18 CRC tumors was 0.94 × 10(−3) (minimum expression, 0.15 × 10(−3); maximum expression, 8.0 × 10(−3)), and the median MDR1 gene expression level was 7.75 × 10(−3) (minimum, 0.83; maximum, 41.5 × 10(−3)). The gene expression cutoff values for chemotherapy nonresponse were 1.0 x 10(-3) for TS and 10.0 × 10(−3) for MDR1. The response rate for patients with TS < or = 1.0 × 10(−3) (10 of 18 patients) was 60% (6/10), compared with 0% (0/8) for patients with TS greater than 1.0 × 10(−3) (P = 0.013). Patients with MDR1 expression < or = 10.0 × 10(−3) (13 of 18 patients) had a response rate of 46% (6/13), compared with 0% (0/5) for patients with MDR1 expression greater than 10.0 × 10(−3) (P = 0.11). Regarding the combination of TS and MDR1 Expression, low TS and MDR1 expression levels were detected in 8 (44%) of the patients, and 10 patients (56%) had a high TS and/or MDR1 expression level. The response rate was 75% (6/8) for the low TS and MDR1 expressors and 0% (0/10) for the high TS and/or MDR1 expressors (P = 0.001). Conclusions: These data suggest that intratumoral TS and MDR1 mRNA expression levels are independent predictive markers of response to S-1 chemotherapy in metastatic colorectal cancer. No significant financial relationships to disclose.
Epidermal growth factor receptor (EGFR) mutation rate in advanced ovarian cancer (AOC): Results of a prospective study in Caucasian patients (pts)
Authors: Mustea A. , Koensgen D. , Zeillinger R. , Castillo-Tong D. C. , Sun P. , Mobus V. , Blohmer J. , Pirvulescu C. , Lichtenegger W. , Sehouli J. 
Published: March 2020

13127 Background: The EGFR is over expressed in 55% to 98% of advanced epithelial ovarian carcinoma. Different studies demonstrated EGFR status as an independent prognostic factor for OC. Recent studies in non small cell lung cancer suggest that the presence of the clinical response to tyrosine kinase inhibitors (e.g. ZD 1839) correlates with the somatic mutations in the kinase domain of EGFR, exons 18–21. For pts with OC data are not available on EGFR gene mutation. Methods: Shock-frozen samples from 32 patients (pts) with primary of ovarian cancer were stratified in two groups according to disease-free interval: ≤6 months (17 pts.) and <6 months (15 pts.). All pts were prospectively collected within Tumor bank Ovarian Cancer Project. Patient collective consisted only from west European Caucasian women. Additionally, 9 commercial available ovarian cancer cell lines (TOV-90, TOV-112D, TOV-21G, OVCAR-3, A2780, A2780 ADR, ES-2, SK-OV-3, and Caov-3) and 32 established ovarian cancer lines were analysed. Exon sequencing of genomic DNA was used to detect L858R deletion mutations of EGFR within exons 21 of the kinase domain. PCR and capillary electrophoresis (Chip-Format) were used to analyse 15 bp deletion in Exon 19. We focused on descriptive analysis. The Log-Rank test was applied to confirm statistically significance (p-value of <0.05). Results: Overall, 74.6% of the pts. were diagnosed FIGO stage III-IV. Median follow-up period was: 14.17 month (range: 2–42 months). Whether in cell lines, nor in tumor samples, stratified to response of platinum therapy any mutation of EGFR gene was observed. Conclusions: Our study indicates that the prevalence of mutation in the kinase domain of EGFR, exons 19 and 21 seems to be very low in pts. with AOC. Further studies should investigate other ethical groups of pts. No significant financial relationships to disclose.
Intervertebral administration of 153Samarium with kyphoplasty for vertebral metastases
Authors: Ashamalla H. , Cardoso E. , Weng L. , Rafla S. , Macedon M. , Panigrahi N. 
Published: March 2020

13136 Background: Kyphoplasty is an effective procedure to alleviate pain in metastatic vertebrae. 153Samarium-EDTMP (153Sm) is used for palliative treatment of multiple bone metastases. The hematological toxicity is the main limiting factor. Objectives: Study the feasibility of intervertebral administration of 153 SM with Kyphoplasty. Assess procedure related morbidities specifically haematological since a direct vertebral route is planned though to a much smaller dose. Methods: IRB approval for an off label use of 153Sm-EDTMP was obtained. Six patients with documented vertebral bone metastasis and pathological compression fractures were studied (Thoracic in 2 and lumbar in 4). Primary cancer was lung in 2, prostate (1), maxillary sinus (1), myeloma (1) and colon (1). Serial dilution of 153 SM was performed to obtain 2 mci/1ml. Kyphoplasty procedure was carried out using the known protocol. 2 mCi of 153Sm was admixed with the bone cement and administered under tight radiation safety measures. Serial nuclear body scans were obtained. Pain assessment was evaluated using analog pain score at 1, 7 and 30 days. Serial blood counts are followed. Results: All patients tolerated procedure well. No immediate procedure(s) related morbidities were noted. One case was not technically satisfactory and no significant uptake was detected in the injected vertebra. Nuclear scan done on 0 revealed excellent radiotracer uptake in the other 5 vertebrae injected. The absorbed radiotracer was seen to target other skeletal metastatic lesions in 2 patients. There was no significant change in WBC, HCT or Platelets seen in blood counts obtained over one month post-procedure. Except for the first patient, no appreciable radiation leakage was encountered. Pain score was reduced from a mean of 8.5 to 3.2 during the first week and was maintained below score of 4 at one month assessment. Conclusions: The combination of intervertebral administration of 153SM and Kyphoplasty seems to be well tolerated. No haematological side effects were encountered; probably due to the use of only 2 mci compared to over 70 mci in intravenous administration. Pain control seems to be satisfactory at areas treated. Analysis of procedure related radiological changes is underway. No significant financial relationships to disclose.
Enzastaurin a protein kinase Cbeta-selective inhibitor, inhibits the growth of SCLC and NSCLC cell lines
Authors: Nakajima E. , Helfrich B. , Chan D. , Zhang Z. , Hirsch F. R. , Chen V. , Ma D. , Bunn P. A. 
Published: March 2020

13138 Background: PKCβ is a member of the PKC family of serine-threonine protein kinases involved in tumor cell proliferation and apoptosis. Inhibition of PKCs induced differentiation and enhanced chemotherapy. PKCβ activation is required for tumor-induced angiogenesis. The PKCβ-selective inhibitor enzastaurin, originally developed as an antiangiogenic agent, inhibited tumor cell proliferation in prostate, colon and glioblastoma cell lines in vitro. In NSCLC lines, enhanced phosphorylation and altered PKC expression was demonstrated. In SCLC lines specific PKC isoforms were associated with cisplatin resistance. Methods: The growth inhibitory effects of enzastaruin were evaluated by 6-day MTT assays; the cell cycle effects by FACS analysis; the effects on downstream phophorylated signaling molecules by western blotting. Results: Enzastaurin inhibited the growth of 11 SCLC lines (IC50s 3–10 μM) and 4 NSCLC cell lines (IC50s 3–10 μM). An increase of 7–31% of cells in the G2/M phase of the cell cycle compared to untreated control was observed following 48 hour exposure to the IC50 dose of enzastaurin in both SCLC and NSCLC cell lines. PKCβ has been shown to phosphorylate both GSK3β and Akt. A 24-hour IC50 enzastaurin exposure significantly reduced phosphorylation of GSK3β (Ser9) in both SCLC and NSCLC lines. No changes were observed in phospho-AKT (Thr308) in either SCLC or NSCLC cell lines. Phospho-ribosomal protein S6 (Ser240/244) was also reduced in both SCLC and NSCLC cell lines. Potential synergy was studied between enzastaurin and pemetrexed in SCLC and NSCLC lines and the results were analyzed using the Calcusyn Program by Chou and Talalay. Synergistic (CI <1) to additive interactions were observed between pemetrexed (IC20–70) and enzastaurin (≤ IC50) in both SCLC lines (N = 3) and NSCLC lines (N = 2). Conclusions: We conclude that enzastaruin produces in vitro growth inhibition of SCLC and NSCLC cell lines through inhibition of GSK3β ser9 phosphorylation and has synergistic growth inhibition with pemetrexed. [Table: see text]
OncoVEX: A family of oncolytic herpes simplex viruses optimised for therapeutic use
Authors: Coffin R. S. , Liu B. , Han Z. , Assenberg M. , Thomas S. , Hu J. , Simpson G. 
Published: March 2020

13139 HSV in which ICP34.5 is deleted directs tumour selective cell lysis and has proven safe in Phase I clinical trials. To produce oncolytic HSV with enhanced anti-tumour properties, we have deleted ICP34.5 from a clinical isolate of HSV-1, which enhances the tumour cell killing capabilities of the virus, deleted ICP47 (which blocks antigen presentation), and inserted the gene encoding GM-CSF. This aimed to maximize anti-tumour immune responses following intra-tumoural injection and provide an in situ, patient-specific, anti-tumour vaccine, combined with oncolysis. In vivo, both injected and non-injected tumours could be cured and animals were then protected against tumour cell challenge. A Phase I clinical trial with the virus (OncoVEXGM-CSF) has been conducted including patients with cutaneous or sub-cutaneous deposits of a number of tumour types (Lead Investigator: Professor Charles Coombes, Hammersmith Hospital, London). This demonstrated the virus to have a good safety profile, the main side effects being ‘flu-like symptoms, similar to those which have previously been observed with other oncolytic products. Virus replication and GM-CSF expression was demonstrated together with inflammation, flattening and necrosis of injected lesions which was in some cases considerable and which was also in some cases observed in lesions which had not themselves been injected. In all cases where necrosis was observed in biopsies, this correlated with areas of staining for HSV, suggesting the virus had caused the effect. Following this promising data, Phase II studies are underway in multiple tumour types. In addition to OncoVEXGM-CSF, further versions of OncoVEX expressing other active genes have been constructed and tested in pre-clinical models. These include a virus expressing TNF∝, intended to be synergistic with radiotherapy, and versions of the virus expressing a pro-drug activating gene combined with the delivery of a fusogenic glycoprotein designed to maximize the properties of the virus for local tumour control. Each of these have shown promising results in pre-clinical tumour models, including in combination with chemotherapy and radiotherapy where benefits which are at least additive have been demonstrated. [Table: see text]
Compassionate treatment (CTr) with re-irradiation, carboplatin (Cb) and Cetuximab (C) in very advanced head and neck cancer (HNC)
Authors: Numico G. , Colantonio I. , Heouaine A. , Occelli M. , Fea E. , Russi E. G. , Vigna Taglianti R. , Lanzillotta L. , Merlano M. C. 
Published: March 2020

13153 Background: Extremely locally advanced HNC is a dramatic clinical situation, causing pain, repeated infections, speech and swallowing impairmen, malnutrition and cosmetic disasters. Re-irradiation may partially palliate some pt, but the low dose of radiation that can safely be delivered limits this approach. Recently the combination of C and radiation has shown improvement of clinical outcome over radiation alone. Methods: We started a CTr with re-irradiation concurrent with Cb and C in pts with heavily symptomatic, pretreated HNC. CTr consisted of: RT (30 Gy) 2 Gy/d, 5 d/week given every other week; Cb AUC 6 d 1, 22 and 43; C, 400 mg/m2 loading dose and 250 mg/m2 maintenance, weekly until day 43 (6 administrations). Results: From January 04 to June 05, 8 pts pre-treated with surgery (6 pts), radiation (8) and chemotherapy (6) entered the CTr. All pts but one had bulky soft tissue invasion and 2 had skin ulceration. One had only bulky nodal relapse. One pt died after the 2nd week due to pneumonia. The other pts had a fast response to CTr: within 5–7 d from the start of therapy they reached a clinical benefit (major or complete pain relief, improvement of swallowing and/or neck movements) and subsequently a rapid tumor shrinkment. All pts achieved an objective response (complete response in 2). No significant local or systemic toxicity occurred in any of the pts, but a mild skin rush. The first 4 pts did not receive further treatment after CTr. These pts showed tumor re-growth within 4–6 weeks from the end of treatment. However one of them underwent salvage surgery and is alive and disease free 14 months after CTr. The 3 other pts received maintenance treatment with weekly C until disease progression. One of them died due to cancer unrelated causes without PD 11 weeks after RT. The 2nd pt developed PD during RT. The 3rd pt is progression-free and alive at 30 weeks from the end of RT. Overall, TTP of the 7 pts ranges between 2 and 7+ months (median 3); survival from the end of RT ranges between 3 and 14+ months (median 7+). Conclusions: CTr with re-irradiation, Cb and C seems feasible even in this poor prognosis, very advanced HNC. No additional toxicity was recorded by adding C. Palliation was achieved in almost all pts and the results deserve further investigations. No significant financial relationships to disclose.
Arsenic trioxide for treatment of myelodysplastic syndrome: An experience from India
Authors: Mukhopadhyay Sr. A. , Das S. , Dey S. , Choudhury R. , Ahmed R. , Gupta P. , Dhara A. , Chakraborty S. , Halder B. , Mukhopadhyay S. 
Published: March 2020

13156 Background: Myelodysplastic Syndrome (MDS) is a heterogeneous group of clonal diseases of the haematopoietic stem cells. The hallmark of the disease is ineffective haematopoiesis characterized by dysplasia with incomplete maturation and progressive increase in the percentage of myeloblast. No standard treatment is currently available for MDS. The early clinical experience has confirmed the activity of arsenic trioxide in MDS. The drug is able to induce differentiation and apoptosis and to inhibit cell proliferation or angiogenesis. It has the potential to be active in tumour models in MDS. The preliminary result of ongoing studies conducted in patients with MDS suggests that arsenic trioxide produces haematological improvement including durable transfusion independence in 30% of patients. The aim of our study was to see the response of MDS with arsenic trioxide and to see the toxicity profile of arsenic trioxide in Asian Indian population. Methods: During period from July 2005 to December 2005 we selected consecutive 10 patients of MDS in Refractory Anaemia, Refractory anaemia with ringed sideroblasts, Refractory anaemia with blast excess, Refractory anaemia with blast excess in transformations and chronic myelo monocytic leukemia phases. All patients had performance status more than 60%, some karyotypic abnormalities & in cytopenic phase. Median age of the patients 65 years (range 42 to 70 years). All patients were treated with arsenic trioxide 10mg (Alkem/India) daily for 2 hours infusion 28 days. In 15 days interval 3 courses were repeated. Response assessments were done by haematological, cytogenetic & quality of life assessment. All patients were evaluated after 3 courses of arsenic trioxide. Result: Sixty percent (6 patients) patients had shown major haematological response, forty percent minor & twenty percent has major cytogenetic response. Twenty percent of the patients has disease progression where as 20% has stable disease. The only mild adverse effects were seen in forms of nausea, vomiting, diarrhea, abdominal pain & dermatitis in 30% of patients. Only one patient (10%) had QT prolongation in ECG. Conclusion: We concluded that arsenic trioxide is very useful drug in myelodysplastic syndrome. It is also well tolerated in Asian Indian Population. No significant financial relationships to disclose.
Prognostic significance of fascin overexpression in rectal cancer
Authors: Roh M. S. , Lee J. H. , Kwon H. , Park K. J. , Choi H. J. , Cho S. 
Published: March 2020

13517 Background: Fascin is an actin-bundling protein that induces cell membrane protrusions and increases motility of normal and various transformed epithelial cells. In normal epithelial cells, fascin expression is usually absent or very low, but is often upregulated in several types of human neoplasms. However, the clinicopathological features of fascin expression in rectal cancer are still unknown. Methods: Immunohistochemistry for fascin was performed in 79 rectal cancers. Staining more than 5% of tumor cells was recorded as positive immunoreactivity. Results: Overall, fascin immunoreactivity was detected in 63 (79.7%) out of a total 79 cases. Increased immunoreactivity of fascin was sometimes seen at the invading edge of the tumor. Fascin expression was correlated with TNM staging (p=0.001), positive lymph node metastasis (p=0.001), tumor budding (p=0.001), lymphovascular invasion (p=0.001) and perineural invasion (p=0.039); however, recurrence was not statistically significant (p=0.068). Overall survival rate of patients with fascin-positive tumors was significantly lower than that of patients with fascin-negative tumors (p=0.012). Conclusions: Therefore, we suggest that the overexpression of fascin in rectal cancer may be implicated not only in tumor growth but also in the development of metastases. Our findings indicate that the immunohistochemical detection of fascin could provide useful information as one of the prognostic factor in rectal cancer. No significant financial relationships to disclose.
Hepatic metastasectomy following FOLFOX therapy in patients with colorectal metastases
Authors: Arciero C. A. , Salem R. R. , Lacy J. , Sigurdson E. R. , Hoffman J. P. , Watson J. C. , Joseph N. , Cooper H. S. , Meropol N. J. , Burtness B. 
Published: March 2020

13523 Background: Advances in systemic therapy for metastatic colon cancer may render patients (pts) candidates for hepatic metastasectomy (HM) with curative intent. We retrospectively reviewed our experience with HM following oxaliplatin chemotherapy. Methods: Pts were identified from the records of 5 surgeons who performed HM at two institutions. Pts were included if FOLFOX (bolus 5-FU/leucovorin d1 or d 1 + 2, followed by 46 hour 5-FU infusion; oxaliplatin 85–130mg/m2 d 1 q 14 d) chemotherapy had been given for > 1 cycle prior to HM and complete resection of hepatic metastases was achieved. Data on radiographic (RECIST) and pathologic response and outcome were collected. Pathologic complete response (pCR) was defined as no residual cancer. Near pCR was defined as residual mucin in the liver, without residual cancer cells, or necrosis with atypical glands. Results: Thirty-six pts were identified. Males 21/36, median age 55 (range 37–77), rectum/rectosigmoid primary 5 (13.9%), adenocarcinoma 100%, synchronous metastases or metastases within 6 months (m) of primary diagnosis 24/32 (75%), median cycles of FOLFOX = 7 (range 2 to >30), bevacizumab (B) 9 (25%). Mean number of hepatic lesions pre-chemotherapy 1.9 (range 1–7), tumor size 1 to >10cm. Radiographic responses to pre-operative FOLFOX included partial response (PR) 9/30 (30%), CR 2/30 (6.7%), progressive disease 3/30 (10%), stable disease 16/30 (53.5%). Operations included right (R) hepatectomy 12, extended (ext) R hepatectomy 3, partial R hepatectomy 2, left (L) hepatectomy 3, partial L hepatectomy 1, ext L hepatectomy 1, trisegmentectomy 2, caudate lobectomy 1, multiple wedge resections ± radiofrequency ablation 7. pCR 2 (5.6%); near pCR 3 (8.3%). At a median follow up of 12.9 m from HM, 9/36 (25%) recurred; liver only (3), portal lymph nodes (1), other extrahepatic sites (5). One pt died at 18.3 m. Conclusions: HM after FOLFOX chemotherapy, with or without B, results in a high progression-free and overall survival at 12.9 m. This retrospectively identified population included pts with conventionally adverse prognostic features including rectal cancers, synchronous metastases, large lesions and/or high lesion number. Prospective studies of the utility of pre-HM chemotherapy are warranted. [Table: see text]