bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum glycan analysis in metastatic breast cancer
Authors: Chew H. K. , Miyamoto S. , An H. , Rocke D. , Lebrilla C.
Published: March 2020

11504

Background: There is a need for a reliable breast cancer biomarker that can predict a patient’s response to therapy. Serum glycans, or oligosaccharides, are of particular interest as over half of all proteins are glycosylated and alterations in glycosylation influence growth, adhesion, metastasis and immune surveillance of tumor, among other important functions. Serum glycans can be analyzed by high resolution mass spectrometry. Methods: Sera from patients with known metastatic breast cancer and age-matched healthy controls without medical problems were prospectively analyzed by mass spectroscopy. Women over the age of 18, who were not pregnant or breastfeeding, and who were without other active cancers were eligible. Samples were de-identified for laboratory personnel who analyzed sera by matrix-assisted laser desoprtion/ionization (MALDI) and Fourier transform ion-cyclotron resonance mass sepctrometry (FT ICR MS). Glycans were also profiled by chromatographic separation using a microchip nanoLC (Agilent) with a time-of-flight (TOF) mass analyzers. Results: Sera from 25 patients with metastatic breast cancer and 25 controls were evaluated. The mass profiles were obtained corresponding to both N-linked oligosaccharides (N-glycans) and O-linked oligosaccharides (O-glycans). Distinct variations in glycosylation were observed among sera analyzed from patients with metastatic breast cancer compared to controls. Specific glycan masses were analyzed and found to correspond to N-glycans. The chromatographic glycan profile showed individual glycans that were distinct for the cancer patients. Conclusions: Analysis of serum gylcans by mass spectrometry represents a new paradigm of cancer biomarker studies, focusing on post-translational modifications of proteins, rather than protein expression. Further refinement of this technology may be clinically useful in monitoring response to therapy in metastatic breast cancer.

No significant financial relationships to disclose.
Altered chemotherapeutic response of primary human breast cancer epithelial cells (HBCEC) and breast cancer cell lines
Authors: Hass R. , Lueck H. , von Wasielewski R. , Jin H. , Pich A. , Kuehnle H. , Grothuesmann D. , Hille U. , Bertram C.
Published: March 2020

11506

Background: A novel technique to obtain individual primary cultures of human breast cancer biopsies was filed for patent (PCT/DE 2006/000608). The different individualized HBCEC (human breast cancer epithelial cell) cultures will be characterized and chemotherapeutic effects will be compared to established breast cancer cell lines. Methods: Primary HBCEC from 20 different breast cancer patients were characterized for epithelial cell and tumor markers by immunofluorescence and PCR. Following treatment with 1μM epirubicin for 1h up to 72h differences in protein expression patterns were compared to the similarly treated MCF-7 cell line by 2D gel electrophoresis. Differentially expressed protein spots were identified by mass spectrometry and confirmed by appropriate Western blot analysis. Results: Characterization of primary HBCEC revealed continuous mitosis and cell cycle progression for more than one year in culture with no significant contamination by fibroblasts or other cell types. Whereby HBCEC underwent cell death within 72h of epirubicin treatment analysis by 2D gel and subsequent protein identification by MALDI-TOF/TOF mass spectrometry exhibited a variety of differences compared to MCF-7 cells including HSP27 and prohibitin. Appropriate Western blots confirmed these differences and revealed altered expression levels for HSP27 and prohibitin in the course of epirubicin exposure in HBCEC and MCF-7 cells, respectively, suggesting altered signalling pathways in either primary breast cancer cells or the tumor cell line. Conclusions: Individualized primary HBCEC from various patients could provide a cellular platform beyond breast cancer cell lines, which eventually meet the requirements for an appropriate breast cancer testing system including the characterization of biomarkers and the identification of potential molecular targets.

No significant financial relationships to disclose.
HER2-positive breast cancer cells percentage and progression to trastuzumab treatment in metastatic patients
Authors: García-García Y. , Martínez-Fernández A. , Muñoz Mateu M. , Fernández-Ruiz P. , García-Albéniz X. , Mármol-Casas M. , Domingo-Doménech J. , Pineda-Losada E. , Visa-Turmo L. , Gascón Vilaplana P.
Published: March 2020

11510

Background: Immunohistochemistry (IHC) assay for HER2 in breast cancer (BC) identify patients (pts) who are at benefit from Trastuzumab (T) therapy. The percentage (%) of positive cells is not known to have prognostic significance. Methods: We analyze pts that received T as a treatment for metastatic BC in our center, in monotherapy or in combination with other agents, and to ascertain whether the % of her-2 positive cells can be a predictive factor of response to therapy with T. We define HER-2 positive cells according to the Envision method 3+, valuating the percentage of cells with positive result. If the result of the IHC was 2+, we use fluorescence in situ hybridation (FISH). For a total of 36 patients treated, the results of the % were available only for 21 patients. The median of positive cells was 90% (range 30–100%) and it was taken to define low percentage of positive cell tumors (LPPCT) or high percentage of positive cells tumors (HPPCT). We evaluated the initial response (disease progression-stability versus parcial-complete response), the time to progression (TTP) and the overall survival (OS) of pts on T. We used the log-rank test to determinate the TTP and Fisher’s exact text to determinate the initial response and the OS on therapy with T. Results: TTP to T was significantly higher in LPPCT (median 19 months, CI 10–28) than in HPPCT (median 13 months, CI 7–19) (p=0.037). We didn’t find significant differences regarded to baseline characteristics of the patients, response nor OS. Conclusions: We find that the % of HER2-positive cells is significantly correlated with the TTP in patients on T therapy. The percentage of HER2-positive cells can be at clinical interest as a predictive factor of response to her-2 targeted therapy and it must be confirmed with a large number of pts.

No significant financial relationships to disclose.
Bevacizumab, a monoclonal antibody to the vascular endothelial growth factor (VEGF), and irinotecan for treatment of recurrent primary malignant brain tumors in adults
Authors: Lassen U. , Grunnet K. , Kosteljanetz M. , Hasselbalch B. , Laursen H. , Poulsen H. S.
Published: March 2020

12503

Background: The prognosis of recurrent malignant brain tumors is poor, and no efficacious therapy exists in patients previously treated with radiotherapy and standard chemotherapy. Bevacizumab (B) binds to VEGF and inhibits tumor angiogenesis, and treatment with this drug might induce tumor regression and prolongation of life. Irinotecan (I) is a topoisomerase 1 inhibitor with modest effect on recurrent primary brain tumors. The combination of B and I in recurrent malignant gliomas was presented at ASCO 2006 and showed very encouraging responses. Methods: We report confirmatory results of the combination of B and I in a consecutive series of patients with primary malignant brain tumors recurring after standard primary and secondary treatment (surgery, radiotherapy and standard or secondline chemotherapy).With standard inclusion criteria, including PS 0–2, patients received B as 10mg/kg, and I 125 mg/m2 in patients not treated with enzyme inducing antiepileptic drugs (EIAED) or 340 mg/m2 in patients treated with EIAED every other week until progression or non-manageable toxicity. Response evaluation was performed by MacDonald criteria and MRI scans. Results: The results of 31 patients is presented, 15 with grade IV tumors (Glioblastoma multiforme), 7 with grade III anaplastic astrocytomas, 5 with anaplastic oligodendrogliomas, 1 with anaplastic ependymoma, 1 with hemangiopericytoma, 1 with prolactinoma, and 1 with medulloblastoma. Four patients had complete response, 3 grade IV tumors and 1 anaplastic oligodendroglioma. One patient had partial response (> 50% tumor reduction), 12 had stable disease (3 had tumor reduction between 31 - 45 %). 14 progressed. No grade 4 toxicity was observed and most patients experienced grade 1–2 toxicity. Two tromboembolic events and 1 intestinal perforation were observed. Conclusion: The combination of B and I is safe, induces tumor regression in a substantial number of patients, and can be used as treatment to patients recurring after standard treatment.

No significant financial relationships to disclose.
Temozolomide and irinotecan for relapsed glioma: Charing Cross Hospital experience
Authors: Young A. G. , Mulholland P. J. , Waldman A. D. , Roncaroli F. , O’Neill K. S. , Davidson S. J. , Glaser M. G. , Brock C. S. , Newlands E. S.
Published: March 2020

12504

Background: Patients (pts) with relapsed glioma have poor prognosis with few treatment options. Methods: Retrospective analysis was made of toxicity and outcome in pts with relapsed glioma treated between 2001–06 with temozolomide (TMZ, 75mg/m2/day, D1–21) & irinotecan (IRINO, 125mg/m2, D1, 8, 15), q35. Toxicity was graded using NCI-CTC version 2.0. Progression free survival (PFS) was calculated from start of TMZ/IRINO to relapse. Results: 24 pts (M:F, 15:9) were treated, comprising glioblastoma multiforme (GBM) (n=11); anaplastic astrocytoma (AA) (n=7); astrocytoma (n=4); oligoastrocytoma (n=2). Primary treatment following biopsy (n=12) or debulking surgery (n=12) was radiotherapy (RT) alone (n=12) or in combination with TMZ (n=12) (Stupp et al, 2005). At relapse, 10/24 pts received TMZ/IRINO as second-line therapy following TMZ+RT. 12/24 pts received third-line TMZ/IRINO, after TMZ alone (n=9), or TMZ/procarbazine (PCB) (n=2) or IRINO alone (n=1). 2/24 pts received fourth-line TMZ/IRINO, after TMZ then IRINO (n=1) & after TMZ/PCB then IRINO (n=1). 19/21 pts took enzyme-inducing antiepileptic drugs (EIAED). EIAEDs can potentially reduce IRINO exposure. 218 chemotherapy cycles (median, 5; range 1–42+) were given. Grade (G) 3 or 4 hematological toxicities were leucopenia (G3, n=3, 1.4%), neutropenia (G3, n=3, 1.4%; G4, n=1, 0.5%), lymphopenia (G3, n=64, 29%). 5 pts (20.8%) had cotrimoxazole prophylaxis; 1 pt developed PCP on it. 1 pt developed G3 urogenital sepsis. There were no other G3 or G4 toxicities. 13 cycles were delayed due to G2 infection (5.9%). 3 pts had dose reductions.1 pt died from AML; in retrospect symptoms appear to pre-date treatment start. Overall median PFS was 6 months (mo) (range 1.5–39.75+ mo). Overall 2 yr PFS was 28% (95%CI: 10–47%). Median PFS was: GBM 2.5mo (range 1.5–27.25+ mo); AA 11.5 mo (range 2–33.5+ mo). Median 2yr PFS was: GBM 27% (95%CI: 1–53%); AA 14% (95%CI: 0–40%) Conclusions: TMZ/IRINO is well tolerated in heavily pre- treated pts & warrants further evaluation. Long PFS was seen in pts with relapsed GBM & AA. Importantly, re-challenge including TMZ can induce durable response.

[Table: see text]
NT-3/TRK-C regulated proteins in the biology of medulloblastoma
Authors: Gruber-Olipitz M. , Strobel T. , Quehenberger F. , Grotzer M. A. , Lubec G. , Slavc I.
Published: March 2020

12519

Background: Medulloblastoma (MB) is the most common malignant childhood brain tumor. Because of its high risk of leptomeningeal dissemination, standard postoperative treatment includes craniospinal irradiation and chemotherapy. Such treatment produces significant sequelae including neurocognitive dysfunction, endocrine and growth disturbances. These therapy-induced morbidities warrant a novel less toxic approach possibly targeting key molecules within specific pathways of medulloblastoma biology. Recent reports identified high neurotrophin receptor TrkC mRNA expression as a powerful independent predictor of a favorable survival outcome in MB patients. However, the role of activated TrkC receptors in the development and biology of MB remains unclear. Methods: To determine downstream effector proteins of TrkC signaling, the medulloblastoma cell line DAOY was stably transfected with a vector containing the full-length TrkC cDNA sequence or an empty vector control. Accounting for the complexity of ligand-induced changes in cellular pathways and effector proteins, we investigated proteomic changes at multiple time points for up to 48 hrs following neurotrophin-3 induced TrkC receptor activation. Results: We identified 18 proteins differentially expressed: Caldesmon; Cathepsin D; Metastasis inhibition factor nm23; Multidrug resistance-associated protein Mgr1-Ag; Vimentin; Vinculin; Superoxide dismutase (Mn); Glutathione S-transferase P; Stathmin, Lamin A/C, Valosin-containing protein, Annexin A1; ULIP protein; DJ-1 protein; Fascin; Mitofilin; Heterogeneous nuclear ribonucleoprotein H and K. Conclusion: The proteins affected play substantial roles in differentiation, migration, invasion, proliferation, apoptosis and drug resistance. Almost all of the proteins have been described as being essential in the pathogenesis of different solid tumors, but have not been related to MB pathogenesis so far.

No significant financial relationships to disclose.
Comparison of chemotherapy regimens for malignant gliomas with positive MGMT protein expression: Experience of 51 cases
Authors: Zhang J. , WU Q. , Chen Z.
Published: March 2020

12522

Background: To compare the efficacy and toxicity of three chemotherapy regimens for MGMT positive gliomas. Methods: Fifty-one patients with histologically confirmed malignant gliomas and MGMT positive expression were enrolled in this study. The glioma tissues were examined for MGMT protein expression by immunohistochemistry. The patients were treated with: 1, regimen contained of nitrosourea (nitrosourea group) 11 cases; 2, regimen contained of temozolomide (temozolomide group) 18 cases; regimen contained of neither nitrosourea nor temozolomide(no alkylating agent group) 22 cases. Response to chemotherapy was evaluated according WHO criteria, and toxicity was evaluated according National Cancer Institute (NCI) criteria. Results: The overall objective response rate (CR + PR) for 51 cases with MGMT position gliomas was 20%, and disease control rate (CR+PR+SD) was 59%. The objective response rate and disease control rate in nitrosourea group, temozolomide group, and no alkylating agent group were 0%,18.2%,16.7% and 61.1%,31.8%,77.3%, respectively. There was significant difference between no alkylating agent group and nitrosourea group (P<0.05). Hematological toxicity and nausea/vomiting were main side-effect observed in nitrosourea group. While there was comparative lower incidence of side-effect in temozolomide group. Hematological toxicity, nausea/vomiting, and alopecia were main side-effect observed in no alkylating agent group. Though there was higher incidence of 3–4 grade hematological toxicity in this group, but it could recovered by oneself in one week or through treatment with G-CSF for 3–5 days. Conclusions: Regimen contained no alkylating agent group can obtain higher response rate and thus is worth of recommending to patients with MGMT positive gliomas. However, since modest response rate and good toleration, regimen with temozolomide shouldn’t be given up in MGMT position gliomas. Nevertheless, It is necessary to discover more efficiency way of using temozolomide. Nitrosourea should not be recommended to MGMT position glioma patients.

No significant financial relationships to disclose.
Adjuvant chemotherapy with temozolomide and radiation therapy in patients with high grade gliomas
Authors: Pedersini R. , Vattemi E. , Lusso M. , Baier S. , Campello M. , Broger M. , Schwarz A. , Maffei M. , Lukas P. , Graiff C.
Published: March 2020

12534

Background: Temozolomide, a novel alkylating agent, has shown activity in the treatment of patients with high-grade gliomas. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant chemo- radiotherapy according to Stupp regimen. Methods: We reviewed our experience with a combination of radiotherapy (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). Results: 43 patients , median ECOG PS= 0, were treated with concomitant RT and Temozolomide at our institution since March 2004. Median age was 63 (range 33–73), with 62% over 60 years. All patients had histologically confirmed high grade gliomas: glioblastoma multiforme (32), grade III oligodendroglioma (3), grade III oligoastrocytoma (2), grade III astrocytoma (6). 2/43 patients underwent only a biopsy, the remaining underwent debulking surgery. At a median follow-up of 17 months, the median progression-free survival (PFS) was 6 mo and median overall survival (OS) was 12 mo. Median PFS and median OS were similar in elderly ( = 60 years). Treatment was well tolerated. Only one patient had grade IV haematological toxicity. One patient discontinued treatment due to hepatotoxicity. Conclusions: Our findings confirm the results of the EORTC trial(Stupp R et al., 2005)

No significant financial relationships to disclose.
Phase I study of the antifolate pralatrexate given with vitamin B12 and folic acid supplementation in patients (pts) with advanced non-small cell lung cancer (NSCLC)
Authors: Azzoli C. G. , Krug L. , Miller V. , Bekele S. , Tyson L. , Dunne M. , Huntington M. , Saunders M. , Kris M. G.
Published: March 2020

13006

Background: Pralatrexate is a novel antifolate that has shown promising activity in the treatment of pts with previously- treated NSCLC at doses of 135–150 mg/m2 IV every other week (q2w). [Krug, Clin Cancer Res 9(6), 2003; 6(9), 2000] The addition of vitamin B12 and folic acid supplementation may mitigate toxicity from pralatrexate and improve efficacy by allowing higher doses to be delivered. Methods: This study is designed to determine the maximum tolerated dose (MTD) of pralatrexate in combination with vitamin B12 and folic acid supplementation in pts with NSCLC. Key eligibility criteria include confirmed stage IIIB or IV NSCLC; at least 1 prior chemotherapy regimen; Karnofsky performance status (KPS) = 70%; and no other active concurrent malignancy. Using a rapid escalation design, pralatrexate was initially administered at a dose of 150 mg/m2 IV q2w, escalating by 40 mg/m2 increments in successive cohorts, with one patient per cohort if no dose limiting toxicity (DLT) is encountered. All pts receive vitamin B12 1 mg intramuscular q 8–10 weeks and folic acid 1 mg by mouth once a day beginning at least 7 days prior to pralatrexate. All patients undergo pharmacokinetic testing following their first and second dose of pralatrexate. Results: Between 1/05–12/06, a total of 9 pts have been treated at the following dose levels: 150 (n=1), 190 (n=1), 230 (n=1), and 270 (n=6). Patient characteristics include: 2 male/7 female; median age 63 (range 52–73); KPS 80–90%; all pts had stage 4 NSCLC; 5 pts received 1 prior regimen and 4 pts received 2 or more prior regimens. Grade 3 esophagitis was a DLT in one patient at the 270 mg/m2 dose. Three other patients experienced grade 1–2 mucositis at this dose level without limiting drug delivery. The trial is ongoing, and enrollment is planned at 310 mg/m2 q2w to determine the MTD. Conclusions: When given in combination with vitamin B12 and folic acid supplementation, pralatrexate has been well tolerated in this pt population, with an MTD at least twice as high as achieved in previous phase 1 testing without supplementation. We plan to conduct a phase 2 trial of pralatrexate with vitamin B12 and folic acid supplementation to see if a higher dose will improve efficacy.

No significant financial relationships to disclose.
Ifosfamide given once every other week: A clinical and pharmacological study
Authors: Cacheux W. , Gourmel B. , Alexandre J. , Germann N. , Rabillon F. , Goldwasser F.
Published: March 2020

13008

Background. Ifosfamide (IFM) is a bi-functional alkylator with wide spectrum of activity in solid tumors and has an auto-inductive liver metabolism through P450 cytochromes. Auto-induction might permit a better therapeutic index for combination therapy. Methods. A phase I trial with interpatient dose escalation of a single dose of IFM given every 2 wks in advanced solid tumor pts. IFM, its dechloroethylated and active 4-hydroxy metabolites, were measured at cycle 1 & 2 at the end of infusion, 2 and 5h later, using gas chromatography. IFM elimination was considered as following a monocompartimental model kinetics. Results From January 2004 to June 2006; 20 pts of PS<2 were included :10 F, 10 M, median age 61 years (39–78), median previous chemotherapies: 2 (0–5). Primary tumor was most often ovarian (5), peritoneal (3), sarcoma (2), melanoma (2), or miscellaneous (8). 10 pts received 2.5g/m2 and other 10 pts received 3g/m2. A total of 79 cycles were evaluable for toxicity. median number of cycles: 4 (1–8). No Grade (Gr) 3–4 hematologic toxicity, no alopecia. Gr2 nausea and fatigue were the most common toxicities at 3g/m2. No toxicity-related fatal event was noted. One objective response was noted in pancreatic cancer pt and one sustained CA125 decline in a heavily pretreated ovarian cancer pt. A slight (7–10%) but reproducible decrease of AUC was detectable at cycle 2, at both dose levels, related to auto-inductive metabolism (see table below). The other PK results are available and will be presented (Table). Intra individual variations (large SD) were noticed for each pharmacokinetic (PK) parameter. Conclusions: A slight non dose- dependent but rather patient-dependent auto-induction of IFM metabolism was detected. The toxicity profile allows the development of every 2 wks IFM-based combination therapies. [Table: see text]

No significant financial relationships to disclose.
Importance of timing of PET scan after therapy in oncology
Authors: Mullai N. , Baker W. , Simons L.
Published: March 2020

13014

Background: Growth factors are routine after systemic chemotherapy both as primary and secondary prophylaxis. Similarly PET scan is increasingly used for initial staging and follow-up of response. Timing of both is important since false positive results are noted due to high sensitivity of the test. Methods: Records of four patients with super positive PET scan with diffuse uptake in the axial skeleton were analyzed for the timing of administration of white cell growth factor before imaging and confirmation of bone finding with a follow- up bone scan to rule out mets. Results: Two patients were treated for stage IIIB/IV non-small cell lung cancer, one patient with breast cancer was receiving adjuvant treatment for stage IIIA breast cancer, and the last patient was treated for metastatic pancreatic cancer. All had negative scans for bone mets before the start of treatment. PET scan was done for staging in one patient and evaluation of abnormal CT scan in another, and follow-up of response in two patients. It was inadvertently obtained 10–14 days after the filgrastim/pefilgrastim administration. Based on the unusual uptake in bony skeleton, bone scan was ordered to rule out bone mets in all four patients. Since their bone scans were negative for metastatic disease they were continued on their treatment plan as scheduled. Conclusions: PET scan has been sparingly used until 1990’s due to high cost. Currently Medicare has approved it for wider indications. PET scan in general has high sensitivity and low specificity and false positive results are more common from metabolically active infection and inflammation. Granulocyte colony stimulating factor used with cancer treatments can increase the FDG uptake in PET scan. Diffuse increased uptake in bone marrow by PET scan can be seen in reactive marrow following growth factor therapy. Usually FDG uptake is modest with SUV of less than 3, uniform and diffuse if due to growth factor stimulation in contrast to greater intensity with SUV around 6 with non uniform distribution. Awareness of this pitfalls associated with PET scan allows image interpretation accurately. PET-CT fusion may increase the diagnostic specificity. However timing of the scan in relation to growth factor administration may also help to avoid the unnecessary anxiety and further follow up testing which adds to the health care costs.

No significant financial relationships to disclose.
A phase I study of modified irinotecan (CPT-11) plus cisplatin (CDDP) [m-IP] against paclitaxel/carboplatin [TC] -resistant and recurrent ovarian cancer
Authors: Suzuki T. , Morishita M. , Matsuura M. , Fujimoto T. , Tanaka R. , Ito E. , Ebina Y. , Saito T.
Published: March 2020

13015

Background: CPT-11/CDDP is effective regimen for ovarian cancer. Particularly against ovarian cancer resistant to prior chemotherapy, a 40% response rate was reported (Sugiyama T Cancer Letters, 1998). However, every 4 weeks treatment with CPT-11 day 1, 8, and 15, administration on day 15 was skipped in about 60% due to toxicity, and the relative dose intensity of IP was 66.7% in non-small cell lung cancer (Saito H Am J Clin Oncol 2006). We planed Phase I study, in consideration of the effect of prior chemotherapy in TC-resistant ovarian cancer, a modified CPT-11 (day 1, 8) and CDDP (day 1) for every 4 weeks treatment (m-IP). The aim of this study conducted to examine the dose limiting toxicity (DLT), to evaluate the maximum tolerated dose (MTD), and define the recommended dose (RD) for a phase II study. Methods: Patients with TC-resistant ovarian cancer having a PS 0–1, age 30–75 years, normal organ functions, and written informed consent. CPT-11 was administered intravenously over 90 minutes on day 1 and day 8, plus CDDP was day 1, repeated every 4 weeks. The dose escalation schedule was defined: Doses of CPT-11/CDDP (mg/m2) were 60/60 at level 1, 70/60 at level 2 and 70/70 at level 3. DLT were determined as Grade 4 hematological toxicity and = Grade 3 non-hematological toxicity occurred, and when dosing on day 8 was delayed for more than 8 days due to toxicity. Results: Nine patients were enrolled (level 1/2/3: 3/3/3). DLTs, at level 1 and 2, no patients developed. At level 3, grade 3 nausea and vomiting and delayed treatment on day 8 due to anorexia, were observed in all of 3 patients. Therefore, MTD was determined to be level 3 and RD was determined to be level 2 (CPT-11: 70mg/m2, CDDP: 60mg/m2). Major =Grade 3 toxicities observed were leukopenia, neutropenia, nausea, and vomiting. No Grade 4 hematological toxicities were observed. Diarrhea was mild. Antitumor effect at RD was observed in 1 patient with CR, 1 patient with PR and 1 patient with PD. Conclusions: The MTD of m-IP was CPT-11 70mg/m2 and CDDP 70mg/m2 (level 3), the RD was CPT-11 70mg/m2 and CDDP 60mg/m2 (level 2). Preliminary response are promissing associated with tolerable toxicity for TC-resistant and recurrent ovarian cancer. A Phase II study is currently conducted.

No significant financial relationships to disclose.
Phase I study of topotecan (T) with weekly 5-fluorouracil (5FU)/leucorin (LV) in patients with advanced malignancies
Authors: Axelrod R. S. , Rose L. , Biermann W.
Published: March 2020

13018

Background: Topotecan (T) is a semi-synthetic camptothecin analog with a broad spectrum of activity targeting the nuclear enzyme topoisomerase I. Daily iv schedules (up to 5) can result in dose limiting neutropenia. Reported synergy in vitro between topoisomerase I inhibitor and 5 FU/LV led us to explore a weekly schedule of 5FU, LV, and T in refractory tumors. Methods: Entry criteria: metastatic or locally advanced solid tumors; up to two prior chemotherapy regimens; prior adjuvant regimen admissible; no chemotherapy or radiation therapy within 4 weeks; adequate hepatic, hematologic, renal function. Exclusion: active second malignancy; CNS metastases; prior topotecan; allergy to related agents; active uncontrolled infection or conditions that would interfere with the study. Treatment was administered days 1, 8, 15, 22 of a 42 day cycle as LV 20 mg/meter (m)2 over 15 minutes intravenously (iv), 5 FU 400mg/m2 bolus, iv, and T at the specified dose (1.5mg/m2, 1.75, 2.0, up to 4 mg) over 30 minutes iv. Cohorts were advanced after at least three pts had completed 42 d. Study is reported through cohort 9: 5 FU 400/m2, LV 20/m2, topotecan 4 mg/m2. Results: Pt characteristics: 19 F, 25 M; ages 29–80, median 62. Tumor types: Pancreas (9), colorectal (6), lung (6), liver (3), salivary gland (5), sinus (2), nasopharynx (2) esophagus (2), and tongue, larynx, ovary granulosa cell tumor (gct), endometrium, mixed mullerian, mesothelioma, sarcoma, gastric (1 each). Related toxicities: gr 3/4 neutropenia 9%/2%, Hb 11%/0, platelets 4.5%/0, fatigue 4.5%/0. Stable disease of ≥ 4 cycles was observed in 18%: pancreas (2), ovarian (1), endometrium (1), salivary gland (3) (2 adenoid cystic, 1 adenocarcinoma). Conclusions: 5 FU, LV and T is well tolerated as a weekly out patient schedule (4 of 6 wks). It achieved minor response in one patient with gct for 8+ cycles and stable disease for ≥ 4 cycles in 6 pts. It is worthy of further exploration for gynecologic, salivary gland and pancreatic cancers.

No significant financial relationships to disclose.
The primary clinical trial of dendritic cell vaccine pulsed with apoptosis tumor cell in patients with malignant cancers
Authors: Qian K. , Wang Y. , Shi H. , Yajun Wang G. , Ye Heng , Min Haiyan , Lu Xiao , Ning Yongling
Published: March 2020

13509

Background: We evaluated the feasibility, safety, and immunogenicity of mature, apoptosis tumor cells-pulsed dendritic cell (DC) vaccines administered by intradermal injection. Methods: We performed a randomized study in 16 patients with malignant tumors, including 4 cases for gastric cancer, 3 cases for prostate cancer, 2 cases for breast cancers, one case for lung cancer, esophageal carcinoma, liver cancer , colorectal cancer, kidney cancer, ovarian cancer, endometrial cancer respectively.The vaccine used mature DCs (CD11c++, HLA-DR++, CD83+, and CD86+++) generated from peripheral blood monocytes in the presence of GM-CSF and IL-4. After 5 days, DCs were matured with a defined cocktail of cytokines (IL-1+ TNF-a+PGE2) and simultaneously pulsed with apoptosis autologous tumor cells or heterologous tumor cell lines, for 2 days.Patients were administrated four DC vaccinations (5×106 per time) at 7th day, 14th day, 21st day and 42nd day by intradermal injection(ID). Toxicity effect, life quality, immune function and clinical efficacy were monitored during the whole therapy. Results: Fourteen (82.4%) of 17 patients completed all four vaccinations. Vaccinations were well tolerated; a few patients exhibited less than grade 1 toxicities including rash, transient fever, transient debilitation and injection site reaction. The life quality of most patients had improved to certain degree, including sleep, appetite, mental status, and a good recovery from surgery and chemotherapy. Moreover, the serum level of IL-2 of 10/14 patients increased more than several times to twenty times, and 6/10 patients had a long increase for more than forty days. Serum level of IL-12 were increase in 11/14(9/11 patients increased for more than forty days) patients, Serum level of IFN-? were increase in 11/14(5/11 patients increased for more than forty days ) patients. Conclusions: Administration of this apoptosis tumor cell-pulsed mature DC vaccine by ID routes is feasible and safe. This administration seems to result in superior immunological sensitization as measured by in vitro serum level of immune cell factor such as IL-2, IL-12 and IFN-?.

No significant financial relationships to disclose.
Therapeutic monoclonal antibodies target phenotypically-differing human breast cancer
Authors: Hahn S. E. , da Cruz L. A. , Sayegh D. , Ferry A. , O’Reilly K. , Pereira D. S. , Rubinstein D. B. , Findlay H. , Young D. S.
Published: March 2020

13510

Background: CD44 (an adhesion molecule and stem cell antigen), CD59 (a complement-inhibitory molecule), MCSP (an adhesion and cell-cell interactions), and Trop-2 (EpCam a related signaling molecule) represent a group of biologically-significant cancer proteins acting through distinct mechanisms. We have described Abs with in vitro and in vivo cancer suppressive activity to this group of targets. However, their effectiveness depends on the phenotype of malignant cells; cell response should correlate with expression of its Ag, and tumor cells represent a heterogeneous group of non-synchronous cells. The present study describes the efficacy of those antibodies in breast cancer models and the prevalence of their antigen targets in a survey of human breast cancer tissues. Methods: In vivo activity of antibodies ARH460–16–2 (anti-CD44), AR36A36.11.1 (anti-CD59), AR11BD-2E11–2 (anti-MCSP), and AR47A6.4.2 (anti-Trop-2) in estrogen-dependent and hormone sensitive xenograft models of human breast cancer was examined. In addition, distribution of the antigens in breast cancer was determined by immunohistochemistry using tumor tissue arrays of breast cancer sections from distinct patients. Results: Treatment of an established breast cancer model with ARH460–16–2 resulted in 51% median tumor xenograft suppression (p<0.05), as well as increased survival in an MDA-MB-231 (breast cancer) grafted model. 63% of human breast cancer sections expressed the CD44 antigen. Treatment with anti-CD59 antibody AR36A36.11.1 resulted in 68% xenograft tumor suppression (p<0.005). AR47A6.4.2 anti-Trop-2 antibody bound to 100% of human breast cancer sections tested, and showed efficacy in the estrogen- dependent MCF-7 breast cancer model. Anti-MCSP antibody AR11BD-2E11–2 demonstrated 80% tumor growth inhibition (p<0.001), increased survival in an estrogen-dependent model of breast cancer, and was found to stain 62% of breast cancer tissues examined. Conclusions: The heterogeneity of breast cancer cell phenotypes in in vitro and in vivo studies and variable composite cellular antigen targets is the basis for the therapeutic use of multiple antibodies, each with independent mechanisms of action, and offers a rationale for combined antibody therapy in selected patients.

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A phase I dose escalation trial of the VEGFR tyrosine kinase inhibitor, PTK787/ ZK222584 (PTK/ZK), used in combination with paclitaxel in patients with advanced solid tumors with pharmacokinetic (PK) analysis
Authors: Malireddy S. R. , Chiorean E. , Foster A. , Jones D. , Waddell M. , Margol M. , Hall S. , Schneider B. , Sweeney C. J.
Published: March 2020

14012

Background: The aim of this study was to define the maximum tolerated dose (MTD) for weekly paclitaxel administered in combination with daily PTK/ZK and assess for a potential PK drug interaction. Methods: 17 patients (pts) with refractory metastatic solid tumors, were enrolled. During cycle 1 (C1) paclitaxel was given on days 1 and 15 in combination with PTK/ZK on days 3 to 28. PTK/ZK was administered once daily each night. During cycle 2 (C2) and beyond, paclitaxel was given on days 1, 8 and 15 every 28 days. PTK/ZK was taken orally each night. A “3+3” design was used. In addition to the standard definitions of dose limiting toxicity (DLT) occurring in C1 and C2, the inability to give day 8 or 15 of paclitaxel or > 7 days of missed PTK/ZK due to toxicity was also deemed dose limiting. Therapy was given until disease progression. Results: 60 cycles (range: 1 to 8) have been administered to 16 evaluable pts. No DLTs were observed when 75 mg/m2 of paclitaxel was combined with PTK/ZK doses of 250 mg, 500 mg and 750 mg. Two of 5 pts treated with paclitaxel 85 mg/m2 and PTK/ZK 1,000 mg had Grade 3 transaminase elevation (defined DLT) in C1 after day 15. The MTD was therefore 75 mg/m2 paclitaxel and 750 mg PTK/ZK. Paclitaxel PK was obtained in 14 patients: 13 of 14 patients had a faster clearance (L/hr) of paclitaxel on C1 day 15 versus day 1 (average % increase: 79%, range 14–256%, SD: 69). Only one patient had a slower clearance: 26% decrease. Activity included 2 partial responses (prostate and esophageal cancer), and 8 pts had stable disease lasting 2–9+ months, including ovarian cancer pts previously treated with paclitaxel. Conclusion: The MTD for weekly paclitaxel plus daily PTK/ZK is 75 mg/m2 and 750 mg. DLTs were liver transaminase elevation. This combination was well tolerated, and responses and prolonged disease stabilization were seen. PK analysis revealed an increase in rate of paclitaxel clearance in most patients.

No significant financial relationships to disclose.
Targeting the human double minute (HDM)-2 ubiquitin ligase as a strategy against non-Hodgkin’s lymphoma
Authors: Jones R. J. , Leopold L. , Yang D. , Orlowski R. Z.
Published: March 2020

14016

Background: The ubiquitin-proteasome pathway has been validated as a target for non-Hodgkin lymphoma (NHL) with the recent approval of bortezomib for mantle cell lymphoma (MCL). In addition to anti-tumor activity, however, proteasome inhibitors have pleiotropic effects, including activation of an anti-apoptotic heat shock protein response, and their use clinically is complicated by toxicities such as peripheral neuropathy. By targeting E3 ubiquitin ligases, which are involved in ubiquitination of only a small subset of cellular proteins, it may be possible to achieve more specific anti-tumor effects with a better therapeutic index. One attractive target is HDM-2, which is responsible for ubiquitination of the p53 tumor suppressor. Methods: To evaluate the therapeutic potential of agents targeting HDM-2, we studied the impact of the small molecule MI-63, an inhibitor of the HDM-2-p53 interaction, in both p53 wild-type and -mutant cell line models. Results: Treatment of wild-type p53 MCL, NHL, and acute lymphocytic leukemia (ALL) cell lines with MI-63 induced a dose- and time- dependent inhibition of proliferation, with an IC50 in the 1.0–5.0 μM range. This was associated with G1/S cell cycle arrest , and apoptosis mediated by caspase-3. MI-63 induced accumulation and phopshorylation of p53 and also enhanced MDM-2 levels. Multiple p53 target genes were induced, including p21Cip1 and p53-upregulated modulator of apoptosis (PUMA), resulting in cleavage of poly-ADP-ribose-polymerase (PARP). Cell lines expressing certain p53 mutants were sensitive to the effects of MI-63, resulting in activation of caspases 3, 8, 9 and apoptosis. Cells without p53 expression were resistant to MI-63, but at higher drug concentrations proliferation was still inhibited, indicating a possible impact on HDM-2-mediated but p53-independent cell death pathways. Combinations of MI-63 with other anti-tumor agents showed enhanced anti-proliferative effects that met the criteria for synergistic interactions. Conclusions: Inhibition of the HDM-2-p53 interaction is a promising approach both by itself, and in combination with currently used chemotherapeutics, against lymphoid malignancies, providing a rational for translation of this agent into the clinic.

No significant financial relationships to disclose.
Real-time ultrasound elastography for monitoring tumor response to neoadjuvant chemotherapy in primary breast cancer
Authors: Bando H. , Ishii M. , Tohno E. , Ueno E.
Published: March 2020

14023

Background: Response to neoadjuvant treatment is vital to predict a patient’s long-term survival. Precise detection of residual tumor cells after neoadjuvant chemotherapy would allow a better cosmetic results avoiding over surgery and reduce second operation due to positive margin status. Moreover, accurate prediction of pathological CR will yield no surgical intervention in certain population. Recently, a new generation of ultrasound platforms with real-time freehand elastography that enables the imaging of elasticity of the lesion by using the extended combined autocorrelation method (CAM) has become available. We are currently applying this technology to our patients with primary breast cancer in an attempt to assess response to neoadjuvant chemotherapy in comparison with MRI, conventional ultrasound and pathological findings. Methods: A total of 38 patients with primary breast cancer who underwent neoadjuvant chemotherapy and following surgical resection From May 2005 to Dec 2006 were included in this study. Board certified radiologists assessed the tumor response by MRI, US and US Elastography prior to surgery. Positive predictive value (PPV), and negative predictive value (NPV) for pathological CR (pCR) was assessed. Tsukuba Elastography score was applied for the assessment of Elastography. Results: 11/38 patients (28.9%) achieved a pCR in breast to neoadjuvant chemotherapy while no patients demonstrated progressive disease. The PPV for pCR of MRI and US was 54.5% and 36.3% respectively. The NPV of MRI and US was both 90.9%. None of the residual tumor mass with score 4 or 5 cases diagnosed by Elastography achieved pCR. When residual tumor image was detected by US, pCR was present in all 4 cases with score 1 or 2 Elatography. If the cut-off line is determined between score 3 and 4, the PPV and NPV for pCR by Elastography was 100% and 66.6% respectively. Conclusions: Elastography is easy to perform and it can provide an inexpensive, non-invasive, real-time tool for assessment of response to neoadjuvant chemotherapy among patients with primary breast cancer. In particular, Elastography might more effectively diagnose pathological CR. More patients are needed to evaluate the sensitivity and specificity of this new technology.

No significant financial relationships to disclose.
Responses to the combination of the glycolytic inhibitor 2-deoxy-glucose (2DG) and docetaxel (DC) in patients with lung and head and neck (H/N) carcinomas
Authors: Raez L. E. , Langmuir V. , Tolba K. , Rocha-Lima C. M. , Papadopoulos K. , Kroll S. , Brawer M. , Rosenblatt J. , Ricart A. , Lampidis T.
Published: March 2020

14025

Background: We demonstrated in mouse xenografts that the combination of docetaxel chemotherapy with 2DG is feasible and increases responses against tumors (CancerRes; 2004 64:31–4). Methods: To determine the maximum tolerated dose (MTD) of daily oral doses of 2DG given alone and in combination with weekly docetaxel (DC) in patients (pts) with advanced malignancies who had relapsed after chemotherapy, and to evaluate the pharmacokinetics (PK) of 2DG alone and in combination with weekly DC. 2DG was initially administered orally once daily for 7 days every other week starting at a dose of 2 mg/kg, and DC was administered at 30mg/m2 for 3 of every 4 weeks. A modified accelerated titration design was used. Following completion of the every other week (EOW) 2DG dosing regimen, 3 weeks on and 1 week off (3–1W) dosing; and then continuous (CW) 2DG dosing were investigated. Results: 21 pts were enrolled in the EOW dosing at 2DG doses up to 88 mg/kg/day; another 10 pts were enrolled in the other dosing regimens. 5 pts had lung cancer (4 NSCLC + 1 SCLC); and another 6 pts had H/N cancers. One pt discontinued for DC-related sensory neuropathy. Single cases of DLT occurred - asymptomatic (64mg/kg) and symptomatic (88 mg/kg) Grade 3 hyperglycemia. The MTD was not reached with the EOW regimen. 2DG is rapidly absorbed (Tmax 0.5–1h) with a half-life of 5–10h. 2DG exhibits linear PK following single and multiple doses with minimal accumulation after multiple doses at 63 and 88 mg/kg. 2DG PK and DC PK do not alter each other. One of 18 evaluable pts in the EOW dosing with breast cancer had a partial response (PR). Another 8 pts achieved disease stabilization (SD) among them: 2 of 4 pts with NSCLC, 2 of 6 pts with H/N cancers, 1 pt with thyroid cancer, and 1 of 3 pts with adenoidcystic carcinoma. The others were unknown primary and a breast lymphoma. Also the MTD was not reached at 63mg/kg (3–1W) dosing where one patient with H/N cancer achieved stabilization of his disease. Enrollment of pts in the CW regimen is ongoing now. Conclusions: The combination of 2DG and DC appears to be feasible and safe with no evidence of PK interactions. Evidence of anti-tumor activity was observed in patients with NSCLC and H/N cancers.

No significant financial relationships to disclose.
Phase I and pharmacokinetic (PK) study of 17-allylamino-17 demethoxygeldanamycin (17-AAG) in combination with weekly paclitaxel for advanced solid malignancies
Authors: Musquire L. A. , Ramalingam S. , Egorin M. J. , Sikorski R. P. , Chatta G. S. , Ramanathan R. K. , Friedland D. , Potter D. , Ivy S. P. , Belani C. P.
Published: March 2020

14028

Background: 17-AAG inhibits heat shock protein 90, promotes degradation of oncoproteins & exhibits synergy with paclitaxel in vitro. We conducted a phase I study in patients (pts) with advanced malignancies to determine the recommended phase II dose (RP2D) of the combination of 17-AAG & paclitaxel. Methods: Key eligibility criteria were: histologically confirmed malignancy; lack of standard or proven treatment options; age > 18 years; ECOG PS 0–2; adequate hepatic, renal & bone marrow function & willingness to sign informed consent. Patients with neuropathy > grade 1 and those on therapeutic anticoagulation were excluded. 17-AAG (80–225 mg/m2) was given on days 1, 4, 8, 11, 15 & 18 of each 4-week cycle to sequential cohorts of patients. Paclitaxel (80–100 mg/m2) was administered on days 1, 8 & 15. PK sampling was done on days 1, 4 & 8 of cycle 1. Dose-limiting toxicity (DLT) was assessed during cycle 1. 17-AAG & paclitaxel were quantitated with validated HPLC and LC/MS assays, respectively. Results: 25 pts were accrued to 5 dose levels. Patient demographics were: male 18; median age 61; PS 0–14 pts, 1–10 pts, 2–1 pt. Primary tumor sites were prostate (5), lung (4), esophagus (4), ovary (2), colon (2) & others (8). The median number of cycles was 2. Chest pain (Gr 3) & fatigue (Gr 4) were dose-limiting at dose level 4 (17-AAG 225 mg/m2, paclitaxel 80 mg/m2). Other toxicities included neutropenia, fatigue, neuropathy, nausea, arthralgia and myalgia. The RP2D for the regimen is 17-AAG (175 mg/m2 administered biweekly) & paclitaxel (80 mg/m2/wk.) for 3 weeks in a 4 wk. cycle. None of the 6 patients at this dose level experienced DLT. One patient with fibrosarcoma experienced a PR & 4 (esophageal, prostate, gall bladder cancer) had SD. Paclitaxel PK were compatible with previous reports in literature and were similar on days 1 & 8. 17-AAG PK were linear and similar when given alone and in combination with paclitaxel. Conclusions: The combination of biweekly 17-AAG (175 mg/m2) and weekly paclitaxel (80 mg/m2/week) is tolerated well and was associated with anti-cancer activity. There was no evidence of drug-drug PK interactions. Support: NCI U01 CA099168–01, NIH/NCCR/GCRC grant 5M01RR 00056

No significant financial relationships to disclose.