bluuebunny/crossref_metadata_2025 huggingface dataset:
Four years trial in elderly people of appraisal and comparison by geriatric assessment instruments: Use of high potency opioids for cancer pain control and quality of life
Authors: Ferrero G. , Testore F. , Milanese S. , Porcile G. , Caroti C. , D’Amico M. , Folco U. , Gozza A.
Published: March 2020

18610

Background: Pain is probably under-recognized and under-treated in the Elderly with advanced cancer disease but the effect of a therapy with high potency opioids is not studied so much in geriatric age people. To evaluate efficacy and tollerability of escalating doses of Transdermal Fentanyl (TTS-F) or equipollent doses of oral morphine long acting with Immediate Release Oral Morphine (IROM) as rescue medication for treatment of moderate-severe cancer pain, we have started a Multicentric Observational Analysis in four cancer centres of north-western Italy. Studies of oncological palliation using valid measures of quality of life show that patients may be willing to accept some side effects of treatment as long as they gain relief from tumor-related symptoms Methods: -TIQ (Therapy Impact Questionnaire) -VAS (Visual Analogic Scale): 0 to 10 -Toxicity (WHO criteria) -Geriatric Assessment for pts aged >70 yrs (only at time 0): CIRS (Comorbility Index) IADL/ADL (Instrumental Activities Daily Living/Activities Daily Living). Patients characteristics -159 pts -Total Median Age: 66 yrs (range 38–86) -Median ECOG PS: 1 (range 0–2) -Elderly (>70 yrs): 75. Pain Starting situation -Median starting VAS: 5.5 (range 3–9) -TIQ: depression 70 pts, cachexia 55 pts, dispnoea 40 pts -CIRS (Comorbidity index): comorbidity were present among 66 pts. TTS-Fentanyl starting dose: 25 mcg/h every 72 h (range 25–50 mcg) or oral morphine long acting 60–90 mg plus IROM 10 mg every 4–6 hours for breakthrough pain present in 38 pts Results: -Quickly pain VAS downloading during first two weeks of treatment (median VAS 1) -Analgesic doses were not significantly increased after two months and not exceeded WHO grade 2 -IROM rescue was similar to that observed for the overall population -TIQ, ADL and IADL were not influenced by therapy. Conclusions: High potency opioids (TTS-F or long acting morphine equipollent doses, plus Rescue-IROM) offers durable long term maintenance pain relief wild acceptable toxicity also in elderly people, is particularly useful for cancer pts with compliance problems and may be considered as first-line treatment for moderate/severe cancer pain.

No significant financial relationships to disclose.
Coping and survival in breast cancer patients evaluated in a 5-year follow-up
Authors: Andritsch E. , Dietmaier G. , Hofmann G. , Ladinek V. , Zloklikovits S. , Petru E. , Samonigg H.
Published: March 2020

18624

Background: A notable amount of studies investigated possible relations between the kind of coping with the disease and the survival in cancer patients. There is some evidence that distress is a predictor of shortened survival and that active coping is related to better chances. Nevertheless many of those studies were limited by small sample sizes or a retrospective design and the published data are inconsistent. Methods: This investigation of 212 breast cancer patients (stage I and II) in an adjuvant, disease free situation started 5 years ago about 3 years after the initial diagnoses and was carried out at three different measuring times (5 and 4 years ago and at present). It was an attempt to explore whether the preferred coping styles implicate survival. Results: At present 3.8% (N = 8) of the patients have died because of their cancer and 10.8% (N = 23) are suffering from a relapse. Significant relations between recurrence and avoidance (F1;178 = 3.973; p = 0.048) measured with the IES (Impact of Event Scale) five years ago and between recurrence and avoidance (F1;164 = 6.788; p = 0.010) and aggression (F1;164 = 3.277; p = 0.038) measured with the BSI (Brief Symptom Inventory) four years ago were found with MANOVAs. Patients, who stated a higher level of avoidance and aggression, were at higher risk to become a relapse or metastases. Patients having a progressive course of disease tended to be younger (57.2 years) than patients being free of disease (61.3 years, F1;179 = 3.294; p = 0.070). Regarding the 8 year survival those patients, who had died, stated a higher level of anxious preoccupation measured with the MAC (Mental Adjustment to Cancer Scale) 5 years ago (M-W-U = 397.5; p = 0.48). Conclusions: The results of this study provide an essential aspect for psychological support and of the necessity to include psychooncological elements in physician-patient-communication.

No significant financial relationships to disclose.
Competency building for self-management and self-care: evidence informed development of an empowerment course for breast cancer survivors
Authors: Nyhof-Young J. , Regehr M. , Secord S. , Jusko Friedman A. , Catton P.
Published: March 2020

18626

Purpose: To improve survivorship outcomes by empowering and preparing survivors to self- manage their health. We describe the evidence-informed development of a patient empowerment course “Managing Your Cancer Journey” offered in the Breast Cancer Survivorship Program at Princess Margaret Hospital in Toronto, Canada. Methods: Audio-taped and transcribed focus groups (3; n = 16 patients, August 2004), interviews (n = 8 lymphedema patients, spring 2004, n = 8 patients, spring 2005) were held for patient directed guidance in survivorship course and program development. A comprehensive literature review was conducted to develop a theoretical framework for empowerment. Three main competencies: knowing, navigating and negotiating emerged and were developed into 5 ×1.5 hour classes facilitated by two social workers in collaboration with health professionals and community organizations. Feedback from survivors in a community forum (n = 40) and during piloting with survivors (n = 10) and educators was solicited. Analysis of transcripts and observer/consultant debriefings were analyzed for emergent themes. Results: Respondents recommended program interventions that allowed people to gain mastery or a perceived sense of control over their lives with cancer. Survivors and expert consultants prioritized 3 major domains for the survivorship program: psychosocial support, information provision, and support for dealing with the physical effects of breast cancer. In response, outcome measures for empowerment will include: patient satisfaction, cancer knowledge, self-efficacy in disease management, empowerment, and depression. Conclusions: Ongoing iterative feedback from and piloting with the survivor target audience and embedding the course within the hospital’s strategic plan for patient centred care and competency building are keys to successful course implementation.

No significant financial relationships to disclose.
Survival of patients with soft tissue sarcoma (STS) correlated to tumor grade, size, site of origin & cell type. Does the high risk group need adjuvant systemic therapy?
Authors: Elias E. G. , Brown S. D. , Dorsi O. K. , You C. J. , Nitz A. M.
Published: March 2020

19510

Background: The prognosis of patients with STS depends on the tumor stage, which includes tumor size (T) and grade (G). Patients with low-grade tumors (G1) are managed by radical resection only. Patients with moderate (G2) and high-grade (G3) tumors require postoperative adjuvant radiation therapy (RT); this became standard therapy. This study was conducted to determine the efficacy of standard therapy on survival. Methods: This is a retrospective study of patients with primary STS, excluding those with skin, subcutaneous tissue and GIST. All patients underwent radical resections (S). Postoperative RT was requested for G2 and G3 tumors; 6 patients with G3 tumors received chemotherapy (C) prior to RT. Results: 52 patients were studied with a median follow-up of 84 mo. The overall survival ranged from 3 to 264 mo. with a median of 52 mo. The incidence of tumor grade and size were correlated to the survival. 37 patients had STS of the extremities and torso; 24 are alive. 10 patients had intra- and retro-peritoneal STS; 5 are alive. 4 of the 6 patients who received C are alive, 3 are disease-free for a period of 3 to 7 years. Life table analysis of patients with G3T2 tumors comparing the 3 treatment groups (S vs. S+RT vs. S+C+RT) showed no statistical difference in survival, but there was a trend in favor of S+C+RT. Conclusions: 1. Radical resection and postoperative RT may be insufficient for systemic control. 2. Adjuvant systemic chemotherapy may improve the survival, and may be safer than RT in the management of retroperitoneal and visceral sarcomas.

[Table: see text]

No significant financial relationships to disclose.
Phase I study to determine tolerability and pharmacokinetics (PK) of SB-743921, a novel kinesin spindle protein (KSP) inhibitor
Authors: Holen K. D. , Belani C. P. , Wilding G. , Ramalingam S. , Heideman J. L. , Ramanathan R. K. , Bowen C. J. , Williams D. D. , Hodge J. P. , Dar M. M.
Published: March 2020

2000

Background: SB-743921, a potent and selective inhibitor of KSP (Ki =100 pM; >40,000-fold selectivity vs other kinesins), causes mitotic arrest, potent inhibition of tumor cell proliferation, and demonstrates activity in a broad range of human tumor xenografts. Methods: A phase I study was conducted to determine the maximum tolerated dose (MTD) and PK profile of SB-743921 when administered IV over 60 minutes every 21 (Q 21) days (d). Results: 44 patients (pts) (M/F 19/25), median age 61.5 yrs (range 32–80, with solid tumors were treated at doses of 2 (n=2), 4 (n=27), 5 (n=6), 6 (n=3), and 8 (n=6) mg/m2 (median cycles 2, range 1–10, total cycles 101). Frequent tumor types included colorectal (n=11), ovarian (n=5), NSCLC (n=5), esophageal (n=4), and pancreatic (n=4). Dose-limiting toxicities (DLTs) at 8 mg/m2 consisted of (max CTC grade/pt) prolonged grade (gr) 4 neutropenia (n=2), gr 3 elevated ALT/AST (n=1), and gr 3 elevated bilirubin (n=1). DLTs at 6 mg/m2 were gr 3 hyponatremia (n=1) and prolonged gr 4 neutropenia (n=1). DLTs at 5 mg/m2 were limited to febrile neutropenia (n=2). The 4 mg/m2 dose level was determined as the phase II dose. Toxicities at 4 mg/m2 included gr 1 fatigue (n=8) and neutropenia [gr 1 (n=4), gr 2 (n=7), gr 3 (n=3), gr 4 (n=2)]. Neutropenia nadir was day 6–8 with recovery to gr ≤2 by day 15. Gr 3 non-hematologic toxicities at 4 mg/m2 included gr 3 ALT (n=1), gr 3 AST (n=2), gr 3 hyperbilirubinemia (n=1), gr 3 hypophosphatemia (n=1), and gr 3 alkaline phosphatase elevation (n=1). Median PK values in cycle 1 at 4 mg/m2 were: Cmax 473 ng/ml, AUC0-∞ 5207 ng.hr/ml, and t½ 36 hr. AUC0-∞ and Cmax were proportional to dose. No consistent correlation was observed between DLTs and PK parameters. Stable disease for ≥ 4 cycles (range 4–11) was observed in 6 pts (4 pts at 4 mg/m2; 1 pt at 6 mg/m2; 1 pt at 8 mg/m2). A pt with cholangiocarcinoma had evidence of radiographic tumor regression (post cycle 10) and a >50% decrease in her CA 19–9. Conclusions: The recommended phase II dose of SB-743921 on the Q 21 day schedule is 4 mg/m2. The observed toxicities at the recommended phase II dose are manageable and reversible. The onset and duration of neutropenia is predictable.

[Table: see text]
Screening a library of FDA-approved drugs identifies agents that induce lytic viral infection in EBV-associated tumors
Authors: Chen J. , Chong C. , Hsieh W. , Fu D. , Lemas V. , Liu J. O. , Ambinder R. F.
Published: March 2020

2002

Background: Epstein-Barr virus (EBV) is associated with a variety of tumors including AIDS lymphoma, Burkitt’s lymphoma, nasopharyngeal carcinoma and Hodgkin’s lymphoma. We hypothesized that drugs used in practice might alter viral gene expression in tumor cells in ways that might be important to understand. For example induction of lytic viral gene expression leads to expression of immunodominant CD8 T cell antigens and expression of the viral thymidine kinase (which phosphorylates ganciclovir and other nucleotide analogues). Methods: A library of FDA-approved drugs that includes 2720 agents was screened to identify those that upregulated EBV lytic gene expression. The screen involved a Burkitt’s cell line with a recombinant GFP-EBV that assayed the impact of agents on replication of the complete viral genome, and assay of a lytic promoter reporter construct. Results: The assay identified 146 agents in the whole virus replication assay, 195 agents in the promoter assay, and 54 agents that were active in both assays. Agents with activity could be grouped into 4 families: anti-tubulin drugs, glucocorticoid and other steroid hormones, DNA damaging agents and nucleotide analogues (including cytarabine and gemcitabine), and the proteasome inhibitor bortezomib. Anti-tubulin drugs and nucleotide analogues were less active in thes whole virus assay than the promoter assay whereas bortezomib showed similar activity in both assays. Followup studies confirmed that bortezomib is a potent viral lytic activator that increases expression of the viral thymidine kinase and virion production in several different Burkitt’s lymphoma and primary effusion lymphoma cell lines. Although bortezomib decreases NFKB levels, in vitro investigations with an IKB repressor suggests that inhibition of NFKB alone does not account for lytic activation. Conclusions: Many cancer chemotherapeutic agents are upregulators of EBV lytic expression. Bortezomib is among the most potent. As strategies for using lytic induction therapeutically evolve, these agents may have an important role to play.

No significant financial relationships to disclose.
Wavelet-based prognostic model with comparative genomic hybridization (CGH) data in patients with hepatocellular carcinoma (HCC)
Authors: Zee B. C. , Lee J. , Wong N. , Yeo W. , Lai P. , Chan L. , Hui P. , Wong H. , Lam K. , Ho W. , Chan A. T.
Published: March 2020

20026

Background: In order to obtain a good prognostic model for HCC, clinical data alone may not be adequate. DNA microarray technology has enabled quantification of thousands of genes in a single assay but it has the inborn drawback of high background noise. In order to deal with the problem of information overflow, we developed multivariate dependencies approach using CGH to guide the initial modeling process. This approach takes into account the multivariate nature and potential interaction among the genes during the prognostic modeling process. Methods: The study includes 165 patients with CGH data containing 858 regions/bands. The clinical outcome is survival at 1.72 years. Potential prognostic factors include CGH regions, albumin, ALT, bilirubin, AFP, ascites, alkaline phosphatase (ALP), tumor size, and encephalopathy. We used a blocked wavelet-shrinkage principal component analysis (BWSPCA) to reduce the dimension of CGH data with respect to clinical outcome and followed by logistic regression. We compared the BWSPCA with PCA alone, supervised PCA (Bair et al. 2004), and supervised BWSPCA. Results: Among the 165 patients, 133 (80%) were male, average age of 54.8 years, 78 (47%) stage I-II and 75 (45%) ECOG 0–2. PCA alone and supervised PCA models failed to identify significant CGH regions. BWSPCA model includes tumor size (p = 0.005), albumin (p = 0.047), ALP (p = 0.025), Chr.6q25.1 (p = 0.031), Chr.12q24.32 (p = 0.012), Chr.Xq28 (p = 0.035). Supervised BWSPCA approach includes tumor size (p = 0.016), ALP (p = 0.002), Chr.12q24.11 (p = 0.047). The area under the receiver operating curve (ROC) for the BWSPCA model was 0.78 with a sensitivity and specificity about 0.8 and 0.6 respectively. Conclusions: PCA alone is not effective in identifying CGH regions as prognostic factors. Supervised learning approach did not improve the results. The BWSPCA method identified a number of significant CGH regions associated with survival outcome for HCC patients. These results would be verified in future study. This method will be extended and applied to develop prognostic models using both CGH and DNA microarray data. Acknowledgement: This study is funded by the Research Grant Council of Hong Kong #CUHK4469/03M.

No significant financial relationships to disclose.
First-in-human phase I trial of a novel epothilone, KOS-1584
Authors: Villalona-Calero M. , Goel S. , Schaaf L. , McCracken B. , Desai K. , Cropp G. , Zhou Y. , Johnson R. G. , Hannah A. L. , Mani S.
Published: March 2020

2003

Background: KOS-1584 (9,10-didehydroepothilone D) was discovered as part of a screening program to develop a new generation of epothilones with higher potency and an improved pharmacologic/pharmacokinetic (PK) profile. Epothilones stabilize microtubule polymerization, inducing rapid G2/M arrest and apoptosis. Antitumor activity of KOS-1584 (Chou et al 2003) is approximately 3–12 fold more potent when compared to the structurally related Epothilone D. KOS-1584 demonstrates enhanced tumor tissue penetration and reduced exposure to selected tissues (including CNS). We report the results of the initial dose-escalation trial in which KOS-1584 was administered to pts with advanced solid malignancies. Methods: Define the MTD, toxicity profile and PK of KOS-1584 when administered via 3-hour infusion every 3 weeks. PK was determined after the 1st and 2nd infusion. Pharmacodynamics were assessed by serial sampling of PBMCs for microtubule bundle formation. Results: 27 pts (17 F; median age 60; median ECOG PS 1; median prior regimens 3, range 0–7) enrolled in 8 dose levels (between 0.8 - 11.3 mg/m2). To date, no Cycle 1 DLT has been seen. Toxicities (n=24) did not show obvious dose dependency; common toxicity (Grade 1–2) included gastrointestinal (diarrhea, constipation, nausea), fatigue, and ↑AST. Drug-related Grade 3 toxicity: constipation, fatigue and ↑AST (1 each). Drug-related neurotoxicity was not notable. PK/parent (n=25): t½ 17.7 ± 4.6h, Vz 741±330 L and CL 30.2± 16.5 L/h. At 8.5 mg/m2 Cmax 78 ± 29 ng/mL; AUCtot 631 ± 337 ng*h/mL. Cmax and AUCtot increased linearly with dose over the range tested. Vz is ∼5-fold and t½ 2-fold higher than that of Epothilone D. Dose dependent increases in microtubule bundle formation were observed (8.5 mg/m2: 40–50% at end of infusion, compared to 60–65% for ixabepilone and 50–60% for Epothilone D using the same assay at their phase 2 dose). A sigmoidal Emax model described the relationship between plasma concentration and microtubule bundle formation. Activity consisted of 4 pts with extended stable disease (6 cycles leiomyosarcoma and ovarian cancer; 5 cycles colon cancer; a 2nd patient with ovarian cancer is active at 5 cycles). Of these, 3 had document progressive disease prior to study. Conclusions: Accrual is continuing in order to define the optimal dose on the 3-week regimen.

[Table: see text]
Biological characteristics in triple negative high risk breast cancer and their clinical implications
Authors: Herr A. , Gluz O. , Ting E. , Mohrmann S. , Werner F. , Schuett G. , Schmutzler R. , Poremba C. , Nitz U. , Danebrock R.
Published: March 2020

20032

Background: Hormone receptor and Her2neu negative breast cancer (triple negative, TN) presents an aggressive biological subtype with decreased survival. Basal-like BC identified by gene expression arrays (Perou CM, et al. Nature 2000) may be associated with TN breast cancer. Several studies defined the origin of TN or BBC breast cancer in a progenitor epithelial cell that is undifferentiated. Other studies investigated the association of TN with EGFR expression or BRCA1 mutations. The aim of our study was to analyze the expression of stem cell or basal markers in TN high risk breast cancer. Methods: We examined 236 patients from central tumour bank from high risk breast cancer patients (>9 positive LN), who were randomized to the WSG AM-01 trial (phase III tandem HDC versus DD CT). The following markers were profiled by IHC in TMA for all patients: ER, PR, Her2neu, MIB-1, EGFR, p53, Ck 5/6, CK17, c-kit, p63, Vimentin, ABCA3, and BCRP. Their correlation with survival was studied. Results: 65 patients (30%) of 218 patients assessable for hormone receptor and Her2neu staining, were identified as TN, surprisingly not indicating any higher incidence of TN tumors in this selected high risk collective, when compared to other more heterogeneous populations. This phenotype was significantly more frequent in premenopausal women, and was significantly associated with G3, MIB1 and EGFR, CK5/6 and 17, c-kit, vimentin, p53 and BCRP expression. No association with p63 and ABCA3 was found. Poor grading, MIB1+, CK5/6 and 17, c-kit, vimentin and BCRP+ strongly correlated with relapse. Patients with TN tumors had significantly worse overall survival (p = 0.002) in comparison to the remaining group. Conclusions: The triple negative BC-type is frequent in patients with multiple positive lymph nodes and has a poor prognosis. Its association with age and basal and progenitor cell molecular markers suggests correlation with BRCA1 mutations as a potential marker for resistance to alkylating agents (Sorlie, PNAS 2003). Modern experimental (chemo)-therapy designs in this subgroup should take into account the higher incidence of EGFR and basal stem cell marker expression, p53 mutations, the poor differentiation, the expression of chemoresistance markers and the high proliferative activity.

No significant financial relationships to disclose.
Changes in the serum proteome associated with docetaxel chemotherapy
Authors: James N. D. , Ward D. , Martin A. , Barton D. , Dunn J. , Porfiri E.
Published: March 2020

20036

Background: Trapeze is a randomised phase II clinical study involving Docetaxel chemotherapy ± Zoledronic Acid and strontium 89 for the treatment of hormone refractory prostate cancer. A proteomic sub-study is designed to identify novel biomarkers to monitor treatment. Methods: Surface-Ehanced Laser Desorption/Ionisation (SELDI) time-of-flight mass spectrometry combines retentate chromatography and mass spectrometry in a high-throughput platform for proteomic profiling of biological samples. A biofluid such as serum is applied to a ‘proteinchip array’, certain proteins will bind and non-binding species are removed by washing. The bound proteins are vaporised using a laser and detected by mass spectrometry. The peak intensities in the resulting “profiles” can be compared between patient cohorts to identify potential biomarkers. Results: The serum from 6 patients was analysed both before and after 2 cycles of chemotherapy using copper loaded IMAC30 proteinchip arrays. The intensities of 103 peaks were compared between pre- and post-treatment and 11 were found to differ significantly (p < 0.01, paired t-test). Hierarchical clustering was able to distinguish pre- and post-treatment sera. Initial results show these changes to continue in sequential samples taken from the same patient. Conclusions: Chemotherapy produces significant and detectable changes in the serum proteome. This is a significant difference from a recent lung cancer study carried out in our Institution (submitted separately), which showed no detectable changes in pre and post operative lung cancer patients once acute post-operative changes had settled. Work is currently underway to identify the discriminatory proteins in the SELDI profiles. The current Trapeze study accrual rate of approximately 10 patients per month will mean that 80 patients will be included in this treatment cohort by May 2006 and subject to initial findings, individual proteins of interest will be identified and followed throughout the phase II and subsequent phase III to determine if they can be used to assess patients individual response to chemotherapy and provide a biomarker to monitor prostate cancer therapy.

No significant financial relationships to disclose.
Capsaicin induces G1/S cell cycle arrest leading to apoptosis of multiple myeloma cells through suppression of STAT3 activation and STAT3-regulated gene products
Authors: Bhutani M. , Pathak A. K. , Sethi G. , Aggarwal B. B.
Published: March 2020

20039

Background: Agents that can block activated STAT3, a central player for proliferation, cell survival and chemoresistance, have a potential as therapeutic agents for the treatment of Multiple Myeloma (MM). Capsaicin, a spicy component of hot pepper, is a homovanillic acid derivative that preferentially induces certain cancer cells to undergo apoptosis. We have previously shown that Capsaicin blocked activation of NF-kappa B in human myeloid ML-1a cells. In this study we evaluated the effect of Capsaicin on STAT3 in MM cells. Methods: We used U266, a well-characterized MM cell line, which constitutively expresses activated STAT3. MM cells treated with Capsaicin were subjected to western blot analysis with specific antibodies to STAT3, tyrosyl phosphorylated STAT3 and STAT5. The effect of Capsaicin on nuclear-cytoplasmic compartment of STAT3 was studied by immunocytochemistry. The antiproliferative effect of Capsaicin was determined by the MTT assay and the effect on the cell cycle was determined by flowcytometry. Apoptosis of cells was measured using the Live and Dead assay. To determine the downstream targets like antiapoptotic proteins (Bcl-xL, Bcl-2, and Survivin), and cell cycle-regulators (cyclin D1) immunoblot analysis of Capsaicin treated cells was performed. Results: Capsaicin suppressed the constitutive activation of STAT3 in human MM cells in a dose- and time-dependent manner, prior to cell death. Capsaicin’s effect on STAT3 was specific as STAT5 was unaffected. Capsaicin depleted nuclear pool of STAT3 in U266 cells. Abrogation of constitutive STAT3 phosphorylation in MM cells induced G1 cell cycle arrest. The antiapoptotic proteins BCl-xl, suvivin, cyclin D1, and Bcl-2, which are encoded in target genes of STAT3, were down regulated by Capsaicin, followed by induction of apoptosis through activation of caspase-3. We further demonstrated that low dose combined Capsaicin and thalidomide/ bortezomib treatment triggered synergistic cytotoxicity. Conclusions: These findings suggest that the antitumor activity of Capsaicin is at least partially due to inhibition of STAT3 pathway and provide a basis for potential application of Capsaicin for treatment of relapsed and refractory MM.

No significant financial relationships to disclose.
High expression of tenascin-C extra domains, markers of angiogenesis, in human lung cancer
Authors: Hillinger S. , Silacci M. , Arni S. , Brack S. , Weder W. , Neri D.
Published: March 2020

20051

Background: Tumor-associated extracellular matrix molecules are isoforms of proteins with a wide distribution in normal adult tissues, such as fibronectin and tenascin. Large Tenascin-C isoforms are present in almost all normal adult tissues but are upregulated in fetal, regenerating, and neoplastic tissues. In this study we investigated the expression of three tenascin isoforms in tumor tissue samples from lung cancer patients to evaluate the diagnostic and therapeutic value for clinical applications. Methods: In total, 35 corresponding tissue samples (tumor and normal lung tissue of the same patient) have been analyzed by immunohistochemistry using three different human monoclonal antibodies to domains A1 (F16), C (G11) and D (P12). All tumor specimens have been non-small cell lung cancer types. Results: Three isoforms G11, F16 and P12 have exhibited a very intense staining of all types of lung cancer. Almost all samples of squamous cell carcinomas, adenocarcinomas as well as large cell carcinomas have been positively stained. In contrast, none of the corresponding normal lung tissue specimens showed an expression of either tenascin domains. Conclusions: The results show that tenascin-C isoforms are highly expressed around the neovasculature and in the stroma of the majority of non-small cell lung cancers but is undetectable in the normal lung tissue. Therefore these isoforms could represent valuable candidates for the development of antibody based biopharmaceuticals for the treatment of lung cancer.

No significant financial relationships to disclose.
Active epidermal growth factor (EGFR) level is a predictive factor for response and survival in patients with lung cancer
Authors: Tek I. , Akbulut H. , Yalcin B. , Buyukcelik A. , Utkan G. , Demirkazik A. , Icli F.
Published: March 2020

20058

Background: Over expression of epidermal growth factor receptor (EGFR) has been reported as a poor prognostic factor in patients with cancer. However, active EGFR released from the apoptotic tumor cells could serve as a marker for the prediction of clinical outcome in cancer patients. In this study we aimed to study the role of the level of serum active epidermal growth factor receptor in patients with non-small cell lung cancer as a predictive parameter for response and survival. Methods: Thirty-three consecutive patients with advanced non-small cell lung cancer patients (12 with stage IIIB and 21 stage IV or relapsed disease) were included. The median age was 52 (range: 35–69). The patients were given cisplatinum and docetaxel combination regimen as first line treatment. The serum samples were collected before the first cycle of the chemotherapy and every 2 cycles and kept at -80 C. Response to treatment was evaluated every 2 cycles according to the WHO criteria. Serum active EGFR levels were measured by ELISA (BioSource, Camarillo Ca, USA). Results: Median 4 cycles of chemotherapy (range: 2–6) were administered. Median follow-up time was 11 months. Objective response rate was 18.2%. One-year estimated survival rate was 65.9%. There were no significant differences between the extend of the disease and basal active EGFR levels. Likewise, there was no difference between the basal active EGFR levels of responders and non-responders (0,19 ± 0.09 vs 0.21 ± 0,11 fmol/mL, p = 0.899, respectively). However, the patients responded to the treatment had significantly higher level of active EGFR than the non-responders after 2 cycles (3,74 ± 3,65 vs. 0,174 ± 0,13 fmol/mL, p = 0.028, respectively). While the patients with positive basal EGFR levels (higher than the cutoff level of 0.080 fmol/mL) had lower survival rates than that of negative patients (1 yr survival rate: 62.8% vs. 75%, respectively), active EGFR positive patients after 2 cycles of chemotherapy had longer survival than the negative patients (1 yr survival rate: 70.6% vs. 60%, respectively). Conclusions: Our preliminary results show that serum active EGFR levels could be a predictive marker for response evaluation and survival in patients with non-small cell lung cancer treated with chemotherapy.

No significant financial relationships to disclose.
Gene expression profile of enzymes involved in gemcitabine (Gem) metabolism in bone marrow mononuclear cells as predictors of myelosuppression
Authors: Ganti A. K. , Parr A. , Nguyen D. , Grem J. L.
Published: March 2020

2007

Background: The dose-limiting toxicity of gemcitabine (Gem) is hematologic toxicity (heme tox), and there is wide intra-patient variability in the degree of heme tox. This study was done to assess the possible impact of gene expression of enzymes involved in Gem metabolism or mechanism of action on heme tox. Methods: Pre-therapy mononuclear cells were isolated from bone marrow aspirates collected from 71 consenting patients with various advanced malignancies enrolled in an IRB-approved phase I trial in which single agent Gem was given over 30 min weekly for 2 of 3 weeks during cycle 1 at doses ranging from 750–1,560 mg/m2. Gene expression of deoxycytidine kinase (DCK), an activating enzyme, cytidine deaminase (CD) and deoxycytidylate deaminase (DCD), deactivating enzymes, and ribonucleotide reductase M2 (RNR), which is inhibited by Gem diphosphate, was measured by real-time RT-PCR. Target gene expression was relative to beta-actin. Heme tox was calculated as the % decrease in white blood cells (WBC), neutrophils (ANC) and platelets (PLT) from baseline. Results: 71 patients (26 females, 35 males) with a median age of 56 years (range: 20–75) were included in the analysis. The median (25th %, 75th %) gene expression was as follows (x10e3/beta-actin): DCK, 0.34 (0.19, 0.64); CD, 1.88 (1.33, 2.92); DCD, 2.48 (1.15, 7.78); and RNR, 0.39 (0.19, 0.80). A strong linear correlation was noted only between RNR & DCD gene expression (Pearson r = 0.89). When gene expression was categorized as above or below the median value, only CD appeared to influence heme tox (mean ± std dev) ( Table ). T-test p value is shown. Conclusions: Gem is rapidly metabolized to its inactive metabolite by CD. Subjects with a higher relative gene expression of CD tended to have a lesser degree of heme tox following Gem. Correlation with Gem pharmacokinetics in these subjects is planned.

[Table: see text]

No significant financial relationships to disclose.
Feasibility of testing core needle biopsies ex vivo in the ChemoFx assay
Authors: O’Shaughnessy J. A. , Holmes F. , Beitsch P. , Cunningham J. , Gallion H. , Backner A. , Hellerstedt B. , Pippen J. , Vukelja S. , Dupree B.
Published: March 2020

20073

Background: Multiple chemotherapy options exist for the treatment of primary breast cancer. While response rates are good, many patients are treated with unnecessary or ineffective chemotherapy. Inadequate treatments are partly due to the lack of accurate predictors of response in individual patients. To predict an individual’s response to therapy, ex vivo chemosensitivity and resistance assays (CSRAs) have long been evaluated, but have been limited by technical difficulties, including the need for large (1–2 gm) amounts of fresh tissue. However, these problems have largely been overcome with new technology. Novel methods used in Precision Therapeutics’ ChemoFx assay allow for testing smaller amounts of tissue (35 mg). The reduced tissue requirement is crucial in the breast cancer setting, as the diagnosis is often made by percutaneous biopsy. The goals of the study were to determine the growth success rate of culturing epithelial cells from breast tissue core needle biopsies and the feasibility of testing the cells in the assay. Methods: A prospective feasibility study involving women with invasive primary breast cancer. One to four core needle biopsy specimens were collected using a 14 gauge needle (est. per patient yield <50 mg) and submitted to Precision Therapeutics. A primary culture of each specimen was established and the ex vivo chemoresponse profiles of each culture were evaluated. Drugs tested included capecitabine, cisplatin, cyclophosphamide, docetaxel, doxorubicin, epirubicin, etoposide, 5-fluorouracil, gemcitabine, irinotecan, paclitaxel, and vinorelbine. Results: 21 of 25 (84%, 95% CI: 68% to 97%) specimens grew successfully; all 21 were tested for chemoresponsiveness with the assay. Of the 4 subjects with unsuccessful ex vivo cultures, 2 had no growth, 1 failed plating for culture, and 1 failed IHC testing due to overgrowth of non-epithelial cells. The average number of drugs tested for each specimen was 7 (range: 1–15). Conclusions: This study demonstrates that core needle biopsies from primary breast tumors can be successfully cultured and tested for chemoresponsiveness using the ChemoFx assay. The ability to perform ex vivo chemoresponse testing on core needle biopsies greatly increases the utility of the assay in adjuvant or neoadjuvant primary breast cancer settings.

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Immunoproteomics strategy for automation of chemoresistance and chemosensitivity array
Authors: Adler Y. , Adler M. J. , Weisenthal L. , Reed J. , Krajewska M. , Olson A. , Krajewski S.
Published: March 2020

20076

Background: Chemotherapy sensitivity and resistance assays (CSRAs) often guide therapeutic regimen selection based on patient cancer cells response to chemotherapeutics in culture. Current CSRAs rely on highly time- and skill- dependent biochemical and microscopic endpoint assays of apoptosis. Instead, the assay under development uses immunoproteomic array readout of biomarkers. Such automation may broaden the use of CSRAs for guiding clinical use of increasingly costly chemotherapeutic options. Methods: Specimens from 30 ovarian cancer patients were cultured with and without cisplatinum according to established CSRA procedures (http://weisenthal.org/w_ovarian_cp.pdf). Cells pelleted and fixed at experimental points (0 and 96 hrs cisplatin, and 96 hrs non-treated) were paraffin embedded for construction of immunoproteomic microarrays. A panel of 57 NIH cancer cell lines was similarly arrayed. Protein profiling is performed with monospecific antibodies for 35 select markers of cell cycle, apoptosis, cell signalling, and transcription. Immunostaining results, including rate of cell death and marker expression level are quantitated manually (immunoscore assigned for cell core) and automatically (algorithm by Aperio, Inc). Results: Evaluation of readouts differentiates responders from non-responders aiming to predict clinical chemotherapy outcome. For a subset of imunoproteomic markers, observed expression corresponds to either induced apoptosis or to cisplatin resistance. Selected markers were subjected to cytologic analysis and time line westerns; results corroborate protein profiling data. Correspondence to the results of the classic CSRAs and individual patient therapeutic response will be unblinded. Conclusions: Use of immunoproteomic arrays to replicate classic CSRAs by establishing concordant results may allow automated guidance for chemotherapeutic choices.

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Pharmacokinetics of gefitinib predicts the antitumor activity for advanced non-small cell lung cancer (NSCLC)
Authors: Nakamura Y. , Sano K. , Fukuda M. , Takatani H. , Nagashima S. , Kinoshita A. , Fukuda M. , Soda H. , Oka M. , Kohno S.
Published: March 2020

2009

Background: Little is known about the relationship between the pharmacokinetics and efficacy of gefitinib. Methods: Plasma trough levels of gefitinib were measured on days 0, 3 (D3), and 8 (D8) by HPLC in advanced NSCLC patients treated with gefitinib 250 mg daily. Eligibility criteria included: performance status (PS) ≤ 3, age ≤ 80, stage IIIB-IV, and written informed consent. Results: Fifty patients were enrolled, and 44 patients were assessable. The median [25%-75%] values of D3 and D8 was 662 [440–937] and 1064 [782–1405] ng/ml, respectively. D8/D3 rate was categorized by 1.587 of the median value. In 44 patients, the median time to progression (TTP) was 83 days, and the median overall survival (OS) was 224 days. The differences in TTP were compared by Kaplan-Meier method and log-rank test: D8/D3 (high D8/D3, median 209 days vs. low D8/D3, 43 days; P = 0.0299), smoking (never-smokers, 224 days vs. smokers, 32 days; P = 0.0467), and histology (adenocarcinoma, 97 days vs. non-adenocarcinoma, 27 days; P = 0.0096). Sex, age, PS, previous treatments, and the use of antacids were not significant. Multivariate analysis showed that TTP was associated with D8/D3 (hazard rate, 95%CI; 0.458, 0.234–0.898) and smoking (2.005, 1.030–3.903). Never-smokers with high D8/D3 showed the best TTP, and smokers with low D8/D3 showed the worst TTP. Never-smokers with low D8/D3 and smokers with high D8/D3 showed similar TTP curves. In contrast, OS was associated with smoking (hazard rate, 95%CI; 3.182, 1.506–6.724), but not D8/D3. Conclusions: High D8/D3 was independently associated with better TTP in gefitinib-treated NSCLC patients. Our findings suggest that pharmacokinetics of gefitinib may be involved in its anti-tumor activity.

No significant financial relationships to disclose.
Clinical pharmacokinetics of erlotinib (E) in glioblastoma multiforme (GBM) patients and its implication for dosing
Authors: Lu J. , Eppler S. , Ling J. , Prados M. , Klencke B. , Lum B.
Published: March 2020

2010

Background: E is an orally active, highly potent and selective inhibitor of the epidermal growth factor receptor (EGFR). Preliminary results from both Phase I and Phase II trials of E in GBM patients have been reported (ASCO 2003, Abs#394 and ASCO 2004, Abs#1555). The purpose of this analysis is to characterize E PK in this patient population when administered with or without CYP3A4 enzyme inducing anti-epileptic drugs (EIAEDs) and to identify a dose to provide equivalent exposure during concomitant therapy in GBM patients. Methods: Intensive PK data were collected in the Phase I study and plasma trough concentration data were collected in the Phase II study at steady-state. A total of 775 E concentrations from 107 patients were available for the analysis. A population PK approach (NONMEM) was used to characterize the clinical PK in this patient population and the effect of EIAEDs on the PK of E. Results: Co-administration of EIAEDs was shown to increase the E clearance (CL/F) by 230% in GBM patients. This effect is similar to that seen in a previous drug-drug interaction study with a CYP3A4 enzyme inducer (rifampicin) in healthy volunteers. For patients with no EIAEDs, population estimates and the %CV of inter-individual variance for CL/F and Vc/F of erlotinib were 5.63 L/hr (44%) and 388 L (40%), respectively. Conclusions: Based on the modeling results, for GBM patients with EIAEDs, an estimate of erlotinib dose of 500 mg/d is needed to achieve an equivalent exposure as patients who receive the dose of 150 mg/d with no EIAEDs. The new population PK model provides an operational tool to predict E exposure during treatment, and simulate alternative dosing regimens for GBM patients.

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Identification of genes involved in endometrial cancer etiopathogenesis by the mean of MacroArray technique
Authors: Kubiatowski T. , Rózynska K. , Futyma K. , Smolen A. , Tarkowski R. , Staroslawska E. , Kotarski J. , Wojcierowski J.
Published: March 2020

20102

Endometrial cancer is one of the most common neoplasms of reproductive system. According to data accumulated in last decades it has been concluded that microsatellite instability and PTEN, K-ras, β-catenin gene mutations are crucial for endometrial cancer etiopathogenesis. Moreover, it is well known that all genes encoded proteins involved in cell cycle regulation, cell differentiation or surrounding tissues infiltration contribute to tumor and metastases development. It has been stressed that different factors such as VEGF, which play a key role in neoplastic angiogenesis are also very important for tumor growth. Complexity of molecular mechanisms leading to endometrial cancer development implies that only experiments utilizing array technique can collect enough data to understand all relationships between different molecular pathways during tumor development and to identify new clinically usable markers of neoplasm. Using MacroArray technique we analyzed expression profile of neoplastic tissue derived from 40 patients diagnosed with endometrial cancer. After data collection all genes present on chip were assigned to different groups according to their role in oncogenesis and artificial neuronal network analysis were performed in order to individuate genes those expression was significantly different in neoplastic tissue regarding to controls. Such procedure allowed us to give shape to preliminary gene expression profile typical for neoplastic tissue and to estimate protein expression of the most significant predictors of neoplastic transformation. Comparison of obtained data with tumor grade can reveal new markers of endometrial cancer useful in routine diagnostic procedures.

No significant financial relationships to disclose.
An analysis and epidemiologic study on new cancer patients admitted to our department between 1999–2003
Authors: Dernek B. O. , Akboru M. H. , Yoney A. , Altin S. , Unsal M.
Published: March 2020

20108

Background: Cancer is one of the most important health problems existing 10.1 millions of new patients and 6.2 millions dead in 2000. 15 millions of new patients will be supposed to be seen in 2020. Method: In this study; between 1999–2003, 41,564 new patients diagnosed as cancer admitted to our center were analyzed. International Classification Disease of Oncology (ICD-O) was used to classify the patients. Basal cell carcinoma and epidermoid carcinoma of the skin were not included. Rest of 41116 patients were reviewed according to their age, sex, diagnosis and coming region. Results: 55.6% of the patients were male. Top five location of the disease can be listed as follows: respiratory system (25.6%), gastrointestinal system (19.2%), breast (15.1%), genitourinary system (11.3%) and lymphoma (4.7%). Analysis according to gender is illustrated in Table . Most cases have come from Marmara Region. While peak incidence was detected between 60–69 years of age in males, it was 50–59 years of age in females. Least comings were seen below 20 years of ages in both sexes. Conclusions: Admission to our department increases gradually while it was 7,020 patients in 1999, it reached to 10,035 person in 2003. General population and population insured by Social Insurance Institution are mostly living in Marmara Region (48.16% of the population are insured by this institution and 41.72% of them reside in Marmara Region). Our department was unique active center in Social Insurance Institution’s order at that time. According to SEER (U.S. Surveillance Epidemiology and EndResults) data in United States (US); although prostate cancer is mostly seen cancer (15%) and lung cancer is recorded in just 13% of cases it is the leading data in our study (22.4%) and prostate cancer is only seen 3.8% of cases. This difference can be explained by effective screening programs in US and prostatic cancer patients mostly prefer to apply the Urology Department in our country. Smoking and environmental conditions may be the reason of high incidence in lung cancer.

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No significant financial relationships to disclose.
BRCA mutations: An Appalachian experience
Authors: Mirza M. A. , Sehbai A. , Nestor T. , Brown V. , Abraham J.
Published: March 2020

20111

Background: BRCA1 and 2 mutations are rare in general population and women with these mutations confer a significantly increased risk of invasive breast and ovarian cancer (65% to 85%, and 15% to 65% cumulative lifetime risk, respectively). A few of these are variant mutations also known as Variant of unknown significance (VUS). Methods: Observational study of 155 patients who presented to MBRCC, WVU for genetic counseling between November 2001 and March 2005. Patients underwent genetic testing after detailed genetic counseling. Clinical data, such as patient’s age, ethnic origin, follow up period, Myriad risk of mutation, clinical outcome i.e., Mastectomy versus Bilateral Salpingo-oophorectomy versus Surveillance, total numbers of patients screened, tested and reason for not testing, and other data, were available for statistical analysis. Results: In out patient population who underwent genetic counseling, 46% (71 out of 155) underwent genetic testing. A large number of patients (54%; 84 out of 155) who underwent genetic counseling could not undergo the genetic testing. Total number of patients not genetically tested were 84, out of which, 27 were low risk, 35 had insurance denial, 7 were not interested, 14 were awaiting results or insurance approval and 1 was deceased. 27 out of 71 patients (38%) who underwent genetic testing were positive for a mutation. Among these patients (n = 27), 8 had BRCA 1; 3 had BRCA1 VUS; 7 had BRCA 2 and 9 had BRCA2 VUS. The average age for patients who had a genetic mutation was 42 years. The most prevalent genetic mutation in our study population was BRCA2 VUS (33%; 9 out of 27) followed by BRCA 1 mutation (29%; 8 out of 27). 11 out of 27 (40%) who had a mutation underwent mastectomy. 13 out of 27 patients (48%) who had a mutation underwent bilateral salpingo-oophorectomy. 7 out of 27 patients (26%) who had a mutation underwent total abdominal hysterectomy. 4 out of 27 patients (15%) who had a germline mutation were lost to followup. Conclusion: We report the prevalence and the clinical outcomes in patients with BRCA mutations in the state of West Virginia, which is comparable to the national database. High number of patients could not undergo genetic testing because of insurance denial.

No significant financial relationships to disclose.